Conditions: Postpartum Depression
Keywords: Moderate Postpartum Depression SAGE-547
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 108
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine if SAGE-547 Injection infused intravenously at up to 90 μg/kg/h for 60 hours reduces depressive symptoms in participants with moderate postpartum depression (PPD) compared to placebo injection as assessed by the change from baseline in Hamilton Rating Scale for Depression (HAM-D) total score.

Detailed description:

Arms:
arm 1: Participants received an infusion rate equivalent to the 90 micrograms per kilogram per hour (μg/kg/h) group. arm 2: Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).

Interventions: intervention 1: Placebo intervention 2: SAGE-547 90 μg/kg/h
Intervention descriptions: intervention 1: Intravenous infusion of matching placebo for SAGE-547. intervention 2: Intravenous infusion of SAGE-547

Protocol document:
Prot_000.pdf: 
Clinical Study Report 
 
547-PPD-202C 
16.1 Study Information 
 
1 
 
 
  
 
1. 
PROTOCOL AND AMENDMENTS 
Version Number 
Date 
Title 
Amendment 4 
16 March 2017 
A Multicenter, Randomized, Double-Blind, Parallel-
Group, Placebo-Controlled Study Evaluating the 
Efficacy, Safety, and Pharmacokinetics of SAGE-547 
Injection in the Treatment of Adult Female Subjects With 
Severe Postpartum Depression and Adult Female 
Subjects with Moderate Postpartum Depression 
Amendment 3 
31 January 2017 
A Multicenter, Randomized, Double-Blind, Parallel-
Group, Placebo-Controlled Study Evaluating the 
Efficacy, Safety, and Pharmacokinetics of SAGE-547 
Injection in the Treatment of Adult Female Subjects With 
Severe Postpartum Depression and Adult Female 
Subjects with Moderate Postpartum Depression 
Amendment 2 
30 June 2016 
A Multicenter, Randomized, Double-Blind, Parallel-
Group, Placebo-Controlled Study Evaluating the 
Efficacy, Safety, and Pharmacokinetics of SAGE-547 
Injection in the Treatment of Adult Female Subjects With 
Severe Postpartum Depression and Adult Female 
Subjects with Moderate Postpartum Depression 
Amendment 1 
22 December 2015 
A Multicenter, Randomized, Double-Blind, Parallel-
Group, Placebo-Controlled Study Evaluating the 
Efficacy, Safety, and Pharmacokinetics of SAGE-547 
Injection in the Treatment of Adult Female Subjects With 
Severe Postpartum Depression 
Original 
18 September 2015 
A Multicenter, Randomized, Double-Blind, Parallel-
Group, Placebo-Controlled Study Evaluating the 
Efficacy, Safety, and Pharmacokinetics of SAGE-547 
Injection in the Treatment of Adult Female Subjects With 
Severe Postpartum Depression 
Administrative Letter – 01 June 2017 
Administrative Letter – 30 June 2017  
Administrative Letter – 01 August 2017 
Table 1: 
Summary of Amendment Changes 
Version 
Date 
Amendment 1 
22 December 2015 
Amendment 2 
30 June 2016 
Amendment 3 
02 February 2017 
Amendment 4 
16 March 2017 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
1 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, PLACEBO-
CONTROLLED STUDY EVALUATING THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF SAGE-547 INJECTION IN THE TREATMENT OF ADULT 
FEMALE SUBJECTS WITH SEVERE POSTPARTUM DEPRESSION AND ADULT 
FEMALE SUBJECTS WITH MODERATE POSTPARTUM DEPRESSION 
NUMBER: 547-PPD-202 / NCT02942017 
IND NUMBER: 122,279 
EUDRA CT NUMBER:  2016-005137-68 
Investigational Product: 
SAGE-547 Injection (allopregnanolone) 
Clinical Phase: 
3 
Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact: 
Helen Colquhoun, M.D. 
Senior Medical Director 
Phone: 
 
 
Sponsor Medical Monitor: 
CRO Medical Monitor: 
, M.D., FAAP 
Study Medical Lead 
Phone: 
 
 
, M.D. 
Phone: 
  
24/7 Hotline: 
  
 
Date of Original Protocol: 
Date of Amendment 1: 
Date of Amendment 2: 
Date of Amendment 3: 
Date of Amendment 4: 
Version 1.0, 18 September 2015 
Version 2.0, 22 December 2015 
Version 3.0, 30 June 2016 
Version 4.0, 31 January 2017 
Version 5.0, 16 Mar 2017 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee.  
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from the Sponsor. 




Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
3 
Investigator Agreement 
By signing this page, I attest that I have read and understand the contents of Clinical Protocol 
547-PPD-202 and any current amendments.  I agree to adhere to the design, conduct, and 
reporting requirements of the study as stated in the clinical protocol and to my obligations to the 
Sponsor as described in the protocol and executed contracts between myself, my Institution, and 
the Sponsor.  I also agree to adhere to any subsequent amendments to the clinical protocol. 
 
Investigator’s Signature:  _____________________________________________ 
 
Investigator’s Name:  
_____________________________________________ 
 
Institution:  
 
 
 
_____________________________________________ 
 
Date (dd/mmm/yyyy): 
_____________________________________________  
 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
4 
2. 
SYNOPSIS 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No.  547-PPD-202 
Phase: 3 
Name of Investigational Product: 
SAGE-547 Injection 
Name of Active Ingredient: 
Allopregnanolone 
Title of the Protocol: 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study Evaluating the 
Efficacy, Safety, and Pharmacokinetics of SAGE-547 Injection in the Treatment of Adult Female 
Subjects With Severe Postpartum Depression and Adult Female Subjects with Moderate Postpartum 
Depression 
Study Sites: Up to 100 global sites 
Duration of Subject Participation: Up to 37 days 
Primary Objective: 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours at up to 90 μg/kg/h 
reduces depressive symptoms in subjects with severe postpartum depression (PPD) compared 
to placebo injection as assessed by the change from baseline in Hamilton Rating Scale for 
Depression (HAM-D) total score.  This objective applies to both Parts A and B. 
Secondary Objectives (unless otherwise specified, these objectives apply to Parts A, B, and C): 
• 
To determine if SAGE-547 infusion at up to 60 μg/kg/h for 60 hours reduces depressive 
symptoms in subjects with severe PPD compared to placebo injection as assessed by the 
change from baseline in HAM-D total score.  This objective applies to Part B. 
• 
To determine if SAGE-547 Injection infused intravenously at up to 90 μg/kg/h for 60 hours 
reduces depressive symptoms in subjects with moderate PPD compared to placebo injection as 
assessed by the change from baseline in HAM-D total score.  This objective applies to Part C. 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces depressive 
symptoms compared to placebo injection as assessed by HAM-D response, HAM-D remission, 
change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score, 
Clinical Global Impression – Improvement (CGI-I) response, and changes from baseline in 
HAM-D subscale and individual item scores.   


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
5 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces other mood 
symptoms compared to placebo injection as assessed by changes from baseline in the 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) total score. 
• 
To evaluate the safety and tolerability of SAGE-547 Injection compared with placebo as 
assessed by the incidence of adverse events (AEs), vital sign measurement, clinical laboratory 
evaluations, electrocardiogram (ECG) parameters, and the Columbia Suicide Severity Rating 
Scale (C-SSRS). 
Other Objectives: 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces subject-
reported depressive symptoms compared to placebo injection as assessed by the change from 
baseline in Edinburgh Postnatal Depression Scale (EPDS) total score and the change from 
baseline in Patient Health Questionnaire (PHQ-9) total score. 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours improves maternal 
behaviors compared to placebo injection as assessed by the change from baseline in Barkin 
Index of Maternal Functioning (BIMF) total and sub-scale scores.   
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours improves the general 
health status compared to placebo as assessed by the change from baseline in the Short 
Form-36 (SF-36) total score at Day 7 and Day 30. 
Pharmacokinetic Objective: 
To assess the pharmacokinetic (PK) profile of SAGE-547, metabolites of SAGE-547, and betadex 
sulfobutyl ether sodium (SBECD). 
Study Design and Methodology:  
This protocol comprises three multicenter, randomized, double-blind, parallel-group, 
placebo-controlled studies of the efficacy, safety, and PK of SAGE-547 Injection in adult female 
subjects diagnosed with severe or moderate PPD.  Each study will be independently conducted, 
analyzed, and reported.  In this protocol, Study 547-PPD-202A is hereafter referred to as Part A; 
Study 547-PPD-202B is hereafter referred to as Part B; and Study 547-PPD-202C is hereafter referred 
to as Part C.  In Parts A and C, subjects will be randomized to one of two treatment groups (SAGE-547 
90 µg/kg/hour or placebo) on a 1:1 basis.  In Part B, subjects will be randomized to one of three 
treatment groups (SAGE-547 60 µg/kg/hour, SAGE-547 90 µg/kg/hour, or placebo) on a 1:1:1 basis.  
In each part, the continuous IV infusions of blinded study drug will increase and then taper.  Subjects 
must remain as inpatients during the study Treatment Period, which is approximately 72 hours/3 days 
in duration (60 hours of treatment and an additional 12 hours for completion of 72-hour assessments).  
The Screening Period assessments may be conducted on an inpatient or an outpatient basis.  The 
Follow-up Period assessments are conducted on an outpatient basis. 
Screening Period: The Screening Period begins with the signature of the informed consent form (ICF).  
Eligibility is determined by applying the inclusion/exclusion criteria.  The diagnosis of PPD must be by 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I).  A full medical and family 
history will be taken from the subject, including recording of all depression, other Axis I and Axis II 
disorders, and postpartum depression episodes in primary probands. 
Treatment Period: In Parts A and C, once subjects are confirmed as eligible for the study, they will be 
randomized to one of two treatment groups (SAGE-547 or placebo) on a 1:1 basis.  Continuous 
intravenous (IV) infusions of blinded study drug will be administered, with a new bag hung at least 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
6 
every 24 hours during the 60-hour infusion.  Infusion rates will increase and then taper, with subjects in 
the SAGE-547 group receiving 30 µg/kg/hour (0-4 hours), then 60 µg/kg/hour (4-24 hours), then 
90 µg/kg/hour (24-52 hours), followed by 60 µg/kg/hour (52-56 hours), and 30 µg/kg/hour (56-
60 hours).  Placebo subjects will receive infusion rates equivalent to SAGE-547 90 µg/kg/hour.  In 
Part B, once subjects are confirmed as eligible for the study, they will be randomized to one of three 
treatment groups (SAGE-547 60 µg/kg/hour, SAGE-547 90 µg/kg/hour, or placebo) on a 1:1:1 basis.  
For the 60 µg/kg/hour group, subjects will receive 30 µg/kg/hour (0-4 hours), then 60 µg/kg/hour 
(4-56 hours), and 30 µg/kg/hour (56-60 hours).  For the 90 µg/kg/hour group, subjects will receive 
30 µg/kg/hour (0-4 hours), then 60 µg/kg/hour (4-24 hours), then 90 µg/kg/hour (24-52 hours), 
followed by 60 µg/kg/hour (52-56 hours), and 30 µg/kg/hour (56-60 hours).  Subjects in the placebo 
group will randomly receive infusion rates equivalent to either the 60 µg/kg/hour or 90 µg/kg/hour 
group.  Parts B and C will run concurrently. 
In all parts, subjects may be discharged after the 72-hour assessments have been completed (12 hours 
after completion of the study drug infusion).  If their clinical condition does not allow discharge, 
normal standard of care will be employed in their ongoing management. 
Initiation of benzodiazepines, narcotics, antibiotics, neuroleptics, and other anti-anxiety medications 
will not be allowed between screening and completion of the 72-hour assessments.  Doses of 
psychotropics, which must have been initiated at least 14 days prior to screening, must remain at a 
stable dose until completion of the 72-hour assessments.  If at the 72-hour assessment there has been no 
treatment response (HAM-D total score remains above 13), treatment with antidepressant medication 
may be optimized prior to discharge, and the subject may remain in the unit or be followed at an 
outpatient clinic, as clinically indicated. 
Efficacy and safety assessments will be performed periodically during the study, and blood samples 
will be collected for analysis of SAGE-547, metabolites of SAGE-547, and SBECD concentrations, as 
outlined in the Schedule of Events (Table 1).  Blood samples will be collected, and outcome measures 
will be obtained at pre-specified times over 72 hours during the Treatment Period.   
Follow-up Period: For Part A, Follow-up Visits will be conducted one week (7±1 day), approximately 
two weeks (12±2 days), and one month (30±3 days) after the initiation of the study drug infusion.  For 
Parts B and C, Follow-up Visits will be conducted one week (7±1 day), two weeks (14±2 days), three 
weeks (21±3 days), and one month (30±3 days) after the initiation of the study drug infusion.  The 
blind will be maintained through the Follow-up period. 
Number of Subjects: 
Up to 32 subjects will be randomized in Part A, up to 120 subjects will be randomized in Part B, and up 
to 100 subjects will be randomized in Part C. 
Inclusion Criteria:  
The following inclusion criteria must be met for individuals to be eligible for the study: 
1. Subject has signed an ICF prior to any study-specific procedures being performed 
2. Subject is an ambulatory female aged between 18 and 45 years of age, inclusive 
3. Subject is in good physical health and has no clinically significant findings, as determined by 
the Investigator, on physical examination, 12-lead ECG, or clinical laboratory tests 
4. Subject agrees to adhere to the study requirements 
5. Subject either must have ceased lactating at screening; or if still lactating or actively breast 
feeding at screening, must agree to temporarily cease giving breastmilk to their infant(s) from 
just prior to receiving study drug through 4 days (Study Day 7) after the end of infusion.   


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
7 
6. Subject must have a negative pregnancy test at screening and Day 1 prior to the start of study 
drug infusion 
7. Subject has had a Major Depressive Episode that began no earlier than the third trimester and 
no later than the first 4 weeks following delivery, as diagnosed by Structured Clinical 
Interview for DSM-IV Axis I Disorders (SCID-I) 
8. For Part A and B, subject has a HAM-D total score of ≥26 at screening and Day 1 (prior to 
dosing).  For Part C, subject has a HAM-D total score of ≥20 and ≤25 at screening and Day 1 
(prior to dosing) 
9. Subject is ≤6 months postpartum at screening 
10. Subject is willing at screening to delay the start of any new pharmacotherapy regimens, 
including antidepressant or anti-anxiety medication, until the study drug infusion and 72-hour 
assessments have been completed; if the subject is taking psychotropic medications, these must 
be at a stable dose from 14 days prior to screening until the 72-hour assessments have been 
completed.   
11. (Removed) 
12. Subject must use one of the following methods of birth control during participation in the study 
and for 30 days following the end of the study drug infusion: 
• 
Total abstinence (no sexual intercourse) 
• 
Hormonal contraceptives (birth control) including birth control pills, implantable or 
injectable contraceptives (Norplant® or Depo-Provera®) 
• 
A barrier form of contraception such as a condom or occlusive cap with a spermicide 
• 
An intrauterine device 
Exclusion Criteria: 
Subjects will be excluded if they meet any of the following exclusion criteria: 
1. Subject has renal failure requiring dialysis or fulminant hepatic failure or is anemic 
(hemoglobin ≤10 g/dL) 
2. Known allergy to progesterone or allopregnanolone 
3. Active psychosis per Investigator assessment 
4. Attempted suicide associated with index case of postpartum depression 
5. (Removed) 
6. Medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder. 
7. History of active alcoholism or drug abuse (including benzodiazepines) in the 12 months prior 
to screening.  A positive urine drug screen (except benzodiazepines under certain 
circumstances [see Section 10.3.3 and Section 11.1.2.6]) is exclusionary. 
8. Exposure to another investigational medication or device within 30 days prior to screening 
9. (Removed) 
10. Subject has previously participated in this study or any other study employing SAGE-547 
11. Administration of electroconvulsive therapy (ECT) within 14 days prior to screening and/or 
plans to administer ECT before the Study Day 7 Visit 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
8 
Investigational Product, Dosage, and Mode of Administration:  
SAGE-547 Injection, IV administration: SAGE-547 Injection is a sterile, clear, colorless 5 mg/mL 
solution of SAGE-547 (allopregnanolone) and 250 mg/mL SBECD buffered with 10 mM citrate at a 
pH of 6.0, supplied in single-use 20 mL vials for IV administration.  As supplied, SAGE-547 Injection, 
which is hypertonic, requires further dilution with Sterile Water for Injection (SWFI) to render it 
isotonic for IV infusion.  The specific infusion dose of SAGE-547 Injection will be calculated based on 
weight for each subject at screening and administered according to the randomization schedule.  
Infusion bags will be changed at least every 24 hours.  Details about the preparation and administration 
of the study drug infusions will be included in the Pharmacy Manual. 
Part A and Part C:  
 
Infusion Rate (µg/kg/hour)  
SAGE-547 Dose 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2-3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
90 µg 
30 
60 
90 
60 
30 
Part B: 
 
Infusion Rate (µg/kg/hour) 
SAGE-547 Dose 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2-3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
60 µg 
30  
60  
60  
60  
30  
90 µg 
30  
60  
90  
60  
30  
 
 
 
 
 
 
Reference Therapy, Dosage, and Mode of Administration:  
An identical placebo IV infusion will be prepared for IV administration consisting of the same 
formulation without allopregnanolone.  For each part of the study, the placebo infusion rate will match 
that of the SAGE-547 rate(s) used in that part.   
Randomization: 
Randomization will be stratified by antidepressant use at baseline and will follow the computer-
generated randomization schedule.  Subjects will be randomized within stratum to receive SAGE-547 
Injection or placebo; subjects, clinicians, and study team will be blinded to treatment allocation.  The 
pharmacist, who will prepare the infusion bags according to the randomization schedule, will be 
unblinded.  In Parts A and C, the infusion rates are the same for all subjects within a particular dosing 
period (0-4 hours, 4-24 hours, etc.) regardless of randomized treatment.  In Part B, the infusion rates 
will vary according to the randomized dose group.   


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
9 
Criteria for Evaluation: 
Primary Endpoint 
The primary outcome measure will be the 17-item Hamilton Rating Scale for Depression (HAM-D).  
The HAM-D will be administered before, during, and after the infusion of blinded study drug.  The 
HAM-D total score will be calculated as the sum of the 17 individual item scores.  The change from 
baseline in HAM-D total score at +60 hours will be the primary efficacy endpoint with comparison 
between the SAGE-547 and placebo treatment groups used to evaluate the efficacy of SAGE-547 in 
treating the depressive symptoms of PPD. 
For Part A and Part C, the primary comparison will be between 90 µg SAGE-547 and placebo at the 
60-hour assessment.  For Part B, the primary comparison will be between 90 µg SAGE-547 and 
placebo at the 60-hour assessment; if this comparison is significant at the 0.05 level, then the 60 µg 
group will be compared to placebo at the 0.04 level of significance.  More details will be provided in 
the statistical analysis plans (SAPs) regarding strong control of overall level of significance for 
multiple testing, including testing of key secondary endpoints.   
Secondary Endpoints 
The change from baseline in HAM-D total score at Day 30 will be included in the secondary endpoints.  
Additional measures of depressive symptom severity will be administered, including the Montgomery-
Asberg Depression Rating Scale (MADRS), and the Clinical Global Impression (CGI) scale.  Total 
scores and changes from baseline will be calculated where applicable.  Changes from baseline at +60 
hours and other time points will be evaluated as secondary efficacy endpoints with comparisons 
between the two treatment groups used to support the efficacy of SAGE-547 in treating the depressive 
symptoms of PPD.  In addition to the above scales, the individual item scores and subscale scores from 
the HAM-D scale will also evaluated as secondary efficacy endpoints.  GAD-7 will also be 
administered, and scores from these scales will be evaluated to assess the efficacy in other mood 
disorder and anxiety symptoms.   
Safety and tolerability of SAGE-547 Injection will be evaluated by summarization of AEs by 
frequency, severity, and seriousness; clinical laboratory measures, vital signs, and ECGs (including 
changes from baseline); and concomitant medication usage.  Suicidality will be monitored using the 
C-SSRS. 
The doses of all anti-depressant medications will be recorded throughout the study.  No changes and/or 
additions to antidepressant or anxiolytic medicine will be allowing during the dosing period.  An 
analysis of time to starting/increasing the dose/decreasing the dose of each different anti-depressant 
medication will be undertaken for subjects discharged. 
Plasma will be collected to assay for concentrations of SAGE-547, SAGE-547 metabolites, and 
SBECD.  The following PK parameters will be derived from the plasma concentrations (where 
evaluable): area under the concentration-time curve (AUC) from time zero to 60 hours (AUC0-60), AUC 
from time zero to infinity (AUC∞), maximum (peak) plasma concentration (Cmax), time at maximum 
(peak) plasma concentration (tmax), steady-state drug concentration in the plasma during constant-rate 
infusion (Css), and average drug concentration in the plasma at steady state during a dosing interval 
(Cavg). 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
10 
Other Endpoints 
Additional measures of symptoms and function related to the current episode of postpartum depression 
severity will be administered, including the EPDS, PHQ-9, BIMF, and SF-36. 
Subscale and total scores and changes from baseline will be calculated where applicable.  Changes 
from baseline at +60 hours and other time points will be evaluated as secondary efficacy endpoints 
with comparisons between the two treatment groups used to support the efficacy of SAGE-547 in 
treating the depressive symptoms of PPD.  In addition to the above scales, the individual item scores 
will also be evaluated as other endpoints. 
Statistical Methods: 
For the purpose of all safety, efficacy, and other analyses where applicable, baseline is defined as the 
last measurement prior to the start of blinded study drug infusion. 
Interim Analysis 
In Part A, an interim analysis will be conducted by an independent statistician for sample size 
re-estimation purposes when at least 16 subjects have completed efficacy assessments through 
60 hours.  Since the sponsor will be kept uninformed of the response rates at the time of the interim 
analysis, no statistical adjustment will be made to the level of significance for hypothesis testing at the 
end of the study.  A detailed description of the interim analysis for sample size re-estimation will be 
included in the statistical analysis plan. 
There will be no interim analysis for Parts B or C. 
Sample Size Calculation 
Using a two-sided t-test at an alpha level of 0.05, a sample size of 10 evaluable subjects per group for 
Part A would provide 70% power to detect an effect size of 1.2 between the SAGE-547 and placebo 
groups with regard to the primary outcome variable of change from baseline in HAM-D total score.  
An effect size of 1.2 corresponds to a placebo-adjusted difference of 12 points in the change from 
baseline in HAM-D total score at 60 hours with an assumed standard deviation of 10 points.  By 
including two treatment groups and using a 1:1 randomization ratio, a total of 20 evaluable subjects are 
required for Part A.   
Based on the results of the interim analysis, the sample size in Part A could be increased to a maximum 
of 32 randomized subjects.  This adjustment to the sample size would allow for an effect size of 1.0 to 
be detected.   
For Part B, a sample size of 40 evaluable subjects per group (120 total) would provide 90% power to 
detect a treatment difference of 9.0 between the SAGE-547 and placebo groups and a common standard 
deviation of 12 points (for an effect size of 0.75) using a two-sided t-test at an alpha level of 0.05.   
For Part C, a sample size of 50 evaluable subjects per group (100 total) would provide 90% power to 
detect a treatment difference of 8.0 between the SAGE-547 and placebo groups and a common standard 
deviation of 12 points (for an effect size of 0.667) using a two-sided t-test at an alpha level of 0.05.   


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
11 
Efficacy Analysis 
The Efficacy Population will include all subjects who start the infusion of study drug and have a valid 
baseline HAM-D assessment and at least one post-baseline HAM-D assessment.  Subjects will be 
classified and summarized by randomized treatment.  Separate summaries will be produced for each 
part of the study. 
For efficacy analysis purposes, centers with fewer than 15 subjects per center for Part B or 10 subjects 
per center for Part C will be pooled within regions (eg, North America region centers will be pooled 
separately those in Europe).  For each part, the change from baseline in HAM-D total score will be 
analyzed using a mixed effects model for repeated measures; the model will include center (pooled), 
treatment, baseline score, visit time point, and visit time point-by-treatment terms as explanatory 
variables.  Center and all other explanatory variables will be treated as fixed effects.  The primary 
comparison between each SAGE-547 dose and placebo will be at the 60-hour time point.  Comparisons 
at other time points, including the Day 30 time point, will be conducted to support the findings for the 
primary comparison.  To account for multiple testing in Part B, (90 µg vs placebo and 60 µg vs 
placebo), the 90 µg group will be compared to placebo first.  If this dose comparison is significant at 
the 0.05 level, then the 60 µg group will be compared to placebo at the 0.04 level.  More details will be 
provided in the SAPs regarding strong control of overall level of significance for multiple testing, 
including testing of key secondary endpoints.   
Changes from baseline in other rating scale scores will be analyzed with methods similar to the primary 
endpoint.  Dichotomous response variables will be analyzed using Generalized Estimating Equation 
(GEE) method for repeated binary responses.   
In addition to formal analysis, efficacy rating scale scores (including recorded and change from 
baseline values) will be summarized by descriptive statistics, including n, mean, standard deviation 
(SD), median, and minimum and maximum values.  Categorical efficacy endpoints (including HAM-D, 
MADRS, and CGI-I response variables) will be summarized by frequency and percentage. 
Safety Analysis 
The Safety Population is defined as all randomized subjects who start the infusion of study drug.  
Subjects will be classified and summarized by actual treatment.  Separate summaries will be produced 
for each part of the study. 
Safety will be assessed using AEs, vital signs, ECG, clinical laboratory tests, C-SSRS, and concomitant 
medication data.  Continuous safety data (including absolute and change from baseline values) will be 
summarized by descriptive statistics, including n, mean, standard deviation (SD), median, and 
minimum and maximum values.  Categorical endpoints will be summarized by frequency and 
percentage.   
Safety data will be examined for possible relationships between subject characteristics and plasma 
allopregnanolone concentrations, as appropriate. 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
12 
Table 1: Schedule of Events 
 
Screening 
Period 
Treatment Period 
Clinic Period (Day 1 to Day 3) 
Follow-up Period 
Visit Days / Hours 
Screening 
D-7
a
 to -1 
D1 
H0* 
D1 
H2 
D1 
H4 
D1 
H8 
D1 
H12 
D1 
H18 
D1 
H24 
D2 
H30 
D2 
H36 
D2 
H42 
D2 
H48 
D3 
H54 
D3 
H60 
D3 
H66 
D3 
H72 
D7/ET 
(±1d) 
D14a 
(+2d) 
D21a 
(+3d) 
D30 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Lab 
Assessments
b
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Urinalysisb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Drug & Alcohol Screen
c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test
d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Genetic Sample
e 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs
f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
12-Lead ECG
g 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
C-SSRS
h 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
Confinement 
 
X 
 
 
 
 
CGI-I
i 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-I 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAM-Di 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
MADRSi 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
BIMFi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
13 
 
Screening 
Period 
Treatment Period 
Clinic Period (Day 1 to Day 3) 
Follow-up Period 
Visit Days / Hours 
Screening 
D-7
a
 to -1 
D1 
H0* 
D1 
H2 
D1 
H4 
D1 
H8 
D1 
H12 
D1 
H18 
D1 
H24 
D2 
H30 
D2 
H36 
D2 
H42 
D2 
H48 
D3 
H54 
D3 
H60 
D3 
H66 
D3 
H72 
D7/ET 
(±1d) 
D14a 
(+2d) 
D21a 
(+3d) 
D30 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EPDSi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
GAD-7i 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
PHQ-9i 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
SF-36 (acute version) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
HCRU 
X 
X 
Plasma PK
j 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
Instructions for 
Lactating Subjects
k 
 
X 
X 
X 
 
 
 
 
Study Drug Infusion 
 
X 
 
 
 
 
 
 
Adverse Events 
X 
Prior/Concomitant 
Medications
l 
X 
BIMF = Barkin Index of Maternal Functioning; CGI-I = Clinical Global Impression of Improvement; C-SSRS = Columbia Suicide Severity Rating Scale; 
D = Day; ECG = electrocardiogram; EPDS = Edinburgh Postnatal Depression Scale; GAD-7 = Generalized Anxiety Disorder 7-Item Scale; HAM-D = 
Hamilton Rating Scale for Depression, 17-item; HCRU = Health Care Resource Utilization; MADRS = Montgomery-Asberg Depression Rating Scale; 
PHQ-9 = Patient Health Questionnaire; PK = pharmacokinetic; SF-36 = Short Form-36; SCID-I = Structured Clinical Interview for DSM-IV Axis I Disorders. 
O = optional; * = All H0 procedures to be completed prior to dosing 
a The screening period for Part A is from Day -5 to Day -1.  Follow-up Visits for Part A are on Days 7, 12, and 30. 
b Safety laboratory tests will include hematology, serum chemistry, coagulation, and select hormone parameters.  The urine test will include a urinalysis.  Lab 
assessments are to be completed within ±30 minutes of the scheduled time point. 
c Urine for selected drugs of abuse and alcohol (serum or breath) 
d Serum at screening and urine for all other time points; lactation status (ie, subject is breastfeeding, subject is lactating but not breastfeeding, or subject is not 
lactating) will be recorded at screening 
e A blood sample for genetic testing, where consent is given 
f Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing).  Vital signs will be obtained within ±30 minutes 
of the scheduled time point, unless the subject is asleep between the hours of 23.00h and 06.00h. 
g Performed within ±30 minutes of the scheduled time point on Day 2. 
h The “Baseline/Screening” C-SSRS form will be completed on Day 1.  The “Since Last Visit” C-SSRS form will be completed at all subsequent time points. 
i To be completed within ±30 minutes of the scheduled time point during the Treatment Period. 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
14 
j Blood samples for PK analysis will be collected at pre-infusion and at 4 (before change in infusion rate, if applicable), 8, 12, 24 (before change in infusion rate, 
if applicable), 30, 36, 48, 60 (before end of infusion), and 72 hours after the start of the infusion.  PK blood draws after the start of infusion will have a window 
of ±10 minutes.  In the event of an unplanned dose adjustment, an unscheduled PK sample should be collected just prior to the infusion rate change. 
k Breast milk will be pumped and discarded by subjects who are lactating.  On Day 3, subjects who are lactating will be reminded that they must continue to 
pump and discard breast milk through Day 7 of the study.  
l To include those taken within 60 days prior to signing the informed consent through the Day 30 visit. 
Note:  In Part A only, SSS is completed within ±15 minutes of each time point through the 72-hour assessments, unless the subject is asleep between 23.00h and 
06.00h. 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
15 
3. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ................................................................................ 2 
2. 
SYNOPSIS ............................................................................................... 4 
3. 
TABLE OF CONTENTS ....................................................................... 15 
LIST OF TABLES ..................................................................................................... 20 
LIST OF FIGURES ................................................................................................... 20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 21 
4. 
INTRODUCTION AND RATIONALE ................................................. 24 
4.1. 
Role of Allopregnanolone in Affective Disturbances ............................ 25 
4.1.1. 
Rationale for Allopregnanolone Treatment of PPD ............................... 25 
4.2. 
SAGE-547 Injection (Allopregnanolone) ............................................... 26 
4.3. 
Summary of Nonclinical and Clinical Experience with SAGE-547 ...... 27 
4.3.1. 
Nonclinical Pharmacology ...................................................................... 27 
4.3.2. 
Clinical Experience ................................................................................. 27 
4.4. 
Potential Risks and Benefits ................................................................... 28 
4.5. 
Study No.  547-PPD-202 ........................................................................ 29 
4.5.1. 
Study Population ..................................................................................... 29 
4.5.2. 
Route of Administration, Dosage, Dosage Regimen, and Treatment 
Period ...................................................................................................... 29 
4.5.3. 
Dose Rationale ........................................................................................ 29 
5. 
ETHICS .................................................................................................. 31 
5.1. 
Institutional Review Board or Independent Ethics Committee .............. 31 
5.2. 
Ethical Conduct of the Study .................................................................. 31 
5.3. 
Subject Information and Informed Consent ........................................... 31 
6. 
STUDY OBJECTIVES .......................................................................... 33 
6.1. 
Primary Objective ................................................................................... 33 
6.2. 
Secondary Objectives ............................................................................. 33 
6.3. 
Other Objectives ..................................................................................... 33 
6.4. 
Pharmacokinetic Objective ..................................................................... 34 
7. 
INVESTIGATIONAL PLAN ................................................................. 35 
7.1. 
Overview of Study Design ...................................................................... 35 
7.2. 
Blinding and Randomization .................................................................. 38 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
16 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS .......................... 39 
8.1. 
Inclusion Criteria .................................................................................... 39 
8.2. 
Exclusion Criteria ................................................................................... 40 
8.3. 
Subject Withdrawal/Study Termination ................................................. 40 
8.3.1. 
Withdrawal/Discontinuation of Individual Subjects .............................. 40 
8.3.2. 
Subject Withdrawal from the Study ....................................................... 40 
8.3.3. 
Discontinuation of Study Drug by the Investigator ................................ 40 
8.3.4. 
Study Termination .................................................................................. 41 
9. 
INVESTIGATIONAL PRODUCT ........................................................ 42 
9.1. 
Identity of Investigational Product ......................................................... 42 
9.2. 
Clinical Supplies ..................................................................................... 42 
9.2.1. 
SAGE-547 ............................................................................................... 42 
9.2.2. 
Placebo .................................................................................................... 42 
9.3. 
Preparation of SAGE-547 Injection or Placebo for Dosing ................... 42 
9.4. 
Administration and Accountability ......................................................... 42 
10. 
TREATMENT OF SUBJECTS .............................................................. 44 
10.1. 
Dosing Schedule ..................................................................................... 44 
10.1.1. 
Dose Regimen ......................................................................................... 45 
10.1.2. 
Route of Administration ......................................................................... 46 
10.1.3. 
Treatment Period .................................................................................... 46 
10.1.4. 
Dosing of Intravenous SAGE-547 in the Case of AEs ........................... 46 
10.2. 
Dosing Compliance ................................................................................ 46 
10.3. 
Prior Medications, Concomitant Medications, and Restrictions ............ 46 
10.3.1. 
Prior Medications .................................................................................... 46 
10.3.2. 
Concomitant Medications ....................................................................... 46 
10.3.3. 
Prohibited Medications ........................................................................... 47 
10.3.4. 
Restrictions ............................................................................................. 47 
11. 
STUDY ASSESSMENTS ...................................................................... 48 
11.1. 
Safety Assessments ................................................................................. 48 
11.1.1. 
Adverse Events ....................................................................................... 48 
11.1.2. 
Clinical Laboratory Tests ....................................................................... 48 
11.1.2.1. 
Hematology, Serum Chemistry, Coagulation ......................................... 49 
11.1.2.2. 
Hormones and Exploratory Biochemistry .............................................. 49 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
17 
11.1.2.3. 
Pregnancy Tests ...................................................................................... 49 
11.1.2.4. 
Genetic Testing ....................................................................................... 49 
11.1.2.5. 
Urinalysis ................................................................................................ 50 
11.1.2.6. 
Drugs of Abuse and Alcohol .................................................................. 50 
11.1.3. 
Physical Examination ............................................................................. 50 
11.1.4. 
Vital Signs .............................................................................................. 50 
11.1.5. 
ECG ........................................................................................................ 50 
11.1.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................... 50 
11.2. 
Efficacy Assessments ............................................................................. 51 
11.2.1. 
Primary Efficacy Outcome Measure ...................................................... 51 
11.2.1.1. 
Hamilton Rating Scale for Depression (HAM-D) .................................. 51 
11.2.2. 
Secondary Efficacy Outcome Measures ................................................. 51 
11.2.2.1. 
Montgomery Asberg Depression Rating Scale (MADRS) ..................... 52 
11.2.2.2. 
Clinical Global Impression (CGI) Scale ................................................. 52 
11.2.2.3. 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) ........................... 53 
11.2.3. 
Patient Reported Outcome Measures...................................................... 53 
11.2.3.1. 
Edinburgh Postnatal Depression Scale (EPDS) ...................................... 53 
11.2.3.2. 
Patient Health Questionnaire (PHQ-9) ................................................... 53 
11.2.3.3. 
Barkin Index of Maternal Functioning (BIMF) ...................................... 53 
11.2.3.4. 
Short Form-36 (SF-36) ........................................................................... 54 
11.2.3.5. 
Healthcare Resource Utilization (HCRU) .............................................. 54 
11.3. 
Pharmacokinetics .................................................................................... 54 
12. 
STUDY PROCEDURES ........................................................................ 56 
12.1. 
Screening Period ..................................................................................... 56 
12.2. 
Study Drug Treatment Period (Day 1 to Day 3, Hours 0-72) ................. 57 
12.2.1. 
Day 1 ....................................................................................................... 57 
12.2.2. 
Day 2 ....................................................................................................... 58 
12.2.3. 
Day 3 ....................................................................................................... 58 
12.3. 
Follow-up Period (Day 7 through Day 30) ............................................. 59 
12.3.1. 
Day 7 (±1 day) ........................................................................................ 59 
12.3.2. 
Day 12 (±2 days) (Part A); Day 14 (±2 days) and Day 21 (±3 days) 
(Parts B and C) ........................................................................................ 59 
12.3.3. 
Day 30 (±3 days) .................................................................................... 60 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
18 
12.3.4. 
Early Termination Visit .......................................................................... 60 
13. 
STATISTICAL METHODS AND CONSIDERATIONS ..................... 61 
13.1. 
Data Analysis Sets .................................................................................. 61 
13.2. 
Handling of Missing Data ....................................................................... 62 
13.3. 
Demographics and Baseline Characteristics ........................................... 62 
13.4. 
Primary Endpoints .................................................................................. 62 
13.5. 
Secondary Endpoints .............................................................................. 62 
13.5.1. 
Efficacy Analysis .................................................................................... 62 
13.5.2. 
Safety Analysis ....................................................................................... 63 
13.5.2.1. 
Adverse Events ....................................................................................... 63 
13.5.2.2. 
Clinical laboratory evaluations ............................................................... 63 
13.5.2.3. 
Physical examinations ............................................................................ 64 
13.5.2.4. 
Vital signs ............................................................................................... 64 
13.5.2.5. 
12-Lead ECG .......................................................................................... 64 
13.5.2.6. 
Concomitant medications ....................................................................... 64 
13.5.2.7. 
C-SSRS ................................................................................................... 64 
13.5.2.8. 
SSS (Part A only).................................................................................... 64 
13.5.2.9. 
PK Analysis ............................................................................................ 64 
13.6. 
Determination of Sample Size ................................................................ 65 
13.7. 
Interim Analysis ...................................................................................... 65 
13.8. 
Changes from Protocol Specified Analyses ........................................... 65 
14. 
ADVERSE EVENTS.............................................................................. 66 
14.1. 
Adverse Event Definitions ...................................................................... 66 
14.1.1. 
Adverse Event ......................................................................................... 66 
14.1.2. 
Suspected Adverse Reaction ................................................................... 66 
14.1.3. 
Life-Threatening ..................................................................................... 66 
14.1.4. 
Serious .................................................................................................... 66 
14.1.5. 
Unexpected ............................................................................................. 67 
14.2. 
Investigator Responsibilities ................................................................... 67 
14.2.1. 
Identification and Documentation of Adverse Events by Investigator ... 67 
14.2.2. 
Adverse Event Classification .................................................................. 68 
14.2.2.1. 
Relationship to Investigational Drug ...................................................... 68 
14.2.2.2. 
Severity ................................................................................................... 69 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
19 
14.2.2.3. 
Action Taken with Investigational Drug ................................................ 69 
14.2.2.4. 
Assessment of Outcome ......................................................................... 69 
14.2.3. 
Investigator Reporting to Sponsor and Sponsor Emergency Contact .... 69 
14.2.4. 
Medical Monitor and Emergency Contact Information.......................... 70 
14.2.5. 
SAE Reporting Contact Information ...................................................... 70 
14.2.6. 
Reporting to Institutional Review Boards/Independent Ethics 
Committees ............................................................................................. 70 
14.3. 
Sponsor/Medical Monitor Responsibilities ............................................ 70 
14.3.1. 
Monitoring of Adverse Event Data ......................................................... 70 
14.3.2. 
Reporting to Regulatory Authorities ...................................................... 70 
14.4. 
Emergency Identification of Study Medication ...................................... 71 
15. 
STUDY ADMINISTRATION ............................................................... 72 
15.1. 
Quality Control and Quality Assurance .................................................. 72 
15.2. 
Data Handling and Recordkeeping ......................................................... 72 
15.2.1. 
Data Handling ......................................................................................... 72 
15.2.2. 
Case Report Form Completion ............................................................... 72 
15.2.3. 
Retention of Study Records .................................................................... 73 
15.3. 
Confidentiality ........................................................................................ 73 
15.4. 
Publication Policy ................................................................................... 73 
15.5. 
Protocol Amendments ............................................................................ 74 
16. 
REFERENCES ....................................................................................... 75 
APPENDICES ........................................................................................................... 80 
APPENDIX 1. COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) 81 
APPENDIX 2. HAMILTON RATING SCALE FOR DEPRESSION, 17-ITEM 
(HAM-D) ................................................................................................ 88 
APPENDIX 3. MONTGOMERY ASBERG DEPRESSION RATING SCALE 
(MADRS) ............................................................................................... 93 
APPENDIX 4. CLINICAL GLOBAL IMPRESSION–IMPROVEMENT SCALE 
(CGI-I) AND SEVERITY SCALE (CGI-S) .......................................... 96 
APPENDIX 5. EDINBURGH POSTNATAL DEPRESSION SCALE (EPDS) .... 98 
APPENDIX 6. GENERALIZED ANXIETY DISORDER 7-ITEM SCALE (GAD-
7) 
100 
APPENDIX 7. PATIENT HEALTH QUESTIONNAIRE (PHQ-9) .................... 102 
APPENDIX 8. BARKIN INDEX OF MATERNAL FUNCTIONING (BIMF) .. 104 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
20 
APPENDIX 9. SHORT FORM-36 (ONE WEEK RECALL) .............................. 105 
APPENDIX 10. HEALTH RESOURCE UTILIZATION QUESTIONNAIRE ... 111 
 
LIST OF TABLES 
Table 1: 
Schedule of Events ................................................................................. 12 
Table 2: 
Adverse Events That Occurred in More than One Subject ..................... 28 
Table 3: 
Infusion Rates for Part A and C .............................................................. 45 
Table 4: 
Infusion Rates for Part B ........................................................................ 45 
 
LIST OF FIGURES 
Figure 1: 
Study Design - Part A ............................................................................. 35 
Figure 2: 
Study Design - Part B ............................................................................. 36 
Figure 3: 
Study Design - Part C ............................................................................. 36 
Figure 4: 
Study Design and Timeline for Dosing – Part A .................................... 44 
Figure 5: 
Study Design and Timeline for Dosing – Part B .................................... 44 
Figure 6: 
Study Design and Timeline for Dosing – Part C .................................... 45 
 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition  
AE 
adverse event 
ALLO 
allopregnanolone 
ALT 
alanine aminotransferase 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC∞  
area under the concentration-time curve from time zero to infinity 
AUC0-60 
area under the concentration-time curve from time zero to 60 hours 
BIMF 
Barkin Index of Maternal Functioning 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Cavg 
average drug concentration in the plasma at steady-state during a dosing 
interval 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression–Improvement 
CGI-S 
Clinical Global Impression–Severity 
cGMP 
Current Good Manufacturing Practice 
Cmax 
maximum (peak) plasma concentration of the drug 
CNS 
central nervous system 
CRF 
case report form 
CS 
clinically significant 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
Css 
steady-state drug concentration in the plasma during constant-rate infusion 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture  
EEG 
electroencephalography 
EFF 
Efficacy Population 
Ph. Eur. 
European Pharmacopeia  
EPDS 
Edinburgh Postnatal Depression Scale 
ERα 
estrogen receptor alfa 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
22 
Abbreviation  
Definition  
ERß 
estrogen receptor beta 
ET  
early termination 
GABA 
gamma-aminobutyric acid  
GABAA 
gamma-aminobutyric acid–gated chloride channel 
GAD-7 
Generalized Anxiety Disorder 7-Item Scale  
GCP 
Good Clinical Practice 
GEE 
Generalized Estimating Equation 
GGT 
gamma glutamyl transferase 
h 
hour 
HAM-D 
Hamilton Rating Scale for Depression, 17-item 
hCG 
human chorionic gonadotropin 
HCRU 
Healthcare Resource Utilization 
Hct 
hematocrit 
HEENT 
head, eyes, ears, nose, and throat 
Hgb 
hemoglobin 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
intravenous 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MCH 
mean corpuscular hemoglobin 
MCS 
mental component summary 
MCV 
mean corpuscular volume 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
PCS 
physical component summary 
PHQ-9 
Patient Health Questionnaire  
PK 
pharmacokinetic(s) 
PKP 
Pharmacokinetic Population 
PMID 
PubMed identification 
PP 
Per-Protocol Population 
PPD 
postpartum depression 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
23 
Abbreviation  
Definition  
PR 
progesterone receptor 
PT/INR 
prothrombin time/international normalized ratio 
RBC 
red blood cell 
RSE 
refractory status epilepticus 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBECD 
betadex sulfobutyl ether sodium 
SCID-I 
Structured Clinical Interview for DSM-IV Axis I Disorders 
SD 
standard deviation 
SF-36 
Short Form-36 
SOC 
system organ class 
SOP 
standard operating procedure 
SRSE 
super refractory status epilepticus 
SSRI 
selective serotonin reuptake inhibitors 
SSS 
Stanford Sedation Scale 
SWFI 
sterile water for injection 
t1/2 
half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum (peak) plasma concentration 
TSH 
thyroid stimulating hormone 
US 
United States 
USP 
United States Pharmacopeia 
VAS 
visual analogue scale 
Vd 
volume of distribution 
WBC 
white blood cell 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
24 
4. 
INTRODUCTION AND RATIONALE 
This study is designed to evaluate the efficacy, safety, and pharmacokinetics (PK) of 
SAGE-547 (allopregnanolone) as a treatment for women with severe or moderate postpartum 
depression (PPD), an area of high unmet medical need. 
PPD is considered to be moderate to severe depression in women who have recently given 
birth, otherwise defined as the occurrence of major depressive disorder (MDD) within 
4 weeks of delivery (DSM-V 2013) or up to a year after giving birth (Okun 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-V 2013), 
although this diagnosis may be confounded by the relative frequency of symptoms such as 
sleep disturbance or appetite problems in pregnant and postpartum women.  Most women 
experience onset of symptoms within the first 3 months following delivery, and PPD is most 
prevalent at 10 to 14 weeks following childbirth (Okun 2013). 
During pregnancy, estradiol and progesterone levels increase dramatically but then rapidly 
decline in the acute postpartum period (Gavin 2005).  The onset of PPD symptoms coincides 
with the rapid decrease of the gonadal steroids postpartum.  The duration of a PPD episode 
has been estimated as shorter than depressive episodes in the general population 
(approximately 5 months), while other studies indicate time to remission is approximately the 
same (Chaudron 2003). 
PPD is common and has devastating consequences for the woman and for her family 
(Fihrer 2009, Verbeek 2012).  Perinatal depression is reported to be the most underdiagnosed 
obstetric complication in America (Earls 2010).  Furthermore, it is the most common 
psychiatric illness to occur in the puerperium (O’Hara 2014).  A meta-analysis of 30 studies 
(Gaynes 2005) found that the point prevalence of major and minor depression ranged 
between 6.5% and 12.9% at different times during the first postpartum year.  Overall 
incidence is estimated at around 15% to 20% with up to 10% being considered severe 
(Edge 2007, O’Hara 2014). 
Current standard of care for severe PPD comprises cautious use of pharmacological therapies 
in nursing mothers combined with other interventions.  Evidence for efficacy of tricyclic 
antidepressants and/or selective serotonin reuptake inhibitors (SSRIs) is based on use in the 
general population rather than any extensive studies in PPD (Austin 2013), and SSRIs tend to 
be preferred due to better data on safety while breastfeeding (Altshuler 2001).  Based on the 
level of evidence for antidepressants in major depressive disorder (Kirsch 2008, 
Fournier 2010), there is a considerable need for improved pharmacological therapy for PPD. 
Drugs may be combined with a number of counseling, behavioral, and other non-
pharmacological therapy approaches, which are generally used as the first-line therapy in less 
severe PPD (Altshuler 2001).  Urgent referral and potentially admission are recommended 
for mothers at risk of self-harm, with their infants, if such facilities exist (Austin 2013).  
Therapeutic options in severe PPD are currently limited, and it is not clear whether the 
current standard of care impacts the natural history of the disease, although most women 
recover within a year. 


Protocol 547-PPD-202 
Sage Therapeutics 
Amendment 4, version 5.0 
CONFIDENTIAL 
25 
4.1. 
Role of Allopregnanolone in Affective Disturbances 
The neurosteroid metabolite of progesterone, allopregnanolone, acutely regulates neuronal 
function (Gangisetty 2010) and appears to play a significant role in affective disturbances 
that occur with changes in reproductive endocrine function, such as during the postpartum 
period (Amin 2006, Nappi 2001, Epperson 2006). 
Neurosteroids are metabolites of cholesterol-derived steroid hormones that are synthesized in 
the brain and nervous system; they modulate the major inhibitory and excitatory central 
nervous system (CNS) neurotransmitter systems: γ-aminobutyric acid (GABA) and 
glutamate, respectively.  Neurosteroids are among the most potent and effective modulators 
of GABAA receptors and augment GABAergic inhibition (Belelli 2005).  The powerful 
anxiolysis that accompanies this potentiation of GABAA receptors has led to the speculation 
that neurosteroid dysregulation plays a central role in the etiology of affective disorders, 
including reproductive mood disorders, such as PPD (Amin 2006). 
There is increasing evidence supporting the role of neurosteroids in affective dysregulation.  
Allopregnanolone and pregnanolone have been shown to modulate the GABA receptor 
positively (Majewska 1986).  Several groups have demonstrated decreased allopregnanolone 
levels in MDD, with an increase seen in both plasma and cerebrospinal fluid (CSF) following 
successful antidepressant treatment (Uzunova 1998, Romeo 1998, Ströhle 1999, 
Schüle 2006, Eser 2006, Schüle 2007).  In addition, allopregnanolone has demonstrated 
anxiolytic effects in several animal anxiety models (Bitran 1991; Wieland 1991; 
Bitran 1993).   
Allopregnanolone may also exert antidepressant effects by reducing the physiological impact 
of stress, promoting neuroprotection, and protecting against the pro-inflammatory immune 
activation and cytokine hypersecretion associated with MDD.  In animals, allopregnanolone 
increases in response to stress, reduces pain sensitivity, and is thought to restore physiologic 
homeostasis following stress (Frye 1994, Morrow 1995).  Allopregnanolone also exerts 
neuroprotective effects by reducing the expression of pro-apoptotic proteins and apoptotic 
DNA fragmentation (Djebaili 2005, Sayeed 2009), thereby reducing the cell death and gliosis 
associated with depression (Glantz 2010, Shelton 2011).  Neuroprotection is mediated by 
immune regulation in depression (Licinio 1999), and allopregnanolone reduces the 
expression of the pro-inflammatory cytokine TNF-α (He 2004), which is elevated in 
depressed individuals (Dowlati 2010).  Thus, allopregnanolone modulates biological 
processes dysregulated in MDD. 
4.1.1. 
Rationale for Allopregnanolone Treatment of PPD 
Genetic susceptibility to affective dysregulation may be unmasked during periods of 
reproductive hormone change such as during pregnancy and postpartum (Maguire 2008).  
Maguire and Mody demonstrated that a GABA receptor subunit mutation was behaviorally 
silent until the animal was exposed to pregnancy and the postpartum state, at which time the 
dams showed depressive-like behaviors and cannibalized their offspring (Maguire 2008).  
During pregnancy, the expression of the GABAA receptor δ-subunit is down-regulated as 
allopregnanolone levels increase, and at parturition, the expression of the GABAA receptor 
δ-subunit is recovered in response to rapidly declining neurosteroid levels (Maguire 2009).  
In contrast, the GABAA receptor δ-subunit-deficient mice fail to adapt to the dramatic 


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changes in allopregnanolone and experience depression-like and anxiety-like behavior and 
abnormal maternal behaviors, which are reversed by administration of allopregnanolone 
(Maguire 2008).  This model provides compelling support for the hypothesis that changes in 
neurosteroid concentrations during pregnancy and postpartum are capable of provoking 
affective dysregulation, particularly in those with a genetically-determined susceptibility.  
The capacity of changes in neurosteroids, such as allopregnanolone, to function as behavioral 
switches suggests a potentially important treatment role of this hormone metabolite in 
reproductive endocrine-related mood disorders such as PPD. 
The onset of PPD symptoms coincides with the rapid decrease of the gonadal steroids 
postpartum and has been reproduced in a pivotal clinical study (Bloch 2000).  The authors 
investigated the possible role of changes in gonadal steroid levels in PPD by simulating 
2 hormonal conditions related to pregnancy and parturition in euthymic women, 8 with and 
8 without a history of PPD.  They induced hypogonadism with leuprolide, adding back 
supra-physiologic doses of estradiol and progesterone for 8 weeks to simulate pregnancy.  
They then withdrew both steroids under double-blind conditions to mimic the rapid decrease 
of sex steroids upon delivery.  Five of the 8 women with a history of postpartum depression 
(62.5%) and 0% of the comparison group developed significant mood symptoms typical of 
PPD during the withdrawal period. 
Although progesterone levels were measured in this study, allopregnanolone was not.  
However, since allopregnanolone is the major active metabolite of progesterone, it can be 
assumed that the decrease in progesterone would cause a similar precipitate drop in 
allopregnanolone levels, as observed in the postpartum period (Gilbert Evans 2005, 
Paoletti 2006, Nappi 2001).  These data provide direct evidence in support of the 
involvement of progesterone and its metabolites in the development of postpartum 
depression in a subgroup of women.  Further, they suggest that women with a history of 
postpartum depression are differentially sensitive to mood-destabilizing effects of gonadal 
steroids (Bloch 2000). 
Additional details regarding the role of allopregnanolone in the etiology of affective 
disorders and its nonclinical pharmacology and PK are presented in the Investigator’s 
Brochure. 
4.2. 
SAGE-547 Injection (Allopregnanolone) 
Allopregnanolone is an endogenous, naturally occurring neuroactive steroid formed in the 
corpus luteum of the ovary, adrenal cortex, and CNS (Holzbauer 1985, Ottander 2005, 
Paul 1992).  Allopregnanolone is a metabolite of progesterone created by the actions of 5-α 
reductase and 3-α hydroxy-steroid dehydrogenase.  Allopregnanolone is a potent positive 
allosteric modulator of both synaptic and extra-synaptic GABAA receptors. 
SAGE-547 Injection is a solution of 5 mg/mL allopregnanolone in Sterile Water for Injection 
(SWFI), United States Pharmacopeia (USP), and 250 mg/mL betadex sulfobutyl ether 
sodium buffered with 10 mM citrate at a pH of 6.0, and will be administered intravenously.  
SAGE-547 Injection is also being developed for the treatment of adult patients with 
refractory status epilepticus (RSE), inclusive of super refractory status epilepticus (SRSE), 
who have not responded to standard treatment regimens, and investigated for the treatment of 
adults with essential tremor. 


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4.3. 
Summary of Nonclinical and Clinical Experience with SAGE-547 
4.3.1. 
Nonclinical Pharmacology 
The primary pharmacological effects of allopregnanolone or SAGE-547 are described earlier 
in the rationale (Section 4.1 and Section 4.1.1).  Secondary pharmacologic effects comprise 
mainly the binding and consequent increased activity of steroid hormone receptors (androgen 
receptor [(AR], progesterone receptor [PR], and estrogen receptor beta [ERß]), with some 
evidence of inhibition at the highest doses (AR and estrogen receptor alfa [ERα]).  These 
non-target effects may yield some adverse events (AEs) in the clinic. 
Nonclinical toxicology studies largely illustrate the sedative and anesthetic effects of 
allopregnanolone and/or SAGE-547 at higher equivalent doses than the proposed dose for the 
current study.  PK data in animals indicate a short half-life (t½) and rapid clearance with a 
moderate volume of distribution and cerebral levels higher than plasma.  Refer to the 
SAGE-547 Investigator’s Brochure for more details. 
4.3.2. 
Clinical Experience 
The clinical PK data with intravenous (IV) administration of allopregnanolone in healthy 
women, men, and women on oral contraceptives confirmed the PK observations in animals 
of Cmax achievable at approximately third trimester levels (150 nM), rapid clearance and 
moderate volume of distribution (Vd).  Refer to the SAGE-547 Investigator’s Brochure for 
more details. 
An open-label, proof-of-concept study (547-PPD-201) evaluating the safety, tolerability, PK, 
and efficacy of SAGE-547 Injection in the treatment of adult female subjects with severe 
postpartum depression was started in 2014.  This was the first study in this indication.  Four 
women experienced significant improvement in depressive symptoms within 24 hours after 
administration of open-label IV SAGE-547.  During the SAGE-547 Treatment Period, all 
four subjects rapidly achieved remission, as measured by the HAM-D total score.  All four 
subjects also demonstrated consistent improvement as measured by the CGI-I score.  SAGE-
547 was well-tolerated in all subjects treated with no serious adverse events (SAEs) observed 
during therapy or during the 30-day Follow-up Period.  A total of 14 AEs were reported in 
four subjects.  The only AE reported in more than one subject was sedation, observed in two 
subjects.  This study was initially planned to enroll ten women; however, due to the observed 
clinical activity, Study 547-PPD-201 was stopped early with the plan to initiate a placebo-
controlled clinical study as rapidly as possible.   
There are six reported studies of allopregnanolone, mainly in healthy individuals and none in 
PPD (Timby 2006, Timby 2011a and 2011b, van Broekhoven 2007, Kask 2008, Kask 2009, 
Navarro 2003).  Data indicate that normal physiological allopregnanolone levels in women 
vary during the menstrual cycle up to a maximum of 6 to 10 nM, with lower levels present 
post-menopause (Genazzani 1998).  The highest physiological levels observed are in the 
third trimester of pregnancy, up to around 160 nM at time of delivery (Luisi 2000).  Levels 
drop precipitously to baseline (<10 nM) with removal of the placenta (Klak 2003).   


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One study demonstrated subjective improvements in contentedness in women 
(van Broekhoven 2007).  The clinical safety data are presented below in the Risks and 
Benefits section (Section 4.4). 
4.4. 
Potential Risks and Benefits 
In the open-label clinical study of SAGE-547 in PPD (547-PPD-201), a total of 14 AEs were 
reported in four subjects.  The only AE reported in more than one subject was sedation, 
observed in two subjects.   
In the recently completed 547-PPD-202A, there were no SAEs or discontinuations due to 
AEs.  Out of 10 subjects who received SAGE-547, four reported AEs, and of 11 subjects 
who received placebo, eight reported AEs (Table 2).  Three subjects in each treatment group 
reported dizziness, sedation or somnolence.  Psychiatric disorder AEs, including abnormal 
dreams, insomnia and anxiety, were all reported in the group that received placebo.  Three 
subjects in the placebo group and one in the SAGE-547 group reported nausea.  Other AEs 
reported by more than one subject were infusion site pain and headache, all reported on 
placebo.  One subject did not tolerate 60 μg/kg/hour due to sedation, thought to be associated 
with concomitant administration of a high dose of benzodiazepine, so the dose was reduced 
to 30 μg/kg/hour from 12 to 24 hours.  The subject received 60 µg/kg/hour from 24 to 
30 hours and 30 µg/kg/hour from 30 to 60 hours and completed the study. 
Table 2: 
Adverse Events That Occurred in More than One Subject 
 
Placebo (n=11) 
SAGE-547 (n=10) 
 
No. of Subjects
a 
n (%) 
No of Events 
No. of Subjects
a 
n (%) 
No of Events 
Subjects with at least 1 TEAE 
8 (72.7) 
23 
4 (40.0) 
17 
Dizziness 
3 (27.3) 
3 
2 (20.0) 
3 
Somnolence 
-- 
-- 
2 (20.0) 
3 
Nausea 
3 (27.3) 
3 
1 (10.0) 
1 
Infusion Site Pain 
2 (18.2) 
3 
-- 
-- 
Headache 
2 (18.2) 
2 
-- 
-- 
Abnormal Dreams 
2 (18.2) 
2 
-- 
-- 
Insomnia 
2 (18.2) 
2 
-- 
-- 
Source: 547-PPD-202A, Table 14.3.2.2 
a Subjects who have more than 1 AE per preferred term are counted only once 
 
Consistent with these observations, published reports of human administration of exogenous 
allopregnanolone indicate that for exposures in men and women up to 150 nM, the most 
commonly reported AEs were sedation (recorded as sleepiness or tiredness), feelings of 
intoxication (like alcohol), flushing, vertigo, mild nausea, impaired episodic memory, and 
mild headache (Timby 2006, 2011a, and 2001b; van Broekhoven 2007).  One subject 
experienced what was potentially a withdrawal effect, an anxiety attack (Timby 2011b).  No 
SAEs were reported in the six clinical studies conducted to date (Timby 2006, Timby 2011a 
and 2011b, van Broekhoven 2007, Kask 2008, Kask 2009, Navarro 2003).   


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There is also a potential risk of synergistic sedative effects with other drugs interacting with 
the GABAA receptor, such as benzodiazepines and anti-epileptic medications 
(Norberg 1999); therefore, the Investigator is advised to avoid co-medication if possible and 
to exercise caution with these drug classes.   
In 547-PPD-202A, the primary endpoint of the mean change from baseline in HAM-D total 
score at 60 hours compared with placebo [LS mean treatment difference of 12.2] was highly 
significant (p=0.008).  In addition, the significant separation between the active and placebo 
groups was evident at 24 hours, and remained so at subsequent time points through 72 hours, 
7 days, and 30 days after initiation of treatment.   
In view of the limited nature of the demonstrated risks of exogenous allopregnanolone 
infusion and the potential for benefit in PPD, there is a favorable benefit-risk evaluation for 
the continued conduct of the present study. 
4.5. 
Study No.  547-PPD-202 
4.5.1. 
Study Population 
This study will evaluate the efficacy, safety, and PK of SAGE-547 Injection in the treatment 
of adult female subjects diagnosed with severe or moderate postpartum depression.   
Parts A and B of this study will study women with severe PPD, and Part C will study women 
with moderate PPD (Parts B and C will run concurrently).  Moderate severity level will be 
studied because the pathogenesis of severe postpartum depression may not be generalized to 
those patients with a less severe form of illness.  For example, outside of postpartum 
depression, findings suggest that patient’s treatment-resistant depression may respond more 
favorably to certain pharmacotherapy options such as ketamine (Coyle 2015).  Therefore, in 
order to determine the efficacy of SAGE-547 in women with less severe levels of symptoms, 
a separate group with moderate PPD with the same doses of the study drug used in the severe 
group will be investigated. 
4.5.2. 
Route of Administration, Dosage, Dosage Regimen, and Treatment Period 
SAGE-547 Injection or placebo will be administered over a 60-hour period by an IV infusion 
according to the dose regimens shown in Table 3 and Table 4 (see Section 10.1.1). 
The specific infusion dose of SAGE-547 Injection will be calculated based on weight for 
each subject.  Infusion bags will be changed at least every 24 hours.  Details about the 
preparation and administration of the study drug infusions will be included in the Pharmacy 
Manual. 
4.5.3. 
Dose Rationale 
The infusion rate of SAGE-547 to be studied in Parts A and C of this study was chosen to 
achieve a mean exposure of 150 nM, roughly equivalent to the highest endogenous 
concentrations measured in third trimester pregnancy at approximately 157 nM (Luisi 2000).  
Since pregnant women tolerate this level without apparent AEs, 150 nM was selected as the 
target exposure for this study.  This level of exposure has already been achieved in Study 
547-PPD-201 as well at higher levels in a study in subjects with essential tremor (Study 


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547-ETD-201) and subjects with super refractory status epilepticus (Study 547-SSE-201), 
with no drug-related SAEs reported.  Since the most common AE in 547-ETD-201 was 
sedation, dose adjustment rules are included in this protocol to ensure that all subjects can 
remain on treatment for 60 hours.  A similar Cmax was also achieved in several other studies 
conducted with IV allopregnanolone (Timby 2011b), with excellent tolerability (see the 
current SAGE-547 Investigator’s Brochure for details of safety profile). 
The selection of exposure in the current study is based on a cautious approach adapted to the 
anticipated benefit-risk in the PPD patient population, and on previous experience from the 
ongoing clinical studies of SAGE-547 in adult subjects with SRSE (Study 547-SSE-201) and 
of SAGE-547 in female subjects with PPD (Study 547-PPD-201).  In the ongoing SRSE 
study, as determined by simulation, loading and maintenance infusions are required to 
achieve the target exposure.  In contrast, in the current study, subjects will instead begin 
treatment with a 4-hour dose-titration phase.  The starting dose is approximately 9- to 18-fold 
lower than the no observed adverse effect level (NOAEL) observed in rats and dogs, 
although this is not the first in human study.  In Parts A and C, doses will be increased as 
follows: 30 µg/kg/hour (0-4 hours), then 60 µg/kg/hour (4-24 hours), then 90 µg/kg/hour 
(24-52 hours), followed by a decrease to 60 µg/kg/hour (52-56 hours), and 30 µg/kg/hour 
(56-60 hours).   
In Part B, a lower target dose will also be explored (ie, 60 µg/kg/hour).  The use of this dose 
is based on observations in the open-label 547-PPD-201 study in which subjects achieved 
substantial improvements in their HAM-D scores within the first 12 hours of the SAGE-547 
infusion.  In this study, subjects received a dose of 21.5 μg/kg/h for the first 4 hours, then 
43 μg/kg/h for the next 4 hours, and then 64.5 μg/kg/h for the following 4 hours before 
receiving the target dose of 86 μg/kg/h at 12 hours.  Therefore, the 12-hour data from 
547-PPD-201 suggests that SAGE-547 at target doses of 60 μg/kg/h may also be efficacious 
in reducing depressive symptoms associated with PPD.   
Subjects will be treated in an inpatient setting and continually monitored for safety, and if 
any severe tolerability issues arise, the infusion may be terminated or the infusion rate 
reduced.  The protocol includes a formal dose interruption and reduction scheme based on 
the occurrence of intolerable AEs. 


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5. 
ETHICS 
5.1. 
Institutional Review Board or Independent Ethics Committee 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) as appropriate.  The Investigator must submit written approval to Sage 
Therapeutics or designee before he or she can enroll any subject into the study.   
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to 
the protocol in accordance with local requirements.  In addition, the IRB or IEC must 
approve all advertising used to recruit subjects for the study.  The protocol must be re-
approved by the IRB or IEC upon receipt of amendments and annually, as local regulations 
require. 
The Principal Investigator is also responsible for providing the IRB or IEC with reports of 
any reportable serious adverse drug reactions from any other study conducted with the 
investigational product.  Sage Therapeutics or designee will provide this information to the 
Principal Investigator.   
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB or IEC according to local regulations and guidelines.   
5.2. 
Ethical Conduct of the Study 
This study will be conducted according to the principles of the World Medical Association 
Declaration of Helsinki and the most recent amendment (2008).   
The Sponsor, the Medical Monitor, and the Investigator must comply with all instructions, 
regulations, and agreements in this protocol, and must also conduct the study in accordance 
with International Council on Harmonisation (ICH) Guidelines on Good Clinical Practice 
(GCP) standards as well as local regulations.   
5.3. 
Subject Information and Informed Consent 
Prior to subject participation in the study, written informed consent must be obtained from 
each subject according to ICH GCP and in accordance with local regulations.  Written 
informed consent is required for each subject prior to any testing under this protocol not 
considered standard of care, including screening tests, SAGE-547 infusion, and study 
evaluations.  Each subject’s signature must be dated by each signatory and the informed 
consent form (ICF) retained by the investigator as part of the study records.  As an additional 
assessment, the ICF will contain provisions for optional consent for the collection of blood 
for genetic testing during screening.  The ICF, as specified by the clinical site’s IRB, must 
follow the Protection of Human Subjects regulations listed in the CFR, Title 21, Part 50. 
It is the responsibility of the Investigator to obtain consent and to provide the subject a copy 
of the signed and dated ICF.  The ICF for subject participation must also be available as part 
of the subject’s file for review by the site’s dedicated study monitor. 


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All ICFs used in this study must be approved by the appropriate IRB/IEC and by the 
Sponsor.  The ICF must not be altered without the prior agreement of the relevant IRB/IEC 
and the Sponsor.   


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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of this study is to determine if SAGE-547 Injection infused 
intravenously for 60 hours at up to 90 μg/kg/h reduces depressive symptoms in subjects with 
severe PPD compared to placebo injection as assessed by the change from baseline in 
HAM-D total score.  This objective applies to both Parts A and B. 
6.2. 
Secondary Objectives 
The secondary objectives of the study apply to Parts A, B, and C unless otherwise stated, and 
are: 
• To determine if SAGE-547 infusion at up to 60 μg/kg/h for 60 hours reduces 
depressive symptoms in subjects with severe PPD compared to placebo injection 
as assessed by the change from baseline in HAM-D total score (applies to Part B 
only). 
• To determine if SAGE-547 Injection infused intravenously at up to 90 μg/kg/h for 
60 hours reduces depressive symptoms in subjects with moderate PPD compared 
to placebo injection as assessed by the change from baseline in HAM-D total 
score (applies to Part C only). 
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
depressive symptoms compared to placebo injection as assessed by HAM-D 
response, HAM-D remission, change from baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) total score, Clinical Global Impression – 
Improvement (CGI-I) response, and changes from baseline in HAM-D subscale 
and individual item scores 
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
other mood symptoms compared to placebo injection as assessed by changes from 
baseline in the Generalized Anxiety Disorder 7-Item Scale (GAD-7) total score 
• To evaluate the safety and tolerability of SAGE-547 Injection compared with 
placebo as assessed by the incidence of AEs, vital sign measurement, clinical 
laboratory evaluations, electrocardiogram (ECG) parameters, and the Columbia 
Suicide Severity Rating Scale (C-SSRS) 
6.3. 
Other Objectives 
The other objectives of the study are: 
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
subject-reported depressive symptoms compared to placebo injection as assessed 
by the change from baseline in Edinburgh Postnatal Depression Scale (EPDS) 
total score and the change from baseline in Patient Health Questionnaire (PHQ-9) 
total score 


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• To determine if SAGE-547 Injection infused intravenously for 60 hours improves 
maternal behaviors compared to placebo injection as assessed by the change from 
baseline in Barkin Index of Maternal Functioning (BIMF) total and sub-scale 
scores 
• To determine if SAGE-547 Injection infused intravenously for 60 hours improves 
the general health status compared to placebo as assessed by the change from 
baseline in the Short Form-36 (SF-36) total score at Day 7 and Day 30 
6.4. 
Pharmacokinetic Objective 
The PK objective of the study is: 
• To assess the PK profile of SAGE-547, metabolites of SAGE-547, and betadex 
sulfobutyl ether sodium (SBECD) 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overview of Study Design 
This protocol describes three multicenter, randomized, double-blind, parallel-group, placebo-
controlled studies of the efficacy, safety, and PK of SAGE-547 Injection in adult female 
subjects diagnosed with severe or moderate PPD.  Each study will be independently 
conducted, analyzed, and reported.  In this protocol, Study 547-PPD-202A is hereafter 
referred to as Part A; Study 547-PPD-202B is hereafter referred to as Part B; and 
Study 547-PPD-202C is hereafter referred to as Part C.   
The study designs for Part A, Part B, and Part C are presented in Figure 1, Figure 2, and 
Figure 3, respectively; Parts B and C will run concurrently.  For all parts, the study will 
consist of a Screening Period (up to 5-days [Day -5 to -1; Part A] or up to 7-days [Day -7 
to -1; Parts B and C]), a 3-day (60 hours of treatment and an additional 12 hours for 
completion of 72-hour assessments) Treatment Period, and a 30-day Follow-up Period.  
Subjects must remain as inpatients during the study Treatment Period, which is 
approximately 72 hours/3 days in duration.  The Screening Period assessments may be 
conducted on an inpatient or an outpatient basis.  The Follow-up Period assessments are 
conducted on an outpatient basis.   
Figure 1: 
Study Design - Part A 
 
Day -5 to -1
Day 1
Day 3
Day 4
Day 30
Visit
Screening
Treatment Period
Follow-up Period
Randomization (1:1) 
SAGE-547 30 µg/kg/hr N = 16
Day 7
Visit
Day 12 
Visit
Placebo N = 16


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Figure 2: 
Study Design - Part B 
 
 
Figure 3: 
Study Design - Part C 
 
 
SAGE-547 Injection or placebo will be administered at the study center.  Subjects will be 
monitored for safety during the Treatment and Follow-up Periods (through Study Day 30 
[±3 days]) including monitoring for AEs/SAEs, routine clinical laboratory assessments, 
physical examination, vital signs, and ECG. 
All study-related procedures will occur after written informed consent is obtained at the 
screening visit, which will occur during the Screening Period window (Day -5 through 
Day -1 for Part A; Day -7 through Day -1 for Parts B and C).  If applicable, standard of care 
data collected prior to obtaining informed consent may also be included as screening data, if 
appropriate, such as laboratory tests, ECG, physical examination, and vital signs conducted 
within the preceding 48 hours, as long as the requirement for the screening assessment to be 
Day -7 to -1
Day 1
Day 3
Day 4
Day 30
Visit
Screening
Treatment Period
Follow-up Period
Randomization 
SAGE-547 60 µg/kg/hr N = 40
SAGE-547 90 µg/kg/hr N = 40
Day 7
Visit
Day 14 
Visit
Placebo N = 40
Day 21 
Visit
Day -7 to -1
Day 1
Day 3
Day 4
Day 30
Visit
Screening
Treatment Period
Follow-up Period
Randomization 
SAGE-547 90 µg/kg/hr N = 50
Day 7
Visit
Day 14 
Visit
Placebo N = 50
Day 21 
Visit


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collected retrospectively is met in full.  If applicable, to ensure protocol compliance, any 
standard of care data eligible for inclusion as screening data must include the precise nature 
and timing of data collection. 
The end of the Screening Period coincides with the beginning of the Treatment Period.  The 
Treatment Period is the period of Day 1 of study drug IV infusion through completion of the 
infusion on Day 2 and up to Day 3.  Subjects will be confined to the study center from Day 1 
until after the 72-hour assessments have been conducted on Day 3. 
In Parts A and C, once subjects are confirmed as eligible for the study, they will be 
randomized to one of two treatment groups (SAGE-547 90 µg/kg/hour or placebo) on a 1:1 
basis.  On the morning of dosing (Day 1), subjects will begin a 4-hour dose titration period of 
30 µg/kg/hour (0-4 hours), then 60 µg/kg/hour (4-24 hours), then 90 µg/kg/hour 
(24-52 hours); followed by a decrease to 60 µg/kg/hour (52-56 hours), and 30 µg/kg/hour 
(56-60 hours).  Subjects in the placebo group will receive infusion rates equivalent to the 
90 µg/kg/hour group. 
In Part B, once subjects are confirmed as eligible for the study, they will be randomized to 
one of three treatment groups (SAGE-547 60 µg/kg/hour, SAGE-547 90 µg/kg/hour, or 
placebo) on a 1:1:1 basis.  For the 60 µg/kg/hour group, subjects will receive 30 µg/kg/hour 
(0-4 hours), then 60 µg/kg/hour (4-56 hours), followed by 30 µg/kg/hour (56-60 hours).  For 
the 90 µg/kg/hour group, subjects will begin a 4-hour dose titration period of 30 µg/kg/hour 
(0-4 hours), then 60 µg/kg/hour (4-24 hours), then 90 µg/kg/hour (24-52 hours); followed by 
a decrease to 60 µg/kg/hour (52-56 hours), and 30 µg/kg/hour (56-60 hours).  Subjects in the 
placebo group will receive infusion rates equivalent to either the 60 µg/kg/hour or 
90 µg/kg/hour group.  Parts B and C will run concurrently. 
See dose regimen presented in Section 10.1.1.  Total SAGE-547 Injection or placebo dosing 
will occur over 60 hours. 
Study-specific assessments for safety, PK, efficacy, and other outcome measures will be 
completed at pre-specified times over the duration of the study: 
• The safety and tolerability of SAGE-547 Injection will be assessed by AEs, 
clinical laboratory measures, physical examinations (including cognitive and 
mental health examinations), vital signs, ECG, use of concomitant medication, 
and the Columbia Suicide Severity Rating Scale (C-SSRS) during the Screening, 
Treatment, and Follow-up Periods (through Study Day 30 [±3 days]) 
• Plasma will be collected to formally assay for SAGE-547, metabolite, and 
SBECD levels prior to dosing through the Treatment Period and up to 12 hours 
post infusion on Day 3 and on Day 7  
• Primary efficacy assessment of the HAM-D will be completed as scheduled 
during the Screening, Treatment, and Follow-up Periods (through Study Day 30 
[±3 days]) 
• Secondary efficacy assessments of MADRS, CGI-I, EPDS, Generalized Anxiety 
Disorder 7-Item Scale (GAD-7), PHQ-9 will be completed as scheduled during 
the Screening, Treatment, and Follow-up Periods (through Study Day 30 
[±3 days]) 


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The end of the Treatment Period coincides with the beginning of the Follow-up Period. 
Subjects will attend the clinic for safety follow-up assessment at 1 week (7±1d), 12 days 
(Part A), 2 weeks (14±2d [Part B and C]), 3 weeks (21±1d [Part B and C]), and 1 month 
(30±3d) after the initiation of the study drug infusion. 
Scheduled assessments for all safety, PK, efficacy, and other outcome measures planned for 
the study are summarized in Table 1.  All subjects who receive treatment with SAGE-547 are 
to complete all study assessments through Study Day 30 (±3 days). 
The Medical Monitor will review AEs on an ongoing basis. 
7.2. 
Blinding and Randomization 
This is a double-blind study.  Subjects will be randomized to receive SAGE-547 or placebo; 
subjects, clinicians, and the clinical site study team will be blinded to treatment allocation 
until the study is unblinded at final database lock.  The pharmacist, who will prepare the 
infusion bags according to the randomization schedule, and an unblinded Monitor, who will 
perform drug accountability during the study, will be unblinded.   
Randomization will be stratified by antidepressant use at baseline (yes/no).  Subjects will be 
randomized within stratum to receive SAGE-547 or placebo according to a computer-
generated randomization schedule.   
Only the clinic pharmacist, who is responsible for preparing the infusions, will be unblinded.  
In the event of a medical emergency, the Principal Investigator will discuss with the Medical 
Monitor if unblinding is warranted.  If there is agreement to unblind treatment assignment, 
the unblinding procedure described in the Safety Management Plan for the study will be 
followed.  In all cases where the study drug allocation for a subject is unblinded, pertinent 
information (including the reason for unblinding) must be documented in the subject’s 
records and on the electronic case report form (eCRF).   


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Inclusion Criteria 
The following inclusion criteria must be met for individuals to be eligible for the study: 
1. Subject has signed an ICF prior to any study-specific procedures being performed 
2. Subject is an ambulatory female aged between 18 and 45 years of age 
3. Subject is in good physical health and has no clinically significant findings, as 
determined by the Investigator, on physical examination, 12-lead ECG, or clinical 
laboratory tests 
4. Subject agrees to adhere to the study requirements 
5. Subject either must have ceased lactating at screening; or if still lactating or actively 
breastfeeding at screening, must agree to temporarily cease giving breastmilk to their 
infant(s) from just prior to receiving study drug through 4 days (Study Day 7) after 
the end of the infusion.   
6. Subject must have a negative pregnancy test at screening and Day 1 prior to the start 
of study drug infusion 
7. Subject has had a Major Depressive Episode that began no earlier than the third 
trimester and no later than the first 4 weeks following delivery, as diagnosed by 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) 
8. For Part A and B, subject has a HAM-D total score of ≥26 at screening and Day 1 
(prior to dosing).  For Part C, subject has a HAM-D total score of ≥20 and ≤25 at 
screening and Day 1 (prior to dosing) 
9. Subject is ≤6 months postpartum at screening 
10. Subject is willing at screening to delay the start of any new pharmacotherapy 
regimens, including antidepressant or anti-anxiety medication, until the study drug 
infusion and 72-hour assessments have been completed; if the subject is taking 
psychotropic medications, these must be at a stable dose from 14 days prior to 
screening until the 72-hour assessments have been completed.   
11. (Removed) 
12. Subject must use one of the following methods of birth control during participation in 
the study and for 30 days following the end of the study drug infusion: 
• Total abstinence (no sexual intercourse) 
• Hormonal contraceptives (birth control) including birth control pills, implantable 
or injectable contraceptives (Norplant® or Depo-Provera®) 
• A barrier form of contraception such as a condom or occlusive cap with a 
spermicide 
• An intrauterine device  


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8.2. 
Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria: 
1. Subject has renal failure requiring dialysis or fulminant hepatic failure or is anemic 
(hemoglobin ≤10 g/dL) 
2. Known allergy to progesterone or allopregnanolone 
3. Active psychosis per Investigator assessment 
4. Attempted suicide associated with index case of postpartum depression 
5. (Removed) 
6. Medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder. 
7. History of active alcoholism or drug abuse (including benzodiazepines) in the 12 months 
prior to screening.  A positive urine drug screen (except benzodiazepines under certain 
circumstances [see Section 10.3.3 and Section 11.1.2.6]) is exclusionary. 
8. Exposure to another investigational medication or device within 30 days prior to 
screening 
9. (Removed) 
10. Subject has previously participated in this study or any other study employing SAGE-547 
11. Administration of electroconvulsive therapy (ECT) within 14 days prior to screening 
and/or plans to administer ECT before the Study Day 7 Visit 
8.3. 
Subject Withdrawal/Study Termination 
8.3.1. 
Withdrawal/Discontinuation of Individual Subjects  
The reasons for study drug discontinuation and/or subject withdrawal from the study must be 
recorded in the subject’s eCRF.  The Investigator must notify the Sponsor and/or the Medical 
Monitor immediately when a subject has been discontinued/withdrawn for any reason, 
including withdrawal due to an AE. 
8.3.2. 
Subject Withdrawal from the Study 
Subjects may withdraw from the study at any time for any reason without compromising the 
subject’s medical care.  The Investigator will also withdraw subjects upon the request of 
Sage Therapeutics or upon termination of the study. 
8.3.3. 
Discontinuation of Study Drug by the Investigator 
If it is necessary for the Investigator to discontinue the study drug earlier than planned, 
subjects should continue to be followed per protocol to capture safety and efficacy 
assessments for the duration of the study period.   
The Investigator may withdraw the subject from the study drug for any of the following 
reasons: 
• The subject is unwilling or unable to adhere to the protocol 


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• The subject experiences an intolerable AE that does not respond to a dose 
reduction 
• During the course of the study, the subject develops symptoms or conditions 
listed in the exclusion criteria 
• Other medical reason, at the discretion of the Investigator and/or the Medical 
Monitor 
Subjects who discontinue the study due to an AE, regardless of Investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the Investigator 
determines the event is no longer clinically significant.   
8.3.4. 
Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
subjects, or for administrative reasons.  In the event of study termination, Sage Therapeutics 
will provide written notification to the Investigator.  Investigational sites must promptly 
notify their IRB/IEC and initiate withdrawal procedures for participating subjects.   


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9. 
INVESTIGATIONAL PRODUCT 
9.1. 
Identity of Investigational Product 
SAGE-547 Injection (allopregnanolone) 
9.2. 
Clinical Supplies 
9.2.1. 
SAGE-547 
SAGE-547 Injection and ancillary supply kits containing IV administration bags, solution 
sets, and IV bag labels will be provided to the sites. 
SAGE-547 Injection is a preservative-free, sterile, clear, colorless 5 mg/mL solution of 
SAGE-547 (allopregnanolone) and 250 mg/mL betadex sulfobutyl ether sodium buffered 
with 10 mM citrate at a pH of 6.0, intended for IV injection.  All inactive excipients used in 
the formulation are compendial grade and conform to current United States Pharmacopeia 
(USP) and European Pharmacopeia (Ph. Eur.) standards.  The product is aseptically 
processed, sterile filtered, and filled into 20 mL Type 1 parenteral glass vials with West 
FluroTec® coated stopper container closure systems, under current Good Manufacturing 
Practice (cGMP) conditions.  SAGE-547 Injection is intended to be used as a single-use vial.  
An appropriate number of single-use vials to support the dosing duration of the study are 
packaged and delivered to the site.  SAGE-547 Injection vials should be stored under 
refrigerated conditions (2–8°C).  Ancillary supply kits should be stored at controlled room 
temperature (20–25°C). 
All study drug labels will contain information to meet the applicable regulatory requirements. 
9.2.2. 
Placebo 
Placebo will be identical to SAGE-547 and presented in identical vials.  Placebo will be 
manufactured in a similar way to SAGE-547 and consisting of the same formulation without 
allopregnanolone.  Placebo vials should be stored under refrigerated conditions (2–8°C).   
9.3. 
Preparation of SAGE-547 Injection or Placebo for Dosing 
The pharmacy will be responsible for preparing SAGE-547 Injection or placebo for subject 
dosing.  The prepared admixture will be administered at room temperature.  The prepared 
admixture will be assigned a room temperature (20–25 °C) storage shelf life of 30 hours from 
time of compounding.   
SAGE-547 Injection or placebo is not intended to be administered to subjects undiluted.  
Each single-use vial of SAGE-547 Injection, which is hypertonic, will require dilution with 
an appropriate volume of SWFI to render it isotonic.  Refer to the Pharmacy Manual for 
specific instructions regarding infusion preparation and administration instructions. 
9.4. 
Administration and Accountability 
The pharmacy will maintain accurate records of all investigational drug product supplies 
received, stored, dispensed, and discarded.  Accurate records will be kept regarding the 


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volume of SAGE-547 Injection or placebo used for each IV preparation, as well as the 
required infusion rate (or rates), and the date and time of preparation.  Reasons for departure 
from the expected dosing regimen must be recorded.  To satisfy regulatory requirements 
regarding drug accountability, all study medication needs to be reconciled in full.   
Refer to the Pharmacy Manual for complete details on preparation and administration. 


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Dosing Schedule 
This is a double-blind study.  Subjects will be randomized to receive 60 hours of IV 
treatment with either SAGE-547 Injection or placebo, according to a computer-generated 
randomization schedule.  In Parts A and C, subjects randomized to SAGE-547 will receive 
the target dose of 90 µg/kg/hour; in Part B, SAGE-547 subjects will receive target doses of 
either 60 or 90 µg/kg/hour.   
The timing of infusion is shown in Figure 4, Figure 5, and Figure 6.   
Figure 4: 
Study Design and Timeline for Dosing – Part A 
 
 
Figure 5: 
Study Design and Timeline for Dosing – Part B 
 
Note: Day 3, 4-hour taper applies only to the 90 μg/kg/h dose group. 
 


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Figure 6: 
Study Design and Timeline for Dosing – Part C  
 
 
Clinical supply and preparation of SAGE-547 Injection for dosing is described Section 9.2 
and Section 9.3, respectively. 
10.1.1. 
Dose Regimen 
The specific infusion dose of SAGE-547 Injection will be calculated based on weight 
(obtained at screening) for each subject and administered according to dose regimen shown 
in Table 3 and Table 4).  The infusion rates are the same for all subjects within a particular 
dosing period (0-4 hours, 4-24 hours, etc.).   
Table 3: 
Infusion Rates for Part A and C 
 
Infusion Rate (µg/kg/hour)  
SAGE-547 Dose 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2-3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
90 µg 
30 
60 
90 
60 
30 
 
Table 4: 
Infusion Rates for Part B 
 
Infusion Rate (µg/kg/hour) 
SAGE-547 Dose 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2-3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
60 µg 
30  
60  
60  
60  
30 
90 µg 
30  
60  
90  
60  
30  
 
Dosing is to begin in the morning (on Day 1) to avoid awakening subjects during the night 
for completion of study assessments.   
If any subject has an intolerable AE, such as profound sleepiness or sedation outside of 
normal sleeping hours, the infusion rate for this subject will be decreased to the next lowest 
infusion dose level (or turned off if this occurs on the 30 µg/kg/hour dose level).   


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10.1.2. 
Route of Administration 
SAGE-547 Injection is intended for IV administration only.  The compatibility of SAGE-547 
with other drugs is unknown, and the product should be administered via a dedicated 
peripheral IV line with the study-approved IV administration bags and lines. 
10.1.3. 
Treatment Period 
Total dosing with SAGE-547 or placebo will occur over 60 hours. 
10.1.4. 
Dosing of Intravenous SAGE-547 in the Case of AEs 
Since allopregnanolone levels in the proposed clinical study are similar to physiological 
levels seen in the third trimester of pregnancy, and all the AEs reported with SAGE-547 or 
allopregnanolone to date in healthy volunteers and subjects with postpartum depression were 
mild and non-serious, it is anticipated that the AEs associated with SAGE-547 in this study 
will be mild and manageable without dose interruption or reduction.  Based on the safety data 
in subjects with PPD collected to date, no subjects reported events that were serious or severe 
or led to discontinuation of study drug (two subjects reported sedation that led to a dose 
reduction, one of these subjects also reported dizziness; one subject reported rash that led to a 
dose reduction; refer to the current Investigator’s Brochure for more information).   
However, in the case of intolerable AEs occurring, the investigator is advised to reduce the 
infusion to the next lowest dose (or stop the infusion if this event occurs on the 
30 µg/kg/hour dose level) until the AE has resolved, at which time re-escalation to the 
maintenance rate may be considered.  If the AE recurs, the study drug infusion may be 
reduced again or permanently discontinued. 
10.2. 
Dosing Compliance 
Investigational product will be prepared in the site pharmacy, administered as a continuous 
IV infusion by the study staff, and will be documented in the study record.  There should be 
no adjustments in dosing except those described in Section 10.1.4. 
10.3. 
Prior Medications, Concomitant Medications, and Restrictions 
10.3.1. 
Prior Medications 
The start and end dates, route, dose/units, and frequency of all medications taken within 
60 days prior to signing the informed consent will be recorded, as well as all medications 
given to treat the current PPD episode that are recorded on the SCID-I during the screening 
visit.   
10.3.2. 
Concomitant Medications 
All medications taken from signing the informed consent through the Day 30 (±3 days) visit 
will be recorded on the eCRF.  Subjects will receive standard of care for adult female 
patients diagnosed with PPD.  Any concomitant medication determined necessary for the 
welfare of the subject may be given at the discretion of the Investigator at any time during 
the study under the guidance outlined in Section 10.3.   


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10.3.3. 
Prohibited Medications 
Restrictions on specific classes of medications include the following: 
• 
Subjects may not start new pharmacotherapy regimens, including antidepressant or 
anti-anxiety medications, from the time of informed consent until the study drug 
infusion and 72-hour assessments have been completed.  If clinically indicated, new 
antidepressant medications may be started or existing antidepressant medication 
regimens may be changed once the 72-hour assessments have been completed.  
Consideration should also be given to deferring, starting, or changing antidepressant 
medication regimens until the Day 7, Day 12 (Part A only) or Day 14 (Parts B and C 
only), Day 21 (Parts B and C only), or Day 30 visits if the HAM-D score has 
improved.   
• 
If the subject is taking psychotropic medications, these must be at a stable dose from 
14 days prior to screening to completion of the 72-hour assessments.   
• 
Benzodiazepines are to be avoided as much as possible owing to the potential for a 
synergistic sedative effect.  Eligible subjects taking a benzodiazepine at the time of 
study entry will be permitted to continue to take their current dose of the 
benzodiazepine (to prevent acute withdrawal), but no new benzodiazepine use will be 
permitted during the course of the study.   
10.3.4. 
Restrictions 
• 
Electroconvulsive therapy (ECT) is prohibited from 14 days prior to screening until 
after the Day 7 visit. 


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11. 
STUDY ASSESSMENTS 
11.1. 
Safety Assessments 
The safety and tolerability of SAGE-547 Injection will be evaluated by summarization of 
AEs by frequency, severity and seriousness, mean changes from baseline in clinical 
laboratory measures, physical examination, vital signs, ECGs, and concomitant medication 
usage.  Suicidality will be monitored using the C-SSRS.  All safety assessments should be 
performed per the study center’s standard of care and will be collected according to the 
Schedule of Events (Table 1).  All safety assessments are to be completed within 
±30 minutes of the scheduled time point. 
In addition to the schedule outlined in Table 1, completion of safety assessments including 
physical examination, vital signs, and clinical laboratory tests should occur in the event of an 
emergency or SAE, when possible.   
11.1.1. 
Adverse Events 
Adverse events will be collected after the ICF has been signed through the end of the study 
(see Section 14.2.1 for additional details).  Medical conditions or AEs that occur after the 
ICF has been signed and prior to completion of screening will be captured on the Medical 
History eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) coding system (version 18.0 or higher).   
11.1.2. 
Clinical Laboratory Tests 
Blood samples will be collected for hematology, serum chemistry, coagulation, specific 
hormone parameters, and exploratory biochemistry; pregnancy testing; and genetic analysis.  
Urine samples for urinalysis and selected drugs of abuse will also be collected.  All samples 
will be analyzed at the central laboratory.  Patients may be considered eligible for the study 
based on local laboratory results, however screening samples must also be sent to the central 
laboratory.  Both local and central screening labs must adhere to the visit window provided in 
the Schedule of Events (Table 1). 
These assessments will be performed in accordance with the Schedule of Events (Table 1) 
and as outlined individually below. 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as Abnormal; not clinically significant (NCS) or Abnormal; clinically significant 
(CS).  Screening results considered Abnormal; CS will be recorded as medical history.  
Clinical laboratory results that are Abnormal; CS during the study and indicate a worsening 
from baseline will be considered AEs, assessed according to Section 14, and recorded in the 
eCRF.   


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11.1.2.1. Hematology, Serum Chemistry, Coagulation 
Blood samples will be collected for analysis of the following:  
• Hematology: complete blood count (CBC) including white blood cell (WBC) count 
with differential (basophils, eosinophils, lymphocytes, monocytes, and neutrophils) 
platelet count, red blood cell (RBC) count, hemoglobin (Hgb) and hematocrit (Hct), 
mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) 
• Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin (total), blood urea nitrogen (BUN), 
calcium, chloride, creatinine, gamma glutamyl transferase (GGT), glucose phosphate, 
potassium, sodium, total protein, and triglycerides (screening only) 
• Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT), 
and international normalized ratio (INR) 
11.1.2.2. Hormones and Exploratory Biochemistry 
Blood samples will be collected and may be analyzed for thyroid stimulating hormone 
(TSH), estrogen, progesterone, progesterone metabolites, oxytocin, tryptophan, kynurenine, 
and markers of inflammation. 
11.1.2.3. Pregnancy Tests 
All subjects will be tested for pregnancy by serum human chorionic gonadotropin (hCG) at 
screening and urine hCG on Day 1 prior to administration of study drug and on Day 30.  
Subjects with a positive pregnancy test at screening or Day 1 will be ineligible for study 
participation. 
11.1.2.4. Genetic Testing 
A blood sample for genetic testing will be collected at screening, where consent is given.   
The objective of this research is to collect and store blood samples for possible DNA 
extraction and exploratory research into how genes or specific genetic variation may 
influence response (ie, distribution, safety, tolerability, and efficacy) to SAGE-547.  Specific 
genetic variations of interest include but are not limited to: classes of metabolizing enzymes 
(eg, Cytochrome P450 supra-family genes), genes encoding enzymes involved in the 
production and metabolism of allopregnanolone (eg, AKR1C4 (3a-hydroxysteroid 
dehydrogenase)), genes associated with the GABA receptor (eg, GABRA1-A6, 
GABRB1-B3, GABRD, GABRE, GABRG1-3) and genes associated with the production and 
degradation of GABA.    
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to SAGE-547 but also susceptibility to disorders for which SAGE-547 may be 
evaluated.  Thus, the genetic research may involve study of additional unnamed genes or 
gene categories, but only as related to disease susceptibility and drug action. 


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11.1.2.5. Urinalysis 
Urinalysis will include assessment of bilirubin, glucose, ketones, leukocytes, nitrite, pH, 
protein, and specific gravity.   
11.1.2.6. Drugs of Abuse and Alcohol 
Urine assessment for selected drugs of abuse will be performed at screening (including 
amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine, 
and propoxyphene).  Use of benzodiazepines at screening is not necessarily exclusionary, as 
subjects will be allowed to take psychotropics that have been initiated at least 14 days prior 
to admission to the study center at a stable dose (see Section 10.3.3).  A positive urine drug 
screen for any of the tested drugs of abuse (except benzodiazepines) is exclusionary.  
Alcohol will be assessed in plasma at screening and via breathalyzer or urine dipstick on 
Day 1.   
11.1.3. 
Physical Examination 
Body weight and height will be measured at screening.  Body mass index (BMI) will be 
programmatically calculated in the eCRF. 
Any condition present at the post-treatment physical examination that was not present at or 
worsened since the baseline examination is to be documented as an AE.  Whenever possible, 
the same individual is to perform all physical examinations.  Physical examinations will 
include assessment of body systems (eg, HEENT, heart, lungs, abdomen, and extremities) as 
well as cognitive and neurological examination and mental status examination.   
11.1.4. 
Vital Signs 
Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure 
(supine and standing).  A full set of vital signs will be obtained at all specified time points 
(±30 minutes), unless the subject is asleep between the hours of 23.00h and 06.00h each day.   
11.1.5. 
ECG 
A baseline 12-lead ECG will be performed during screening.  The following ECG parameters 
will be recorded: heart rate, PR, QRS, QT, and QTc.  All ECG results will be interpreted by 
the Investigator as Normal, Abnormal; not clinically significant (NCS), or Abnormal; 
clinically significant (CS).  If Abnormal, details will be provided.   
11.1.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011).  This scale 
consists of a pre-dose evaluation that assesses the lifetime and recent experience of the 
subject with suicidal ideation and behavior, and a post-baseline evaluation that focuses on 
suicidality since the last study visit.  The C-SSRS includes “yes” or “no” responses for 
assessment of suicidal ideation and behavior as well as numeric ratings for severity of 
ideation, if present (from 1 to 5, with 5 being the most severe).  The “Baseline/Screening” 
C-SSRS form will be completed on Day 1 prior to dosing.  The “Since Last Visit” C-SSRS 
form will be completed for all subsequent assessments.   


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Copies of the C-SSRS are provided in Appendix 1. 
11.2. 
Efficacy Assessments 
For all efficacy assessments, the baseline values will be calculated as the last recorded value 
prior to the start of infusion of randomized treatment.  Change from baseline values will be 
calculated as the assessment score minus the baseline value.  Change from baseline values 
will be calculated for each item and total score.   
11.2.1. 
Primary Efficacy Outcome Measure 
The primary outcome measure is the HAM-D.  The HAM-D will be administered before, 
during, and after the infusion of blinded study drug.   
11.2.1.1. Hamilton Rating Scale for Depression (HAM-D)  
The 17-item HAM-D will be used to rate the severity of depression in subjects who are 
already diagnosed as depressed (Hamilton 1960).  The 17-item HAM-D is comprised of 
individual ratings related to the following symptoms: depressed mood (sadness, hopeless, 
helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and 
activities, retardation (slowness of thought and speech; impaired ability to concentrate; 
decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms 
(gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and 
insight.  The HAM-D assessments are to be completed within ±30 minutes of the scheduled 
time point, but prior to starting dosing on D1 H0.  Every effort should be made for the same 
rater to perform all HAM-D assessments for a single subject. 
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  Item 
16 can be rated according to history (item 16A) or actual weight change (item 16B).  The 
item 16 score is calculated as the item 16 response that is not equal to 3 (ie, “Not assessed”).   
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D.  HAM-D subscale 
scores will be calculated as the sum of the items comprising each subscale.  HAM-D 
response will be defined as having a 50% or greater reduction from baseline in HAM-D total 
score.  HAM-D remission will be defined as having a HAM-D total score of ≤7.   
A copy of the HAM-D is provided in Appendix 2. 
11.2.2. 
Secondary Efficacy Outcome Measures 
Secondary efficacy assessments include evaluation of depressive symptom severity by the 
HAM-D total score at the Day 30 time point, MADRS (Section 11.2.2.1), and CGI 
(Section 11.2.2.2).  Additional assessments of depressive symptom severity and reproductive 
mood disorders will be measured by the following clinician- and subject-rated outcome 
measures: EPDS (Section 11.2.3.1), GAD-7 (Section 11.2.2.3), and PHQ-9 
(Section 11.2.3.2). 


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11.2.2.1. Montgomery Asberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire which psychiatrists use to measure the 
severity of depressive episodes in patients with mood disorders.  It was designed as an 
adjunct to the HAM-D which would be more sensitive than the HAM-D with regards to 
changes brought on by antidepressants and other forms of treatment. 
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 
6.  The overall score ranges from 0 to 60 (McDowell 2006, Müller-Thomsen 2005). 
The questionnaire includes questions on the following symptoms  
1. Apparent sadness  
2. Reported sadness  
3. Inner tension  
4. Reduced sleep  
5. Reduced appetite  
6. Concentration difficulties  
7. Lassitude  
8. Inability to feel  
9. Pessimistic thoughts  
10. Suicidal thoughts 
The MADRS total score will be calculated as the sum of the 10 individual item scores. 
A copy of the MADRS is provided in Appendix 3. 
11.2.2.2. Clinical Global Impression (CGI) Scale 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the patient’s condition.  The CGI scale 
is comprised of three items.  Only the first two items are being used in this study.   
The CGI-Severity (CGI-S) item uses a 7-point Likert scale to rate the severity of the patient’s 
illness at the time of assessment, relative to the clinician’s past experience with patients who 
have the same diagnosis.  Considering total clinical experience, a patient is assessed on 
severity of mental illness at the time of rating 1=normal, not at all ill, 2=borderline mentally 
ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7=extremely ill.  The 
CGI-S will be rated by the clinician at screening and on Day 1 (prior to dosing). 
The CGI-Improvement (CGI-I) item employs a 7-point Likert scale to measure the overall 
improvement in the patient’s condition post-treatment.  The investigator will rate the 
patient’s total improvement whether or not it is due entirely to drug treatment.  Response 
choices include: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally 
improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse.  The 
CGI-I is only rated at post-treatment assessments.  By definition, all CGI-I assessments are 


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evaluated against baseline conditions.  CGI-I response will be defined as having a CGI-I 
score of “very much improved” or “much improved.”   
A copy of the CGI is provided in Appendix 4. 
11.2.2.3. Generalized Anxiety Disorder 7-Item Scale (GAD-7) 
The GAD-7 is a patient-rated generalized anxiety symptom severity scale (Spitzer 2006).  
Scoring for GAD-7 generalized anxiety is calculated by assigning scores of 0, 1, 2, and 3 to 
the response categories, respectively, of “not at all sure,” “several days,” “over half the 
days,” and “nearly every day.” GAD-7 total score for the seven items ranges from 0 to 21, 
where a score of 0 to 4=minimal anxiety, 5 to 9=mild anxiety, 10 to 14=moderate anxiety, 
and 15 to 21=severe anxiety.  All assessments are to be completed within ±30 minutes of the 
scheduled time point. 
The GAD-7 total score will be calculated as the sum of the 7 individual item scores. 
A copy of the GAD-7 is provided in Appendix 6. 
11.2.3. 
Patient Reported Outcome Measures 
Other efficacy assessments include evaluation of depressive symptom severity and 
reproductive mood disorders.  These will be measured by the following clinician- and 
subject-rated outcome measures: EPDS, PHQ-9, BIMF, and SF-36. 
11.2.3.1. Edinburgh Postnatal Depression Scale (EPDS) 
The EPDS is a patient-rated depressive symptom severity scale specific to the perinatal 
period (Cox 1987).  The EPDS total score will be calculated as the sum of the 10 individual 
item scores. 
A copy of the EPDS is provided in Appendix 5. 
11.2.3.2. Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is a patient-rated depressive symptom severity scale.  To monitor severity over 
time for newly diagnosed patients or patients in current treatment for depression, patients 
may complete questionnaires at baseline and at regular intervals thereafter.  Scoring is total 
based on responses to specific questions, as follows:  not at all=0; several days=1; more than 
half the days=2; and nearly every day=3.  All assessments are to be completed within 
±30 minutes of the scheduled time point. 
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores.  The 
PHQ-9 total score will be categorized as follows: 1-4=minimal depression, 5-9=mild 
depression, 10-14=moderate depression, 15-19=moderately severe depression; and 
20-27=severe depression. 
A copy of the PHQ-9 is provided in Appendix 7. 
11.2.3.3. Barkin Index of Maternal Functioning (BIMF)  
The BIMF is a patient reported outcome scale BIMF covers a broad range of functional areas 
(self-care, infant care, mother-child interaction, psychological well-being of mother, social 


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support, management, adjustment).  This new application of maternal functional status is a 
robust construct where the physical and mental health of the mother is essential to optimal 
functioning.  Each item is rated on a scale of 0 (strongly disagree) to 6 (strongly agree).  
A copy of the BIMF is provided in Appendix 8. 
11.2.3.4. Short Form-36 (SF-36) 
The Medical Outcomes Study Short Form-36 (SF-36v2) is a 36-item measure of health status 
that has undergone validation in many different disease states (Ware 2007).  The SF-36 
covers eight health dimensions including four physical health status domains (physical 
functioning, role participation with physical health problems [role-physical], bodily pain, and 
general health) and four mental health status domains (vitality, social functioning, role 
participation with emotional health problems [role-emotional], and mental health).  In 
addition, two summary scores, physical component summary (PCS) and mental component 
summary (MCS), are produced by taking a weighted linear combination of the eight 
individual domains.  The SF-36v2 is available with two recall periods: the standard recall 
period is 4 weeks and the acute recall period is 1 week.  This study will use the acute version, 
which asks patients to respond to questions as they pertain to the past week.  Higher SF-36 
scores indicate a better state of health.  The SF-36 requires approximately 10 minutes to 
complete and can be self-administered or completed by interview in person or by telephone. 
A copy of the SF-36 is provided in Appendix 9. 
11.2.3.5. Healthcare Resource Utilization (HCRU) 
Subject-reported healthcare resource utilization data, including baseline diagnosis history, 
baseline antidepressant treatment history, and healthcare visits, inpatient visits, and 
medication use, will be collected at screening and on Day 30 of follow-up (or at early 
termination).  A copy of the health resource utilization questionnaire is provided in 
Appendix 10.  
11.3. 
Pharmacokinetics 
Blood samples for PK analysis will be collected in accordance with the Schedule of Events 
(Table 1).  Scheduled time points for PK blood draws after the start of infusion will have a 
window of ±10 minutes.  Samples will be processed according to the PK Manual, and may be 
analyzed for concentrations of SAGE-547, metabolites of SAGE-547, and SBECD.  
Additionally, PK samples may be obtained outside the planned collection times if issues 
administering study drug are encountered, such as incorrect infusion rate, interrupted 
infusion, or other administration deviations where PK level assessment may be important in 
understanding subject state.  In the event of an unplanned dose adjustment, an unscheduled 
PK sample should be collected just prior to the infusion rate change. 
The following PK parameters will be derived from the plasma concentrations (where 
evaluable): area under the concentration-time curve (AUC) from time zero to 60 hours 
(AUC0-60), AUC from time zero to infinity (AUC∞), maximum (peak) plasma concentration 
(Cmax), time at maximum (peak) plasma concentration (tmax), steady-state drug concentration 
in the plasma during constant-rate infusion (Css), and average drug concentration in the 


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plasma at steady state during a dosing interval (Cavg).  Each PK parameter will be derived 
separately for each part of the study. 
The plasma samples will be drawn from the arm contralateral to that used for study drug 
administration.  Instructions on sample collection, processing methods, storage, and shipping 
conditions for subject-specific plasma PK kits will be provided in the study laboratory 
manual. 


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12. 
STUDY PROCEDURES 
The study procedures listed below by study day reflect the data collection times for this 
protocol.   
Scheduled assessments for all safety, efficacy, PK, and other outcome measures planned for 
the study are summarized in Table 1 (Schedule of Events).  All subjects who receive 
treatment with SAGE-547 should complete all study assessments through Study Day 30 (±3 
days). 
Subjects who complete the assessments at Hour 60 and Day 30 (±3 days) will be defined as 
study completers.   
12.1. 
Screening Period 
The Screening Period consists of a window from Day -7 through Day -1 prior to starting 
SAGE-547 treatment (up to 5-days [Day -5 to -1; Part A] or up to 7-days [Day -7 to -1; 
Parts B and C]).  The Screening Period begins with the signature of the ICF.  Eligibility is 
determined by applying the inclusion/exclusion criteria.  The diagnosis of PPD must be by 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I).  A full medical and 
family history will be taken from the subject using a SCID-I interview, including recording 
of all depression (major depressive disorders, premenstrual dysphoric disorder, menstrual 
migraine, and other psychiatric disorders per DSM), other Axis I and Axis II disorders, and 
pregnancy history including birth complications, and postpartum depression episodes.  
Family history will be collected from the subject for primary probands, including all 
depression (major depressive disorders, premenstrual dysphoric disorder, menstrual 
migraine, and other psychiatric disorders per DSM), other Axis I disorders, and postpartum 
depression episodes.   
The following assessments/procedures will be conducted at the screening visit, which will 
occur during the Screening Period window.  Standard of care data collected prior to obtaining 
informed consent may also be included as screening data, if appropriate, such as laboratory 
tests, ECG, physical examinations, and vital signs conducted within the preceding 48 hours, 
as long as the requirement for the screening assessment to be collected retrospectively is met 
in full, and all screening assessments are completed, reviewed and approved by the 
Investigator prior to administration of study drug. 
Subjects will be confined to the study center from Day 1 until after the 72-hour assessments 
have been conducted on Day 3. 
• Written informed consent will be obtained 
• Inclusion/exclusion criteria will be reviewed to determine subject eligibility 
• Demographic information and medical/family history will be collected 
• Lactation status (ie, subject is breastfeeding, subject is lactating but not 
breastfeeding, or subject is not lactating) will be recorded 
• Blood will be collected for a pregnancy test 


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• Completion of physical examination, including body weight.  Height should be 
recorded.  BMI will be calculated. 
• Vital signs will be recorded 
• Blood and urine samples will be collected for clinical laboratory testing, including 
drug and alcohol screening 
• Blood sample will be taken for genetic analysis with subject consent 
• An ECG reading will be taken 
• The HAM-D, CGI-S, and MADRS will be completed 
• Concomitant medications will be recorded 
• AEs will be monitored 
12.2. 
Study Drug Treatment Period (Day 1 to Day 3, Hours 0-72) 
All safety, efficacy, PK, and other outcome assessments described in this section are to be 
completed within ±30 minutes of the scheduled time points, unless otherwise stated.  
Windows for PK collection time points are specified by respective time point for Study 
Days 1 to 3 in Section 12.2.1 to Section 12.2.3, respectively (see Section 11.3 for additional 
details).  Subjects will be confined to the study center from Day 1 until after the 72-hour 
assessments have been conducted on Day 3.   
Psychiatric follow-up outside the study visits will be arranged and documented, as 
appropriate.   
12.2.1. 
Day 1 
• Inclusion/exclusion criteria will be reviewed to determine subject eligibility 
• Randomization 
• Urine will be collected for a pregnancy test 
• Study drug administration will begin for dose titration in the morning followed by 
maintenance infusion 
• Vital signs will be recorded prior to infusion and at 2, 4, 8, 12, 18, and 24 hours 
on Day 1 (±30 minutes), unless the subject is asleep between the hours of 23.00h 
and 06.00h each day 
• Blood and urine samples will be collected for drug and alcohol screening 
• A blood sample for PK analysis will be collected prior to infusion (ie, morning of 
Day 1 prior to dosing), and at Hours 4 (before change in infusion rate, if 
applicable), 8, 12, and 24 (before change in infusion rate, if applicable) after the 
start of the infusion.  PK blood draws after the start of infusion will have a 
window of ±10 minutes.  In the event of an unplanned dose adjustment, an 
unscheduled PK sample should be collected just prior to the infusion rate change. 


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• The HAM-D will be completed prior to dosing and at Hours 2, 4, 8, 12, and 24 on 
Day 1 (±30 minutes) 
• The MADRS will be completed prior to dosing and at Hour 24 on Day 1 
(±30 minutes) 
• The CGI-S will be completed prior to dosing and the CGI-I at Hours 2, 4, 12, and 
24 on Day 1 (±30 minutes) 
• The following questionnaires will be completed prior to dosing: BIMF, EPDS, 
GAD-7, SF-36, and PHQ-9 (±30 minutes) 
• AEs will be monitored 
• Concomitant medications will be recorded 
• The “Baseline/Screening” C-SSRS form will be completed prior to dosing.  The 
“Since Last Visit” C-SSRS form will be completed at Hour 24 (± 30 minutes) 
• Breast milk will be pumped and discarded by subjects who are lactating 
12.2.2. 
Day 2 
• Ongoing study drug maintenance infusion administration 
• Vital signs will be recorded at Hours 30, 36, 42, and 48 (±30 minutes), unless the 
subject is asleep between the hours of 23.00h and 06.00h each day 
• A blood sample for PK analysis will be collected at Hours 30, 36, and 48.  PK 
blood draws will have a window of ±10 minutes.  In the event of an unplanned 
dose adjustment, an unscheduled PK sample should be collected just prior to the 
infusion rate change 
• The HAM-D will be completed at Hour 36 and Hour 48 (±30 minutes) 
• The CGI-I will be completed at Hour 36 and Hour 48 (±30 minutes) 
• The MADRS will be completed at Hour 48 (±30 minutes) 
• An ECG reading will be taken at Hour 48 
• AEs will be monitored 
• Concomitant medications will be recorded 
• Breast milk will be pumped and discarded by subjects who are lactating 
12.2.3. 
Day 3 
• Ongoing study drug maintenance infusion administration until Hour 60 
• A physical examination will be completed at Hour 72 
• Vital signs will be recorded at Hours 54, 60, 66, and 72 (±30 minutes) 


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• A blood sample for PK analysis will be collected at Hours 60 and 
72 (±10 minutes).  In the event of an unplanned dose adjustment, an unscheduled 
PK sample should be collected just prior to the infusion rate change 
• Blood sample will be collected for clinical laboratory testing at Hour 72 
• The HAM-D and MADRS will be completed at Hours 60 and 72 (±30 minutes) 
• The CGI-I will be completed at Hours 60 and 72 (±30 minutes) 
• The following questionnaires will be completed at Hour 60: EPDS, GAD-7, and 
PHQ-9 (±30 minutes) 
• AEs will be monitored 
• Concomitant medications will be recorded 
• The C-SSRS will be completed at Hours 60 and 72 
• Subjects who are lactating will pump and discard breast milk and be reminded 
that they must continue to pump and discard breast milk through Day 7 of the 
study  
12.3. 
Follow-up Period (Day 7 through Day 30) 
12.3.1. 
Day 7 (±1 day) 
The following assessments should be completed: 
• A physical examination will be completed 
• Vital signs will be recorded 
• Blood and urine samples will be collected for clinical laboratory testing 
• An ECG reading will be taken 
• The C-SSRS, HAM-D, MADRS, CGI-I, EPDS, GAD-7, PHQ-9, SF-36, and 
BIMF will be completed 
• Subjects who are lactating will be reminded to continue to pump and discard 
breast milk for the remainder of the day; subjects will be instructed that they may 
resume breastfeeding their infant in the morning of Day 8 
• AEs will be monitored 
• Concomitant medications will be recorded 
12.3.2. 
Day 12 (±2 days) (Part A); Day 14 (±2 days) and Day 21 (±3 days) (Parts B 
and C) 
The following assessments should be completed: 
• The C-SSRS, HAM-D, MADRS, CGI-I, EPDS, GAD-7, PHQ-9, SF-36, and 
BIMF will be completed 
• AEs will be monitored 


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• Concomitant medications will be recorded 
12.3.3. 
Day 30 (±3 days) 
The following assessments should be completed: 
• Urine will be collected for a pregnancy test 
• The C-SSRS, HAM-D, MADRS, CGI-I, EPDS, GAD-7, PHQ-9, SF-36, and 
BIMF will be completed 
• AEs will be monitored 
• Concomitant medications will be recorded 
12.3.4. 
Early Termination Visit 
The following assessments should be completed if the subject discontinues from the study 
prior to the Day 7 Visit: 
• A physical examination will be completed 
• Vital signs will be recorded 
• Blood and urine samples will be collected for clinical laboratory testing 
• An ECG reading will be taken 
• The C-SSRS, HAM-D, MADRS, CGI-I, EPDS, GAD-7, PHQ-9, SF-36, and 
BIMF will be completed 
• AEs will be monitored 
• Concomitant medications will be recorded 
The visit should occur within 3 days of notification of the subject discontinuing. 


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13. 
STATISTICAL METHODS AND CONSIDERATIONS 
In general, summary statistics for all study endpoints will be presented as mean, standard 
deviation (SD), median, and ranges for continuous endpoints, and as counts and percentages 
for categorical endpoints.  For the purpose of all safety, efficacy, and other analyses where 
applicable, baseline is defined as the last pre-dose measurement closest to the start of blinded 
study drug infusion. 
A separate statistical analysis plan (SAP) will be generated for each study (Parts A, B, and C) 
and approved prior to the respective database lock of each study.  All statistical analyses will 
be conducted using SAS for Windows (version 9.1.3, or higher; Cary, NC), unless otherwise 
specified.   
Any deviations from the planned analyses will be described and justified in the final clinical 
study report (CSR). 
13.1. 
Data Analysis Sets 
The All Enrolled Population will include all subjects who have given written informed 
consent.  This population will be used for subject disposition and demographic characteristic 
summaries. 
The All Randomized Population will include the subset of subjects from the All Enrolled 
Population who have been randomized.  Subjects will be classified according to randomized 
treatment.  This population will be used for subject disposition, demographic characteristic, 
and baseline characteristic summaries. 
The Safety Population will include all randomized subjects who start the infusion of study 
drug.  Subjects will be classified according to actual treatment received.  This analysis 
population will be used for all safety analyses. 
The Efficacy Population (EFF) will include the subset of the Safety Population who have a 
valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment.  
Subjects will be classified according to randomized treatment.  This analysis population will 
be used for all efficacy analyses. 
The Per Protocol Population (PP) will include the subset of the Efficacy Population who 
complete the full infusion without significant protocol violations or deviations.  Subjects will 
be classified according to randomized treatment.  This analysis population will be used for 
sensitivity analyses of the primary and select secondary endpoints. 
The PK Population (PKP) will include the subset of the Safety Population who have at least 
one evaluable PK sample.  Subjects will be classified according to actual treatment received.  
This analysis population will be used for all PK analyses. 
The number and percentage of subjects who receive SAGE-547 Injection or placebo, 
prematurely discontinue, and complete the study will be summarized.  The number and 
percentage of subjects will also be summarized for each reason for premature 
discontinuation.  In addition, the number of subjects whose data should be used for the 
planned analyses will be identified for each respective analysis population (ie, Safety, EFF, 
PKP, and PP). 


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13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data.  All subjects will be used in the analyses, 
as per the analysis populations, using all non-missing data available.  A sensitivity analysis 
may be carried out to investigate the impact of missing data if more than 5% of subjects are 
missing primary endpoint assessments.  Any rules/statistical methods for the imputation of 
missing data will be described in the SAP. 
13.3. 
Demographics and Baseline Characteristics 
Demographics such as age, race, and ethnicity will be summarized.  In addition, baseline 
characteristics such as height, weight, and BMI will be summarized.  Categorical summaries, 
such as race and ethnicity, will be summarized by frequency and percentage.  Continuous 
summaries, such as age, height, weight, BMI and baseline vital signs, will be summarized 
using descriptive statistics such as n, mean, SD, median, minimum, and maximum. 
Drug, alcohol, and pregnancy screening results will be collected and listed but not 
summarized, as they are considered part of the inclusion/exclusion criteria.   
Medical/family history will be collected and listed by subject. 
13.4. 
Primary Endpoints 
For efficacy analysis purposes, centers with fewer than 15 subjects per center for Part B or 
10 subjects per center for Part C will be pooled within regions (eg, North America region 
centers will be pooled separately those in Europe).  Change from baseline to each assessment 
in HAM-D total score will be analyzed using a mixed effects model for repeated measures 
(MMRM); the model will include center (pooled), treatment, baseline HAM-D total score, 
visit time point, and visit time point-by-treatment terms.  Center and all other explanatory 
variables will be treated as fixed effects.  For Parts A and C, the primary comparison will be 
between 90 µg SAGE-547 and placebo at the 60-hour assessment.  For Part B, the primary 
comparison will be between 90 µg SAGE-547 and placebo at the 60-hour assessment; if this 
comparison is significant at the 0.05 level, then the 60 µg group will be compared to placebo 
at the 0.04 level of significance.  More details will be provided in the SAPs regarding strong 
control of overall level of significance for multiple testing, including testing of key secondary 
endpoints.  Comparisons at other time points, including the Day 30 time point, will be 
conducted to support the findings for the primary comparison.  Model-based point estimates 
(ie, LS means), 95% confidence intervals, and p-values will be reported for each assessment.   
Summaries of HAM-D total scores and changes from baseline values will include n, mean, 
SD, median, minimum, and maximum.   
13.5. 
Secondary Endpoints 
13.5.1. 
Efficacy Analysis 
MMRM methods similar to those described in Section 13.4 will be used for the analysis of 
the following variables: MADRS total score, EPDS total score, GAD-7 total score, PHQ-9 
total score, and select individual item and subscale scores.  Separate models will be fit for 
each part of the study.  For each model, the comparison of interest will be between each 


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SAGE-547 dose and placebo at the 60-hour assessment.  Model based point estimates 
(ie, LS means), 95% confidence intervals, and p-values will be reported.   
Generalized Estimating Equation (GEE) methods will be used for the analysis of the 
following response variables: HAM-D response, HAM-D remission, and CGI-I response.  
GEE models will include terms for center, treatment, and baseline score.  Separate models 
will be fit for each part of the study.  The comparison of interest will be the difference 
between each SAGE-547 dose and placebo at the 60-hour assessment.  Model based point 
estimates (ie, odds ratios), 95% confidence intervals, and p-values will be reported.  For the 
CGI-I response analysis, baseline CGI-S score will be included in the model.   
Descriptive statistics for all scores, change from baseline values, and response variables will 
be presented by treatment and assessment time point.  Summaries will include n, mean, SD, 
median, minimum, and maximum.   
13.5.2. 
Safety Analysis 
Safety and tolerability of SAGE-547 Injection will be evaluated by AEs, concomitant 
medications, changes from baseline in physical examination, vital signs, CBC, serum 
chemistry, urinalysis, and 12-lead ECG.  Suicidality will be monitored by the C-SSRS.  In 
Part A only, sedation will be assessed using the Stanford Sleepiness Scale (SSS) and an 
analysis of SSS data will be performed comparing the treatment groups in the same way as 
for the primary endpoint.  Safety data will be listed by individual and summarized by 
treatment group.  All safety summaries will be performed on the Safety Population. 
Safety data will be examined for possible relationships between subject characteristics and 
plasma allopregnanolone concentrations, as appropriate. 
Scheduled visits for all safety assessments are described in Section 12 and summarized in 
Table 1. 
13.5.2.1. Adverse Events 
The analysis of AEs will be based on the concept of treatment-emergent AEs (TEAEs).  A 
TEAE is defined as an AE with onset after the start of study drug infusion, or any worsening 
of a pre-existing medical condition/AE with onset after the start of study drug infusion.  The 
incidence of TEAEs will be summarized overall and by MedDRA System Organ Class 
(SOC) and preferred term (PT).  Incidences will be presented in order of decreasing 
frequency.  In addition, summaries will be provided by severity (mild, moderate, severe) and 
by causality (related, not related) to study drug (see Section 14.2.2.1). 
TEAEs leading to discontinuation and SAEs (see Section 14.1.4 for definition) with onset 
after the start of randomized infusion will also be summarized. 
All AEs and SAEs (including those with onset or worsening before the start of randomized 
infusion) through the Day 30 Follow-up Visit (±3 days) will be listed. 
13.5.2.2. Clinical laboratory evaluations 
Results will be listed by Subject ID and timing of collection.  Mean changes from baseline in 
clinical laboratory measures will be evaluated. 


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13.5.2.3. Physical examinations 
Physical examinations will be evaluated at screening and Day 7.  Any clinically significant 
change in physical examination compared to those observed at screening should be noted as 
an AE.   
13.5.2.4. Vital signs 
Vital signs, including oral temperature (°C), respiratory rate, heart rate, and blood pressure 
(supine and standing) will be obtained at the scheduled time points described in 
Section 11.1.4.  Mean changes from baseline (pre-infusion) in vital signs will be evaluated.   
13.5.2.5. 12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, and 
QTc.  Any clinically significant abnormalities or changes in ECGs should be listed as an AE.  
ECG findings will be listed by subject and visit. 
13.5.2.6. Concomitant medications 
A summary of all concomitant medications taken during the course of the study will be 
presented in tabular form by therapeutic drug class and generic drug name using the WHO 
Collaborating Centre for Drug Statistics Methodology Norwegian Institute of Public Health 
(http://www.whocc.no). 
13.5.2.7. C-SSRS 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be listed for all subjects.  Listings will include behavior type and/or category for Suicidal 
Ideation and Suicidal Behavior of the C-SSRS. 
13.5.2.8. SSS (Part A only) 
Changes in score over time will be represented graphically, and change from baseline will be 
measured. 
13.5.2.9. PK Analysis 
Plasma will be collected to assay for concentrations of SAGE-547, metabolites of 
SAGE-547, and SBECD.  The following PK parameters will be derived from the plasma 
concentrations (where evaluable): AUC0-60, AUC∞, Cmax, time at maximum (peak) plasma 
concentration (tmax), steady-state drug concentration in the plasma during constant-rate 
infusion (Css), and average drug concentration in the plasma at steady state during a dosing 
interval (Cavg). 
Plasma concentrations will be listed by subject and summarized by nominal collection time 
point.  PK parameters will be listed by subject and summarized by collection time point.  
Correlations between concentrations and AEs or tolerability measures may be performed as 
deemed necessary. 
In addition to typical descriptive statistics, summaries should include geometric mean, 
coefficient of variation, and geometric coefficient of variation. 


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13.6. 
Determination of Sample Size 
Using a two-sided test at an alpha level of 0.05, a sample size of 10 evaluable subjects per 
group for Part A would provide 70% power to detect an effect size of 1.2 between the 
SAGE-547 and placebo groups with regard to the primary outcome variable of change from 
baseline in HAM-D total score.  An effect size of 1.2 corresponds to a placebo-adjusted 
difference of 12 points in the change from baseline in HAM-D total score at 60 hours with an 
assumed standard deviation of 10 points.  By including two treatment groups and using a 1:1 
randomization ratio, a total of 20 evaluable subjects are required for Part A.   
Based on the results of the interim analysis (Section 13.7), the sample size for Part A could 
be increased to a maximum of 32 randomized subjects.  This adjustment to the sample size 
would allow for an effect size of 1.0 to be detected.   
For Part B, a sample size of 40 evaluable subjects per group (120 total) would provide 90% 
power to detect a treatment difference of 9.0 between the SAGE-547 and placebo groups and 
a common standard deviation of 12 points (for an effect size of 0.75) using a two-sided t-test 
at an alpha level of 0.05.   
For Part C, a sample size of 50 evaluable subjects per group (100 total) would provide 90% 
power to detect a treatment difference of 8.0 between the SAGE-547 and placebo groups and 
a common standard deviation of 12 points (for an effect size of 0.667) using a two-sided 
t-test at an alpha level of 0.05.   
13.7. 
Interim Analysis 
In Part A, an interim analysis will be conducted by an independent statistician for sample size 
re-estimation purposes when at least 16 subjects have completed efficacy assessments 
through 60 hours in Part A.  Since the Sponsor will be kept uninformed of the response rates 
at the time of the interim analysis, no statistical adjustment will be made to the level of 
significance for hypothesis testing of Part A of the study.  A detailed description of the 
interim analysis for sample size re-estimation will be included in the SAP. 
No interim analyses are planned for Parts B and C of the study. 
13.8. 
Changes from Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the 
final SAP.   
Upon the completion of each study (547-PPD-202A, 547-PPD-202B, and 547-PPD-202C), 
the data will be unblinded and analyzed separately, and a separate final CSR will report the 
findings of each study.   


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14. 
ADVERSE EVENTS 
Section 14.1 lists important AE definitions. 
Section 14.2 summarizes Investigator responsibilities regarding the identification and 
documentation of AEs, the classification of AEs for relationship to study drug and severity, 
and the reporting of AE information to the Sponsor and the IRB/IEC. 
Section 14.3 summarizes Sponsor/Medical Monitor Responsibilities regarding monitoring of 
AE data and reporting relevant safety information to regulatory authorities. 
14.1. 
Adverse Event Definitions 
14.1.1. 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.   
14.1.2. 
Suspected Adverse Reaction  
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the AE.  Suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any AE caused by a 
drug. 
14.1.3. 
Life-Threatening  
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either 
the Investigator or Sponsor, its occurrence places the subject at immediate risk of death.  It 
does not include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death. 
14.1.4. 
Serious  
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
• Death 
• A life-threatening AE (see definition in Section 14.1.3) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability or incapacity  
• A congenital anomaly or birth defect 
• Other medically important condition (as described below)  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include 


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allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
14.1.5. 
Unexpected  
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed.  
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the Investigator’s Brochure referred only to elevated hepatic enzymes or 
hepatitis.  Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the Investigator’s Brochure listed only cerebral vascular 
accidents.   
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the Investigator’s Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.   
In the clinical trial setting, the term “expected” would not mean “anticipated” for the 
condition being treated or population being studied since “expected” would indicate being 
“listed in the Investigator’s Brochure.”  For example, some AEs can be anticipated to occur 
as a result of a disease or condition or in a certain population (eg, cancer-related deaths in a 
cancer trial, strokes or acute myocardial infarctions in an older population).  However, for 
reporting purposes, these anticipated events are not considered “expected” if they are not 
listed in the Investigator’s Brochure (ie, the investigational drug is not suspected or known to 
cause them).  
14.2. 
Investigator Responsibilities 
14.2.1. 
Identification and Documentation of Adverse Events by Investigator 
Subjects will be evaluated and questioned generally (if possible) to identify AEs during the 
course of the study.  AEs will be collected during subject preparation, study drug 
administration during screening, after the initiation of study drug administration through to 
Day 3, and at the Follow-up Visits through Day 30 (±3 days).  SAEs will also be collected 
until the Day 30 (±3 days) follow-up visit.  Medical conditions that occur prior to completion 
of the screening visit will be captured on the Medical History eCRF.  Adverse events that 
occur after completion of the screening visit will be recorded on the AE page of the eCRF 
(AE eCRF).   
All AEs revealed by observation, physical examinations, other diagnostic procedures, or 
spontaneously reported by the subject and/or in response to an open question from study 
personnel will be recorded on the AE eCRF.  Any clinically significant deterioration from 
baseline in laboratory assessments or other clinical findings is considered an AE and must be 
recorded on the AE eCRF, unless otherwise stated.  AE information recorded on AE eCRF 
will be entered into the database on an ongoing basis.  The database, including AE 
information, will be transferred to the Sponsor on a pre-defined schedule for review.   


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All AEs, regardless of investigator-determined causality, should be followed until the event 
is resolved or the Investigator determines the event is stable or no longer clinically 
significant.   
For all SAEs, an SAE report form must be completed with as much information as possible 
and submitted in the time frame described in Section 14.2.3.  When new significant 
information is obtained as well as when the outcome of an event is known, the SAE report 
form should be updated on a follow-up report.  If the subject was an outpatient at the time of 
the SAE and was re-hospitalized due to the SAE, a copy of relevant hospital records 
(eg, admission report, laboratory test results, discharge summary) may be requested to be 
included as part of the subject’s medical file.   
All SAEs will be followed until the events are resolved or improved and a stable status has 
been achieved, or the subject is lost to follow-up.   
Female patients who become pregnant during the study should be followed to determine the 
outcome of the pregnancy.  The pregnancy must be reported to the sponsor within 24 hours 
of the site becoming aware of the pregnancy.  If the pregnancy ends for any reason before the 
anticipated date, the investigator should notify the sponsor.  At the completion of the 
pregnancy, the investigator will document the outcome of the pregnancy.  If the outcome of 
the pregnancy meets the criteria for immediate classification as an SAE (ie, postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the 
investigator should follow the procedures for reporting an SAE. 
14.2.2. 
Adverse Event Classification 
Definitions for the categories of AE classification are included in this section.   
14.2.2.1. Relationship to Investigational Drug 
Not Related:  
No relationship between the experience and the administration of study 
drug; related to other etiologies such as concomitant medications or 
subject’s clinical state. 
Possibly Related:  A reaction that follows a plausible temporal sequence from 
administration of the study drug and follows a known response pattern to 
the suspected study drug or 
The reaction might have been produced by the subject’s clinical state or 
other modes of therapy administered to the subject, but this is not known 
for sure.   
Probably Related:  A reaction that follows a plausible temporal sequence from 
administration of the study drug and follows a known response pattern to 
the suspected study drug.   
The reaction cannot be reasonably explained by the known 
characteristics of the subject’s clinical state or other modes of therapy 
administered to the subject  


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14.2.2.2. Severity 
The severity of an adverse experience will be defined as follows and reported as indicated on 
the AE eCRF: 
Mild: 
  
Discomfort noticed, but no disruption to daily activity.   
Moderate: 
Discomfort sufficient to reduce or affect normal daily activity, but is 
not hazardous to health; prescription drug therapy may be employed to 
treat the AE. 
Severe: 
Inability to work or perform normal daily activity and represented a 
definite hazard to health; prescription drug therapy and/or 
hospitalization may be employed to treat the AE. 
14.2.2.3. Action Taken with Investigational Drug 
Action taken with regard to administration of study drug for this study will be recorded using 
the one of following categories (the category “dose increased” does not apply to this study):  
• Drug withdrawn: An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication 
• Dose not changed: An indication that a medication schedule was maintained 
• Drug interrupted: An indication that a medication schedule was modified by 
temporarily terminating a prescribed regimen of medication 
• Dose reduced: An indication that a medication schedule was modified to a 
reduced rate/dose 
• Unknown: Unknown, not known, not observed, not recorded, or refused 
• Not applicable: Determination of a value is not relevant in the current context 
14.2.2.4. Assessment of Outcome 
Assessment of outcome of AEs will be categorized as one of the following:  
• Ongoing: At the end of the study, the event has not resolved or stabilized 
• Resolved: The event has resolved or the subject recovered without sequelae 
• Resolved with sequelae: The event has at least 1 secondary outcome that may 
result in permanent disability and/or functional limitation 
• Unknown: The status of the event is unknown 
• Death: The subject has expired 
14.2.3. 
Investigator Reporting to Sponsor and Sponsor Emergency Contact 
All SAEs that occur during the course of the study must be reported by the Investigator 
immediately, with the designated report form sent to the Medical Monitor within 24 hours 
from the point in time when the Investigator becomes aware of the SAE.  Investigators must 
report any SAE, whether or not considered drug related.  The initial report must be as 


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complete as possible, including assessment of the causal relationship (ie, assessment of 
whether there is a reasonable possibility that the drug caused the event).  The Medical 
Monitor will contact the investigator via telephone for follow-up information regarding the 
SAE, as appropriate. 
Information not available at the time of the initial report must be documented on a follow-up 
report.  As additional information becomes available, the designated report form must be 
updated and supporting information, including hospital records, laboratory and diagnostic 
testing results, etc.  All supporting documentation must be de-identified.  In addition, all 
SAEs that occur up to and including 30 days after administration of study drug must be 
reported within 24 hours from when the Investigator becomes aware of the SAE.  A final 
report to document resolution of all SAEs is required. 
In a medical emergency (ie, an event that requires immediate attention regarding the 
treatment of a subject, operation of the clinical study, and/or the use of investigational drug), 
study site staff will apply appropriate medical intervention according to current standards of 
care and contact the Medical Monitor. 
14.2.4. 
Medical Monitor and Emergency Contact Information 
 
, MD  
Office (9-5 EST): 
  
24/7 Hotline: 
  
 
14.2.5. 
SAE Reporting Contact Information 
Contact information and reporting instructions are provided in the Safety Management Plan. 
14.2.6. 
Reporting to Institutional Review Boards/Independent Ethics Committees 
It is the responsibility of the Investigator to promptly notify the institution’s IRB/IEC of all 
SAEs that occur at his or her site if applicable per the IRB’s/IEC’s requirements. 
14.3. 
Sponsor/Medical Monitor Responsibilities 
14.3.1. 
Monitoring of Adverse Event Data 
The Medical Monitor or designee will review SAEs/AEs on an ongoing basis. 
14.3.2. 
Reporting to Regulatory Authorities 
The Sponsor or its designee is responsible for SUSAR notification to the relevant regulatory 
authorities per applicable regulations.  All investigators participating in the study will also be 
informed as required by regulations in order to inform their IRBs/IECs.   


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In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to regulatory authorities as required by national 
laws. 
14.4. 
Emergency Identification of Study Medication 
In exceptional circumstances and for the safety of the study subject, the Investigator may 
request unblinding of an individual subject’s treatment from the Medical Monitor.  The 
Investigator will not unblind the Medical Monitor during that discussion.  The process of 
unblinding will be described in the Safety Management Plan for the study.   


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15. 
STUDY ADMINISTRATION 
15.1. 
Quality Control and Quality Assurance 
The Investigators and institutions will permit study-related monitoring, audits, IRB review, 
and regulatory inspections as requested by regulatory authorities, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs, etc.) in 
addition to CRFs. 
Quality assurance and quality control systems with written standard operating procedures 
(SOPs) will be followed to ensure that this study will be conducted and data will be 
generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements.   
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals 
during the study.  The monitoring visits must be conducted according to the applicable ICH 
and GCP guidelines to ensure protocol adherence, quality of data, drug accountability, 
compliance with regulatory requirements, and continued adequacy of the investigational site 
and its facilities.  During these visits, CRFs and other data related to the study will be 
reviewed and any discrepancies or omissions will be identified and resolved.  The study 
monitor will be given access to study-relevant source documents (including medical records) 
for purposes of source data verification. 
During and/or after completion of the study, quality assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits.  The 
Investigator is expected to cooperate with any audit and provide assistance and 
documentation (including source data) as requested.   
Quality control will be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties 
involved with the clinical study will be in writing in a separate agreement. 
15.2. 
Data Handling and Recordkeeping 
15.2.1. 
Data Handling 
Procedures for data handling (including electronic data) used in this protocol will be 
documented in a Data Management Plan.   
15.2.2. 
Case Report Form Completion 
Electronic CRFs (eCRFs) will be completed for each study subject.  It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
subject’s eCRF.  Source documentation supporting the eCRF data should indicate the 
subject’s participation in the study and should document the dates and details of study 
procedures, AEs, and subject status. 


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The Investigator will have access to the electronic data capture (EDC) system and will 
receive a copy of the subject eCRF data at the end of the study.  For subjects who discontinue 
or terminate from the study, the eCRFs will be completed as much as possible, and the reason 
for the discontinuation or termination clearly and concisely specified on the appropriate 
eCRF. 
15.2.3. 
Retention of Study Records 
The Investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirements.  Records will be retained for at least two years after the last 
marketing application approval and until there are no pending or contemplated marketing 
applications or two years after formal discontinuation of the clinical development of the 
investigational product or according to applicable regulatory requirements.  If the 
Investigator withdraws from the responsibility of keeping the study records, custody must be 
transferred to an appropriate person willing to accept the responsibility.  The Sponsor must 
be notified in writing if a custodial change occurs.   
15.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the subject by the assigned subject number.  The Investigator 
will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authority(ies) access to the subject’s original medical records for verification of data gathered 
on the CRFs and to audit the data collection process.  The subject’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable 
laws and regulations. 
Subjects will be notified that registration information, results, and other information about 
this study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used. 
All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information.  The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent 
from the Sponsor.  It is understood that there is an obligation to provide the Sponsor with 
complete data obtained during the study.  The information obtained from the clinical study 
will be used towards the development of the investigational product and may be disclosed to 
regulatory authority(ies), other Investigators, corporate partners, or consultants as required. 
15.4. 
Publication Policy 
All information concerning SAGE-547 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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15.5. 
Protocol Amendments 
Changes to the conduct of the study should be prepared as a protocol amendment by the 
Sponsor.  Protocol amendments should receive written IRB/IEC approval prior to 
implementation at the investigative site, except when necessary to eliminate immediate 
hazards to the subjects or when the changes involve only logistical or administrative aspects 
of the study (eg, change of monitor, telephone numbers).  In this case, Sage Therapeutics will 
amend and implement the protocol change and subsequently notify the regulatory authorities 
and the Investigative sites who will notify the respective IRB/IEC, as appropriate. 


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16. 
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Posner K, Brown GK, Stanley B, et al.  The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults.  Am J Psychiatry 2011;168(12):1266-77.  doi: 10.1176/appi.ajp.2011.10111704. 
Romeo E, Ströhle A, Spalletta G, di Michele F, Hermann B, Holsboer F, Pasini A, Rupprecht 
R.  Effects of antidepressant treatment on neuroactive steroids in major depression.  Am J 
Psychiatry 1998;155(7):910-3.  PMID: 9659856. 
Sayeed I, Parvez S, Wali B, Siemen D, Stein DG.  Direct inhibition of the mitochondrial 
permeability transition pore: a possible mechanism for better neuroprotective effects of 
allopregnanolone over progesterone.  Brain Res 2009;1263:165-73.  PMID: 19368823. 
Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, et al.  Influence of 
mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3α-
hydroxysteroid dehydrogenase activity.  Mol Psychiatry 2006;11(3):261-72.  PMID: 
16344854. 
Schüle C, Baghai TC, di Michele F, Eser D, Pasini A, Schwarz M.  Effects of combination 
treatment with mood stabilizers and mirtazapine on plasma concentrations of neuroactive 
steroids in depressed patients.  Psychoneuroendocrinology 2007;32(6):669-80.  PMID: 
17560730. 
Shelton RC, Trivedi MH.  Moderators of antidepressant response in major depression.  J Clin 
Psychiatry 2011;72(10):e32.  PMID: 22075105. 


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Spitzer RL, Kroenke K, Williams JBW, Löwe B.  A Brief Measure for Assessing 
Generalized Anxiety Disorder: The GAD-7.  Arch Intern Med 2006; 166(10):1092-1097.  
doi: 10.1001/archinte.166.10.1092. 
Ströhle A, Romeo E, Hermann B, Pasini A, Spalletta G, di Michele F, et al.  Concentrations 
of 3α-reduced neuroactive steroids and their precursors in plasma of patients with major 
depression and after clinical recovery.  Biol Psychiatry 1999;45(3):274-77.  PMID: 
10023501. 
Timby E, Balgård M, Nyberg S, Spigset O, Andersson A, Porankiewicz-Asplund J, et al.  
Pharmacokinetic and behavioral effects of allopregnanolone in healthy women.  
Psychopharmacology (Berl) 2006;186(3):414-24.  PMID: 16177884. 
Timby E, Hedström H, Bäckström T, Sundström-Poromaa I, Nyberg S, Bixo M.  
Allopregnanolone, a GABAA receptor agonist, decreases gonadotropin levels in women A 
preliminary study.  Gynecol Endocrinol 2011;27(12):1087-93.  PMID: 21190418.  (Timby 
2011a) 
Timby E.  Allopregnanolone effects in women.  Clinical studies in relation to the menstrual 
cycle, premenstrual dysphoric disorder and oral contraceptive use.  Umea University Medical 
Dissertation 2011; New Series No.  1459.  (Timby 2011b) 
Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, et al.  Increase in the 
cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who 
are receiving fluoxetine or fluvoxamine.  Proc Natl Acad Sci 1998;95(6):3239-44.  PMID: 
9501247. 
van Broekhoven F, Bäckström T, van Luijtelaar G, Buitelaar JK, Smits P, Verkes RJ.  Effects 
of allopregnanolone on sedation in men, and in women on oral contraceptives.  
Psychoneuroendocrinology.  2007;32(5):555-64.  PMID: 17470385. 
Verbeek T, Bockting CL, van Pampus MG et al.  Postpartum depression predicts offspring 
mental health problems in adolescence independently of parental lifetime psychopathology.  
J Affect Disord 2012;136(3):948-54.  doi: 10.1016/j.jad.2011.08.035. 
Ware JE, Kosinski M, Bjorner JB, Turner-Bowker DM, Gandek B, Maruish ME. User’s 
Manual for the SF-36v2® Health Survey (2nd ed). 2007. Lincoln, RI: QualityMetric 
Incorporated. 
Wieland S, Lan NC, Mirasedeghi S, Gee KW.  Anxiolytic activity of the progesterone 
metabolite 5α-pregnan-3α-ol-20-one.  Brain Res 1991;565(2):263-8.  PMID: 1688192. 
 


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APPENDICES 
Copies of the rating scales and questionnaires included in Appendix 1 through Appendix 10 
are for reference only. 
 


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APPENDIX 1. COLUMBIA SUICIDE SEVERITY RATING SCALE 
(C-SSRS) 
The “Baseline/Screening” and “Since Last Visit” versions of the C-SSRS begin on the next 
full page (Posner 2011). 
 
 


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APPENDIX 2. HAMILTON RATING SCALE FOR DEPRESSION, 
17-ITEM (HAM-D) 
The HAM-D presents on the next full page (Hamilton 1960). 
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  Item 
16 can be rated according to history (item 16A) or actual weight change (item 16B).  The 
item 16 score is calculated as the item 16 response that is not equal to 3 (ie, “Not assessed). 
 
 


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APPENDIX 3. MONTGOMERY ASBERG DEPRESSION RATING 
SCALE (MADRS) 
The MADRS, presented on the next full page, includes the following 10 symptoms: 
1. Apparent sadness 
2. Reported sadness 
3. Inner tension 
4. Reduced sleep 
5. Reduced appetite 
6. Concentration difficulties 
7. Lassitude 
8. Inability to feel 
9. Pessimistic thoughts 
10. Suicidal thoughts 
 
 


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APPENDIX 4. CLINICAL GLOBAL IMPRESSION–IMPROVEMENT 
SCALE (CGI-I) AND SEVERITY SCALE (CGI-S) 
The CGI-I and CGI-S present on the next full page.  For the purposes of 
Protocol 547-PPD-202, only Items 1 and 2, Severity of Illness and Global Improvement, will 
be assessed in subjects enrolled in the study. 
 


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APPENDIX 5. EDINBURGH POSTNATAL DEPRESSION SCALE 
(EPDS) 
The EPDS presents on the next full page (Cox 1987). 
 


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APPENDIX 6. GENERALIZED ANXIETY DISORDER 7-ITEM 
SCALE (GAD-7) 
The GAD-7 presents on the next full page (Spitzer 2006). 
 
 


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APPENDIX 7. PATIENT HEALTH QUESTIONNAIRE (PHQ-9) 
The PHQ-9 presents on the next full page. 
Developed by Drs. Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke, and colleagues 
with an educational grant from Pfizer Inc.  No permission required to reproduce, translate, 
display or distribute. 
 
 
 


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APPENDIX 8. BARKIN INDEX OF MATERNAL FUNCTIONING 
(BIMF) 
The BIMF is presented below. 
 


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APPENDIX 9. SHORT FORM-36 (ONE WEEK RECALL)  
 
Your Health and Well-Being 
 
This survey asks for your views about your health.  This information will 
help keep track of how you feel and how well you are able to do your 
usual activities. Thank you for completing this survey! 
 
For each of the following questions, please mark an 
 in the one box that 
best describes your answer. 
 
1. In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
2. Compared to one week ago, how would you rate your health in 
general now? 
Much better 
now than one 
week ago 
Somewhat 
better  
now than one 
week ago 
About the 
same as one 
week ago 
Somewhat 
worse  
now than one 
week ago 
Much worse 
now than one 
week ago 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 


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3. The following questions are about activities you might do during a 
typical day.  Does your health now limit you in these activities?  If so, 
how much?  
 
 
 
Yes,  
limited  
a lot 
Yes, 
limited  
a little 
No, not 
limited  
at all 
 
   
a Vigorous activities, such as running, lifting  
heavy objects, participating in strenuous sports ...................... 
 1 ............. 
 2 ............. 
 3 
b Moderate activities, such as moving a table, pushing  
a vacuum cleaner, bowling, or playing golf............................. 
 1 ............. 
 2 ............. 
 3 
c Lifting or carrying groceries .................................................... 
 1 ............. 
 2 ............. 
 3 
d Climbing several flights of stairs ............................................. 
 1 ............. 
 2 ............. 
 3 
e Climbing one flight of stairs .................................................... 
 1 ............. 
 2 ............. 
 3 
f Bending, kneeling, or stooping ................................................ 
 1 ............. 
 2 ............. 
 3 
g Walking more than a mile ........................................................ 
 1 ............. 
 2 ............. 
 3 
h Walking several hundred yards ............................................... 
 1 ............. 
 2 ............. 
 3 
i Walking one hundred yards ..................................................... 
 1 ............. 
 2 ............. 
 3 
j Bathing or dressing yourself .................................................... 
 1 ............. 
 2 ............. 
 3 


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4. During the past week, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health? 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of  
the time 
None of 
the time 
     
a Cut down on the amount of  
time you spent on work or  
other activities .................................. 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
b Accomplished less than you  
would like ........................................ 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
c Were limited in the kind of  
work or other activities .................... 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
d Had difficulty performing the  
work or other activities (for  
example, it took extra effort) ........... 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
 
 
5. During the past week, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or 
anxious)? 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of  
the time 
None of 
the time 
     
a Cut down on the amount of  
time you spent on work or  
other activities .................................. 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
b Accomplished less than you  
would like ........................................ 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
c Did work or other activities  
less carefully than usual ................... 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 


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6. During the past week, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
 
 
 
7. How much bodily pain have you had during the past week? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very severe 
      
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
  
 6 
 
 
 
 
 
8. During the past week, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 


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9. These questions are about how you feel and how things have been with 
you during the past week.  For each question, please give the one 
answer that comes closest to the way you have been feeling.  How much 
of the time during the past week… 
 
 
10. During the past week, how much of the time has your physical health 
or emotional problems interfered with your social activities (like 
visiting with friends, relatives, etc.)? 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of  
the time 
None of 
the time 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of  
the time 
None of 
the time 
     
a Did you feel full of life? ..................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
b Have you been very nervous? ..........
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
c Have you felt so down in the  
dumps that nothing could  
cheer you up? ...................................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
d Have you felt calm and  
peaceful? ..........................................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
e Did you have a lot of energy? ..........
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
f Have you felt downhearted   
and depressed? .................................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
g Did you feel worn out? ....................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
h Have you been happy? .....................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
i Did you feel tired? ...........................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 


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11. How TRUE or FALSE is each of the following statements for you? 
Definitely 
true 
Mostly  
true 
Don’t  
know 
Mostly  
false 
Definitely 
false 




a I seem to get sick a little 
easier than other people .................. 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
b I am as healthy as  
anybody I know .............................. 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
c I expect my health to  
get worse ......................................... 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
d My health is excellent ..................... 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
 
 
 
 
 
 
 
Thank you for completing these questions! 
 
 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust.  
(SF-36v2® Health Survey Acute, United States (English))  
 
 


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APPENDIX 10. HEALTH RESOURCE UTILIZATION 
QUESTIONNAIRE 
 


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Protocol 547-PPD-202 
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Summary of Changes to 
Protocol 547-PPD-202, Amendment 4 
Date of Amendment: 16 March 2017 
The following changes were made to the attached protocol in this amendment.  In addition, minor revisions to formatting, punctuation, 
spelling, and wording (eg, capitalization, abbreviation, word order) that are not listed below were made throughout the protocol.   
Section number 
Original text: 
Changed to: 
Rationale: 
Title Page  
Protocol 547-PPD-202 Amendment 3 
Protocol 547-PPD-202 Amendment 3 4, 
Version 5.0 
 
Administrative update 
Title Page  
31 January 2017 
31 January 2017 Sage Therapeutics 
Confidential  
 
Administrative update 
Title Page  
Confidential [page #] 
Confidential [page #] 
Administrative update 
Title Page 
 
Added Sage Logo 
Administrative update 
Title Page 
Sponsor: Sage Therapeutics 
Sponsor: Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Administrative update 
Title Page 
Medical Monitor: 
, 
M.D., FAAP (with title, address, 
phone, and email) 
Sponsor Medical Monitor: 
, 
M.D., FAAP (with title, address, phone, and 
email) 
Administrative update and role 
clarification 
Title Page 
Medical Monitor: 
, 
M.D. (with title, address, phone, and 
email) 
CRO Medical Monitor: 
, 
M.D. (with title, address, phone, and email) 
Clarified role 
Title Page 
Date of Amendment 3:  
Version 4.0, 31 January 2017 
Date of Amendment 3:  
Version 4.0, 31 January 2017 
Date of Amendment 4: 
Version 5.0, 16 March 2017 
Administrative update 


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Section 2, Synopsis, Inclusion 
Criteria; and Section 8.0 
Selection and Withdrawal of 
Subjects, 8.1 Inclusion Criteria 
5. Subject either must have ceased 
lactating at screening; or if still 
lactating or actively breast feeding at 
screening, must agree to temporarily 
cease giving breastmilk to their 
infant(s) from just prior to receiving 
study drug through 9 days (Study Day 
12) after the end of infusion. 
5. Subject either must have ceased lactating at 
screening; or if still lactating or actively breast 
feeding at screening, must agree to temporarily 
cease giving breastmilk to their infant(s) from 
just prior to receiving study drug through 9 4 
days (Study Day 12 7) after the end of 
infusion. 
Shortened requirement for 
pumping and discarding 
breastmilk based on emerging 
data and advice from the FDA 
that 7 days is sufficient 
Section 2, Synopsis, Table 1: 
Schedule of Events, footnote k; 
and Section 12, Study 
Procedures, 12.2 Study Drug 
Treatment Period (Day 1 to 
Day 3, Hours 0-72), 12.2.3. 
Day 3 
Subjects who are lactating will be 
reminded that they must continue to 
pump and discard breast milk through 
Day 12 of the study. 
Subjects who are lactating will be reminded 
that they must continue to pump and discard 
breast milk through Day 12 7 of the study. 
Shortened requirement for 
pumping and discarding 
breastmilk based on emerging 
data and advice from the FDA 
that 7 days is sufficient 
Section 12 Study Procedures, 
12.3 Follow-up Period (Day 7 
through Day 30), 12.3.1. Day 7 
(±1 Day) 
• 
Subjects who are lactating will be 
reminded to continue to pump 
and discard breast milk through 
Day 12 of the study. 
• 
Subjects who are lactating will be 
reminded to continue to pump and discard 
breast milk through Day 12 of the study 
for the remainder of the day; subjects 
will be instructed that they may resume 
breastfeeding their infant in the 
morning of Study Day 8. 
Shortened requirement for 
pumping and discarding 
breastmilk based on emerging 
data and advice from the FDA 
that 7 days is sufficient 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
Confidential 
1 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL-
GROUP, PLACEBO-CONTROLLED STUDY EVALUATING THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS OF SAGE-547 
INJECTION IN THE TREATMENT OF ADULT FEMALE SUBJECTS 
WITH SEVERE POSTPARTUM DEPRESSION AND ADULT FEMALE 
SUBJECTS WITH MODERATE POSTPARTUM DEPRESSION 
NUMBER: 547-PPD-202 
IND NUMBER: 122,279 
EUDRA CT NUMBER:  2016-005137-68 
Investigational Product: 
SAGE-547 Injection (allopregnanolone) 
Clinical Phase: 
3 
Sponsor: 
Sage Therapeutics 
Sponsor Contact: 
Helen Colquhoun, M.D. 
Senior Medical Director 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Phone: 
 
 
Medical Monitor: 
, M.D., FAAP 
Study Medical Lead 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Phone: 
 
 
, M.D. 
Phone: 
  
24/7 Hotline: 
  
 
Date of Original Protocol: 
Date of Amendment 1: 
Date of Amendment 2: 
Date of Amendment 3: 
Version 1.0, 18 September 2015 
Version 2.0, 22 December 2015 
Version 3.0, 30 June 2016 
Version 4.0, 31 January 2017 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee.  
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from the Sponsor. 




Protocol 547-PPD-202 Amendment 3 
31 January 2017 
Confidential 
3 
Investigator Agreement 
By signing this page, I attest that I have read and understand the contents of Clinical Protocol 
547-PPD-202 and any current amendments.  I agree to adhere to the design, conduct, and 
reporting requirements of the study as stated in the clinical protocol and to my obligations to the 
Sponsor as described in the protocol and executed contracts between myself, my Institution, and 
the Sponsor.  I also agree to adhere to any subsequent amendments to the clinical protocol. 
 
Investigator’s Signature:  _____________________________________________ 
 
Investigator’s Name:  
_____________________________________________ 
 
Institution:  
 
 
 
_____________________________________________ 
 
Date (dd/mmm/yyyy): 
_____________________________________________  
 


Protocol 547-PPD-202 Amendment 3 
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2. 
SYNOPSIS 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No.  547-PPD-202 
Phase: 3 
Name of Investigational Product: 
SAGE-547 Injection 
Name of Active Ingredient: 
Allopregnanolone 
Title of the Protocol: 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study Evaluating the 
Efficacy, Safety, and Pharmacokinetics of SAGE-547 Injection in the Treatment of Adult Female 
Subjects With Severe Postpartum Depression and Adult Female Subjects with Moderate Postpartum 
Depression 
Study Sites: Up to 100 global sites 
Duration of Subject Participation: Up to 37 days 
Primary Objective: 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours at up to 90 μg/kg/h 
reduces depressive symptoms in subjects with severe postpartum depression (PPD) compared 
to placebo injection as assessed by the change from baseline in Hamilton Rating Scale for 
Depression (HAM-D) total score.  This objective applies to both Parts A and B. 
Secondary Objectives (unless otherwise specified, these objectives apply to Parts A, B, and C): 
• 
To determine if SAGE-547 infusion at up to 60 μg/kg/h for 60 hours reduces depressive 
symptoms in subjects with severe PPD compared to placebo injection as assessed by the 
change from baseline in HAM-D total score.  This objective applies to Part B. 
• 
To determine if SAGE-547 Injection infused intravenously at up to 90 μg/kg/h for 60 hours 
reduces depressive symptoms in subjects with moderate PPD compared to placebo injection as 
assessed by the change from baseline in HAM-D total score.  This objective applies to Part C. 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces depressive 
symptoms compared to placebo injection as assessed by HAM-D response, HAM-D remission, 
change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score, 
Clinical Global Impression – Improvement (CGI-I) response, and changes from baseline in 
HAM-D subscale and individual item scores.   


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5 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces other mood 
symptoms compared to placebo injection as assessed by changes from baseline in the 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) total score. 
• 
To evaluate the safety and tolerability of SAGE-547 Injection compared with placebo as 
assessed by the incidence of adverse events (AEs), vital sign measurement, clinical laboratory 
evaluations, electrocardiogram (ECG) parameters, and the Columbia Suicide Severity Rating 
Scale (C-SSRS). 
Other Objectives: 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces subject-
reported depressive symptoms compared to placebo injection as assessed by the change from 
baseline in Edinburgh Postnatal Depression Scale (EPDS) total score and the change from 
baseline in Patient Health Questionnaire (PHQ-9) total score. 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours improves maternal 
behaviors compared to placebo injection as assessed by the change from baseline in Barkin 
Index of Maternal Functioning (BIMF) total and sub-scale scores.   
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours improves the general 
health status compared to placebo as assessed by the change from baseline in the Short 
Form-36 (SF-36) total score at Day 7 and Day 30. 
Pharmacokinetic Objective: 
To assess the pharmacokinetic (PK) profile of SAGE-547, metabolites of SAGE-547, and betadex 
sulfobutyl ether sodium (SBECD). 
Study Design and Methodology:  
This protocol comprises three multicenter, randomized, double-blind, parallel-group, 
placebo-controlled studies of the efficacy, safety, and PK of SAGE-547 Injection in adult female 
subjects diagnosed with severe or moderate PPD.  Each study will be independently conducted, 
analyzed, and reported.  In this protocol, Study 547-PPD-202A is hereafter referred to as Part A; 
Study 547-PPD-202B is hereafter referred to as Part B; and Study 547-PPD-202C is hereafter referred 
to as Part C.  In Parts A and C, subjects will be randomized to one of two treatment groups (SAGE-547 
90 µg/kg/hour or placebo) on a 1:1 basis.  In Part B, subjects will be randomized to one of three 
treatment groups (SAGE-547 60 µg/kg/hour, SAGE-547 90 µg/kg/hour, or placebo) on a 1:1:1 basis.  
In each part, the continuous IV infusions of blinded study drug will increase and then taper.  Subjects 
must remain as inpatients during the study Treatment Period, which is approximately 72 hours/3 days 
in duration (60 hours of treatment and an additional 12 hours for completion of 72-hour assessments).  
The Screening Period assessments may be conducted on an inpatient or an outpatient basis.  The 
Follow-up Period assessments are conducted on an outpatient basis. 
Screening Period: The Screening Period begins with the signature of the informed consent form (ICF).  
Eligibility is determined by applying the inclusion/exclusion criteria.  The diagnosis of PPD must be by 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I).  A full medical and family 
history will be taken from the subject, including recording of all depression, other Axis I and Axis II 
disorders, and postpartum depression episodes in primary probands. 
Treatment Period: In Parts A and C, once subjects are confirmed as eligible for the study, they will be 
randomized to one of two treatment groups (SAGE-547 or placebo) on a 1:1 basis.  Continuous 
intravenous (IV) infusions of blinded study drug will be administered, with a new bag hung at least 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
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6 
every 24 hours during the 60-hour infusion.  Infusion rates will increase and then taper, with subjects in 
the SAGE-547 group receiving 30 µg/kg/hour (0-4 hours), then 60 µg/kg/hour (4-24 hours), then 
90 µg/kg/hour (24-52 hours), followed by 60 µg/kg/hour (52-56 hours), and 30 µg/kg/hour (56-
60 hours).  Placebo subjects will receive infusion rates equivalent to SAGE-547 90 µg/kg/hour.  In 
Part B, once subjects are confirmed as eligible for the study, they will be randomized to one of three 
treatment groups (SAGE-547 60 µg/kg/hour, SAGE-547 90 µg/kg/hour, or placebo) on a 1:1:1 basis.  
For the 60 µg/kg/hour group, subjects will receive 30 µg/kg/hour (0-4 hours), then 60 µg/kg/hour 
(4-56 hours), and 30 µg/kg/hour (56-60 hours).  For the 90 µg/kg/hour group, subjects will receive 
30 µg/kg/hour (0-4 hours), then 60 µg/kg/hour (4-24 hours), then 90 µg/kg/hour (24-52 hours), 
followed by 60 µg/kg/hour (52-56 hours), and 30 µg/kg/hour (56-60 hours).  Subjects in the placebo 
group will randomly receive infusion rates equivalent to either the 60 µg/kg/hour or 90 µg/kg/hour 
group.  Parts B and C will run concurrently. 
In all parts, subjects may be discharged after the 72-hour assessments have been completed (12 hours 
after completion of the study drug infusion).  If their clinical condition does not allow discharge, 
normal standard of care will be employed in their ongoing management. 
Initiation of benzodiazepines, narcotics, antibiotics, neuroleptics, and other anti-anxiety medications 
will not be allowed between screening and completion of the 72-hour assessments.  Doses of 
psychotropics, which must have been initiated at least 14 days prior to screening, must remain at a 
stable dose until completion of the 72-hour assessments.  If at the 72-hour assessment there has been no 
treatment response (HAM-D total score remains above 13), treatment with antidepressant medication 
may be optimized prior to discharge, and the subject may remain in the unit or be followed at an 
outpatient clinic, as clinically indicated. 
Efficacy and safety assessments will be performed periodically during the study, and blood samples 
will be collected for analysis of SAGE-547, metabolites of SAGE-547, and SBECD concentrations, as 
outlined in the Schedule of Events (Table 1).  Blood samples will be collected, and outcome measures 
will be obtained at pre-specified times over 72 hours during the Treatment Period.   
Follow-up Period: For Part A, Follow-up Visits will be conducted one week (7±1 day), approximately 
two weeks (12±2 days), and one month (30±3 days) after the initiation of the study drug infusion.  For 
Parts B and C, Follow-up Visits will be conducted one week (7±1 day), two weeks (14±2 days), three 
weeks (21±3 days), and one month (30±3 days) after the initiation of the study drug infusion.  The 
blind will be maintained through the Follow-up period. 
Number of Subjects: 
Up to 32 subjects will be randomized in Part A, up to 120 subjects will be randomized in Part B, and up 
to 100 subjects will be randomized in Part C. 
Inclusion Criteria:  
The following inclusion criteria must be met for individuals to be eligible for the study: 
1. Subject has signed an ICF prior to any study-specific procedures being performed 
2. Subject is an ambulatory female aged between 18 and 45 years of age, inclusive 
3. Subject is in good physical health and has no clinically significant findings, as determined by 
the Investigator, on physical examination, 12-lead ECG, or clinical laboratory tests 
4. Subject agrees to adhere to the study requirements 
5. Subject either must have ceased lactating at screening; or if still lactating or actively breast 
feeding at screening, must agree to temporarily cease giving breastmilk to their infant(s) from 
just prior to receiving study drug through 9 days (Study Day 12) after the end of infusion.   


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
Confidential 
7 
6. Subject must have a negative pregnancy test at screening and Day 1 prior to the start of study 
drug infusion 
7. Subject has had a Major Depressive Episode that began no earlier than the third trimester and 
no later than the first 4 weeks following delivery, as diagnosed by Structured Clinical 
Interview for DSM-IV Axis I Disorders (SCID-I) 
8. For Part A and B, subject has a HAM-D total score of ≥26 at screening and Day 1 (prior to 
dosing).  For Part C, subject has a HAM-D total score of ≥20 and ≤25 at screening and Day 1 
(prior to dosing) 
9. Subject is ≤6 months postpartum at screening 
10. Subject is willing at screening to delay the start of any new pharmacotherapy regimens, 
including antidepressant or anti-anxiety medication, until the study drug infusion and 72-hour 
assessments have been completed; if the subject is taking psychotropic medications, these must 
be at a stable dose from 14 days prior to screening until the 72-hour assessments have been 
completed.   
11. (Removed) 
12. Subject must use one of the following methods of birth control during participation in the study 
and for 30 days following the end of the study drug infusion: 
• 
Total abstinence (no sexual intercourse) 
• 
Hormonal contraceptives (birth control) including birth control pills, implantable or 
injectable contraceptives (Norplant® or Depo-Provera®) 
• 
A barrier form of contraception such as a condom or occlusive cap with a spermicide 
• 
An intrauterine device 
Exclusion Criteria: 
Subjects will be excluded if they meet any of the following exclusion criteria: 
1. Subject has renal failure requiring dialysis or fulminant hepatic failure or is anemic 
(hemoglobin ≤10 g/dL) 
2. Known allergy to progesterone or allopregnanolone 
3. Active psychosis per Investigator assessment 
4. Attempted suicide associated with index case of postpartum depression 
5. (Removed) 
6. Medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder. 
7. History of active alcoholism or drug abuse (including benzodiazepines) in the 12 months prior 
to screening.  A positive urine drug screen (except benzodiazepines under certain 
circumstances [see Section 10.3.3 and Section 11.1.2.6]) is exclusionary. 
8. Exposure to another investigational medication or device within 30 days prior to screening 
9. (Removed) 
10. Subject has previously participated in this study or any other study employing SAGE-547 
11. Administration of electroconvulsive therapy (ECT) within 14 days prior to screening and/or 
plans to administer ECT before the Study Day 7 Visit 


Protocol 547-PPD-202 Amendment 3 
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8 
Investigational Product, Dosage, and Mode of Administration:  
SAGE-547 Injection, IV administration: SAGE-547 Injection is a sterile, clear, colorless 5 mg/mL 
solution of SAGE-547 (allopregnanolone) and 250 mg/mL SBECD buffered with 10 mM citrate at a 
pH of 6.0, supplied in single-use 20 mL vials for IV administration.  As supplied, SAGE-547 Injection, 
which is hypertonic, requires further dilution with Sterile Water for Injection (SWFI) to render it 
isotonic for IV infusion.  The specific infusion dose of SAGE-547 Injection will be calculated based on 
weight for each subject at screening and administered according to the randomization schedule.  
Infusion bags will be changed at least every 24 hours.  Details about the preparation and administration 
of the study drug infusions will be included in the Pharmacy Manual. 
Part A and Part C:  
 
Infusion Rate (µg/kg/hour)  
SAGE-547 Dose 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2-3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
90 µg 
30 
60 
90 
60 
30 
Part B: 
 
Infusion Rate (µg/kg/hour) 
SAGE-547 Dose 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2-3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
60 µg 
30  
60  
60  
60  
30  
90 µg 
30  
60  
90  
60  
30  
 
 
 
 
 
 
Reference Therapy, Dosage, and Mode of Administration:  
An identical placebo IV infusion will be prepared for IV administration consisting of the same 
formulation without allopregnanolone.  For each part of the study, the placebo infusion rate will match 
that of the SAGE-547 rate(s) used in that part.   
Randomization: 
Randomization will be stratified by antidepressant use at baseline and will follow the computer-
generated randomization schedule.  Subjects will be randomized within stratum to receive SAGE-547 
Injection or placebo; subjects, clinicians, and study team will be blinded to treatment allocation.  The 
pharmacist, who will prepare the infusion bags according to the randomization schedule, will be 
unblinded.  In Parts A and C, the infusion rates are the same for all subjects within a particular dosing 
period (0-4 hours, 4-24 hours, etc.) regardless of randomized treatment.  In Part B, the infusion rates 
will vary according to the randomized dose group.   


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
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9 
Criteria for Evaluation: 
Primary Endpoint 
The primary outcome measure will be the 17-item Hamilton Rating Scale for Depression (HAM-D).  
The HAM-D will be administered before, during, and after the infusion of blinded study drug.  The 
HAM-D total score will be calculated as the sum of the 17 individual item scores.  The change from 
baseline in HAM-D total score at +60 hours will be the primary efficacy endpoint with comparison 
between the SAGE-547 and placebo treatment groups used to evaluate the efficacy of SAGE-547 in 
treating the depressive symptoms of PPD. 
For Part A and Part C, the primary comparison will be between 90 µg SAGE-547 and placebo at the 
60-hour assessment.  For Part B, the primary comparison will be between 90 µg SAGE-547 and 
placebo at the 60-hour assessment; if this comparison is significant at the 0.05 level, then the 60 µg 
group will be compared to placebo at the 0.04 level of significance.  More details will be provided in 
the statistical analysis plans (SAPs) regarding strong control of overall level of significance for 
multiple testing, including testing of key secondary endpoints.   
Secondary Endpoints 
The change from baseline in HAM-D total score at Day 30 will be included in the secondary endpoints.  
Additional measures of depressive symptom severity will be administered, including the Montgomery-
Asberg Depression Rating Scale (MADRS), and the Clinical Global Impression (CGI) scale.  Total 
scores and changes from baseline will be calculated where applicable.  Changes from baseline at +60 
hours and other time points will be evaluated as secondary efficacy endpoints with comparisons 
between the two treatment groups used to support the efficacy of SAGE-547 in treating the depressive 
symptoms of PPD.  In addition to the above scales, the individual item scores and subscale scores from 
the HAM-D scale will also evaluated as secondary efficacy endpoints.  GAD-7 will also be 
administered, and scores from these scales will be evaluated to assess the efficacy in other mood 
disorder and anxiety symptoms.   
Safety and tolerability of SAGE-547 Injection will be evaluated by summarization of AEs by 
frequency, severity, and seriousness; clinical laboratory measures, vital signs, and ECGs (including 
changes from baseline); and concomitant medication usage.  Suicidality will be monitored using the 
C-SSRS. 
The doses of all anti-depressant medications will be recorded throughout the study.  No changes and/or 
additions to antidepressant or anxiolytic medicine will be allowing during the dosing period.  An 
analysis of time to starting/increasing the dose/decreasing the dose of each different anti-depressant 
medication will be undertaken for subjects discharged. 
Plasma will be collected to assay for concentrations of SAGE-547, SAGE-547 metabolites, and 
SBECD.  The following PK parameters will be derived from the plasma concentrations (where 
evaluable): area under the concentration-time curve (AUC) from time zero to 60 hours (AUC0-60), AUC 
from time zero to infinity (AUC∞), maximum (peak) plasma concentration (Cmax), time at maximum 
(peak) plasma concentration (tmax), steady-state drug concentration in the plasma during constant-rate 
infusion (Css), and average drug concentration in the plasma at steady state during a dosing interval 
(Cavg). 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
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10 
Other Endpoints 
Additional measures of symptoms and function related to the current episode of postpartum depression 
severity will be administered, including the EPDS, PHQ-9, BIMF, and SF-36. 
Subscale and total scores and changes from baseline will be calculated where applicable.  Changes 
from baseline at +60 hours and other time points will be evaluated as secondary efficacy endpoints 
with comparisons between the two treatment groups used to support the efficacy of SAGE-547 in 
treating the depressive symptoms of PPD.  In addition to the above scales, the individual item scores 
will also be evaluated as other endpoints. 
Statistical Methods: 
For the purpose of all safety, efficacy, and other analyses where applicable, baseline is defined as the 
last measurement prior to the start of blinded study drug infusion. 
Interim Analysis 
In Part A, an interim analysis will be conducted by an independent statistician for sample size 
re-estimation purposes when at least 16 subjects have completed efficacy assessments through 
60 hours.  Since the sponsor will be kept uninformed of the response rates at the time of the interim 
analysis, no statistical adjustment will be made to the level of significance for hypothesis testing at the 
end of the study.  A detailed description of the interim analysis for sample size re-estimation will be 
included in the statistical analysis plan. 
There will be no interim analysis for Parts B or C. 
Sample Size Calculation 
Using a two-sided t-test at an alpha level of 0.05, a sample size of 10 evaluable subjects per group for 
Part A would provide 70% power to detect an effect size of 1.2 between the SAGE-547 and placebo 
groups with regard to the primary outcome variable of change from baseline in HAM-D total score.  
An effect size of 1.2 corresponds to a placebo-adjusted difference of 12 points in the change from 
baseline in HAM-D total score at 60 hours with an assumed standard deviation of 10 points.  By 
including two treatment groups and using a 1:1 randomization ratio, a total of 20 evaluable subjects are 
required for Part A.   
Based on the results of the interim analysis, the sample size in Part A could be increased to a maximum 
of 32 randomized subjects.  This adjustment to the sample size would allow for an effect size of 1.0 to 
be detected.   
For Part B, a sample size of 40 evaluable subjects per group (120 total) would provide 90% power to 
detect a treatment difference of 9.0 between the SAGE-547 and placebo groups and a common standard 
deviation of 12 points (for an effect size of 0.75) using a two-sided t-test at an alpha level of 0.05.   
For Part C, a sample size of 50 evaluable subjects per group (100 total) would provide 90% power to 
detect a treatment difference of 8.0 between the SAGE-547 and placebo groups and a common standard 
deviation of 12 points (for an effect size of 0.667) using a two-sided t-test at an alpha level of 0.05.   


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
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11 
Efficacy Analysis 
The Efficacy Population will include all subjects who start the infusion of study drug and have a valid 
baseline HAM-D assessment and at least one post-baseline HAM-D assessment.  Subjects will be 
classified and summarized by randomized treatment.  Separate summaries will be produced for each 
part of the study. 
For efficacy analysis purposes, centers with fewer than 15 subjects per center for Part B or 10 subjects 
per center for Part C will be pooled within regions (eg, North America region centers will be pooled 
separately those in Europe).  For each part, the change from baseline in HAM-D total score will be 
analyzed using a mixed effects model for repeated measures; the model will include center (pooled), 
treatment, baseline score, visit time point, and visit time point-by-treatment terms as explanatory 
variables.  Center and all other explanatory variables will be treated as fixed effects.  The primary 
comparison between each SAGE-547 dose and placebo will be at the 60-hour time point.  Comparisons 
at other time points, including the Day 30 time point, will be conducted to support the findings for the 
primary comparison.  To account for multiple testing in Part B, (90 µg vs placebo and 60 µg vs 
placebo), the 90 µg group will be compared to placebo first.  If this dose comparison is significant at 
the 0.05 level, then the 60 µg group will be compared to placebo at the 0.04 level.  More details will be 
provided in the SAPs regarding strong control of overall level of significance for multiple testing, 
including testing of key secondary endpoints.   
Changes from baseline in other rating scale scores will be analyzed with methods similar to the primary 
endpoint.  Dichotomous response variables will be analyzed using Generalized Estimating Equation 
(GEE) method for repeated binary responses.   
In addition to formal analysis, efficacy rating scale scores (including recorded and change from 
baseline values) will be summarized by descriptive statistics, including n, mean, standard deviation 
(SD), median, and minimum and maximum values.  Categorical efficacy endpoints (including HAM-D, 
MADRS, and CGI-I response variables) will be summarized by frequency and percentage. 
Safety Analysis 
The Safety Population is defined as all randomized subjects who start the infusion of study drug.  
Subjects will be classified and summarized by actual treatment.  Separate summaries will be produced 
for each part of the study. 
Safety will be assessed using AEs, vital signs, ECG, clinical laboratory tests, C-SSRS, and concomitant 
medication data.  Continuous safety data (including absolute and change from baseline values) will be 
summarized by descriptive statistics, including n, mean, standard deviation (SD), median, and 
minimum and maximum values.  Categorical endpoints will be summarized by frequency and 
percentage.   
Safety data will be examined for possible relationships between subject characteristics and plasma 
allopregnanolone concentrations, as appropriate. 


Protocol 547-PPD-202 Amendment 3  
 
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12 
Table 1: Schedule of Events 
 
Screening 
Period 
Treatment Period 
Clinic Period (Day 1 to Day 3) 
Follow-up Period 
Visit Days / Hours 
Screening 
D-7
a
 to -1 
D1 
H0* 
D1 
H2 
D1 
H4 
D1 
H8 
D1 
H12 
D1 
H18 
D1 
H24 
D2 
H30 
D2 
H36 
D2 
H42 
D2 
H48 
D3 
H54 
D3 
H60 
D3 
H66 
D3 
H72 
D7/ET 
(±1d) 
D14a 
(+2d) 
D21a 
(+3d) 
D30 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Lab 
Assessments
b
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Urinalysisb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Drug & Alcohol Screen
c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test
d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Genetic Sample
e 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs
f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
12-Lead ECG
g 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
C-SSRS
h 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
Confinement 
 
X 
 
 
 
 
CGI-I
i 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-I 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAM-Di 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
MADRSi 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
BIMFi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 


Protocol 547-PPD-202 Amendment 3  
 
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Screening 
Period 
Treatment Period 
Clinic Period (Day 1 to Day 3) 
Follow-up Period 
Visit Days / Hours 
Screening 
D-7
a
 to -1 
D1 
H0* 
D1 
H2 
D1 
H4 
D1 
H8 
D1 
H12 
D1 
H18 
D1 
H24 
D2 
H30 
D2 
H36 
D2 
H42 
D2 
H48 
D3 
H54 
D3 
H60 
D3 
H66 
D3 
H72 
D7/ET 
(±1d) 
D14a 
(+2d) 
D21a 
(+3d) 
D30 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EPDSi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
GAD-7i 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
PHQ-9i 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
SF-36 (acute version) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
HCRU 
X 
X 
Plasma PK
j 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
Instructions for 
Lactating Subjects
k 
 
X 
X 
X 
 
 
 
 
Study Drug Infusion 
 
X 
 
 
 
 
 
 
Adverse Events 
X 
Prior/Concomitant 
Medications
l 
X 
BIMF = Barkin Index of Maternal Functioning; CGI-I = Clinical Global Impression of Improvement; C-SSRS = Columbia Suicide Severity Rating Scale; 
D = Day; ECG = electrocardiogram; EPDS = Edinburgh Postnatal Depression Scale; GAD-7 = Generalized Anxiety Disorder 7-Item Scale; HAM-D = 
Hamilton Rating Scale for Depression, 17-item; HCRU = Health Care Resource Utilization; MADRS = Montgomery-Asberg Depression Rating Scale; 
PHQ-9 = Patient Health Questionnaire; PK = pharmacokinetic; SF-36 = Short Form-36; SCID-I = Structured Clinical Interview for DSM-IV Axis I Disorders. 
O = optional; * = All H0 procedures to be completed prior to dosing 
a The screening period for Part A is from Day -5 to Day -1.  Follow-up Visits for Part A are on Days 7, 12, and 30. 
b Safety laboratory tests will include hematology, serum chemistry, coagulation, and select hormone parameters.  The urine test will include a urinalysis.  Lab 
assessments are to be completed within ±30 minutes of the scheduled time point. 
c Urine for selected drugs of abuse and alcohol (serum or breath) 
d Serum at screening and urine for all other time points; lactation status (ie, subject is breastfeeding, subject is lactating but not breastfeeding, or subject is not 
lactating) will be recorded at screening 
e A blood sample for genetic testing, where consent is given 
f Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing).  Vital signs will be obtained within ±30 minutes 
of the scheduled time point, unless the subject is asleep between the hours of 23.00h and 06.00h. 
g Performed within ±30 minutes of the scheduled time point on Day 2. 
h The “Baseline/Screening” C-SSRS form will be completed on Day 1.  The “Since Last Visit” C-SSRS form will be completed at all subsequent time points. 
i To be completed within ±30 minutes of the scheduled time point during the Treatment Period. 


Protocol 547-PPD-202 Amendment 3  
 
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j Blood samples for PK analysis will be collected at pre-infusion and at 4 (before change in infusion rate, if applicable), 8, 12, 24 (before change in infusion rate, 
if applicable), 30, 36, 48, 60 (before end of infusion), and 72 hours after the start of the infusion.  PK blood draws after the start of infusion will have a window 
of ±10 minutes.  In the event of an unplanned dose adjustment, an unscheduled PK sample should be collected just prior to the infusion rate change. 
k Breast milk will be pumped and discarded by subjects who are lactating.  On Day 3, subjects who are lactating will be reminded that they must continue to 
pump and discard breast milk through Day 12 of the study.  
l To include those taken within 60 days prior to signing the informed consent through the Day 30 visit. 
Note:  In Part A only, SSS is completed within ±15 minutes of each time point through the 72-hour assessments, unless the subject is asleep between 23.00h and 
06.00h. 


Protocol 547-PPD-202 Amendment 3 
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15 
3. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ....................................................................................................2 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS ...........................................................................................15 
LIST OF TABLES .........................................................................................................................20 
LIST OF FIGURES .......................................................................................................................20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................21 
4. 
INTRODUCTION AND RATIONALE .....................................................................24 
4.1. 
Role of Allopregnanolone in Affective Disturbances ................................................25 
4.1.1. 
Rationale for Allopregnanolone Treatment of PPD ...................................................25 
4.2. 
SAGE-547 Injection (Allopregnanolone) ...................................................................26 
4.3. 
Summary of Nonclinical and Clinical Experience with SAGE-547 ..........................27 
4.3.1. 
Nonclinical Pharmacology ..........................................................................................27 
4.3.2. 
Clinical Experience .....................................................................................................27 
4.4. 
Potential Risks and Benefits .......................................................................................28 
4.5. 
Study No.  547-PPD-202 ............................................................................................29 
4.5.1. 
Study Population .........................................................................................................29 
4.5.2. 
Route of Administration, Dosage, Dosage Regimen, and Treatment 
Period ..........................................................................................................................29 
4.5.3. 
Dose Rationale ............................................................................................................29 
5. 
ETHICS ......................................................................................................................31 
5.1. 
Institutional Review Board or Independent Ethics Committee ..................................31 
5.2. 
Ethical Conduct of the Study ......................................................................................31 
5.3. 
Subject Information and Informed Consent ...............................................................31 
6. 
STUDY OBJECTIVES ..............................................................................................33 
6.1. 
Primary Objective .......................................................................................................33 
6.2. 
Secondary Objectives .................................................................................................33 
6.3. 
Other Objectives .........................................................................................................33 
6.4. 
Pharmacokinetic Objective .........................................................................................34 
7. 
INVESTIGATIONAL PLAN .....................................................................................35 
7.1. 
Overview of Study Design ..........................................................................................35 
7.2. 
Blinding and Randomization ......................................................................................38 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................39 
8.1. 
Inclusion Criteria ........................................................................................................39 
8.2. 
Exclusion Criteria .......................................................................................................40 
8.3. 
Subject Withdrawal/Study Termination .....................................................................40 
8.3.1. 
Withdrawal/Discontinuation of Individual Subjects ..................................................40 
8.3.2. 
Subject Withdrawal from the Study ...........................................................................40 
8.3.3. 
Discontinuation of Study Drug by the Investigator ....................................................40 
8.3.4. 
Study Termination ......................................................................................................41 
9. 
INVESTIGATIONAL PRODUCT ............................................................................42 
9.1. 
Identity of Investigational Product .............................................................................42 
9.2. 
Clinical Supplies .........................................................................................................42 
9.2.1. 
SAGE-547 ...................................................................................................................42 
9.2.2. 
Placebo ........................................................................................................................42 
9.3. 
Preparation of SAGE-547 Injection or Placebo for Dosing .......................................42 
9.4. 
Administration and Accountability .............................................................................43 
10. 
TREATMENT OF SUBJECTS ..................................................................................44 
10.1. 
Dosing Schedule .........................................................................................................44 
10.1.1. 
Dose Regimen .............................................................................................................45 
10.1.2. 
Route of Administration .............................................................................................46 
10.1.3. 
Treatment Period ........................................................................................................46 
10.1.4. 
Dosing of Intravenous SAGE-547 in the Case of AEs ...............................................46 
10.2. 
Dosing Compliance ....................................................................................................46 
10.3. 
Prior Medications, Concomitant Medications, and Restrictions ................................46 
10.3.1. 
Prior Medications ........................................................................................................46 
10.3.2. 
Concomitant Medications ...........................................................................................46 
10.3.3. 
Prohibited Medications ...............................................................................................47 
10.3.4. 
Restrictions .................................................................................................................47 
11. 
STUDY ASSESSMENTS ..........................................................................................48 
11.1. 
Safety Assessments .....................................................................................................48 
11.1.1. 
Adverse Events ...........................................................................................................48 
11.1.2. 
Clinical Laboratory Tests ...........................................................................................48 
11.1.2.1. 
Hematology, Serum Chemistry, Coagulation .............................................................49 
11.1.2.2. 
Hormones and Exploratory Biochemistry ..................................................................49 


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11.1.2.3. 
Pregnancy Tests ..........................................................................................................49 
11.1.2.4. 
Genetic Testing ...........................................................................................................49 
11.1.2.5. 
Urinalysis ....................................................................................................................50 
11.1.2.6. 
Drugs of Abuse and Alcohol ......................................................................................50 
11.1.3. 
Physical Examination .................................................................................................50 
11.1.4. 
Vital Signs ..................................................................................................................50 
11.1.5. 
ECG ............................................................................................................................50 
11.1.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................50 
11.2. 
Efficacy Assessments .................................................................................................51 
11.2.1. 
Primary Efficacy Outcome Measure ..........................................................................51 
11.2.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................51 
11.2.2. 
Secondary Efficacy Outcome Measures .....................................................................51 
11.2.2.1. 
Montgomery Asberg Depression Rating Scale (MADRS) .........................................52 
11.2.2.2. 
Clinical Global Impression (CGI) Scale .....................................................................52 
11.2.2.3. 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) ...............................................53 
11.2.3. 
Patient Reported Outcome Measures..........................................................................53 
11.2.3.1. 
Edinburgh Postnatal Depression Scale (EPDS) ..........................................................53 
11.2.3.2. 
Patient Health Questionnaire (PHQ-9) .......................................................................53 
11.2.3.3. 
Barkin Index of Maternal Functioning (BIMF) ..........................................................53 
11.2.3.4. 
Short Form-36 (SF-36) ...............................................................................................54 
11.2.3.5. 
Healthcare Resource Utilization (HCRU) ..................................................................54 
11.3. 
Pharmacokinetics ........................................................................................................54 
12. 
STUDY PROCEDURES ............................................................................................56 
12.1. 
Screening Period .........................................................................................................56 
12.2. 
Study Drug Treatment Period (Day 1 to Day 3, Hours 0-72) .....................................57 
12.2.1. 
Day 1 ...........................................................................................................................57 
12.2.2. 
Day 2 ...........................................................................................................................58 
12.2.3. 
Day 3 ...........................................................................................................................58 
12.3. 
Follow-up Period (Day 7 through Day 30) .................................................................59 
12.3.1. 
Day 7 (±1 day) ............................................................................................................59 
12.3.2. 
Day 12 (±2 days) (Part A); Day 14 (±2 days) and Day 21 (±3 days) 
(Parts B and C) ............................................................................................................59 
12.3.3. 
Day 30 (±3 days) ........................................................................................................60 


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12.3.4. 
Early Termination Visit ..............................................................................................60 
13. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................61 
13.1. 
Data Analysis Sets ......................................................................................................61 
13.2. 
Handling of Missing Data ...........................................................................................62 
13.3. 
Demographics and Baseline Characteristics ...............................................................62 
13.4. 
Primary Endpoints ......................................................................................................62 
13.5. 
Secondary Endpoints ..................................................................................................63 
13.5.1. 
Efficacy Analysis ........................................................................................................63 
13.5.2. 
Safety Analysis ...........................................................................................................63 
13.5.2.1. 
Adverse Events ...........................................................................................................63 
13.5.2.2. 
Clinical laboratory evaluations ...................................................................................64 
13.5.2.3. 
Physical examinations ................................................................................................64 
13.5.2.4. 
Vital signs ...................................................................................................................64 
13.5.2.5. 
12-Lead ECG ..............................................................................................................64 
13.5.2.6. 
Concomitant medications ...........................................................................................64 
13.5.2.7. 
C-SSRS .......................................................................................................................64 
13.5.2.8. 
SSS (Part A only)........................................................................................................64 
13.5.2.9. 
PK Analysis ................................................................................................................64 
13.6. 
Determination of Sample Size ....................................................................................65 
13.7. 
Interim Analysis ..........................................................................................................65 
13.8. 
Changes from Protocol Specified Analyses ...............................................................65 
14. 
ADVERSE EVENTS..................................................................................................66 
14.1. 
Adverse Event Definitions ..........................................................................................66 
14.1.1. 
Adverse Event .............................................................................................................66 
14.1.2. 
Suspected Adverse Reaction .......................................................................................66 
14.1.3. 
Life-Threatening .........................................................................................................66 
14.1.4. 
Serious ........................................................................................................................66 
14.1.5. 
Unexpected .................................................................................................................67 
14.2. 
Investigator Responsibilities .......................................................................................67 
14.2.1. 
Identification and Documentation of Adverse Events by Investigator .......................67 
14.2.2. 
Adverse Event Classification ......................................................................................68 
14.2.2.1. 
Relationship to Investigational Drug ..........................................................................68 
14.2.2.2. 
Severity .......................................................................................................................69 


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14.2.2.3. 
Action Taken with Investigational Drug ....................................................................69 
14.2.2.4. 
Assessment of Outcome .............................................................................................69 
14.2.3. 
Investigator Reporting to Sponsor and Sponsor Emergency Contact ........................69 
14.2.4. 
Medical Monitor and Emergency Contact Information..............................................70 
14.2.5. 
SAE Reporting Contact Information ..........................................................................70 
14.2.6. 
Reporting to Institutional Review Boards/Independent Ethics 
Committees .................................................................................................................70 
14.3. 
Sponsor/Medical Monitor Responsibilities ................................................................70 
14.3.1. 
Monitoring of Adverse Event Data .............................................................................70 
14.3.2. 
Reporting to Regulatory Authorities ..........................................................................70 
14.4. 
Emergency Identification of Study Medication ..........................................................71 
15. 
STUDY ADMINISTRATION ...................................................................................72 
15.1. 
Quality Control and Quality Assurance ......................................................................72 
15.2. 
Data Handling and Recordkeeping .............................................................................72 
15.2.1. 
Data Handling .............................................................................................................72 
15.2.2. 
Case Report Form Completion ...................................................................................72 
15.2.3. 
Retention of Study Records ........................................................................................73 
15.3. 
Confidentiality ............................................................................................................73 
15.4. 
Publication Policy .......................................................................................................73 
15.5. 
Protocol Amendments ................................................................................................74 
16. 
REFERENCES ...........................................................................................................75 
APPENDICES ...............................................................................................................................80 
APPENDIX 1. COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) ...................81 
APPENDIX 2. HAMILTON RATING SCALE FOR DEPRESSION, 17-ITEM 
(HAM-D) ............................................................................................................88 
APPENDIX 3. MONTGOMERY ASBERG DEPRESSION RATING SCALE 
(MADRS) ............................................................................................................93 
APPENDIX 4. CLINICAL GLOBAL IMPRESSION–IMPROVEMENT SCALE 
(CGI-I) AND SEVERITY SCALE (CGI-S).......................................................96 
APPENDIX 5. EDINBURGH POSTNATAL DEPRESSION SCALE (EPDS) ........................98 
APPENDIX 6. GENERALIZED ANXIETY DISORDER 7-ITEM SCALE 
(GAD-7) ............................................................................................................100 
APPENDIX 7. PATIENT HEALTH QUESTIONNAIRE (PHQ-9) ............................................2 
APPENDIX 8. BARKIN INDEX OF MATERNAL FUNCTIONING (BIMF) ..........................4 


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APPENDIX 9. SHORT FORM-36 (ONE WEEK RECALL) ......................................................6 
APPENDIX 10. HEALTH RESOURCE UTILIZATION QUESTIONNAIRE ...........................12 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................12 
Table 2: 
Adverse Events That Occurred in More than One Subject .........................................28 
Table 3: 
Infusion Rates for Part A and C ..................................................................................45 
Table 4: 
Infusion Rates for Part B ............................................................................................45 
 
LIST OF FIGURES 
Figure 1: 
Study Design - Part A .................................................................................................35 
Figure 2: 
Study Design - Part B .................................................................................................36 
Figure 3: 
Study Design - Part C .................................................................................................36 
Figure 4: 
Study Design and Timeline for Dosing – Part A ........................................................44 
Figure 5: 
Study Design and Timeline for Dosing – Part B ........................................................44 
Figure 6: 
Study Design and Timeline for Dosing – Part C ........................................................45 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition  
AE 
adverse event 
ALLO 
allopregnanolone 
ALT 
alanine aminotransferase 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC∞  
area under the concentration-time curve from time zero to infinity 
AUC0-60 
area under the concentration-time curve from time zero to 60 hours 
BIMF 
Barkin Index of Maternal Functioning 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Cavg 
average drug concentration in the plasma at steady-state during a dosing interval 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression–Improvement 
CGI-S 
Clinical Global Impression–Severity 
cGMP 
Current Good Manufacturing Practice 
Cmax 
maximum (peak) plasma concentration of the drug 
CNS 
central nervous system 
CRF 
case report form 
CS 
clinically significant 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
Css 
steady-state drug concentration in the plasma during constant-rate infusion 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture  
EEG 
electroencephalography 
EFF 
Efficacy Population 
Ph. Eur. 
European Pharmacopeia  
EPDS 
Edinburgh Postnatal Depression Scale 
ERα 
estrogen receptor alfa 


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Abbreviation  
Definition  
ERß 
estrogen receptor beta 
ET  
early termination 
GABA 
gamma-aminobutyric acid  
GABAA 
gamma-aminobutyric acid–gated chloride channel 
GAD-7 
Generalized Anxiety Disorder 7-Item Scale  
GCP 
Good Clinical Practice 
GEE 
Generalized Estimating Equation 
GGT 
gamma glutamyl transferase 
h 
hour 
HAM-D 
Hamilton Rating Scale for Depression, 17-item 
hCG 
human chorionic gonadotropin 
HCRU 
Healthcare Resource Utilization 
Hct 
hematocrit 
HEENT 
head, eyes, ears, nose, and throat 
Hgb 
hemoglobin 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
intravenous 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MCH 
mean corpuscular hemoglobin 
MCS 
mental component summary 
MCV 
mean corpuscular volume 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
PCS 
physical component summary 
PHQ-9 
Patient Health Questionnaire  
PK 
pharmacokinetic(s) 
PKP 
Pharmacokinetic Population 
PMID 
PubMed identification 
PP 
Per-Protocol Population 
PPD 
postpartum depression 


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Abbreviation  
Definition  
PR 
progesterone receptor 
PT/INR 
prothrombin time/international normalized ratio 
RBC 
red blood cell 
RSE 
refractory status epilepticus 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBECD 
betadex sulfobutyl ether sodium 
SCID-I 
Structured Clinical Interview for DSM-IV Axis I Disorders 
SD 
standard deviation 
SF-36 
Short Form-36 
SOC 
system organ class 
SOP 
standard operating procedure 
SRSE 
super refractory status epilepticus 
SSRI 
selective serotonin reuptake inhibitors 
SSS 
Stanford Sedation Scale 
SWFI 
sterile water for injection 
t1/2 
half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum (peak) plasma concentration 
TSH 
thyroid stimulating hormone 
US 
United States 
USP 
United States Pharmacopeia 
VAS 
visual analogue scale 
Vd 
volume of distribution 
WBC 
white blood cell 


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4. 
INTRODUCTION AND RATIONALE 
This study is designed to evaluate the efficacy, safety, and pharmacokinetics (PK) of 
SAGE-547 (allopregnanolone) as a treatment for women with severe or moderate postpartum 
depression (PPD), an area of high unmet medical need. 
PPD is considered to be moderate to severe depression in women who have recently given 
birth, otherwise defined as the occurrence of major depressive disorder (MDD) within 
4 weeks of delivery (DSM-V 2013) or up to a year after giving birth (Okun 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-V 2013), 
although this diagnosis may be confounded by the relative frequency of symptoms such as 
sleep disturbance or appetite problems in pregnant and postpartum women.  Most women 
experience onset of symptoms within the first 3 months following delivery, and PPD is most 
prevalent at 10 to 14 weeks following childbirth (Okun 2013). 
During pregnancy, estradiol and progesterone levels increase dramatically but then rapidly 
decline in the acute postpartum period (Gavin 2005).  The onset of PPD symptoms coincides 
with the rapid decrease of the gonadal steroids postpartum.  The duration of a PPD episode 
has been estimated as shorter than depressive episodes in the general population 
(approximately 5 months), while other studies indicate time to remission is approximately the 
same (Chaudron 2003). 
PPD is common and has devastating consequences for the woman and for her family 
(Fihrer 2009, Verbeek 2012).  Perinatal depression is reported to be the most underdiagnosed 
obstetric complication in America (Earls 2010).  Furthermore, it is the most common 
psychiatric illness to occur in the puerperium (O’Hara 2014).  A meta-analysis of 30 studies 
(Gaynes 2005) found that the point prevalence of major and minor depression ranged 
between 6.5% and 12.9% at different times during the first postpartum year.  Overall 
incidence is estimated at around 15% to 20% with up to 10% being considered severe 
(Edge 2007, O’Hara 2014). 
Current standard of care for severe PPD comprises cautious use of pharmacological therapies 
in nursing mothers combined with other interventions.  Evidence for efficacy of tricyclic 
antidepressants and/or selective serotonin reuptake inhibitors (SSRIs) is based on use in the 
general population rather than any extensive studies in PPD (Austin 2013), and SSRIs tend to 
be preferred due to better data on safety while breastfeeding (Altshuler 2001).  Based on the 
level of evidence for antidepressants in major depressive disorder (Kirsch 2008, 
Fournier 2010), there is a considerable need for improved pharmacological therapy for PPD. 
Drugs may be combined with a number of counseling, behavioral, and other non-
pharmacological therapy approaches, which are generally used as the first-line therapy in less 
severe PPD (Altshuler 2001).  Urgent referral and potentially admission are recommended 
for mothers at risk of self-harm, with their infants, if such facilities exist (Austin 2013).  
Therapeutic options in severe PPD are currently limited, and it is not clear whether the 


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current standard of care impacts the natural history of the disease, although most women 
recover within a year. 
4.1. 
Role of Allopregnanolone in Affective Disturbances 
The neurosteroid metabolite of progesterone, allopregnanolone, acutely regulates neuronal 
function (Gangisetty 2010) and appears to play a significant role in affective disturbances 
that occur with changes in reproductive endocrine function, such as during the postpartum 
period (Amin 2006, Nappi 2001, Epperson 2006). 
Neurosteroids are metabolites of cholesterol-derived steroid hormones that are synthesized in 
the brain and nervous system; they modulate the major inhibitory and excitatory central 
nervous system (CNS) neurotransmitter systems: γ-aminobutyric acid (GABA) and 
glutamate, respectively.  Neurosteroids are among the most potent and effective modulators 
of GABAA receptors and augment GABAergic inhibition (Belelli 2005).  The powerful 
anxiolysis that accompanies this potentiation of GABAA receptors has led to the speculation 
that neurosteroid dysregulation plays a central role in the etiology of affective disorders, 
including reproductive mood disorders, such as PPD (Amin 2006). 
There is increasing evidence supporting the role of neurosteroids in affective dysregulation.  
Allopregnanolone and pregnanolone have been shown to modulate the GABA receptor 
positively (Majewska 1986).  Several groups have demonstrated decreased allopregnanolone 
levels in MDD, with an increase seen in both plasma and cerebrospinal fluid (CSF) following 
successful antidepressant treatment (Uzunova 1998, Romeo 1998, Ströhle 1999, 
Schüle 2006, Eser 2006, Schüle 2007).  In addition, allopregnanolone has demonstrated 
anxiolytic effects in several animal anxiety models (Bitran 1991; Wieland 1991; 
Bitran 1993).   
Allopregnanolone may also exert antidepressant effects by reducing the physiological impact 
of stress, promoting neuroprotection, and protecting against the pro-inflammatory immune 
activation and cytokine hypersecretion associated with MDD.  In animals, allopregnanolone 
increases in response to stress, reduces pain sensitivity, and is thought to restore physiologic 
homeostasis following stress (Frye 1994, Morrow 1995).  Allopregnanolone also exerts 
neuroprotective effects by reducing the expression of pro-apoptotic proteins and apoptotic 
DNA fragmentation (Djebaili 2005, Sayeed 2009), thereby reducing the cell death and gliosis 
associated with depression (Glantz 2010, Shelton 2011).  Neuroprotection is mediated by 
immune regulation in depression (Licinio 1999), and allopregnanolone reduces the 
expression of the pro-inflammatory cytokine TNF-α (He 2004), which is elevated in 
depressed individuals (Dowlati 2010).  Thus, allopregnanolone modulates biological 
processes dysregulated in MDD. 
4.1.1. 
Rationale for Allopregnanolone Treatment of PPD 
Genetic susceptibility to affective dysregulation may be unmasked during periods of 
reproductive hormone change such as during pregnancy and postpartum (Maguire 2008).  
Maguire and Mody demonstrated that a GABA receptor subunit mutation was behaviorally 
silent until the animal was exposed to pregnancy and the postpartum state, at which time the 
dams showed depressive-like behaviors and cannibalized their offspring (Maguire 2008).  
During pregnancy, the expression of the GABAA receptor δ-subunit is down-regulated as 


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allopregnanolone levels increase, and at parturition, the expression of the GABAA receptor 
δ-subunit is recovered in response to rapidly declining neurosteroid levels (Maguire 2009).  
In contrast, the GABAA receptor δ-subunit-deficient mice fail to adapt to the dramatic 
changes in allopregnanolone and experience depression-like and anxiety-like behavior and 
abnormal maternal behaviors, which are reversed by administration of allopregnanolone 
(Maguire 2008).  This model provides compelling support for the hypothesis that changes in 
neurosteroid concentrations during pregnancy and postpartum are capable of provoking 
affective dysregulation, particularly in those with a genetically-determined susceptibility.  
The capacity of changes in neurosteroids, such as allopregnanolone, to function as behavioral 
switches suggests a potentially important treatment role of this hormone metabolite in 
reproductive endocrine-related mood disorders such as PPD. 
The onset of PPD symptoms coincides with the rapid decrease of the gonadal steroids 
postpartum and has been reproduced in a pivotal clinical study (Bloch 2000).  The authors 
investigated the possible role of changes in gonadal steroid levels in PPD by simulating 
2 hormonal conditions related to pregnancy and parturition in euthymic women, 8 with and 
8 without a history of PPD.  They induced hypogonadism with leuprolide, adding back 
supra-physiologic doses of estradiol and progesterone for 8 weeks to simulate pregnancy.  
They then withdrew both steroids under double-blind conditions to mimic the rapid decrease 
of sex steroids upon delivery.  Five of the 8 women with a history of postpartum depression 
(62.5%) and 0% of the comparison group developed significant mood symptoms typical of 
PPD during the withdrawal period. 
Although progesterone levels were measured in this study, allopregnanolone was not.  
However, since allopregnanolone is the major active metabolite of progesterone, it can be 
assumed that the decrease in progesterone would cause a similar precipitate drop in 
allopregnanolone levels, as observed in the postpartum period (Gilbert Evans 2005, 
Paoletti 2006, Nappi 2001).  These data provide direct evidence in support of the 
involvement of progesterone and its metabolites in the development of postpartum 
depression in a subgroup of women.  Further, they suggest that women with a history of 
postpartum depression are differentially sensitive to mood-destabilizing effects of gonadal 
steroids (Bloch 2000). 
Additional details regarding the role of allopregnanolone in the etiology of affective 
disorders and its nonclinical pharmacology and PK are presented in the Investigator’s 
Brochure. 
4.2. 
SAGE-547 Injection (Allopregnanolone) 
Allopregnanolone is an endogenous, naturally occurring neuroactive steroid formed in the 
corpus luteum of the ovary, adrenal cortex, and CNS (Holzbauer 1985, Ottander 2005, 
Paul 1992).  Allopregnanolone is a metabolite of progesterone created by the actions of 5-α 
reductase and 3-α hydroxy-steroid dehydrogenase.  Allopregnanolone is a potent positive 
allosteric modulator of both synaptic and extra-synaptic GABAA receptors. 
SAGE-547 Injection is a solution of 5 mg/mL allopregnanolone in Sterile Water for Injection 
(SWFI), United States Pharmacopeia (USP), and 250 mg/mL betadex sulfobutyl ether 
sodium buffered with 10 mM citrate at a pH of 6.0, and will be administered intravenously.  
SAGE-547 Injection is also being developed for the treatment of adult patients with 


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refractory status epilepticus (RSE), inclusive of super refractory status epilepticus (SRSE), 
who have not responded to standard treatment regimens, and investigated for the treatment of 
adults with essential tremor. 
4.3. 
Summary of Nonclinical and Clinical Experience with SAGE-547 
4.3.1. 
Nonclinical Pharmacology 
The primary pharmacological effects of allopregnanolone or SAGE-547 are described earlier 
in the rationale (Section 4.1 and Section 4.1.1).  Secondary pharmacologic effects comprise 
mainly the binding and consequent increased activity of steroid hormone receptors (androgen 
receptor [(AR], progesterone receptor [PR], and estrogen receptor beta [ERß]), with some 
evidence of inhibition at the highest doses (AR and estrogen receptor alfa [ERα]).  These 
non-target effects may yield some adverse events (AEs) in the clinic. 
Nonclinical toxicology studies largely illustrate the sedative and anesthetic effects of 
allopregnanolone and/or SAGE-547 at higher equivalent doses than the proposed dose for the 
current study.  PK data in animals indicate a short half-life (t½) and rapid clearance with a 
moderate volume of distribution and cerebral levels higher than plasma.  Refer to the 
SAGE-547 Investigator’s Brochure for more details. 
4.3.2. 
Clinical Experience 
The clinical PK data with intravenous (IV) administration of allopregnanolone in healthy 
women, men, and women on oral contraceptives confirmed the PK observations in animals 
of Cmax achievable at approximately third trimester levels (150 nM), rapid clearance and 
moderate volume of distribution (Vd).  Refer to the SAGE-547 Investigator’s Brochure for 
more details. 
An open-label, proof-of-concept study (547-PPD-201) evaluating the safety, tolerability, PK, 
and efficacy of SAGE-547 Injection in the treatment of adult female subjects with severe 
postpartum depression was started in 2014.  This was the first study in this indication.  Four 
women experienced significant improvement in depressive symptoms within 24 hours after 
administration of open-label IV SAGE-547.  During the SAGE-547 Treatment Period, all 
four subjects rapidly achieved remission, as measured by the HAM-D total score.  All four 
subjects also demonstrated consistent improvement as measured by the CGI-I score.  SAGE-
547 was well-tolerated in all subjects treated with no serious adverse events (SAEs) observed 
during therapy or during the 30-day Follow-up Period.  A total of 14 AEs were reported in 
four subjects.  The only AE reported in more than one subject was sedation, observed in two 
subjects.  This study was initially planned to enroll ten women; however, due to the observed 
clinical activity, Study 547-PPD-201 was stopped early with the plan to initiate a placebo-
controlled clinical study as rapidly as possible.   
There are six reported studies of allopregnanolone, mainly in healthy individuals and none in 
PPD (Timby 2006, Timby 2011a and 2011b, van Broekhoven 2007, Kask 2008, Kask 2009, 
Navarro 2003).  Data indicate that normal physiological allopregnanolone levels in women 
vary during the menstrual cycle up to a maximum of 6 to 10 nM, with lower levels present 
post-menopause (Genazzani 1998).  The highest physiological levels observed are in the 


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third trimester of pregnancy, up to around 160 nM at time of delivery (Luisi 2000).  Levels 
drop precipitously to baseline (<10 nM) with removal of the placenta (Klak 2003).   
One study demonstrated subjective improvements in contentedness in women 
(van Broekhoven 2007).  The clinical safety data are presented below in the Risks and 
Benefits section (Section 4.4). 
4.4. 
Potential Risks and Benefits 
In the open-label clinical study of SAGE-547 in PPD (547-PPD-201), a total of 14 AEs were 
reported in four subjects.  The only AE reported in more than one subject was sedation, 
observed in two subjects.   
In the recently completed 547-PPD-202A, there were no SAEs or discontinuations due to 
AEs.  Out of 10 subjects who received SAGE-547, four reported AEs, and of 11 subjects 
who received placebo, eight reported AEs (Table 2).  Three subjects in each treatment group 
reported dizziness, sedation or somnolence.  Psychiatric disorder AEs, including abnormal 
dreams, insomnia and anxiety, were all reported in the group that received placebo.  Three 
subjects in the placebo group and one in the SAGE-547 group reported nausea.  Other AEs 
reported by more than one subject were infusion site pain and headache, all reported on 
placebo.  One subject did not tolerate 60 μg/kg/hour due to sedation, thought to be associated 
with concomitant administration of a high dose of benzodiazepine, so the dose was reduced 
to 30 μg/kg/hour from 12 to 24 hours.  The subject received 60 µg/kg/hour from 24 to 
30 hours and 30 µg/kg/hour from 30 to 60 hours and completed the study. 
Table 2: 
Adverse Events That Occurred in More than One Subject 
 
Placebo (n=11) 
SAGE-547 (n=10) 
 
No. of Subjects
a 
n (%) 
No of Events 
No. of Subjects
a 
n (%) 
No of Events 
Subjects with at least 1 TEAE 
8 (72.7) 
23 
4 (40.0) 
17 
Dizziness 
3 (27.3) 
3 
2 (20.0) 
3 
Somnolence 
-- 
-- 
2 (20.0) 
3 
Nausea 
3 (27.3) 
3 
1 (10.0) 
1 
Infusion Site Pain 
2 (18.2) 
3 
-- 
-- 
Headache 
2 (18.2) 
2 
-- 
-- 
Abnormal Dreams 
2 (18.2) 
2 
-- 
-- 
Insomnia 
2 (18.2) 
2 
-- 
-- 
Source: 547-PPD-202A, Table 14.3.2.2 
a Subjects who have more than 1 AE per preferred term are counted only once 
 
Consistent with these observations, published reports of human administration of exogenous 
allopregnanolone indicate that for exposures in men and women up to 150 nM, the most 
commonly reported AEs were sedation (recorded as sleepiness or tiredness), feelings of 
intoxication (like alcohol), flushing, vertigo, mild nausea, impaired episodic memory, and 
mild headache (Timby 2006, 2011a, and 2001b; van Broekhoven 2007).  One subject 
experienced what was potentially a withdrawal effect, an anxiety attack (Timby 2011b).  No 


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SAEs were reported in the six clinical studies conducted to date (Timby 2006, Timby 2011a 
and 2011b, van Broekhoven 2007, Kask 2008, Kask 2009, Navarro 2003).   
There is also a potential risk of synergistic sedative effects with other drugs interacting with 
the GABAA receptor, such as benzodiazepines and anti-epileptic medications 
(Norberg 1999); therefore, the Investigator is advised to avoid co-medication if possible and 
to exercise caution with these drug classes.   
In 547-PPD-202A, the primary endpoint of the mean change from baseline in HAM-D total 
score at 60 hours compared with placebo [LS mean treatment difference of 12.2] was highly 
significant (p=0.008).  In addition, the significant separation between the active and placebo 
groups was evident at 24 hours, and remained so at subsequent time points through 72 hours, 
7 days, and 30 days after initiation of treatment.   
In view of the limited nature of the demonstrated risks of exogenous allopregnanolone 
infusion and the potential for benefit in PPD, there is a favorable benefit-risk evaluation for 
the continued conduct of the present study. 
4.5. 
Study No.  547-PPD-202 
4.5.1. 
Study Population 
This study will evaluate the efficacy, safety, and PK of SAGE-547 Injection in the treatment 
of adult female subjects diagnosed with severe or moderate postpartum depression.   
Parts A and B of this study will study women with severe PPD, and Part C will study women 
with moderate PPD (Parts B and C will run concurrently).  Moderate severity level will be 
studied because the pathogenesis of severe postpartum depression may not be generalized to 
those patients with a less severe form of illness.  For example, outside of postpartum 
depression, findings suggest that patient’s treatment-resistant depression may respond more 
favorably to certain pharmacotherapy options such as ketamine (Coyle 2015).  Therefore, in 
order to determine the efficacy of SAGE-547 in women with less severe levels of symptoms, 
a separate group with moderate PPD with the same doses of the study drug used in the severe 
group will be investigated. 
4.5.2. 
Route of Administration, Dosage, Dosage Regimen, and Treatment Period 
SAGE-547 Injection or placebo will be administered over a 60-hour period by an IV infusion 
according to the dose regimens shown in Table 3 and Table 4 (see Section 10.1.1). 
The specific infusion dose of SAGE-547 Injection will be calculated based on weight for 
each subject.  Infusion bags will be changed at least every 24 hours.  Details about the 
preparation and administration of the study drug infusions will be included in the Pharmacy 
Manual. 
4.5.3. 
Dose Rationale 
The infusion rate of SAGE-547 to be studied in Parts A and C of this study was chosen to 
achieve a mean exposure of 150 nM, roughly equivalent to the highest endogenous 
concentrations measured in third trimester pregnancy at approximately 157 nM (Luisi 2000).  
Since pregnant women tolerate this level without apparent AEs, 150 nM was selected as the 


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target exposure for this study.  This level of exposure has already been achieved in Study 
547-PPD-201 as well at higher levels in a study in subjects with essential tremor (Study 
547-ETD-201) and subjects with super refractory status epilepticus (Study 547-SSE-201), 
with no drug-related SAEs reported.  Since the most common AE in 547-ETD-201 was 
sedation, dose adjustment rules are included in this protocol to ensure that all subjects can 
remain on treatment for 60 hours.  A similar Cmax was also achieved in several other studies 
conducted with IV allopregnanolone (Timby 2011b), with excellent tolerability (see the 
current SAGE-547 Investigator’s Brochure for details of safety profile). 
The selection of exposure in the current study is based on a cautious approach adapted to the 
anticipated benefit-risk in the PPD patient population, and on previous experience from the 
ongoing clinical studies of SAGE-547 in adult subjects with SRSE (Study 547-SSE-201) and 
of SAGE-547 in female subjects with PPD (Study 547-PPD-201).  In the ongoing SRSE 
study, as determined by simulation, loading and maintenance infusions are required to 
achieve the target exposure.  In contrast, in the current study, subjects will instead begin 
treatment with a 4-hour dose-titration phase.  The starting dose is approximately 9- to 18-fold 
lower than the no observed adverse effect level (NOAEL) observed in rats and dogs, 
although this is not the first in human study.  In Parts A and C, doses will be increased as 
follows: 30 µg/kg/hour (0-4 hours), then 60 µg/kg/hour (4-24 hours), then 90 µg/kg/hour 
(24-52 hours), followed by a decrease to 60 µg/kg/hour (52-56 hours), and 30 µg/kg/hour 
(56-60 hours).   
In Part B, a lower target dose will also be explored (ie, 60 µg/kg/hour).  The use of this dose 
is based on observations in the open-label 547-PPD-201 study in which subjects achieved 
substantial improvements in their HAM-D scores within the first 12 hours of the SAGE-547 
infusion.  In this study, subjects received a dose of 21.5 μg/kg/h for the first 4 hours, then 
43 μg/kg/h for the next 4 hours, and then 64.5 μg/kg/h for the following 4 hours before 
receiving the target dose of 86 μg/kg/h at 12 hours.  Therefore, the 12-hour data from 
547-PPD-201 suggests that SAGE-547 at target doses of 60 μg/kg/h may also be efficacious 
in reducing depressive symptoms associated with PPD.   
Subjects will be treated in an inpatient setting and continually monitored for safety, and if 
any severe tolerability issues arise, the infusion may be terminated or the infusion rate 
reduced.  The protocol includes a formal dose interruption and reduction scheme based on 
the occurrence of intolerable AEs. 


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5. 
ETHICS 
5.1. 
Institutional Review Board or Independent Ethics Committee 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) as appropriate.  The Investigator must submit written approval to Sage 
Therapeutics or designee before he or she can enroll any subject into the study.   
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to 
the protocol in accordance with local requirements.  In addition, the IRB or IEC must 
approve all advertising used to recruit subjects for the study.  The protocol must be re-
approved by the IRB or IEC upon receipt of amendments and annually, as local regulations 
require. 
The Principal Investigator is also responsible for providing the IRB or IEC with reports of 
any reportable serious adverse drug reactions from any other study conducted with the 
investigational product.  Sage Therapeutics or designee will provide this information to the 
Principal Investigator.   
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB or IEC according to local regulations and guidelines.   
5.2. 
Ethical Conduct of the Study 
This study will be conducted according to the principles of the World Medical Association 
Declaration of Helsinki and the most recent amendment (2008).   
The Sponsor, the Medical Monitor, and the Investigator must comply with all instructions, 
regulations, and agreements in this protocol, and must also conduct the study in accordance 
with International Council on Harmonisation (ICH) Guidelines on Good Clinical Practice 
(GCP) standards as well as local regulations.   
5.3. 
Subject Information and Informed Consent 
Prior to subject participation in the study, written informed consent must be obtained from 
each subject according to ICH GCP and in accordance with local regulations.  Written 
informed consent is required for each subject prior to any testing under this protocol not 
considered standard of care, including screening tests, SAGE-547 infusion, and study 
evaluations.  Each subject’s signature must be dated by each signatory and the informed 
consent form (ICF) retained by the investigator as part of the study records.  As an additional 
assessment, the ICF will contain provisions for optional consent for the collection of blood 
for genetic testing during screening.  The ICF, as specified by the clinical site’s IRB, must 
follow the Protection of Human Subjects regulations listed in the CFR, Title 21, Part 50. 
It is the responsibility of the Investigator to obtain consent and to provide the subject a copy 
of the signed and dated ICF.  The ICF for subject participation must also be available as part 
of the subject’s file for review by the site’s dedicated study monitor. 


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All ICFs used in this study must be approved by the appropriate IRB/IEC and by the 
Sponsor.  The ICF must not be altered without the prior agreement of the relevant IRB/IEC 
and the Sponsor.   


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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of this study is to determine if SAGE-547 Injection infused 
intravenously for 60 hours at up to 90 μg/kg/h reduces depressive symptoms in subjects with 
severe PPD compared to placebo injection as assessed by the change from baseline in 
HAM-D total score.  This objective applies to both Parts A and B. 
6.2. 
Secondary Objectives 
The secondary objectives of the study apply to Parts A, B, and C unless otherwise stated, and 
are: 
• To determine if SAGE-547 infusion at up to 60 μg/kg/h for 60 hours reduces 
depressive symptoms in subjects with severe PPD compared to placebo injection 
as assessed by the change from baseline in HAM-D total score (applies to Part B 
only). 
• To determine if SAGE-547 Injection infused intravenously at up to 90 μg/kg/h for 
60 hours reduces depressive symptoms in subjects with moderate PPD compared 
to placebo injection as assessed by the change from baseline in HAM-D total 
score (applies to Part C only). 
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
depressive symptoms compared to placebo injection as assessed by HAM-D 
response, HAM-D remission, change from baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) total score, Clinical Global Impression – 
Improvement (CGI-I) response, and changes from baseline in HAM-D subscale 
and individual item scores 
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
other mood symptoms compared to placebo injection as assessed by changes from 
baseline in the Generalized Anxiety Disorder 7-Item Scale (GAD-7) total score 
• To evaluate the safety and tolerability of SAGE-547 Injection compared with 
placebo as assessed by the incidence of AEs, vital sign measurement, clinical 
laboratory evaluations, electrocardiogram (ECG) parameters, and the Columbia 
Suicide Severity Rating Scale (C-SSRS) 
6.3. 
Other Objectives 
The other objectives of the study are: 
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
subject-reported depressive symptoms compared to placebo injection as assessed 
by the change from baseline in Edinburgh Postnatal Depression Scale (EPDS) 
total score and the change from baseline in Patient Health Questionnaire (PHQ-9) 
total score 


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• To determine if SAGE-547 Injection infused intravenously for 60 hours improves 
maternal behaviors compared to placebo injection as assessed by the change from 
baseline in Barkin Index of Maternal Functioning (BIMF) total and sub-scale 
scores 
• To determine if SAGE-547 Injection infused intravenously for 60 hours improves 
the general health status compared to placebo as assessed by the change from 
baseline in the Short Form-36 (SF-36) total score at Day 7 and Day 30 
6.4. 
Pharmacokinetic Objective 
The PK objective of the study is: 
• To assess the PK profile of SAGE-547, metabolites of SAGE-547, and betadex 
sulfobutyl ether sodium (SBECD) 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overview of Study Design 
This protocol describes three multicenter, randomized, double-blind, parallel-group, placebo-
controlled studies of the efficacy, safety, and PK of SAGE-547 Injection in adult female 
subjects diagnosed with severe or moderate PPD.  Each study will be independently 
conducted, analyzed, and reported.  In this protocol, Study 547-PPD-202A is hereafter 
referred to as Part A; Study 547-PPD-202B is hereafter referred to as Part B; and 
Study 547-PPD-202C is hereafter referred to as Part C.   
The study designs for Part A, Part B, and Part C are presented in Figure 1, Figure 2, and 
Figure 3, respectively; Parts B and C will run concurrently.  For all parts, the study will 
consist of a Screening Period (up to 5-days [Day -5 to -1; Part A] or up to 7-days [Day -7 
to -1; Parts B and C]), a 3-day (60 hours of treatment and an additional 12 hours for 
completion of 72-hour assessments) Treatment Period, and a 30-day Follow-up Period.  
Subjects must remain as inpatients during the study Treatment Period, which is 
approximately 72 hours/3 days in duration.  The Screening Period assessments may be 
conducted on an inpatient or an outpatient basis.  The Follow-up Period assessments are 
conducted on an outpatient basis.   
Figure 1: 
Study Design - Part A 
 
Day -5 to -1
Day 1
Day 3
Day 4
Day 30
Visit
Screening
Treatment Period
Follow-up Period
Randomization (1:1) 
SAGE-547 30 µg/kg/hr N = 16
Day 7
Visit
Day 12 
Visit
Placebo N = 16


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Figure 2: 
Study Design - Part B 
 
 
Figure 3: 
Study Design - Part C 
 
 
SAGE-547 Injection or placebo will be administered at the study center.  Subjects will be 
monitored for safety during the Treatment and Follow-up Periods (through Study Day 30 
[±3 days]) including monitoring for AEs/SAEs, routine clinical laboratory assessments, 
physical examination, vital signs, and ECG. 
All study-related procedures will occur after written informed consent is obtained at the 
screening visit, which will occur during the Screening Period window (Day -5 through 
Day -1 for Part A; Day -7 through Day -1 for Parts B and C).  If applicable, standard of care 
data collected prior to obtaining informed consent may also be included as screening data, if 
appropriate, such as laboratory tests, ECG, physical examination, and vital signs conducted 
within the preceding 48 hours, as long as the requirement for the screening assessment to be 
Day -7 to -1
Day 1
Day 3
Day 4
Day 30
Visit
Screening
Treatment Period
Follow-up Period
Randomization 
SAGE-547 60 µg/kg/hr N = 40
SAGE-547 90 µg/kg/hr N = 40
Day 7
Visit
Day 14 
Visit
Placebo N = 40
Day 21 
Visit
Day -7 to -1
Day 1
Day 3
Day 4
Day 30
Visit
Screening
Treatment Period
Follow-up Period
Randomization 
SAGE-547 90 µg/kg/hr N = 50
Day 7
Visit
Day 14 
Visit
Placebo N = 50
Day 21 
Visit


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collected retrospectively is met in full.  If applicable, to ensure protocol compliance, any 
standard of care data eligible for inclusion as screening data must include the precise nature 
and timing of data collection. 
The end of the Screening Period coincides with the beginning of the Treatment Period.  The 
Treatment Period is the period of Day 1 of study drug IV infusion through completion of the 
infusion on Day 2 and up to Day 3.  Subjects will be confined to the study center from Day 1 
until after the 72-hour assessments have been conducted on Day 3. 
In Parts A and C, once subjects are confirmed as eligible for the study, they will be 
randomized to one of two treatment groups (SAGE-547 90 µg/kg/hour or placebo) on a 1:1 
basis.  On the morning of dosing (Day 1), subjects will begin a 4-hour dose titration period of 
30 µg/kg/hour (0-4 hours), then 60 µg/kg/hour (4-24 hours), then 90 µg/kg/hour 
(24-52 hours); followed by a decrease to 60 µg/kg/hour (52-56 hours), and 30 µg/kg/hour 
(56-60 hours).  Subjects in the placebo group will receive infusion rates equivalent to the 
90 µg/kg/hour group. 
In Part B, once subjects are confirmed as eligible for the study, they will be randomized to 
one of three treatment groups (SAGE-547 60 µg/kg/hour, SAGE-547 90 µg/kg/hour, or 
placebo) on a 1:1:1 basis.  For the 60 µg/kg/hour group, subjects will receive 30 µg/kg/hour 
(0-4 hours), then 60 µg/kg/hour (4-56 hours), followed by 30 µg/kg/hour (56-60 hours).  For 
the 90 µg/kg/hour group, subjects will begin a 4-hour dose titration period of 30 µg/kg/hour 
(0-4 hours), then 60 µg/kg/hour (4-24 hours), then 90 µg/kg/hour (24-52 hours); followed by 
a decrease to 60 µg/kg/hour (52-56 hours), and 30 µg/kg/hour (56-60 hours).  Subjects in the 
placebo group will receive infusion rates equivalent to either the 60 µg/kg/hour or 
90 µg/kg/hour group.  Parts B and C will run concurrently. 
See dose regimen presented in Section 10.1.1.  Total SAGE-547 Injection or placebo dosing 
will occur over 60 hours. 
Study-specific assessments for safety, PK, efficacy, and other outcome measures will be 
completed at pre-specified times over the duration of the study: 
• The safety and tolerability of SAGE-547 Injection will be assessed by AEs, 
clinical laboratory measures, physical examinations (including cognitive and 
mental health examinations), vital signs, ECG, use of concomitant medication, 
and the Columbia Suicide Severity Rating Scale (C-SSRS) during the Screening, 
Treatment, and Follow-up Periods (through Study Day 30 [±3 days]) 
• Plasma will be collected to formally assay for SAGE-547, metabolite, and 
SBECD levels prior to dosing through the Treatment Period and up to 12 hours 
post infusion on Day 3 and on Day 7  
• Primary efficacy assessment of the HAM-D will be completed as scheduled 
during the Screening, Treatment, and Follow-up Periods (through Study Day 30 
[±3 days]) 
• Secondary efficacy assessments of MADRS, CGI-I, EPDS, Generalized Anxiety 
Disorder 7-Item Scale (GAD-7), PHQ-9 will be completed as scheduled during 
the Screening, Treatment, and Follow-up Periods (through Study Day 30 
[±3 days]) 


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The end of the Treatment Period coincides with the beginning of the Follow-up Period. 
Subjects will attend the clinic for safety follow-up assessment at 1 week (7±1d), 12 days 
(Part A), 2 weeks (14±2d [Part B and C]), 3 weeks (21±1d [Part B and C]), and 1 month 
(30±3d) after the initiation of the study drug infusion. 
Scheduled assessments for all safety, PK, efficacy, and other outcome measures planned for 
the study are summarized in Table 1.  All subjects who receive treatment with SAGE-547 are 
to complete all study assessments through Study Day 30 (±3 days). 
The Medical Monitor will review AEs on an ongoing basis. 
7.2. 
Blinding and Randomization 
This is a double-blind study.  Subjects will be randomized to receive SAGE-547 or placebo; 
subjects, clinicians, and the clinical site study team will be blinded to treatment allocation 
until the study is unblinded at final database lock.  The pharmacist, who will prepare the 
infusion bags according to the randomization schedule, and an unblinded Monitor, who will 
perform drug accountability during the study, will be unblinded.   
Randomization will be stratified by antidepressant use at baseline (yes/no).  Subjects will be 
randomized within stratum to receive SAGE-547 or placebo according to a computer-
generated randomization schedule.   
Only the clinic pharmacist, who is responsible for preparing the infusions, will be unblinded.  
In the event of a medical emergency, the Principal Investigator will discuss with the Medical 
Monitor if unblinding is warranted.  If there is agreement to unblind treatment assignment, 
the unblinding procedure described in the Safety Management Plan for the study will be 
followed.  In all cases where the study drug allocation for a subject is unblinded, pertinent 
information (including the reason for unblinding) must be documented in the subject’s 
records and on the electronic case report form (eCRF).   


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Inclusion Criteria 
The following inclusion criteria must be met for individuals to be eligible for the study: 
1. Subject has signed an ICF prior to any study-specific procedures being performed 
2. Subject is an ambulatory female aged between 18 and 45 years of age 
3. Subject is in good physical health and has no clinically significant findings, as 
determined by the Investigator, on physical examination, 12-lead ECG, or clinical 
laboratory tests 
4. Subject agrees to adhere to the study requirements 
5. Subject either must have ceased lactating at screening; or if still lactating or actively 
breastfeeding at screening, must agree to temporarily cease giving breastmilk to their 
infant(s) from just prior to receiving study drug through 9 days (Study Day 12) after 
the end of the infusion.   
6. Subject must have a negative pregnancy test at screening and Day 1 prior to the start 
of study drug infusion 
7. Subject has had a Major Depressive Episode that began no earlier than the third 
trimester and no later than the first 4 weeks following delivery, as diagnosed by 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) 
8. For Part A and B, subject has a HAM-D total score of ≥26 at screening and Day 1 
(prior to dosing).  For Part C, subject has a HAM-D total score of ≥20 and ≤25 at 
screening and Day 1 (prior to dosing) 
9. Subject is ≤6 months postpartum at screening 
10. Subject is willing at screening to delay the start of any new pharmacotherapy 
regimens, including antidepressant or anti-anxiety medication, until the study drug 
infusion and 72-hour assessments have been completed; if the subject is taking 
psychotropic medications, these must be at a stable dose from 14 days prior to 
screening until the 72-hour assessments have been completed.   
11. (Removed) 
12. Subject must use one of the following methods of birth control during participation in 
the study and for 30 days following the end of the study drug infusion: 
• Total abstinence (no sexual intercourse) 
• Hormonal contraceptives (birth control) including birth control pills, implantable 
or injectable contraceptives (Norplant® or Depo-Provera®) 
• A barrier form of contraception such as a condom or occlusive cap with a 
spermicide 
• An intrauterine device  


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8.2. 
Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria: 
1. Subject has renal failure requiring dialysis or fulminant hepatic failure or is anemic 
(hemoglobin ≤10 g/dL) 
2. Known allergy to progesterone or allopregnanolone 
3. Active psychosis per Investigator assessment 
4. Attempted suicide associated with index case of postpartum depression 
5. (Removed) 
6. Medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder. 
7. History of active alcoholism or drug abuse (including benzodiazepines) in the 12 months 
prior to screening.  A positive urine drug screen (except benzodiazepines under certain 
circumstances [see Section 10.3.3 and Section 11.1.2.6]) is exclusionary. 
8. Exposure to another investigational medication or device within 30 days prior to 
screening 
9. (Removed) 
10. Subject has previously participated in this study or any other study employing SAGE-547 
11. Administration of electroconvulsive therapy (ECT) within 14 days prior to screening 
and/or plans to administer ECT before the Study Day 7 Visit 
8.3. 
Subject Withdrawal/Study Termination 
8.3.1. 
Withdrawal/Discontinuation of Individual Subjects  
The reasons for study drug discontinuation and/or subject withdrawal from the study must be 
recorded in the subject’s eCRF.  The Investigator must notify the Sponsor and/or the Medical 
Monitor immediately when a subject has been discontinued/withdrawn for any reason, 
including withdrawal due to an AE. 
8.3.2. 
Subject Withdrawal from the Study 
Subjects may withdraw from the study at any time for any reason without compromising the 
subject’s medical care.  The Investigator will also withdraw subjects upon the request of 
Sage Therapeutics or upon termination of the study. 
8.3.3. 
Discontinuation of Study Drug by the Investigator 
If it is necessary for the Investigator to discontinue the study drug earlier than planned, 
subjects should continue to be followed per protocol to capture safety and efficacy 
assessments for the duration of the study period.   
The Investigator may withdraw the subject from the study drug for any of the following 
reasons: 
• The subject is unwilling or unable to adhere to the protocol 


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• The subject experiences an intolerable AE that does not respond to a dose 
reduction 
• During the course of the study, the subject develops symptoms or conditions 
listed in the exclusion criteria 
• Other medical reason, at the discretion of the Investigator and/or the Medical 
Monitor 
Subjects who discontinue the study due to an AE, regardless of Investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the Investigator 
determines the event is no longer clinically significant.   
8.3.4. 
Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
subjects, or for administrative reasons.  In the event of study termination, Sage Therapeutics 
will provide written notification to the Investigator.  Investigational sites must promptly 
notify their IRB/IEC and initiate withdrawal procedures for participating subjects.   


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9. 
INVESTIGATIONAL PRODUCT 
9.1. 
Identity of Investigational Product 
SAGE-547 Injection (allopregnanolone) 
9.2. 
Clinical Supplies 
9.2.1. 
SAGE-547 
SAGE-547 Injection and ancillary supply kits containing IV administration bags, solution 
sets, and IV bag labels will be provided to the sites. 
SAGE-547 Injection is a preservative-free, sterile, clear, colorless 5 mg/mL solution of 
SAGE-547 (allopregnanolone) and 250 mg/mL betadex sulfobutyl ether sodium buffered 
with 10 mM citrate at a pH of 6.0, intended for IV injection.  All inactive excipients used in 
the formulation are compendial grade and conform to current United States Pharmacopeia 
(USP) and European Pharmacopeia (Ph. Eur.) standards.  The product is aseptically 
processed, sterile filtered, and filled into 20 mL Type 1 parenteral glass vials with West 
FluroTec® coated stopper container closure systems, under current Good Manufacturing 
Practice (cGMP) conditions.  SAGE-547 Injection is intended to be used as a single-use vial.  
An appropriate number of single-use vials to support the dosing duration of the study are 
packaged and delivered to the site.  SAGE-547 Injection vials should be stored under 
refrigerated conditions (2–8°C).  Ancillary supply kits should be stored at controlled room 
temperature (20–25°C). 
All study drug labels will contain information to meet the applicable regulatory requirements. 
9.2.2. 
Placebo 
Placebo will be identical to SAGE-547 and presented in identical vials.  Placebo will be 
manufactured in a similar way to SAGE-547 and consisting of the same formulation without 
allopregnanolone.  Placebo vials should be stored under refrigerated conditions (2–8°C).   
9.3. 
Preparation of SAGE-547 Injection or Placebo for Dosing 
The pharmacy will be responsible for preparing SAGE-547 Injection or placebo for subject 
dosing.  The prepared admixture will be administered at room temperature.  The prepared 
admixture will be assigned a room temperature (20–25 °C) storage shelf life of 30 hours from 
time of compounding.   
SAGE-547 Injection or placebo is not intended to be administered to subjects undiluted.  
Each single-use vial of SAGE-547 Injection, which is hypertonic, will require dilution with 
an appropriate volume of SWFI to render it isotonic.  Refer to the Pharmacy Manual for 
specific instructions regarding infusion preparation and administration instructions. 


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9.4. 
Administration and Accountability 
The pharmacy will maintain accurate records of all investigational drug product supplies 
received, stored, dispensed, and discarded.  Accurate records will be kept regarding the 
volume of SAGE-547 Injection or placebo used for each IV preparation, as well as the 
required infusion rate (or rates), and the date and time of preparation.  Reasons for departure 
from the expected dosing regimen must be recorded.  To satisfy regulatory requirements 
regarding drug accountability, all study medication needs to be reconciled in full.   
Refer to the Pharmacy Manual for complete details on preparation and administration. 


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Dosing Schedule 
This is a double-blind study.  Subjects will be randomized to receive 60 hours of IV 
treatment with either SAGE-547 Injection or placebo, according to a computer-generated 
randomization schedule.  In Parts A and C, subjects randomized to SAGE-547 will receive 
the target dose of 90 µg/kg/hour; in Part B, SAGE-547 subjects will receive target doses of 
either 60 or 90 µg/kg/hour.   
The timing of infusion is shown in Figure 4, Figure 5, and Figure 6.   
Figure 4: 
Study Design and Timeline for Dosing – Part A 
 
 
Figure 5: 
Study Design and Timeline for Dosing – Part B 
 
Note: Day 3, 4-hour taper applies only to the 90 μg/kg/h dose group. 
 


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Figure 6: 
Study Design and Timeline for Dosing – Part C  
 
 
Clinical supply and preparation of SAGE-547 Injection for dosing is described Section 9.2 
and Section 9.3, respectively. 
10.1.1. 
Dose Regimen 
The specific infusion dose of SAGE-547 Injection will be calculated based on weight 
(obtained at screening) for each subject and administered according to dose regimen shown 
in Table 3 and Table 4).  The infusion rates are the same for all subjects within a particular 
dosing period (0-4 hours, 4-24 hours, etc.).   
Table 3: 
Infusion Rates for Part A and C 
 
Infusion Rate (µg/kg/hour)  
SAGE-547 Dose 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2-3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
90 µg 
30 
60 
90 
60 
30 
 
Table 4: 
Infusion Rates for Part B 
 
Infusion Rate (µg/kg/hour) 
SAGE-547 Dose 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2-3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
60 µg 
30  
60  
60  
60  
30 
90 µg 
30  
60  
90  
60  
30  
 
Dosing is to begin in the morning (on Day 1) to avoid awakening subjects during the night 
for completion of study assessments.   
If any subject has an intolerable AE, such as profound sleepiness or sedation outside of 
normal sleeping hours, the infusion rate for this subject will be decreased to the next lowest 
infusion dose level (or turned off if this occurs on the 30 µg/kg/hour dose level).   


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10.1.2. 
Route of Administration 
SAGE-547 Injection is intended for IV administration only.  The compatibility of SAGE-547 
with other drugs is unknown, and the product should be administered via a dedicated 
peripheral IV line with the study-approved IV administration bags and lines. 
10.1.3. 
Treatment Period 
Total dosing with SAGE-547 or placebo will occur over 60 hours. 
10.1.4. 
Dosing of Intravenous SAGE-547 in the Case of AEs 
Since allopregnanolone levels in the proposed clinical study are similar to physiological 
levels seen in the third trimester of pregnancy, and all the AEs reported with SAGE-547 or 
allopregnanolone to date in healthy volunteers and subjects with postpartum depression were 
mild and non-serious, it is anticipated that the AEs associated with SAGE-547 in this study 
will be mild and manageable without dose interruption or reduction.  Based on the safety data 
in subjects with PPD collected to date, no subjects reported events that were serious or severe 
or led to discontinuation of study drug (two subjects reported sedation that led to a dose 
reduction, one of these subjects also reported dizziness; one subject reported rash that led to a 
dose reduction; refer to the current Investigator’s Brochure for more information).   
However, in the case of intolerable AEs occurring, the investigator is advised to reduce the 
infusion to the next lowest dose (or stop the infusion if this event occurs on the 
30 µg/kg/hour dose level) until the AE has resolved, at which time re-escalation to the 
maintenance rate may be considered.  If the AE recurs, the study drug infusion may be 
reduced again or permanently discontinued. 
10.2. 
Dosing Compliance 
Investigational product will be prepared in the site pharmacy, administered as a continuous 
IV infusion by the study staff, and will be documented in the study record.  There should be 
no adjustments in dosing except those described in Section 10.1.4. 
10.3. 
Prior Medications, Concomitant Medications, and Restrictions 
10.3.1. 
Prior Medications 
The start and end dates, route, dose/units, and frequency of all medications taken within 
60 days prior to signing the informed consent will be recorded, as well as all medications 
given to treat the current PPD episode that are recorded on the SCID-I during the screening 
visit.   
10.3.2. 
Concomitant Medications 
All medications taken from signing the informed consent through the Day 30 (±3 days) visit 
will be recorded on the eCRF.  Subjects will receive standard of care for adult female 
patients diagnosed with PPD.  Any concomitant medication determined necessary for the 
welfare of the subject may be given at the discretion of the Investigator at any time during 
the study under the guidance outlined in Section 10.3.   


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10.3.3. 
Prohibited Medications 
Restrictions on specific classes of medications include the following: 
• 
Subjects may not start new pharmacotherapy regimens, including antidepressant or 
anti-anxiety medications, from the time of informed consent until the study drug 
infusion and 72-hour assessments have been completed.  If clinically indicated, new 
antidepressant medications may be started or existing antidepressant medication 
regimens may be changed once the 72-hour assessments have been completed.  
Consideration should also be given to deferring, starting, or changing antidepressant 
medication regimens until the Day 7, Day 12 (Part A only) or Day 14 (Parts B and C 
only), Day 21 (Parts B and C only), or Day 30 visits if the HAM-D score has 
improved.   
• 
If the subject is taking psychotropic medications, these must be at a stable dose from 
14 days prior to screening to completion of the 72-hour assessments.   
• 
Benzodiazepines are to be avoided as much as possible owing to the potential for a 
synergistic sedative effect.  Eligible subjects taking a benzodiazepine at the time of 
study entry will be permitted to continue to take their current dose of the 
benzodiazepine (to prevent acute withdrawal), but no new benzodiazepine use will be 
permitted during the course of the study.   
10.3.4. 
Restrictions 
• 
Electroconvulsive therapy (ECT) is prohibited from 14 days prior to screening until 
after the Day 7 visit. 


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11. 
STUDY ASSESSMENTS 
11.1. 
Safety Assessments 
The safety and tolerability of SAGE-547 Injection will be evaluated by summarization of 
AEs by frequency, severity and seriousness, mean changes from baseline in clinical 
laboratory measures, physical examination, vital signs, ECGs, and concomitant medication 
usage.  Suicidality will be monitored using the C-SSRS.  All safety assessments should be 
performed per the study center’s standard of care and will be collected according to the 
Schedule of Events (Table 1).  All safety assessments are to be completed within 
±30 minutes of the scheduled time point. 
In addition to the schedule outlined in Table 1, completion of safety assessments including 
physical examination, vital signs, and clinical laboratory tests should occur in the event of an 
emergency or SAE, when possible.   
11.1.1. 
Adverse Events 
Adverse events will be collected after the ICF has been signed through the end of the study 
(see Section 14.2.1 for additional details).  Medical conditions or AEs that occur after the 
ICF has been signed and prior to completion of screening will be captured on the Medical 
History eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) coding system (version 18.0 or higher).   
11.1.2. 
Clinical Laboratory Tests 
Blood samples will be collected for hematology, serum chemistry, coagulation, specific 
hormone parameters, and exploratory biochemistry; pregnancy testing; and genetic analysis.  
Urine samples for urinalysis and selected drugs of abuse will also be collected.  All samples 
will be analyzed at the central laboratory.  Patients may be considered eligible for the study 
based on local laboratory results, however screening samples must also be sent to the central 
laboratory.  Both local and central screening labs must adhere to the visit window provided in 
the Schedule of Events (Table 1). 
These assessments will be performed in accordance with the Schedule of Events (Table 1) 
and as outlined individually below. 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as Abnormal; not clinically significant (NCS) or Abnormal; clinically significant 
(CS).  Screening results considered Abnormal; CS will be recorded as medical history.  
Clinical laboratory results that are Abnormal; CS during the study and indicate a worsening 
from baseline will be considered AEs, assessed according to Section 14, and recorded in the 
eCRF.   


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11.1.2.1. Hematology, Serum Chemistry, Coagulation 
Blood samples will be collected for analysis of the following:  
• Hematology: complete blood count (CBC) including white blood cell (WBC) count 
with differential (basophils, eosinophils, lymphocytes, monocytes, and neutrophils) 
platelet count, red blood cell (RBC) count, hemoglobin (Hgb) and hematocrit (Hct), 
mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) 
• Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin (total), blood urea nitrogen (BUN), 
calcium, chloride, creatinine, gamma glutamyl transferase (GGT), glucose phosphate, 
potassium, sodium, total protein, and triglycerides (screening only) 
• Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT), 
and international normalized ratio (INR) 
11.1.2.2. Hormones and Exploratory Biochemistry 
Blood samples will be collected and may be analyzed for thyroid stimulating hormone 
(TSH), estrogen, progesterone, progesterone metabolites, oxytocin, tryptophan, kynurenine, 
and markers of inflammation. 
11.1.2.3. Pregnancy Tests 
All subjects will be tested for pregnancy by serum human chorionic gonadotropin (hCG) at 
screening and urine hCG on Day 1 prior to administration of study drug and on Day 30.  
Subjects with a positive pregnancy test at screening or Day 1 will be ineligible for study 
participation. 
11.1.2.4. Genetic Testing 
A blood sample for genetic testing will be collected at screening, where consent is given.   
The objective of this research is to collect and store blood samples for possible DNA 
extraction and exploratory research into how genes or specific genetic variation may 
influence response (ie, distribution, safety, tolerability, and efficacy) to SAGE-547.  Specific 
genetic variations of interest include but are not limited to: classes of metabolizing enzymes 
(eg, Cytochrome P450 supra-family genes), genes encoding enzymes involved in the 
production and metabolism of allopregnanolone (eg, AKR1C4 (3a-hydroxysteroid 
dehydrogenase)), genes associated with the GABA receptor (eg, GABRA1-A6, 
GABRB1-B3, GABRD, GABRE, GABRG1-3) and genes associated with the production and 
degradation of GABA.    
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to SAGE-547 but also susceptibility to disorders for which SAGE-547 may be 
evaluated.  Thus, the genetic research may involve study of additional unnamed genes or 
gene categories, but only as related to disease susceptibility and drug action. 


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11.1.2.5. Urinalysis 
Urinalysis will include assessment of bilirubin, glucose, ketones, leukocytes, nitrite, pH, 
protein, and specific gravity.   
11.1.2.6. Drugs of Abuse and Alcohol 
Urine assessment for selected drugs of abuse will be performed at screening (including 
amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine, 
and propoxyphene).  Use of benzodiazepines at screening is not necessarily exclusionary, as 
subjects will be allowed to take psychotropics that have been initiated at least 14 days prior 
to admission to the study center at a stable dose (see Section 10.3.3).  A positive urine drug 
screen for any of the tested drugs of abuse (except benzodiazepines) is exclusionary.  
Alcohol will be assessed in plasma at screening and via breathalyzer or urine dipstick on 
Day 1.   
11.1.3. 
Physical Examination 
Body weight and height will be measured at screening.  Body mass index (BMI) will be 
programmatically calculated in the eCRF. 
Any condition present at the post-treatment physical examination that was not present at or 
worsened since the baseline examination is to be documented as an AE.  Whenever possible, 
the same individual is to perform all physical examinations.  Physical examinations will 
include assessment of body systems (eg, HEENT, heart, lungs, abdomen, and extremities) as 
well as cognitive and neurological examination and mental status examination.   
11.1.4. 
Vital Signs 
Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure 
(supine and standing).  A full set of vital signs will be obtained at all specified time points 
(±30 minutes), unless the subject is asleep between the hours of 23.00h and 06.00h each day.   
11.1.5. 
ECG 
A baseline 12-lead ECG will be performed during screening.  The following ECG parameters 
will be recorded: heart rate, PR, QRS, QT, and QTc.  All ECG results will be interpreted by 
the Investigator as Normal, Abnormal; not clinically significant (NCS), or Abnormal; 
clinically significant (CS).  If Abnormal, details will be provided.   
11.1.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011).  This scale 
consists of a pre-dose evaluation that assesses the lifetime and recent experience of the 
subject with suicidal ideation and behavior, and a post-baseline evaluation that focuses on 
suicidality since the last study visit.  The C-SSRS includes “yes” or “no” responses for 
assessment of suicidal ideation and behavior as well as numeric ratings for severity of 
ideation, if present (from 1 to 5, with 5 being the most severe).  The “Baseline/Screening” 
C-SSRS form will be completed on Day 1 prior to dosing.  The “Since Last Visit” C-SSRS 
form will be completed for all subsequent assessments.   


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Copies of the C-SSRS are provided in Appendix 1. 
11.2. 
Efficacy Assessments 
For all efficacy assessments, the baseline values will be calculated as the last recorded value 
prior to the start of infusion of randomized treatment.  Change from baseline values will be 
calculated as the assessment score minus the baseline value.  Change from baseline values 
will be calculated for each item and total score.   
11.2.1. 
Primary Efficacy Outcome Measure 
The primary outcome measure is the HAM-D.  The HAM-D will be administered before, 
during, and after the infusion of blinded study drug.   
11.2.1.1. Hamilton Rating Scale for Depression (HAM-D)  
The 17-item HAM-D will be used to rate the severity of depression in subjects who are 
already diagnosed as depressed (Hamilton 1960).  The 17-item HAM-D is comprised of 
individual ratings related to the following symptoms: depressed mood (sadness, hopeless, 
helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and 
activities, retardation (slowness of thought and speech; impaired ability to concentrate; 
decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms 
(gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and 
insight.  The HAM-D assessments are to be completed within ±30 minutes of the scheduled 
time point, but prior to starting dosing on D1 H0.  Every effort should be made for the same 
rater to perform all HAM-D assessments for a single subject. 
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  Item 
16 can be rated according to history (item 16A) or actual weight change (item 16B).  The 
item 16 score is calculated as the item 16 response that is not equal to 3 (ie, “Not assessed”).   
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D.  HAM-D subscale 
scores will be calculated as the sum of the items comprising each subscale.  HAM-D 
response will be defined as having a 50% or greater reduction from baseline in HAM-D total 
score.  HAM-D remission will be defined as having a HAM-D total score of ≤7.   
A copy of the HAM-D is provided in Appendix 2. 
11.2.2. 
Secondary Efficacy Outcome Measures 
Secondary efficacy assessments include evaluation of depressive symptom severity by the 
HAM-D total score at the Day 30 time point, MADRS (Section 11.2.2.1), and CGI 
(Section 11.2.2.2).  Additional assessments of depressive symptom severity and reproductive 
mood disorders will be measured by the following clinician- and subject-rated outcome 
measures: EPDS (Section 11.2.3.1), GAD-7 (Section 11.2.2.3), and PHQ-9 
(Section 11.2.3.2). 


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11.2.2.1. Montgomery Asberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire which psychiatrists use to measure the 
severity of depressive episodes in patients with mood disorders.  It was designed as an 
adjunct to the HAM-D which would be more sensitive than the HAM-D with regards to 
changes brought on by antidepressants and other forms of treatment. 
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 
6.  The overall score ranges from 0 to 60 (McDowell 2006, Müller-Thomsen 2005). 
The questionnaire includes questions on the following symptoms  
1. Apparent sadness  
2. Reported sadness  
3. Inner tension  
4. Reduced sleep  
5. Reduced appetite  
6. Concentration difficulties  
7. Lassitude  
8. Inability to feel  
9. Pessimistic thoughts  
10. Suicidal thoughts 
The MADRS total score will be calculated as the sum of the 10 individual item scores. 
A copy of the MADRS is provided in Appendix 3. 
11.2.2.2. Clinical Global Impression (CGI) Scale 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the patient’s condition.  The CGI scale 
is comprised of three items.  Only the first two items are being used in this study.   
The CGI-Severity (CGI-S) item uses a 7-point Likert scale to rate the severity of the patient’s 
illness at the time of assessment, relative to the clinician’s past experience with patients who 
have the same diagnosis.  Considering total clinical experience, a patient is assessed on 
severity of mental illness at the time of rating 1=normal, not at all ill, 2=borderline mentally 
ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7=extremely ill.  The 
CGI-S will be rated by the clinician at screening and on Day 1 (prior to dosing). 
The CGI-Improvement (CGI-I) item employs a 7-point Likert scale to measure the overall 
improvement in the patient’s condition post-treatment.  The investigator will rate the 
patient’s total improvement whether or not it is due entirely to drug treatment.  Response 
choices include: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally 
improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse.  The 
CGI-I is only rated at post-treatment assessments.  By definition, all CGI-I assessments are 


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evaluated against baseline conditions.  CGI-I response will be defined as having a CGI-I 
score of “very much improved” or “much improved.”   
A copy of the CGI is provided in Appendix 4. 
11.2.2.3. Generalized Anxiety Disorder 7-Item Scale (GAD-7) 
The GAD-7 is a patient-rated generalized anxiety symptom severity scale (Spitzer 2006).  
Scoring for GAD-7 generalized anxiety is calculated by assigning scores of 0, 1, 2, and 3 to 
the response categories, respectively, of “not at all sure,” “several days,” “over half the 
days,” and “nearly every day.” GAD-7 total score for the seven items ranges from 0 to 21, 
where a score of 0 to 4=minimal anxiety, 5 to 9=mild anxiety, 10 to 14=moderate anxiety, 
and 15 to 21=severe anxiety.  All assessments are to be completed within ±30 minutes of the 
scheduled time point. 
The GAD-7 total score will be calculated as the sum of the 7 individual item scores. 
A copy of the GAD-7 is provided in Appendix 6. 
11.2.3. 
Patient Reported Outcome Measures 
Other efficacy assessments include evaluation of depressive symptom severity and 
reproductive mood disorders.  These will be measured by the following clinician- and 
subject-rated outcome measures: EPDS, PHQ-9, BIMF, and SF-36. 
11.2.3.1. Edinburgh Postnatal Depression Scale (EPDS) 
The EPDS is a patient-rated depressive symptom severity scale specific to the perinatal 
period (Cox 1987).  The EPDS total score will be calculated as the sum of the 10 individual 
item scores. 
A copy of the EPDS is provided in Appendix 5. 
11.2.3.2. Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is a patient-rated depressive symptom severity scale.  To monitor severity over 
time for newly diagnosed patients or patients in current treatment for depression, patients 
may complete questionnaires at baseline and at regular intervals thereafter.  Scoring is total 
based on responses to specific questions, as follows:  not at all=0; several days=1; more than 
half the days=2; and nearly every day=3.  All assessments are to be completed within 
±30 minutes of the scheduled time point. 
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores.  The 
PHQ-9 total score will be categorized as follows: 1-4=minimal depression, 5-9=mild 
depression, 10-14=moderate depression, 15-19=moderately severe depression; and 
20-27=severe depression. 
A copy of the PHQ-9 is provided in Appendix 7. 
11.2.3.3. Barkin Index of Maternal Functioning (BIMF)  
The BIMF is a patient reported outcome scale BIMF covers a broad range of functional areas 
(self-care, infant care, mother-child interaction, psychological well-being of mother, social 


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support, management, adjustment).  This new application of maternal functional status is a 
robust construct where the physical and mental health of the mother is essential to optimal 
functioning.  Each item is rated on a scale of 0 (strongly disagree) to 6 (strongly agree).   
A copy of the BIMF is provided in Appendix 8. 
11.2.3.4. Short Form-36 (SF-36) 
The Medical Outcomes Study Short Form-36 (SF-36v2) is a 36-item measure of health status 
that has undergone validation in many different disease states (Ware 2007).  The SF-36 
covers eight health dimensions including four physical health status domains (physical 
functioning, role participation with physical health problems [role-physical], bodily pain, and 
general health) and four mental health status domains (vitality, social functioning, role 
participation with emotional health problems [role-emotional], and mental health).  In 
addition, two summary scores, physical component summary (PCS) and mental component 
summary (MCS), are produced by taking a weighted linear combination of the eight 
individual domains.  The SF-36v2 is available with two recall periods: the standard recall 
period is 4 weeks and the acute recall period is 1 week.  This study will use the acute version, 
which asks patients to respond to questions as they pertain to the past week.  Higher SF-36 
scores indicate a better state of health.  The SF-36 requires approximately 10 minutes to 
complete and can be self-administered or completed by interview in person or by telephone. 
A copy of the SF-36 is provided in Appendix 9. 
11.2.3.5. Healthcare Resource Utilization (HCRU) 
Subject-reported healthcare resource utilization data, including baseline diagnosis history, 
baseline antidepressant treatment history, and healthcare visits, inpatient visits, and 
medication use, will be collected at screening and on Day 30 of follow-up (or at early 
termination).  A copy of the health resource utilization questionnaire is provided in 
Appendix 10.  
11.3. 
Pharmacokinetics 
Blood samples for PK analysis will be collected in accordance with the Schedule of Events 
(Table 1).  Scheduled time points for PK blood draws after the start of infusion will have a 
window of ±10 minutes.  Samples will be processed according to the PK Manual, and may be 
analyzed for concentrations of SAGE-547, metabolites of SAGE-547, and SBECD.  
Additionally, PK samples may be obtained outside the planned collection times if issues 
administering study drug are encountered, such as incorrect infusion rate, interrupted 
infusion, or other administration deviations where PK level assessment may be important in 
understanding subject state.  In the event of an unplanned dose adjustment, an unscheduled 
PK sample should be collected just prior to the infusion rate change. 
The following PK parameters will be derived from the plasma concentrations (where 
evaluable): area under the concentration-time curve (AUC) from time zero to 60 hours 
(AUC0-60), AUC from time zero to infinity (AUC∞), maximum (peak) plasma concentration 
(Cmax), time at maximum (peak) plasma concentration (tmax), steady-state drug concentration 
in the plasma during constant-rate infusion (Css), and average drug concentration in the 


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plasma at steady state during a dosing interval (Cavg).  Each PK parameter will be derived 
separately for each part of the study. 
The plasma samples will be drawn from the arm contralateral to that used for study drug 
administration.  Instructions on sample collection, processing methods, storage, and shipping 
conditions for subject-specific plasma PK kits will be provided in the study laboratory 
manual. 


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12. 
STUDY PROCEDURES 
The study procedures listed below by study day reflect the data collection times for this 
protocol.   
Scheduled assessments for all safety, efficacy, PK, and other outcome measures planned for 
the study are summarized in Table 1 (Schedule of Events).  All subjects who receive 
treatment with SAGE-547 should complete all study assessments through Study Day 30 (±3 
days). 
Subjects who complete the assessments at Hour 60 and Day 30 (±3 days) will be defined as 
study completers.   
12.1. 
Screening Period 
The Screening Period consists of a window from Day -7 through Day -1 prior to starting 
SAGE-547 treatment (up to 5-days [Day -5 to -1; Part A] or up to 7-days [Day -7 to -1; 
Parts B and C]).  The Screening Period begins with the signature of the ICF.  Eligibility is 
determined by applying the inclusion/exclusion criteria.  The diagnosis of PPD must be by 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I).  A full medical and 
family history will be taken from the subject using a SCID-I interview, including recording 
of all depression (major depressive disorders, premenstrual dysphoric disorder, menstrual 
migraine, and other psychiatric disorders per DSM), other Axis I and Axis II disorders, and 
pregnancy history including birth complications, and postpartum depression episodes.  
Family history will be collected from the subject for primary probands, including all 
depression (major depressive disorders, premenstrual dysphoric disorder, menstrual 
migraine, and other psychiatric disorders per DSM), other Axis I disorders, and postpartum 
depression episodes.   
The following assessments/procedures will be conducted at the screening visit, which will 
occur during the Screening Period window.  Standard of care data collected prior to obtaining 
informed consent may also be included as screening data, if appropriate, such as laboratory 
tests, ECG, physical examinations, and vital signs conducted within the preceding 48 hours, 
as long as the requirement for the screening assessment to be collected retrospectively is met 
in full, and all screening assessments are completed, reviewed and approved by the 
Investigator prior to administration of study drug. 
Subjects will be confined to the study center from Day 1 until after the 72-hour assessments 
have been conducted on Day 3. 
• Written informed consent will be obtained 
• Inclusion/exclusion criteria will be reviewed to determine subject eligibility 
• Demographic information and medical/family history will be collected 
• Lactation status (ie, subject is breastfeeding, subject is lactating but not 
breastfeeding, or subject is not lactating) will be recorded 
• Blood will be collected for a pregnancy test 


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• Completion of physical examination, including body weight.  Height should be 
recorded.  BMI will be calculated. 
• Vital signs will be recorded 
• Blood and urine samples will be collected for clinical laboratory testing, including 
drug and alcohol screening 
• Blood sample will be taken for genetic analysis with subject consent 
• An ECG reading will be taken 
• The HAM-D, CGI-S, and MADRS will be completed 
• Concomitant medications will be recorded 
• AEs will be monitored 
12.2. 
Study Drug Treatment Period (Day 1 to Day 3, Hours 0-72) 
All safety, efficacy, PK, and other outcome assessments described in this section are to be 
completed within ±30 minutes of the scheduled time points, unless otherwise stated.  
Windows for PK collection time points are specified by respective time point for Study 
Days 1 to 3 in Section 12.2.1 to Section 12.2.3, respectively (see Section 11.3 for additional 
details).  Subjects will be confined to the study center from Day 1 until after the 72-hour 
assessments have been conducted on Day 3.   
Psychiatric follow-up outside the study visits will be arranged and documented, as 
appropriate.   
12.2.1. 
Day 1 
• Inclusion/exclusion criteria will be reviewed to determine subject eligibility 
• Randomization 
• Urine will be collected for a pregnancy test 
• Study drug administration will begin for dose titration in the morning followed by 
maintenance infusion 
• Vital signs will be recorded prior to infusion and at 2, 4, 8, 12, 18, and 24 hours 
on Day 1 (±30 minutes), unless the subject is asleep between the hours of 23.00h 
and 06.00h each day 
• Blood and urine samples will be collected for drug and alcohol screening 
• A blood sample for PK analysis will be collected prior to infusion (ie, morning of 
Day 1 prior to dosing), and at Hours 4 (before change in infusion rate, if 
applicable), 8, 12, and 24 (before change in infusion rate, if applicable) after the 
start of the infusion.  PK blood draws after the start of infusion will have a 
window of ±10 minutes.  In the event of an unplanned dose adjustment, an 
unscheduled PK sample should be collected just prior to the infusion rate change. 


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• The HAM-D will be completed prior to dosing and at Hours 2, 4, 8, 12, and 24 on 
Day 1 (±30 minutes) 
• The MADRS will be completed prior to dosing and at Hour 24 on Day 1 
(±30 minutes) 
• The CGI-S will be completed prior to dosing and the CGI-I at Hours 2, 4, 12, and 
24 on Day 1 (±30 minutes) 
• The following questionnaires will be completed prior to dosing: BIMF, EPDS, 
GAD-7, SF-36, and PHQ-9 (±30 minutes) 
• AEs will be monitored 
• Concomitant medications will be recorded 
• The “Baseline/Screening” C-SSRS form will be completed prior to dosing.  The 
“Since Last Visit” C-SSRS form will be completed at Hour 24 (± 30 minutes) 
• Breast milk will be pumped and discarded by subjects who are lactating 
12.2.2. 
Day 2 
• Ongoing study drug maintenance infusion administration 
• Vital signs will be recorded at Hours 30, 36, 42, and 48 (±30 minutes), unless the 
subject is asleep between the hours of 23.00h and 06.00h each day 
• A blood sample for PK analysis will be collected at Hours 30, 36, and 48.  PK 
blood draws will have a window of ±10 minutes.  In the event of an unplanned 
dose adjustment, an unscheduled PK sample should be collected just prior to the 
infusion rate change 
• The HAM-D will be completed at Hour 36 and Hour 48 (±30 minutes) 
• The CGI-I will be completed at Hour 36 and Hour 48 (±30 minutes) 
• The MADRS will be completed at Hour 48 (±30 minutes) 
• An ECG reading will be taken at Hour 48 
• AEs will be monitored 
• Concomitant medications will be recorded 
• Breast milk will be pumped and discarded by subjects who are lactating 
12.2.3. 
Day 3 
• Ongoing study drug maintenance infusion administration until Hour 60 
• A physical examination will be completed at Hour 72 
• Vital signs will be recorded at Hours 54, 60, 66, and 72 (±30 minutes) 


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• A blood sample for PK analysis will be collected at Hours 60 and 
72 (±10 minutes).  In the event of an unplanned dose adjustment, an unscheduled 
PK sample should be collected just prior to the infusion rate change 
• Blood sample will be collected for clinical laboratory testing at Hour 72 
• The HAM-D and MADRS will be completed at Hours 60 and 72 (±30 minutes) 
• The CGI-I will be completed at Hours 60 and 72 (±30 minutes) 
• The following questionnaires will be completed at Hour 60: EPDS, GAD-7, and 
PHQ-9 (±30 minutes) 
• AEs will be monitored 
• Concomitant medications will be recorded 
• The C-SSRS will be completed at Hours 60 and 72 
• Subjects who are lactating will pump and discard breast milk and be reminded 
that they must continue to pump and discard breast milk through Day 12 of the 
study  
12.3. 
Follow-up Period (Day 7 through Day 30) 
12.3.1. 
Day 7 (±1 day) 
The following assessments should be completed: 
• A physical examination will be completed 
• Vital signs will be recorded 
• Blood and urine samples will be collected for clinical laboratory testing 
• An ECG reading will be taken 
• The C-SSRS, HAM-D, MADRS, CGI-I, EPDS, GAD-7, PHQ-9, SF-36, and 
BIMF will be completed 
• Subjects who are lactating will be reminded to continue to pump and discard 
breast milk through Day 12 of the study 
• AEs will be monitored 
• Concomitant medications will be recorded 
12.3.2. 
Day 12 (±2 days) (Part A); Day 14 (±2 days) and Day 21 (±3 days) (Parts B 
and C) 
The following assessments should be completed: 
• The C-SSRS, HAM-D, MADRS, CGI-I, EPDS, GAD-7, PHQ-9, SF-36, and 
BIMF will be completed 
• AEs will be monitored 


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• Concomitant medications will be recorded 
12.3.3. 
Day 30 (±3 days) 
The following assessments should be completed: 
• Urine will be collected for a pregnancy test 
• The C-SSRS, HAM-D, MADRS, CGI-I, EPDS, GAD-7, PHQ-9, SF-36, and 
BIMF will be completed 
• AEs will be monitored 
• Concomitant medications will be recorded 
12.3.4. 
Early Termination Visit 
The following assessments should be completed if the subject discontinues from the study 
prior to the Day 7 Visit: 
• A physical examination will be completed 
• Vital signs will be recorded 
• Blood and urine samples will be collected for clinical laboratory testing 
• An ECG reading will be taken 
• The C-SSRS, HAM-D, MADRS, CGI-I, EPDS, GAD-7, PHQ-9, SF-36, and 
BIMF will be completed 
• AEs will be monitored 
• Concomitant medications will be recorded 
The visit should occur within 3 days of notification of the subject discontinuing. 


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13. 
STATISTICAL METHODS AND CONSIDERATIONS 
In general, summary statistics for all study endpoints will be presented as mean, standard 
deviation (SD), median, and ranges for continuous endpoints, and as counts and percentages 
for categorical endpoints.  For the purpose of all safety, efficacy, and other analyses where 
applicable, baseline is defined as the last pre-dose measurement closest to the start of blinded 
study drug infusion. 
A separate statistical analysis plan (SAP) will be generated for each study (Parts A, B, and C) 
and approved prior to the respective database lock of each study.  All statistical analyses will 
be conducted using SAS for Windows (version 9.1.3, or higher; Cary, NC), unless otherwise 
specified.   
Any deviations from the planned analyses will be described and justified in the final clinical 
study report (CSR). 
13.1. 
Data Analysis Sets 
The All Enrolled Population will include all subjects who have given written informed 
consent.  This population will be used for subject disposition and demographic characteristic 
summaries. 
The All Randomized Population will include the subset of subjects from the All Enrolled 
Population who have been randomized.  Subjects will be classified according to randomized 
treatment.  This population will be used for subject disposition, demographic characteristic, 
and baseline characteristic summaries. 
The Safety Population will include all randomized subjects who start the infusion of study 
drug.  Subjects will be classified according to actual treatment received.  This analysis 
population will be used for all safety analyses. 
The Efficacy Population (EFF) will include the subset of the Safety Population who have a 
valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment.  
Subjects will be classified according to randomized treatment.  This analysis population will 
be used for all efficacy analyses. 
The Per Protocol Population (PP) will include the subset of the Efficacy Population who 
complete the full infusion without significant protocol violations or deviations.  Subjects will 
be classified according to randomized treatment.  This analysis population will be used for 
sensitivity analyses of the primary and select secondary endpoints. 
The PK Population (PKP) will include the subset of the Safety Population who have at least 
one evaluable PK sample.  Subjects will be classified according to actual treatment received.  
This analysis population will be used for all PK analyses. 
The number and percentage of subjects who receive SAGE-547 Injection or placebo, 
prematurely discontinue, and complete the study will be summarized.  The number and 
percentage of subjects will also be summarized for each reason for premature 
discontinuation.  In addition, the number of subjects whose data should be used for the 


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planned analyses will be identified for each respective analysis population (ie, Safety, EFF, 
PKP, and PP). 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data.  All subjects will be used in the analyses, 
as per the analysis populations, using all non-missing data available.  A sensitivity analysis 
may be carried out to investigate the impact of missing data if more than 5% of subjects are 
missing primary endpoint assessments.  Any rules/statistical methods for the imputation of 
missing data will be described in the SAP. 
13.3. 
Demographics and Baseline Characteristics 
Demographics such as age, race, and ethnicity will be summarized.  In addition, baseline 
characteristics such as height, weight, and BMI will be summarized.  Categorical summaries, 
such as race and ethnicity, will be summarized by frequency and percentage.  Continuous 
summaries, such as age, height, weight, BMI and baseline vital signs, will be summarized 
using descriptive statistics such as n, mean, SD, median, minimum, and maximum. 
Drug, alcohol, and pregnancy screening results will be collected and listed but not 
summarized, as they are considered part of the inclusion/exclusion criteria.   
Medical/family history will be collected and listed by subject. 
13.4. 
Primary Endpoints 
For efficacy analysis purposes, centers with fewer than 15 subjects per center for Part B or 
10 subjects per center for Part C will be pooled within regions (eg, North America region 
centers will be pooled separately those in Europe).  Change from baseline to each assessment 
in HAM-D total score will be analyzed using a mixed effects model for repeated measures 
(MMRM); the model will include center (pooled), treatment, baseline HAM-D total score, 
visit time point, and visit time point-by-treatment terms.  Center and all other explanatory 
variables will be treated as fixed effects.  For Parts A and C, the primary comparison will be 
between 90 µg SAGE-547 and placebo at the 60-hour assessment.  For Part B, the primary 
comparison will be between 90 µg SAGE-547 and placebo at the 60-hour assessment; if this 
comparison is significant at the 0.05 level, then the 60 µg group will be compared to placebo 
at the 0.04 level of significance.  More details will be provided in the SAPs regarding strong 
control of overall level of significance for multiple testing, including testing of key secondary 
endpoints.  Comparisons at other time points, including the Day 30 time point, will be 
conducted to support the findings for the primary comparison.  Model-based point estimates 
(ie, LS means), 95% confidence intervals, and p-values will be reported for each assessment.   
Summaries of HAM-D total scores and changes from baseline values will include n, mean, 
SD, median, minimum, and maximum.   


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13.5. 
Secondary Endpoints 
13.5.1. 
Efficacy Analysis 
MMRM methods similar to those described in Section 13.4 will be used for the analysis of 
the following variables: MADRS total score, EPDS total score, GAD-7 total score, PHQ-9 
total score, and select individual item and subscale scores.  Separate models will be fit for 
each part of the study.  For each model, the comparison of interest will be between each 
SAGE-547 dose and placebo at the 60-hour assessment.  Model based point estimates 
(ie, LS means), 95% confidence intervals, and p-values will be reported.   
Generalized Estimating Equation (GEE) methods will be used for the analysis of the 
following response variables: HAM-D response, HAM-D remission, and CGI-I response.  
GEE models will include terms for center, treatment, and baseline score.  Separate models 
will be fit for each part of the study.  The comparison of interest will be the difference 
between each SAGE-547 dose and placebo at the 60-hour assessment.  Model based point 
estimates (ie, odds ratios), 95% confidence intervals, and p-values will be reported.  For the 
CGI-I response analysis, baseline CGI-S score will be included in the model.   
Descriptive statistics for all scores, change from baseline values, and response variables will 
be presented by treatment and assessment time point.  Summaries will include n, mean, SD, 
median, minimum, and maximum.   
13.5.2. 
Safety Analysis 
Safety and tolerability of SAGE-547 Injection will be evaluated by AEs, concomitant 
medications, changes from baseline in physical examination, vital signs, CBC, serum 
chemistry, urinalysis, and 12-lead ECG.  Suicidality will be monitored by the C-SSRS.  In 
Part A only, sedation will be assessed using the Stanford Sleepiness Scale (SSS) and an 
analysis of SSS data will be performed comparing the treatment groups in the same way as 
for the primary endpoint.  Safety data will be listed by individual and summarized by 
treatment group.  All safety summaries will be performed on the Safety Population. 
Safety data will be examined for possible relationships between subject characteristics and 
plasma allopregnanolone concentrations, as appropriate. 
Scheduled visits for all safety assessments are described in Section 12 and summarized in 
Table 1. 
13.5.2.1. Adverse Events 
The analysis of AEs will be based on the concept of treatment-emergent AEs (TEAEs).  A 
TEAE is defined as an AE with onset after the start of study drug infusion, or any worsening 
of a pre-existing medical condition/AE with onset after the start of study drug infusion.  The 
incidence of TEAEs will be summarized overall and by MedDRA System Organ Class 
(SOC) and preferred term (PT).  Incidences will be presented in order of decreasing 
frequency.  In addition, summaries will be provided by severity (mild, moderate, severe) and 
by causality (related, not related) to study drug (see Section 14.2.2.1). 
TEAEs leading to discontinuation and SAEs (see Section 14.1.4 for definition) with onset 
after the start of randomized infusion will also be summarized. 


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All AEs and SAEs (including those with onset or worsening before the start of randomized 
infusion) through the Day 30 Follow-up Visit (±3 days) will be listed. 
13.5.2.2. Clinical laboratory evaluations 
Results will be listed by Subject ID and timing of collection.  Mean changes from baseline in 
clinical laboratory measures will be evaluated. 
13.5.2.3. Physical examinations 
Physical examinations will be evaluated at screening and Day 7.  Any clinically significant 
change in physical examination compared to those observed at screening should be noted as 
an AE.   
13.5.2.4. Vital signs 
Vital signs, including oral temperature (°C), respiratory rate, heart rate, and blood pressure 
(supine and standing) will be obtained at the scheduled time points described in 
Section 11.1.4.  Mean changes from baseline (pre-infusion) in vital signs will be evaluated.   
13.5.2.5. 12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, and 
QTc.  Any clinically significant abnormalities or changes in ECGs should be listed as an AE.  
ECG findings will be listed by subject and visit. 
13.5.2.6. Concomitant medications 
A summary of all concomitant medications taken during the course of the study will be 
presented in tabular form by therapeutic drug class and generic drug name using the WHO 
Collaborating Centre for Drug Statistics Methodology Norwegian Institute of Public Health 
(http://www.whocc.no). 
13.5.2.7. C-SSRS 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be listed for all subjects.  Listings will include behavior type and/or category for Suicidal 
Ideation and Suicidal Behavior of the C-SSRS. 
13.5.2.8. SSS (Part A only) 
Changes in score over time will be represented graphically, and change from baseline will be 
measured. 
13.5.2.9. PK Analysis 
Plasma will be collected to assay for concentrations of SAGE-547, metabolites of 
SAGE-547, and SBECD.  The following PK parameters will be derived from the plasma 
concentrations (where evaluable): AUC0-60, AUC∞, Cmax, time at maximum (peak) plasma 
concentration (tmax), steady-state drug concentration in the plasma during constant-rate 
infusion (Css), and average drug concentration in the plasma at steady state during a dosing 
interval (Cavg). 


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Plasma concentrations will be listed by subject and summarized by nominal collection time 
point.  PK parameters will be listed by subject and summarized by collection time point.  
Correlations between concentrations and AEs or tolerability measures may be performed as 
deemed necessary. 
In addition to typical descriptive statistics, summaries should include geometric mean, 
coefficient of variation, and geometric coefficient of variation. 
13.6. 
Determination of Sample Size 
Using a two-sided test at an alpha level of 0.05, a sample size of 10 evaluable subjects per 
group for Part A would provide 70% power to detect an effect size of 1.2 between the 
SAGE-547 and placebo groups with regard to the primary outcome variable of change from 
baseline in HAM-D total score.  An effect size of 1.2 corresponds to a placebo-adjusted 
difference of 12 points in the change from baseline in HAM-D total score at 60 hours with an 
assumed standard deviation of 10 points.  By including two treatment groups and using a 1:1 
randomization ratio, a total of 20 evaluable subjects are required for Part A.   
Based on the results of the interim analysis (Section 13.7), the sample size for Part A could 
be increased to a maximum of 32 randomized subjects.  This adjustment to the sample size 
would allow for an effect size of 1.0 to be detected.   
For Part B, a sample size of 40 evaluable subjects per group (120 total) would provide 90% 
power to detect a treatment difference of 9.0 between the SAGE-547 and placebo groups and 
a common standard deviation of 12 points (for an effect size of 0.75) using a two-sided t-test 
at an alpha level of 0.05.   
For Part C, a sample size of 50 evaluable subjects per group (100 total) would provide 90% 
power to detect a treatment difference of 8.0 between the SAGE-547 and placebo groups and 
a common standard deviation of 12 points (for an effect size of 0.667) using a two-sided 
t-test at an alpha level of 0.05.   
13.7. 
Interim Analysis 
In Part A, an interim analysis will be conducted by an independent statistician for sample size 
re-estimation purposes when at least 16 subjects have completed efficacy assessments 
through 60 hours in Part A.  Since the Sponsor will be kept uninformed of the response rates 
at the time of the interim analysis, no statistical adjustment will be made to the level of 
significance for hypothesis testing of Part A of the study.  A detailed description of the 
interim analysis for sample size re-estimation will be included in the SAP. 
No interim analyses are planned for Parts B and C of the study. 
13.8. 
Changes from Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the 
final SAP.   
Upon the completion of each study (547-PPD-202A, 547-PPD-202B, and 547-PPD-202C), 
the data will be unblinded and analyzed separately, and a separate final CSR will report the 
findings of each study.   


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14. 
ADVERSE EVENTS 
Section 14.1 lists important AE definitions. 
Section 14.2 summarizes Investigator responsibilities regarding the identification and 
documentation of AEs, the classification of AEs for relationship to study drug and severity, 
and the reporting of AE information to the Sponsor and the IRB/IEC. 
Section 14.3 summarizes Sponsor/Medical Monitor Responsibilities regarding monitoring of 
AE data and reporting relevant safety information to regulatory authorities. 
14.1. 
Adverse Event Definitions 
14.1.1. 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.   
14.1.2. 
Suspected Adverse Reaction  
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the AE.  Suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any AE caused by a 
drug. 
14.1.3. 
Life-Threatening  
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either 
the Investigator or Sponsor, its occurrence places the subject at immediate risk of death.  It 
does not include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death. 
14.1.4. 
Serious  
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
• Death 
• A life-threatening AE (see definition in Section 14.1.3) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability or incapacity  
• A congenital anomaly or birth defect 
• Other medically important condition (as described below)  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 


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one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
14.1.5. 
Unexpected  
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed.  
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the Investigator’s Brochure referred only to elevated hepatic enzymes or 
hepatitis.  Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the Investigator’s Brochure listed only cerebral vascular 
accidents.   
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the Investigator’s Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.   
In the clinical trial setting, the term “expected” would not mean “anticipated” for the 
condition being treated or population being studied since “expected” would indicate being 
“listed in the Investigator’s Brochure.”  For example, some AEs can be anticipated to occur 
as a result of a disease or condition or in a certain population (eg, cancer-related deaths in a 
cancer trial, strokes or acute myocardial infarctions in an older population).  However, for 
reporting purposes, these anticipated events are not considered “expected” if they are not 
listed in the Investigator’s Brochure (ie, the investigational drug is not suspected or known to 
cause them).  
14.2. 
Investigator Responsibilities 
14.2.1. 
Identification and Documentation of Adverse Events by Investigator 
Subjects will be evaluated and questioned generally (if possible) to identify AEs during the 
course of the study.  AEs will be collected during subject preparation, study drug 
administration during screening, after the initiation of study drug administration through to 
Day 3, and at the Follow-up Visits through Day 30 (±3 days).  SAEs will also be collected 
until the Day 30 (±3 days) follow-up visit.  Medical conditions that occur prior to completion 
of the screening visit will be captured on the Medical History eCRF.  Adverse events that 
occur after completion of the screening visit will be recorded on the AE page of the eCRF 
(AE eCRF).   
All AEs revealed by observation, physical examinations, other diagnostic procedures, or 
spontaneously reported by the subject and/or in response to an open question from study 
personnel will be recorded on the AE eCRF.  Any clinically significant deterioration from 
baseline in laboratory assessments or other clinical findings is considered an AE and must be 
recorded on the AE eCRF, unless otherwise stated.  AE information recorded on AE eCRF 
will be entered into the database on an ongoing basis.  The database, including AE 
information, will be transferred to the Sponsor on a pre-defined schedule for review.   


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All AEs, regardless of investigator-determined causality, should be followed until the event 
is resolved or the Investigator determines the event is stable or no longer clinically 
significant.   
For all SAEs, an SAE report form must be completed with as much information as possible 
and submitted in the time frame described in Section 14.2.3.  When new significant 
information is obtained as well as when the outcome of an event is known, the SAE report 
form should be updated on a follow-up report.  If the subject was an outpatient at the time of 
the SAE and was re-hospitalized due to the SAE, a copy of relevant hospital records 
(eg, admission report, laboratory test results, discharge summary) may be requested to be 
included as part of the subject’s medical file.   
All SAEs will be followed until the events are resolved or improved and a stable status has 
been achieved, or the subject is lost to follow-up.   
Female patients who become pregnant during the study should be followed to determine the 
outcome of the pregnancy.  The pregnancy must be reported to the sponsor within 24 hours 
of the site becoming aware of the pregnancy.  If the pregnancy ends for any reason before the 
anticipated date, the investigator should notify the sponsor.  At the completion of the 
pregnancy, the investigator will document the outcome of the pregnancy.  If the outcome of 
the pregnancy meets the criteria for immediate classification as an SAE (ie, postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the 
investigator should follow the procedures for reporting an SAE. 
14.2.2. 
Adverse Event Classification 
Definitions for the categories of AE classification are included in this section.   
14.2.2.1. Relationship to Investigational Drug 
Not Related:  
No relationship between the experience and the administration of study 
drug; related to other etiologies such as concomitant medications or 
subject’s clinical state. 
Possibly Related:  A reaction that follows a plausible temporal sequence from 
administration of the study drug and follows a known response pattern to 
the suspected study drug or 
The reaction might have been produced by the subject’s clinical state or 
other modes of therapy administered to the subject, but this is not known 
for sure.   
Probably Related:  A reaction that follows a plausible temporal sequence from 
administration of the study drug and follows a known response pattern to 
the suspected study drug.   
The reaction cannot be reasonably explained by the known 
characteristics of the subject’s clinical state or other modes of therapy 
administered to the subject  


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14.2.2.2. Severity 
The severity of an adverse experience will be defined as follows and reported as indicated on 
the AE eCRF: 
Mild: 
  
Discomfort noticed, but no disruption to daily activity.   
Moderate: 
Discomfort sufficient to reduce or affect normal daily activity, but is 
not hazardous to health; prescription drug therapy may be employed to 
treat the AE. 
Severe: 
Inability to work or perform normal daily activity and represented a 
definite hazard to health; prescription drug therapy and/or 
hospitalization may be employed to treat the AE. 
14.2.2.3. Action Taken with Investigational Drug 
Action taken with regard to administration of study drug for this study will be recorded using 
the one of following categories (the category “dose increased” does not apply to this study):  
• Drug withdrawn: An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication 
• Dose not changed: An indication that a medication schedule was maintained 
• Drug interrupted: An indication that a medication schedule was modified by 
temporarily terminating a prescribed regimen of medication 
• Dose reduced: An indication that a medication schedule was modified to a 
reduced rate/dose 
• Unknown: Unknown, not known, not observed, not recorded, or refused 
• Not applicable: Determination of a value is not relevant in the current context 
14.2.2.4. Assessment of Outcome 
Assessment of outcome of AEs will be categorized as one of the following:  
• Ongoing: At the end of the study, the event has not resolved or stabilized 
• Resolved: The event has resolved or the subject recovered without sequelae 
• Resolved with sequelae: The event has at least 1 secondary outcome that may 
result in permanent disability and/or functional limitation 
• Unknown: The status of the event is unknown 
• Death: The subject has expired 
14.2.3. 
Investigator Reporting to Sponsor and Sponsor Emergency Contact 
All SAEs that occur during the course of the study must be reported by the Investigator 
immediately, with the designated report form sent to the Medical Monitor within 24 hours 
from the point in time when the Investigator becomes aware of the SAE.  Investigators must 
report any SAE, whether or not considered drug related.  The initial report must be as 


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complete as possible, including assessment of the causal relationship (ie, assessment of 
whether there is a reasonable possibility that the drug caused the event).  The Medical 
Monitor will contact the investigator via telephone for follow-up information regarding the 
SAE, as appropriate. 
Information not available at the time of the initial report must be documented on a follow-up 
report.  As additional information becomes available, the designated report form must be 
updated and supporting information, including hospital records, laboratory and diagnostic 
testing results, etc.  All supporting documentation must be de-identified.  In addition, all 
SAEs that occur up to and including 30 days after administration of study drug must be 
reported within 24 hours from when the Investigator becomes aware of the SAE.  A final 
report to document resolution of all SAEs is required. 
In a medical emergency (ie, an event that requires immediate attention regarding the 
treatment of a subject, operation of the clinical study, and/or the use of investigational drug), 
study site staff will apply appropriate medical intervention according to current standards of 
care and contact the Medical Monitor. 
14.2.4. 
Medical Monitor and Emergency Contact Information 
 
, MD  
Office (9-5 EST): 
  
24/7 Hotline: 
  
 
14.2.5. 
SAE Reporting Contact Information 
Contact information and reporting instructions are provided in the Safety Management Plan. 
14.2.6. 
Reporting to Institutional Review Boards/Independent Ethics Committees 
It is the responsibility of the Investigator to promptly notify the institution’s IRB/IEC of all 
SAEs that occur at his or her site if applicable per the IRB’s/IEC’s requirements. 
14.3. 
Sponsor/Medical Monitor Responsibilities 
14.3.1. 
Monitoring of Adverse Event Data 
The Medical Monitor or designee will review SAEs/AEs on an ongoing basis. 
14.3.2. 
Reporting to Regulatory Authorities 
The Sponsor or its designee is responsible for SUSAR notification to the relevant regulatory 
authorities per applicable regulations.  All investigators participating in the study will also be 
informed as required by regulations in order to inform their IRBs/IECs.   


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In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to regulatory authorities as required by national 
laws. 
14.4. 
Emergency Identification of Study Medication 
In exceptional circumstances and for the safety of the study subject, the Investigator may 
request unblinding of an individual subject’s treatment from the Medical Monitor.  The 
Investigator will not unblind the Medical Monitor during that discussion.  The process of 
unblinding will be described in the Safety Management Plan for the study.   


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15. 
STUDY ADMINISTRATION 
15.1. 
Quality Control and Quality Assurance 
The Investigators and institutions will permit study-related monitoring, audits, IRB review, 
and regulatory inspections as requested by regulatory authorities, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs, etc.) in 
addition to CRFs. 
Quality assurance and quality control systems with written standard operating procedures 
(SOPs) will be followed to ensure that this study will be conducted and data will be 
generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements.   
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals 
during the study.  The monitoring visits must be conducted according to the applicable ICH 
and GCP guidelines to ensure protocol adherence, quality of data, drug accountability, 
compliance with regulatory requirements, and continued adequacy of the investigational site 
and its facilities.  During these visits, CRFs and other data related to the study will be 
reviewed and any discrepancies or omissions will be identified and resolved.  The study 
monitor will be given access to study-relevant source documents (including medical records) 
for purposes of source data verification. 
During and/or after completion of the study, quality assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits.  The 
Investigator is expected to cooperate with any audit and provide assistance and 
documentation (including source data) as requested.   
Quality control will be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties 
involved with the clinical study will be in writing in a separate agreement. 
15.2. 
Data Handling and Recordkeeping 
15.2.1. 
Data Handling 
Procedures for data handling (including electronic data) used in this protocol will be 
documented in a Data Management Plan.   
15.2.2. 
Case Report Form Completion 
Electronic CRFs (eCRFs) will be completed for each study subject.  It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
subject’s eCRF.  Source documentation supporting the eCRF data should indicate the 
subject’s participation in the study and should document the dates and details of study 
procedures, AEs, and subject status. 


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The Investigator will have access to the electronic data capture (EDC) system and will 
receive a copy of the subject eCRF data at the end of the study.  For subjects who discontinue 
or terminate from the study, the eCRFs will be completed as much as possible, and the reason 
for the discontinuation or termination clearly and concisely specified on the appropriate 
eCRF. 
15.2.3. 
Retention of Study Records 
The Investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirements.  Records will be retained for at least two years after the last 
marketing application approval and until there are no pending or contemplated marketing 
applications or two years after formal discontinuation of the clinical development of the 
investigational product or according to applicable regulatory requirements.  If the 
Investigator withdraws from the responsibility of keeping the study records, custody must be 
transferred to an appropriate person willing to accept the responsibility.  The Sponsor must 
be notified in writing if a custodial change occurs.   
15.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the subject by the assigned subject number.  The Investigator 
will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authority(ies) access to the subject’s original medical records for verification of data gathered 
on the CRFs and to audit the data collection process.  The subject’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable 
laws and regulations. 
Subjects will be notified that registration information, results, and other information about 
this study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used. 
All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information.  The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent 
from the Sponsor.  It is understood that there is an obligation to provide the Sponsor with 
complete data obtained during the study.  The information obtained from the clinical study 
will be used towards the development of the investigational product and may be disclosed to 
regulatory authority(ies), other Investigators, corporate partners, or consultants as required. 
15.4. 
Publication Policy 
All information concerning SAGE-547 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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15.5. 
Protocol Amendments 
Changes to the conduct of the study should be prepared as a protocol amendment by the 
Sponsor.  Protocol amendments should receive written IRB/IEC approval prior to 
implementation at the investigative site, except when necessary to eliminate immediate 
hazards to the subjects or when the changes involve only logistical or administrative aspects 
of the study (eg, change of monitor, telephone numbers).  In this case, Sage Therapeutics will 
amend and implement the protocol change and subsequently notify the regulatory authorities 
and the Investigative sites who will notify the respective IRB/IEC, as appropriate. 


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16. 
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Edge D.  Ethnicity, psychosocial risk, and perinatal depression-a comparative study among 
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depression: prevalence, screening accuracy, and screening outcomes.  Evid Rep Technol 
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precursors during pregnancy and the postpartum period.  Gynecol Endocrinol 2005 21, 268-
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Genazzani AR, Petraglia F, Bernardi F, Casarosa E, Salvestroni C, Tonetti A, et al.  
Circulating levels of allopregnanolone in humans: gender, age, and endocrine influences.  J 
Clin Endocrinol Metab 1998;83(6):2099-103.  PubMed PMID: 9626145. 
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[Article in Chinese].  PMID: 15553820. 


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Holzbauer M, Birmingham MK, De Nicola AF, Oliver JT.  In vivo secretion of 3 alpha-
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PubMed PMID: 19268499. 
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episodic memory in healthy women.  Psychopharmacology (Berl) 2008;199(2):161-8.  
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A Meta-Analysis of Data Submitted to the Food and Drug Administration.  PLoS Med 2008; 
5(2): e45.  PMID: 18303940. 
Klak J, Hill M, Parízek A, Havlíková H, et al.  Pregnanolone isomers, pregnenolone and their 
polar conjugates around parturition. Physiol Res 2003;52(2):211-21.  PMID: 12678664. 
Licinio J, Wong ML.  The role of inflammatory mediators in the biology of major 
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Nappi RE, Petraglia F, Luisi S et al.  Serum allopregnanolone in women with postpartum 
“blues”.  Obstet Gynecol 2001;97 (1):77-80.  PMID: 11152912. 


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Navarro PA, Kaddouz D, de Ziegler D, Silva de Sá MF, Ferriani RA.  Vaginal administration 
of allopregnanolone to postmenopausal women undergoing estrogen replacement therapy: 
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Paoletti AM, Romagnino S, Contu R, et al.  Observational study on the stability of the 
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Spitzer RL, Kroenke K, Williams JBW, Löwe B.  A Brief Measure for Assessing 
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Timby E, Balgård M, Nyberg S, Spigset O, Andersson A, Porankiewicz-Asplund J, et al.  
Pharmacokinetic and behavioral effects of allopregnanolone in healthy women.  
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Timby E, Hedström H, Bäckström T, Sundström-Poromaa I, Nyberg S, Bixo M.  
Allopregnanolone, a GABAA receptor agonist, decreases gonadotropin levels in women A 
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Timby E.  Allopregnanolone effects in women.  Clinical studies in relation to the menstrual 
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van Broekhoven F, Bäckström T, van Luijtelaar G, Buitelaar JK, Smits P, Verkes RJ.  Effects 
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Ware JE, Kosinski M, Bjorner JB, Turner-Bowker DM, Gandek B, Maruish ME. User’s 
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APPENDICES 
Copies of the rating scales and questionnaires included in Appendix 1 through Appendix 10 
are for reference only. 
 
 
 


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Appendix 1. 
COLUMBIA SUICIDE SEVERITY RATING SCALE 
(C-SSRS) 
The “Baseline/Screening” and “Since Last Visit” versions of the C-SSRS begin on the next 
full page (Posner 2011). 
 
 


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Appendix 2. 
HAMILTON RATING SCALE FOR DEPRESSION, 
17-ITEM (HAM-D) 
The HAM-D presents on the next full page (Hamilton 1960). 
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  Item 
16 can be rated according to history (item 16A) or actual weight change (item 16B).  The 
item 16 score is calculated as the item 16 response that is not equal to 3 (ie, “Not assessed). 
 
 


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Appendix 3. 
MONTGOMERY ASBERG DEPRESSION RATING 
SCALE (MADRS) 
The MADRS, presented on the next full page, includes the following 10 symptoms: 
1. Apparent sadness 
2. Reported sadness 
3. Inner tension 
4. Reduced sleep 
5. Reduced appetite 
6. Concentration difficulties 
7. Lassitude 
8. Inability to feel 
9. Pessimistic thoughts 
10. Suicidal thoughts 
 
 


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Appendix 4. 
CLINICAL GLOBAL IMPRESSION–IMPROVEMENT 
SCALE (CGI-I) AND SEVERITY SCALE (CGI-S) 
The CGI-I and CGI-S present on the next full page.  For the purposes of 
Protocol 547-PPD-202, only Items 1 and 2, Severity of Illness and Global Improvement, will 
be assessed in subjects enrolled in the study. 
 


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Appendix 5. 
EDINBURGH POSTNATAL DEPRESSION SCALE 
(EPDS) 
The EPDS presents on the next full page (Cox 1987). 
 


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Appendix 6. 
GENERALIZED ANXIETY DISORDER 7-ITEM 
SCALE (GAD-7) 
The GAD-7 presents on the next full page (Spitzer 2006). 
 
 


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SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
APPENDIX 7. PATIENT HEALTH QUESTIONNAIRE (PHQ-9) 
The PHQ-9 presents on the next full page. 
Developed by Drs. Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke, and colleagues with an 
educational grant from Pfizer Inc.  No permission required to reproduce, translate, display or 
distribute. 
 
 
 


 
 
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SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
 
 
 
 


 
 
Protocol 547-PPD-202 Amendment 3 
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SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
APPENDIX 8. BARKIN INDEX OF MATERNAL FUNCTIONING (BIMF) 
The BIMF is presented on the next full page. 
 
 


 
 
Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
 
 
 


 
 
Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
APPENDIX 9. SHORT FORM-36 (ONE WEEK RECALL)  
 
 
Your Health and Well-Being 
 
 
This survey asks for your views about your health.  This information will help 
keep track of how you feel and how well you are able to do your usual activities. 
Thank you for completing this survey! 
 
For each of the following questions, please mark an 
 in the one box that best 
describes your answer. 
 
1. In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
2. Compared to one week ago, how would you rate your health in general 
now? 
Much better 
now than one 
week ago 
Somewhat 
better  
now than one 
week ago 
About the 
same as one 
week ago 
Somewhat 
worse  
now than one 
week ago 
Much worse 
now than one 
week ago 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
3. The following questions are about activities you might do during a 
typical day.  Does your health now limit you in these activities?  If so, 
how much?  
 
 
 
Yes,  
limited  
a lot 
Yes, 
limited  
a little 
No, not 
limited  
at all 
 
   
a Vigorous activities, such as running, lifting  
heavy objects, participating in strenuous sports ...................... 
 1 ............. 
 2 ............. 
 3 
b Moderate activities, such as moving a table, pushing  
a vacuum cleaner, bowling, or playing golf............................. 
 1 ............. 
 2 ............. 
 3 
c Lifting or carrying groceries .................................................... 
 1 ............. 
 2 ............. 
 3 
d Climbing several flights of stairs ............................................. 
 1 ............. 
 2 ............. 
 3 
e Climbing one flight of stairs .................................................... 
 1 ............. 
 2 ............. 
 3 
f Bending, kneeling, or stooping ................................................ 
 1 ............. 
 2 ............. 
 3 
g Walking more than a mile ........................................................ 
 1 ............. 
 2 ............. 
 3 
h Walking several hundred yards ............................................... 
 1 ............. 
 2 ............. 
 3 
i Walking one hundred yards ..................................................... 
 1 ............. 
 2 ............. 
 3 
j Bathing or dressing yourself .................................................... 
 1 ............. 
 2 ............. 
 3 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
4. During the past week, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health? 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of  
the time 
None of 
the time 
     
a Cut down on the amount of  
time you spent on work or  
other activities .................................. 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
b Accomplished less than you  
would like ........................................ 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
c Were limited in the kind of  
work or other activities .................... 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
d Had difficulty performing the  
work or other activities (for  
example, it took extra effort) ........... 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
 
 
5. During the past week, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or 
anxious)? 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of  
the time 
None of 
the time 
     
a Cut down on the amount of  
time you spent on work or  
other activities .................................. 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
b Accomplished less than you  
would like ........................................ 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 
c Did work or other activities  
less carefully than usual ................... 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
 5 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
6. During the past week, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
 
 
 
7. How much bodily pain have you had during the past week? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very severe 
      
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
  
 6 
 
 
 
 
 
8. During the past week, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
9. These questions are about how you feel and how things have been with 
you during the past week.  For each question, please give the one 
answer that comes closest to the way you have been feeling.  How much 
of the time during the past week… 
 
 
10. During the past week, how much of the time has your physical health 
or emotional problems interfered with your social activities (like 
visiting with friends, relatives, etc.)? 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of  
the time 
None of 
the time 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of  
the time 
None of 
the time 
     
a Did you feel full of life? ..................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
b Have you been very nervous? ..........
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
c Have you felt so down in the  
dumps that nothing could  
cheer you up? ...................................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
d Have you felt calm and  
peaceful? ..........................................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
e Did you have a lot of energy? ..........
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
f Have you felt downhearted   
and depressed? .................................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
g Did you feel worn out? ....................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
h Have you been happy? .....................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
i Did you feel tired? ...........................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
11. How TRUE or FALSE is each of the following statements for you? 
Definitely 
true 
Mostly  
true 
Don’t  
know 
Mostly  
false 
Definitely 
false 




a I seem to get sick a little 
easier than other people .................. 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
b I am as healthy as  
anybody I know .............................. 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
c I expect my health to  
get worse ......................................... 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
d My health is excellent ..................... 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
 
 
 
 
 
 
 
Thank you for completing these questions! 
 
 
 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
Appendix 10. 
HEALTH RESOURCE UTILIZATION 
QUESTIONNAIRE 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
 
 
 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
 
 
 


Protocol 547-PPD-202 Amendment 3 
31 January 2017 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
 
 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
1 
 
Summary of Changes Page 
Protocol 547-PPD-202 
Date 02 February 2017 
The following changes were made to the attached protocol in this amendment.  In addition, minor revisions to formatting, punctuation, 
spelling, and wording (eg, capitalization, abbreviation, word order) that are not listed below were made throughout the protocol.  
Where relevant, the term “SAGE-547” was replaced with “study drug” and “trial” was replaced with “study.” 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Title Page 
Title Page 
 
EUDRA CT NUMBER: 
2016-5137-68 
Added the Eudra CT number 
Title Page and synopsis 
Title Page and synopsis 
Clinical Phase: 2a 
Clinical Phase: 2a3 
Changed clinical phase from 
2a to 3 
Title Page 
Title Page 
Sponsor contact: 
 
, MD, MBA 
(with phone and email) 
Sponsor contact: Helen 
Colquhoun, M.D. 
(with phone and email) 
Changed the sponsor contact 
name, phone, and email 
address 
Title Page 
Title Page 
 
Added 
, M.D, 
FAAP as Medical Monitor 
(with title, address, phone, 
and email) 
Added 
 as the 
sponsor’s Medical Monitor 
Title Page 
Title Page 
Date of Amendment 2:  
30 June 2016 
Date of Amendment 2:  
30 June 2016 
Date of Amendment 3: 
02 February 2017 
Added the date of 
Amendment 3 to the Title 
Page 
Signature Page 
Signature Page 
 
IND No.:  122,279 
Eudra CT No.:  
2016-005137-68 
Added the IND number, 
Eudra CT number, study 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
2 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Study Phase: 3 
Sponsor: Sage Therapeutics 
phase, and sponsor 
Signature Page 
Signature Page 
Sponsor Approval: 
, MD, PhD 
, PhD 
, MPH 
 
(with titles) 
Sponsor Approval: 
Helen Colquhoun, M.D. 
, M.P.H. 
 
 Ph.D. 
(with titles) 
Updated the sponsor approval 
signatories 
Section 2, Synopsis, Study 
Sites 
Section 2, Synopsis, Study 
Sites 
Up to 50 sites in the United 
States and Canada 
Up to 50100 global sites in 
the United States and Canada 
Increased the number of 
study sites and specified that 
the study would be conducted 
globally 
Section 2, Synopsis, Duration 
of Subject Participation 
Section 2, Synopsis, Duration 
of Subject Participation 
Up to 35 days 
Duration of Subject 
Participation: Up to 3537 
days 
Revised the total duration of 
subject participation from 35 
days to 37 days 
Section 2, Synopsis, 
Secondary Objectives 
and 
Section 6.2, Secondary 
Objectives 
Section 2, Synopsis, 
Secondary Objectives 
and 
Section 6.2, Secondary 
Objectives 
• 
To determine if SAGE-
547 Injection infused 
intravenously for 60 hours 
reduces depressive symptoms 
in subjects with moderate 
PPD compared to placebo 
injection as assessed by the 
change from baseline in 
HAM-D total score (applies 
to Part C only). 
• 
To determine if SAGE-
547 Injection infused 
intravenously at up to 90 
μg/kg/h for 60 hours reduces 
depressive symptoms in 
subjects with moderate PPD 
compared to placebo injection 
as assessed by the change 
from baseline in HAM-D 
total score (applies to Part C 
only). 
Specified the dose to be used 
in Part C 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
3 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Section 2, Synopsis, 
Secondary Objectives 
and 
Section 2, Synopsis, Schedule 
of Events (Table 1) 
and 
Section 6.2, Secondary 
Objectives 
and 
Section 12.2.1 
 
To determine if SAGE-547 
Injection infused 
intravenously for 60 hours 
increases sedation levels 
compared to placebo injection 
as assessed by the changes 
from baseline in Stanford 
Sleepiness Scale (SSS) score 
 
• 
Completion of the SSS 
prior to dosing and at Hours 
2, 4, 8, 12, 18, and 24 on Day 
1 (±15 minutes) unless the 
subject is asleep between the 
hours of 23.00h and 06.00h 
each day 
To determine if SAGE-547 
Injection infused 
intravenously for 60 hours 
increases sedation levels 
compared to placebo injection 
as assessed by the changes 
from baseline in Stanford 
Sleepiness Scale (SSS) score 
 
• 
Completion of the SSS 
prior to dosing and at Hours 
2, 4, 8, 12, 18, and 24 on Day 
1 (±15 minutes) unless the 
subject is asleep between the 
hours of 23.00h and 06.00h 
each day 
Deleted evaluation of 
sedation using the SSS score 
as a secondary objective and 
removed it from the Schedule 
of Events and from study 
procedures to be performed 
(Note: the SSS will be 
collected and analyzed during 
Part A only.) 
Section 2, Synopsis, 
Exploratory Objectives 
and 
Section 6.3, Exploratory 
Objectives 
Section 2, Synopsis, Other 
Objectives 
and Section 6.3, Other 
Objectives 
Section 2, Synopsis, 
Exploratory Objectives 
and  
Section 6.3, Exploratory 
Objectives 
Section 2, Synopsis, Other 
Objectives 
and 
Section 6.3, Other Objectives 
Revised Exploratory 
Objectives to be Other 
Objectives 
Section 2, Synopsis, 
Exploratory Objectives 
and 
Section 6.3, Exploratory 
Objectives 
Section 2, Synopsis, Other 
Objectives 
and 
Section 6.3, Other Objectives 
 
Added: 
• 
To determine if SAGE-
547 Injection infused 
intravenously for 60 hours 
improves the general health 
status compared to placebo 
Added the SF-36 as a 
measure of general health 
status 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
4 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
as assessed by the change 
from baseline in the Short 
Form-36 (SF-36) total score 
at Day 7 and Day 30. 
Section 2, Synopsis, 
Pharmacokinetic Objective 
and 
Section 6.4, Pharmacokinetic 
Objective 
Section 2, Synopsis, 
Pharmacokinetic Objective 
and 
Section 6.4, Pharmacokinetic 
Objective 
To assess the 
pharmacokinetic (PK) profile 
of SAGE-547, metabolites of 
SAGE-547, and betadex 
sulfobutyl ether sodium 
(SBECD) and the 
concentration of SAGE-547 
in breast milk when possible. 
To assess the 
pharmacokinetic (PK) profile 
of SAGE-547, metabolites of 
SAGE-547, and betadex 
sulfobutyl ether sodium 
(SBECD) and the 
concentration of SAGE-547 
in breast milk when possible. 
Removed the assessment of 
the concentration of SAGE-
547 in breast milk from the 
PK Objective 
Section 2, Synopsis, Study 
Design and Methodology 
Section 2, Synopsis, Study 
Design and Methodology 
This protocol comprises three 
multicenter, randomized, 
double-blind, parallel-group, 
placebo controlled studies of 
the efficacy, safety, and PK 
of SAGE 547 Injection in 
adult female subjects 
diagnosed with severe or 
moderate PPD.  Subjects 
must remain as inpatients 
during the study Treatment 
Period,. . . 
Added: 
This protocol comprises three 
multicenter, randomized, 
double-blind, parallel-group, 
placebo controlled studies of 
the efficacy, safety, and PK 
of SAGE 547 Injection in 
adult female subjects 
diagnosed with severe or 
moderate PPD.  Each study 
will be independently 
conducted, analyzed, and 
reported.  In this protocol, 
Study 547-PPD-202A is 
hereafter referred to as 
Part A; Study 547-PPD-
Added text to clarify that 
Parts A, B and C refer to 3 
separate studies and that each 
study will be conducted, 
analyzed and reported 
separately.  


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
5 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
202B is hereafter referred 
to as Part B; and Study 547 
PPD-202C is hereafter 
referred to as Part C.  In 
Parts A and C, subjects will 
be randomized to one of two 
treatment groups (SAGE-
547 90 µg/kg/hour or 
placebo) on a 1:1 basis.  In 
Part B, subjects will be 
randomized to one of three 
treatment groups (SAGE-
547 60 µg/kg/hour, SAGE-
547 90 µg/kg/hour, or 
placebo) on a 1:1:1 basis.  
Subjects must remain as 
inpatients during the study 
Treatment Period,. . . 
Section 2, Synopsis, Study 
Design and Methodology 
Section 2, Synopsis, Study 
Design and Methodology 
Subjects in the placebo group 
will receive infusion rates 
equivalent to SAGE-547 
90 µg/kg/hour 
Placebo subjects will receive 
infusion rates equivalent to 
SAGE-547 90 µg/kg/hour 
Made a minor wording 
revision 
Section 2, Synopsis, Study 
Design and Methodology 
and 
Section 7.1, Overview of 
Study Design 
and 
Section 2, Synopsis, Study 
Design and Methodology  
and 
Section 7.1, Overview of 
Study Design 
and 
. . .the study Treatment 
Period, which is 
approximately 60 hours/2.5 
days in duration 
. . .the study Treatment 
Period, which is 
approximately 6072 
hours/2.53 days in duration 
(60 hours of treatment and 
an additional 12 hours for 
Revised wording to include 
the 72-hour assessments in 
the Treatment Period and 
changed 2.5 days to 3 days 
throughout the protocol 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
6 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
relevant sections throughout 
the protocol 
relevant sections throughout 
the protocol 
completion of 72-hour 
assessments) 
Section 2, Synopsis, Study 
Design and Methodology 
Section 2, Synopsis, Study 
Design and Methodology 
A full medical and family 
history will be taken 
including recording of all 
depression, other Axis 1 and 
Axis 2 disorders and 
postpartum depression 
episodes in primary probands 
(who may be subject to a 
SCID-I interview). 
A full medical and family 
history will be taken from 
the subject including 
recording of all depression, 
other Axis 1I and Axis 2II 
disorders and postpartum 
depression episodes in 
primary probands (who may 
be subject to a SCID-I 
interview). 
Removed the potential 
SCID-I interview of primary 
probands with depression, 
other Axis 2 disorders and 
PPD episodes 
Section 2, Synopsis, Study 
Design and Methodology, 
Treatment Period 
Section 2, Synopsis, Study 
Design and Methodology, 
Treatment Period 
. . .a new bag and line hung 
every 24 hours 
. . .a new bag and line hung at 
least every 24 hours 
Clarified the time at which a 
new bag would be hung 
Section 2, Synopsis, Study 
Design and Methodology, 
Treatment Period 
Section 2, Synopsis, Study 
Design and Methodology, 
Treatment Period 
Infusion rates will increase 
and then taper, with subjects 
receiving 30 µg/kg/hour (0-4 
hours), then 60 µg/kg/hour 
(4-24 hours), then 90 
µg/kg/hour (24 52 hours), 
followed by 60 µg/kg/hour 
(52-56 hours), and 30 
µg/kg/hour (56-60 hours).  
Subjects in the placebo group 
will receive infusion rates 
equivalent to SAGE-547 90 
Infusion rates will increase 
and then taper, with subjects 
in the SAGE-547 group 
receiving 30 µg/kg/hour (0-4 
hours), then 60 µg/kg/hour 
(4-24 hours), then 90 
µg/kg/hour (24 52 hours), 
followed by 60 µg/kg/hour 
(52-56 hours), and 30 
µg/kg/hour (56-60 hours).  
Subjects in the placebo 
groupPlacebo subjects will 
Clarified the infusion rates 
for the blinded study drug. 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
7 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
µg/kg/hour 
receive infusion rates 
equivalent to SAGE-547 
90 µg/kg/hour.   
Section 2, Synopsis, Study 
Design and Methodology, 
Follow-up Period 
Section 2, Synopsis, Study 
Design and Methodology, 
Follow-up Period 
For all parts, Follow-up Visits 
will be conducted one week 
(7±1 day) and one month 
(30±3d) after the initiation of 
the study drug infusion. 
For Part A, Follow-up 
Visits will be conducted one 
week (7±1 day), 
approximately two weeks 
(12±2 days), and one month 
(30±3 days) after the 
initiation of the study drug 
infusion.  For Parts B and 
C, Follow-up Visits will be 
conducted one week (7±1 
day), two weeks (14±2 
days), three weeks (21±3 
days), and one month (30±3 
days) after the initiation of 
the study drug infusion.  
The blind will be 
maintained through the 
Follow-up period. 
Added in the specific follow-
up visits for Parts A, B, and 
C; clarified the blind would 
be maintained through the 
Follow-up period. 
Section 2, Synopsis, Number 
of Subjects 
Section 2, Synopsis, Number 
of Subjects 
Up to 32 subjects will be 
randomized in Part A, up to 
60 subjects will be 
randomized in Part B, and up 
to 36 subjects in Part C. 
Up to 32 subjects will be 
randomized in Part A, up to 
60120 subjects will be 
randomized in Part B, and up 
to 36100 subjects will be 
randomized in Part C. 
Increased the number of 
subjects to the randomized 
into Part B and Part C 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
8 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Section 2, Synopsis, Inclusion 
Criteria, Number 8 
and  
Section 8.1, Inclusion 
Criteria, Number 8 
Section 2, Synopsis, Inclusion 
Criteria, Number 8 
and 
Section 8.1, Inclusion 
Criteria, Number 8 
8. For Part A and B, subject 
has a HAM-D total score of 
≥26 at screening and Day 1 
(prior to randomization).  For 
Part C, subject has a HAM-D 
total score of ≥20 and ≤25 at 
screening and Day 1 (prior to 
randomization) 
8. For Part A and B, subject 
has a HAM-D total score of 
≥26 at screening and Day 1 
(prior to dosing).  For Part C, 
subject has a HAM-D total 
score of ≥20 and ≤25 at 
screening and Day 1 (prior to 
dosing) 
Since sites could randomize 
subjects 24 hours in advance 
of dosing, wording was 
changed from prior to 
randomization to prior to 
dosing. 
Section 2, Synopsis, Inclusion 
Criteria, Number 9 
and  
Section 8.1, Inclusion 
Criteria, Number 9 
Section 2, Synopsis, Inclusion 
Criteria, Number 9 
and 
Section 8.1, Inclusion 
Criteria, Number 9 
9. Subject is ≤6 months 
postpartum  
9. Subject is ≤6 months 
postpartum at screening 
Specified that the subject was 
≤6 months postpartum at 
screening  
Section 2, Synopsis, Inclusion 
Criteria, Number 10 
and  
Section 8.1, Inclusion 
Criteria, Number 10 
Section 2, Synopsis, Inclusion 
Criteria, Number 10 
and 
Section 8.1, Inclusion 
Criteria, Number 10 
10. Subject is willing to 
delay the start of other 
antidepressant or anxiety 
mediations and any new 
pharmacotherapy regimens, 
including prn benzodiazepine 
anxiolytics, until the study 
drug infusion and 72-hour 
assessments have been 
completed 
10. Subject is willing at 
screening to delay the start 
of other antidepressant or 
anxiety mediations and any 
new pharmacotherapy 
regimens, including prn 
benzodiazepine anxiolytics 
antidepressant or anti-
anxiety medication, until the 
study drug infusion and 72-
hour assessments have been 
completed; if the subject is 
taking psychotropic 
medications, these must be 
at a stable dose from 14 
Clarified the timing of prior 
use of psychotropic 
medications and that dose 
must have been stable and 
remain stable throughout the 
study. 


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Sage Therapeutics 
Version 4 02 February 2017 
9 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
days prior to screening until 
the 72-hour assessments 
have been completed 
Section 2, Synopsis, Inclusion 
Criteria, Number 11 
and  
Table 1, Schedule of Events 
and 
Section 8.1, Inclusion 
Criteria, Number 11 
and Section 12.1 Screening 
Period 
Section 2, Synopsis, Inclusion 
Criteria, Number 11 
 
Subject has no detectable 
hepatitis B surface antigen 
(HbsAg), anti-hepatitis C 
virus (HCV) and human 
immunodeficiency virus 
(HIV) antibody at Screening 
 
• 
Blood will be collected 
to screen for hepatitis and 
HIV (at screening) 
(Removed) 
Subject has no detectable 
hepatitis B surface antigen 
(HbsAg), anti-hepatitis C 
virus (HCV) and human 
immunodeficiency virus 
(HIV) antibody at Screening 
• 
Blood will be collected 
to screen for hepatitis and 
HIV (at screening) 
Virology was not considered 
relevant at Screening; deleted 
Inclusion 11 and removed 
hepatitis and HIV screen 
from the schedule of events 
and screening visit 
procedures  
Section 2, Synopsis, 
Exclusion Criteria, Number 1 
and  
Section 8.2, Exclusion 
Criteria, Number 1 
Section 2, Synopsis, 
Exclusion Criteria, Number 1 
and  
Section 8.2, Exclusion 
Criteria, Number 1 
Recent history or active 
clinically significant 
manifestations of metabolic, 
hepatic, renal, hematological, 
pulmonary, cardiovascular, 
gastrointestinal, 
musculoskeletal, 
dermatological, urogenital, 
neurological, or eyes, ears, or 
nose and throat disorders, or 
any other acute or chronic 
condition that, in the 
Investigator’s opinion, would 
limit the subject’s ability to 
complete or participate in this 
Subject has renal failure 
requiring dialysis or 
fulminant hepatic failure or 
is anemic (hemoglobin 
≤10 g/dL) 
Specified renal failure or 
anemia as exclusion criteria. 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
10 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
clinical study. 
Section 2, Synopsis, 
Exclusion Criteria, Number 5 
and 
Section 8.2, Exclusion 
Criteria, Number 5 
Section 2, Synopsis, 
Exclusion Criteria, Number 5 
and 
Section 8.2, Exclusion 
Criteria, Number 5 
Medical history of seizures 
(Removed) 
Deleted history of seizures as 
an exclusion criterion 
Section 2, Synopsis, 
Exclusion Criteria, Number 7 
and 
Section 8.2, Exclusion 
Criteria, Number 7 
Section 2, Synopsis, 
Exclusion Criteria, Number 7 
and 
Section 8.2, Exclusion 
Criteria, Number 7 
7. History of active 
alcoholism or drug addiction 
(including benzodiazepines) 
in the 12 months prior to 
screening. 
7. History of active 
alcoholism or drug addiction 
abuse (including 
benzodiazepines) in the 12 
months prior to screening.  A 
positive urine drug screen 
(except benzodiazepines 
under certain 
circumstances [see Section 
10.3.3 and Section 11.1.2.6]) 
is exclusionary. 
Clarified that use of 
benzodiazepines wasn’t 
necessarily exclusionary; 
however, positive drug screen 
for any other drugs of abuse 
was exclusionary. 
Section 2, Synopsis, 
Exclusion Criteria, Number 9 
and 
Section 8.2, Exclusion 
Criteria, Number 9 
Section 2, Synopsis, 
Exclusion Criteria, Number 9 
and 
Section 8.2, Exclusion 
Criteria, Number 9 
9. Administration of 
psychotropics that have been 
initiated within 14 days prior 
to Screening and are not 
being taken at a stable dose. 
(Removed) 
9. Administration of 
psychotropics that have been 
initiated within 14 days prior 
to Screening and are not 
being taken at a stable dose. 
Deleted this exclusion 
criterion 
 
Section 2, Synopsis, 
Exclusion Criteria, Number 
10 
 
Added: 
10. Subject has previously 
participated in this study or 
Added an exclusion criterion 
to exclude subjects who had 
participated in any study of 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
11 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
and 
Section 8.2, Exclusion 
Criteria, Number 10 
any other study employing 
SAGE-547 
SAGE-547 
Section 2, Synopsis, 
Exclusion Criteria, Number 9 
and 
Section 8.2, Exclusion 
Criteria, Number 9 
Section 2, Synopsis, 
Exclusion Criteria, Number 
11 
and 
Section 8.2, Exclusion 
Criteria, Number 11 
9. Administration of 
psychotropics that have been 
initiated within 14 days prior 
to Screening and are not 
being taken at a stable dose 
9. Administration of 
psychotropics that have been 
initiated within 14 days prior 
to Screening and are not 
being taken at a stable dose 
9.11. 
11. Administration 
of electroconvulsive therapy 
(ECT) within 14 days prior 
to screening and/or plans to 
administer ECT before the 
Study Day 7 Visit 
Added an exclusion criterion 
to exclude subjects who 
received ECT within 14 days 
of screening through the 
Day 7 visit 
Section 2, Synopsis, 
Randomization and Stopping 
Rules 
and  
Section 7.2, Blinding and 
Randomization 
Section 2, Synopsis, 
Randomization  
and  
Section 7.2, Blinding and 
Randomization 
Subjects will be randomized 
to receive SAGE-547 
Injection or placebo; 
Removed:  
Stopping Rules  
Added: 
Randomization will be 
stratified by antidepressant 
use at baseline and will 
follow the computer-
generated randomization 
schedule.  Subjects will be 
randomized within stratum 
to receive SAGE-547 
Injection or placebo; 
Removed Stopping Rules 
from the heading since no 
stopping rules were 
discussed; added that 
randomized would be 
stratified by antidepressant 
use at baseline according to 
the randomization schedule 
Section 2, Synopsis, Criteria 
Section 2, Synopsis, Criteria 
For Part B, the primary 
For Part B, the primary 
Removed the statement that 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
12 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
for Evaluation, Primary 
Endpoint 
for Evaluation, Primary 
Endpoint 
comparison will be between 
90 µg SAGE-547 and placebo 
at the 60-hour assessment; if 
this comparison is significant 
at the 0.05 level, then the 60 
µg group will be compared to 
placebo at the same 0.05 level 
of significance; otherwise, the 
comparison will be carried 
out at the 0.025 level of 
significance.   
comparison will be between 
90 µg SAGE-547 and placebo 
at the 60-hour assessment; if 
this comparison is significant 
at the 0.05 level, then the 60 
µg group will be compared to 
placebo at the same 0.054 
level of significance More 
details will be provided in 
Statistical Analysis Plans 
(SAPs) regarding strong 
control of overall level of 
significance for multiple 
testing, including testing of 
key secondary endpoints.   
the level of significance for 
the 60 µg and placebo 
comparison would be 0.025 if 
the comparison between the 
90 µg and placebo group was 
not significant; clarified that 
details regarding the level of 
significance for multiple 
testing would be provided in 
the SAPS. 
Section 2, Synopsis, Criteria 
for Evaluation, Secondary 
Endpoints 
Section 2, Synopsis, Criteria 
for Evaluation, Secondary 
Endpoints 
All secondary endpoints 
apply to Parts A, B and C 
unless otherwise stated. 
Additional measures of 
depressive symptom severity 
will be administered before, 
during, and after the infusion 
of study drug. . . 
GAD-7 will also be 
administered before, during, 
and after the infusion of study 
drug.  As with other 
secondary efficacy endpoints,  
All secondary endpoints 
apply to Parts A, B and C 
unless otherwise stated. 
Additional measures of 
depressive symptom severity 
will be administered before, 
during, and after the infusion 
of study drug. . . 
GAD-7 will also be 
administered before, during, 
and after the infusion of study 
drug.  As with other 
secondary efficacy endpoints 
Removed statements that 
questionnaires would be 
administered before, during 
and after the study drug 
infusion 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
13 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
and 
Section 2, Synopsis, Criteria 
for Evaluation, Sample Size 
Calculation 
and 
Section 13.6, Determination 
of Sample Size 
Section 2, Synopsis, Criteria 
for Evaluation, Sample Size 
Calculation 
and 
Section 13.6, Determination 
of Sample Size 
Assuming a two-sided t-test 
at an alpha level of 0.05, a 
sample size of 10 evaluable 
subjects per group would 
provide 70% power. . . 
For Part B, a sample size of 
40 evaluable subjects per 
group (120 total) would 
provide 90% power to detect 
an effect size of 0.9 between 
the SAGE-547 and placebo 
groups and a common 
standard deviation of 12 
points using a two-sided t-test 
at an alpha level of 0.05.   
For Part C, a sample size of 
50 evaluable subjects per 
group (100 total) would 
provide 90% power to detect 
an effect size of 0.8 between 
the SAGE-547 and placebo 
groups and a common 
standard deviation of 12 
points using a two-sided t-test 
at an alpha level of 0.05. 
Assuming Using a two-sided 
t-test at an alpha level of 
0.05, a sample size of 10 
evaluable subjects per group 
for Part A would provide 
70% power. . . 
For Part B, a sample size of 
40 evaluable subjects per 
group (120 total) would 
provide 90% power to detect  
a treatment difference of an 
effect size of 0.9.0 between 
the SAGE-547 and placebo 
groups and a common 
standard deviation of 12 
points (for an effect size of 
0.75) using a two-sided t-test 
at an alpha level of 0.05.   
For Part C, a sample size of 
50 evaluable subjects per 
group (100 total) would 
provide 90% power to detect 
a treatment difference of an 
effect size of 0.8.0 between 
the SAGE-547 and placebo 
groups and a common 
standard deviation of 12 
Revised the treatment 
difference and effect size 
between the SAGE-547 and 
placebo groups for the sample 
size determination 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
14 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
points (for an effect size of 
0.667) using a two-sided t-
test at an alpha level of 0.05. 
Section 2, Synopsis, Efficacy 
Analysis 
and 
Section 13.4, Primary 
Endpoints 
Section 2, Synopsis, Efficacy 
Analysis 
and 
Section 13.4, Primary 
Endpoints 
Center will be treated as a 
random effect while all other 
explanatory variables will be 
treated as fixed effects. 
Comparisons at other time 
points will be conducted to 
support the findings for the 
primary comparison. 
Center and all other 
explanatory variables will 
be treated as fixed effects.   
Comparisons at other time 
points, including the Day 30 
time point, will be conducted 
to support the findings for the 
primary comparison.   
If this dose comparison is 
significant at the 0.05 level, 
then the 60 µg group will be 
compared to placebo at the 
same 0.05 level of 
significance; otherwise 
comparison of the 60 µg dose 
will be carried out at the 
0.025 level of significance. 
More details will be 
provided in the SAPs 
regarding strong control of 
overall level of significance 
for multiple testing, 
including testing of key 
secondary endpoints.    
Revised center to be treated 
as a fixed effect (rather than a 
random effect); clarified the 
statistical analysis; stated that 
details of the analyses would 
be provided in the SAPs for 
the 3 studies 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
15 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Section 2, Synopsis, Efficacy 
Analysis 
Section 13.5.1, Efficacy 
Analysis 
 
If this dose comparison is 
significant at the 0.05 level, 
then the 60 µg group will be 
compared to placebo. 
Any dichotomous response 
variables will be analyzed 
using logistic regression 
methods. 
For efficacy analysis 
purposes, centers with 
fewer than 15 subjects for 
Part B or 10 subjects for 
Part C per center will be 
pooled within regions (eg, 
North America region 
centers will be pooled 
separately those in Europe). 
If this dose comparison is 
significant at the 0.05 level, 
then the 60 µg group will be 
compared to placebo at the 
0.04 level. 
Logistic regression GEE 
analysis methods will be 
used for the analysis of the 
following response variables: 
Described pooling within 
region for centers with fewer 
than 15 subjects in Part B or 
10 subjects in Part C; inserted 
the significance level for the 
comparison between 60 µg 
and placebo; replaced logistic 
regression methods with GEE 
analysis methods 
Section 2, Synopsis, Schedule 
of Events (Table 1) 
Section 2, Synopsis, Schedule 
of Events (Table 1) 
Screening period, Day -5 to 
Day -1 
Follow-up Period, Day 12 
(+1d) 
Screening period, Day -5-7 to 
Day -1 
Follow-up Period, Day 1214 
(+12d) 
Day 21 (+3d) 
Added footnote “a” to 
Day-7, Day 14, and Day 21:  
The screening period for 
Part A is from Day -5 to 
Revised timing of screening 
period; revised timing of 
follow-up visits to be weekly; 
added a Day 21 visit; added a 
footnote to indicate the 
different days for screening 
and follow-up visits for Part 
A 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
16 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Day -1.  Follow-up Visits for 
Part A are on Days 7, 12, 
and 30. 
Section 2, Synopsis, Schedule 
of Events (Table 1) 
and  
Section 12.2.1, Day 1 
and  
Section 12.2.2, Day 2 
and 
Section 12.2.3, Day 3 
Section 2, Synopsis, Schedule 
of Events (Table 1) 
Pulse Oximetry 
• 
Pulse oximetry will be 
monitored continuously (from 
H0 until H60), and checked 
approximately every 2 hours, 
including during the 
overnight hours, or at the 
alarm 
Pulse Oximetry 
• 
Pulse oximetry will be 
monitored continuously (from 
H0 until H60), and checked 
approximately every 2 hours, 
including during the 
overnight hours, or at the 
alarm 
Removed pulse oximetry 
assessments 
Section 2, Synopsis, Schedule 
of Events (Table 1) 
Section 2, Synopsis, Schedule 
of Events (Table 1) 
 
Added SCID-I at screening 
and collection of HCRU at 
screening and throughout 
study and defined SCID-I and 
HCRU in footnote to table 
SCID-I was used at screening 
to confirm eligibility for 
inclusion in the study 
HCRU was included. 
Section 2, Synopsis, Schedule 
of Events (Table 1) 
and 
Section 12, Study Procedures 
Section 2, Synopsis, Schedule 
of Events (Table 1)  
and 
Section 12, Study Procedures 
 
Added SF-36 at Day 1, 
Day 7, Day 14, Day 21, and 
Day 30 to Schedule of Events 
(Table 1) and defined SF-36 
in footnote to table 
Added SF-36 to study 
procedures specified for Days 
1, 7, 14, 21, and 30. 
Added the SF-36 to the 
exploratory endpoints to 
measure general health status 
at Day 1, Day 7, and Day 30. 
Table of Contents, 12.3 
Table of Contents, 12.3 
Follow-up Period (Day 7 
through Day 60) 
Follow-up Period (Day 7 
through Day 6030) 
Corrected the Follow-up 
Period to be through Day 30 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
17 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
List of Abbreviations and 
Definitions of Terms 
List of Abbreviations and 
Definitions of Terms 
 
Added SF-36 (Short Form-
36), HCRU (Healthcare 
Resource Utilization), MCS 
(mental component 
summary), and PCS (physical 
component summary) 
Deleted abbreviations and 
definitions for BMP, CYP, 
FDA, HCV, HIV, and SSS 
Added the definitions for the 
abbreviation, SF-36, HCRU, 
MCS, and PCS,  and deleted 
abbreviations that are no 
longer used in the protocol 
Section 4.3, Summary of 
Nonclinical and Clinical 
Experience with 
Allopregnanolone or 
SAGE-547 
Section 4.3, Summary of 
Nonclinical and Clinical 
Experience with 
Allopregnanolone or 
SAGE-547 
Summary of Nonclinical and 
Clinical Experience with 
Allopregnanolone or 
SAGE-547 
Summary of Nonclinical and 
Clinical Experience with 
Allopregnanolone or 
SAGE-547 
Removed mention of 
allopregnanolone from the 
title of the heading 
Section 4.3.2, Clinical 
Experience 
Section 4.3.2, Clinical 
Experience 
The clinical PK data with 
intravenous (IV) 
administration of 
allopregnanolone in healthy 
women, men, and women on 
oral contraceptives confirmed 
the PK observations in 
animals of a short half-life 
(t½ 20-40 mins), Cmax 
achievable at approximately 
third trimester levels. . . 
There are currently no 
double-blind, placebo-
The clinical PK data with 
intravenous (IV) 
administration of 
allopregnanolone in healthy 
women, men, and women on 
oral contraceptives confirmed 
the PK observations in 
animals of a short half-life 
(t½ 20-40 mins), Cmax 
achievable at approximately 
third trimester levels . . . 
There are currently no 
double-blind, placebo-
Removed statement about 
half-life in animals 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
18 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
controlled clinical efficacy 
data for SAGE-547 in PPD. 
controlled clinical efficacy 
data for SAGE-547 in PPD. 
Section 4.4, Potential Risks 
and Benefits 
Section 4.4, Potential Risks 
and Benefits 
In the recently completed 
open-label clinical study of 
SAGE-547 in PPD (547-
PPD-201), a total of 14 AEs 
were reported in four 
subjects.   
 
As this is one of the first 
clinical trials of SAGE 547 in 
PPD, the potential benefits in 
this population are unknown, 
although the risks are likely 
to be similar to those 
mentioned above.  Given the 
nonclinical rationale and the 
fact that endogenous 
allopregnanolone in humans 
appears to play a role in 
psychiatric disorders such as 
major depression, 
premenstrual dysphoric 
disorder, and anxiety 
disorders, it is possible that 
subjects may have a clinical 
benefit at the exposures 
selected for this trial.  In view 
In the recently completed 
open-label clinical study of 
SAGE-547 in PPD (547-
PPD-201), a total of 14 AEs 
were reported in four 
subjects.   
In the recently completed 
547-PPD-202A, there were 
no SAEs or discontinuations 
due to AEs.  Out of 10 
subjects who received 
SAGE-547, four reported 
AEs, and of 11 subjects who 
received placebo, eight 
reported AEs (Table 2).  
Three subjects in each 
treatment group reported 
dizziness, sedation or 
somnolence.  Psychiatric 
disorder AEs, including 
abnormal dreams, insomnia 
and anxiety, were all 
reported in the group that 
received placebo.  Three 
subjects in the placebo 
group and one in the 
SAGE-547 group reported 
Revised the text on potential 
risks and benefits to include 
AE data from 547-PPD-202A 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
19 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
of the limited nature of the 
demonstrated risks of 
exogenous allopregnanolone 
infusion and the potential for 
benefit in severe PPD, there 
is a favorable benefit-risk 
evaluation for the conduct of 
the present study. 
 
nausea.  Other AEs 
reported by more than one 
subject were infusion site 
pain and headache, all 
reported on placebo.  One 
subject did not tolerate 60 
μg/kg/hour due to sedation, 
thought to be associated 
with concomitant 
administration of a high 
dose of benzodiazepine, so 
the dose was reduced to 30 
μg/kg/hour from 12 to 24 
hours.  The subject received 
60 µg/kg/hour from 24 to 30 
hours and 30 µg/kg/hour 
from 30 to 60 hours and 
completed the study. 
[inserted an AE table] 
As this is one of the first 
clinical trials of SAGE 547 in 
PPD, the potential benefits in 
this population are unknown, 
although the risks are likely 
to be similar to those 
mentioned above.  Given the 
nonclinical rationale and the 
fact that endogenous 
allopregnanolone in humans 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
20 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
appears to play a role in 
psychiatric disorders such as 
major depression, 
premenstrual dysphoric 
disorder, and anxiety 
disorders, it is possible that 
subjects may have a clinical 
benefit at the exposures 
selected for this trial. 
In 547-PPD-202A, the 
primary endpoint of the 
mean change from baseline 
in HAM-D total score at 60 
hours compared with 
placebo [LS mean 
treatment difference of 
12.2] was highly significant 
(p=0.008).  In addition, the 
significant separation 
between the active and 
placebo groups was evident 
at 24 hours, and remained 
so at subsequent time points 
through 72 hours, 7 days, 
and 30 days after initiation 
of treatment.   
In view of the limited nature 
of the demonstrated risks of 
exogenous allopregnanolone 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
21 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
infusion and the potential for 
benefit in severe PPD, there 
is a favorable benefit-risk 
evaluation for the continued 
conduct of the present study. 
Section 5.1, Institutional 
Review Board or Independent 
Ethics Committee 
Section 5.1, Institutional 
Review Board or Independent 
Ethics Committee 
This trial will be initiated 
only after the protocol has 
been reviewed and approved 
by the Institutional Review 
Board (IRB) where the study 
is to be conducted.  The IRB 
must meet all US Food and 
Drug Administration (FDA) 
requirements governing IRBs 
(Code of Federal Regulations 
[CFR], Title 21, Part 56).  
The same applies for the 
implementation of changes 
introduced by an amendment. 
The final study protocol, 
including the final version 
of the ICF, must be 
approved or given a 
favorable opinion in writing 
by an Institutional Review 
Board (IRB) or 
Independent Ethics 
Committee (IEC) as 
appropriate.  The 
Investigator must submit 
written approval to Sage 
Therapeutics or designee 
before he or she can enroll 
any subject into the study.   
The Principal Investigator 
is responsible for informing 
the IRB or IEC of any 
amendment to the protocol 
in accordance with local 
requirements.  In addition, 
the IRB or IEC must 
approve all advertising used 
to recruit subjects for the 
Clarified that IRB/IEC 
written approval was required 
before a subject could be 
enrolled into the study, that 
the PI was to inform the 
IRB/IEC of any amendments 
to the protocol, which would 
require re-approval, and that 
the IRB/IEC was to approve 
all advertising used to recruit 
subjects. 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
22 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
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 or 
designee will provide this 
information to the Principal 
Investigator.   
Progress reports and 
notifications of serious 
adverse drug reactions will 
be provided to the IRB or 
IEC according to local 
regulations and guidelines.   
Section 7.1, Overview of 
Study Design 
Section 7.1, Overview of 
Study Design 
Figure 1: Study Design – 
Part A and Part C 
Figure 2: Study Design – 
Part B 
Figure 1: Study Design – 
Part A  
Figure 2: Study Design – 
Part B 
Revised the study design 
diagrams to show the 
different follow-up time 
points for Part A and Parts B 
and C 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
23 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Figure 2: Study Design – 
Part C 
[revised the study design 
figures for Parts B and C] 
Section 7.1, Overview of 
Study Design 
Section 7.1, Overview of 
Study Design 
All study-related procedures 
will occur after written 
informed consent is obtained 
at the screening visit, which 
will occur during the 
Screening Period window 
(Day -7 through Day  1).   
Subjects will attend the clinic 
for safety follow-up 
assessment at 1 week (7±1d) 
and 1 month (30±3d) after the 
initiation of the study drug 
infusion. 
All study-related procedures 
will occur after written 
informed consent is obtained 
at the screening visit, which 
will occur during the 
Screening Period window 
(Day -5 through Day -1 for 
Part A; Day -7 through 
Day -1 for Parts B and C). 
Subjects will attend the clinic 
for safety follow-up 
assessment at 1 week (7±1d), 
12 days (Part A), 2 weeks 
(14±2d [Part B and C]), 3 
weeks (21±1d [Part B and 
C]), and 1 month (30±3d) 
after the initiation of the 
study drug infusion. 
Clarified the timing of the 
screening period window and 
the follow-up visits for Part A 
and Parts B and C 
Section 10.1, Dosing 
Schedule 
Section 10.1, Dosing 
Schedule 
Subjects will be randomized 
to receive 60 hours of IV 
treatment with either SAGE-
547 Injection or placebo. 
Subjects will be randomized 
to receive 60 hours of IV 
treatment with either SAGE-
547 Injection or placebo, 
according to a computer-
Added that subjects were 
randomized to a treatment 
group according to a 
computer-generated 
randomization schedule. 


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Version 4 02 February 2017 
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Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
generated randomization 
schedule. 
Section 10.1, Dosing 
Schedule, Figure 3 and 
Figure 4 
Section 10.1, Dosing 
Schedule, Figure 3, Figure 4, 
and Figure 5 
Figure 3: Trial Design and 
Timeline for Dosing – Parts 
A and C 
Figure 4: Trial Design and 
Timeline for Dosing – Part B 
Figure 3: Trial Design and 
Timeline for Dosing – 
Part A  
Figure 4: Trial Design and 
Timeline for Dosing – 
Part B 
Figure 5: Trial Design and 
Timeline for Dosing – 
Part C 
[Figures 4 and 5 were 
revised to indicate follow-up 
on Days 14 and 21; a 
footnote was added to 
Figure 5 to indicate that the 
4-hour taper on Day 3 
applied only to the 
90 µg/kg/h dose group] 
 
Section 10.3, Concomitant 
Medications and Restrictions 
Section 10.3, Prior 
Medications, Concomitant 
Medications, and Restrictions 
Section 10.3, Concomitant 
Medications and Restrictions 
Section 10.3, Prior 
Medications, Concomitant 
Medications, and Restrictions 
Added prior medications to 
section heading 
Section 10.3.1, Concomitant 
Medications 
Section 10.3.1, Prior 
Medications 
No text was provided relating 
to prior medications 
The start and end dates, route, 
dose/units, and frequency of 
all medications taken within 
60 days prior to signing the 
Added information regarding 
use of prior medications 


Protocol 547-PPD-202 
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Version 4 02 February 2017 
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Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
informed consent will be 
recorded, as well as all 
medications given to treat 
the current PPD episode 
that are recorded on the 
SCID-I during the 
screening visit.   
Section 10.3.1, Concomitant 
Medications 
Section 10.3.2, Concomitant 
Medications 
Subjects will receive standard 
of care for adult female 
patients diagnosed with PPD.  
Any concomitant medication 
determined necessary for the 
welfare of the subject may be 
given at the discretion of the 
Investigator at any time 
during the study under the 
guidance outlined in Section 
10.3.  All concomitant 
medications should be 
documented throughout the 
study from Screening through 
Day 30 (±3 days) and 
recorded on the eCRF.  Prior 
medications (ie, those taken 
prior to signing of informed 
consent) that required wash-
out for study entry will also 
be documented. 
All medications taken from 
signing the informed 
consent through the Day 30 
(±3 days) visit will be 
recorded on the eCRF.  
Subjects will receive standard 
of care for adult female 
patients diagnosed with PPD.  
Any concomitant medication 
determined necessary for the 
welfare of the subject may be 
given at the discretion of the 
Investigator at any time 
during the study under the 
guidance outlined in Section 
10.3.  All concomitant 
medications should be 
documented throughout the 
study from Screening through 
Day 30 (±3 days) and 
recorded on the eCRF.  Prior 
medications (ie, those taken 
Clarified the timeframe for 
collecting use of concomitant 
medications. 


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Version 4 02 February 2017 
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Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
prior to signing of informed 
consent) that required wash-
out for study entry will also 
be documented. 
Section 10.3.2, Prohibited 
Medications 
and 
Appendix 10, Selected 
Inducers, Inhibitors, and 
Substrates of CYP2C9 
Section 10.3.3, Prohibited 
Medications 
• 
Initiation of new 
antidepressant therapy is 
prohibited upon admission to 
the study center for those 
eligible subjects who desire 
study participation.  Those 
subjects already taking an 
antidepressant at the time of 
study entry (and meeting all 
study inclusion criteria) will 
be permitted to remain on the 
pre-existing antidepressant at 
their current dose if they were 
on this medication for at least 
30 days prior to study 
enrollment. 
• 
Benzodiazepines are to 
be avoided as much as 
possible.  Eligible subjects 
taking a benzodiazepine at 
the time of study entry will be 
permitted to continue to take 
their current dose of the 
benzodiazepine (to prevent 
acute withdrawal), but no 
• 
Initiation of new 
antidepressant therapy is 
prohibited upon admission to 
the study center for those 
eligible subjects who desire 
study participation.  Those 
subjects already taking an 
antidepressant at the time of 
study entry (and meeting all 
study inclusion criteria) will 
be permitted to remain on the 
pre-existing antidepressant at 
their current dose if they were 
on this medication for at least 
30 days prior to study 
enrollment. 
• 
Subjects may not start 
new pharmacotherapy 
regimens, including 
antidepressant or anti-
anxiety medications, from 
the time of informed 
consent until the study drug 
infusion and 72-hour 
assessments have been 
Revised the medications that 
are prohibited during the 
study; deleted the text 
relating to substrates of 
CYP2C9; deleted the 
Appendix that listed the 
prohibited inducers, 
inhibitors, and substrates of 
CYP2C9  


Protocol 547-PPD-202 
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Version 4 02 February 2017 
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Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
new benzodiazepine use will 
be permitted during the 
course of the study.  
Particular attention should be 
paid to assessment of AEs 
and implementation of the 
dose interruption and 
reduction scheme in subjects 
on concomitant 
benzodiazepines since they 
have been shown to have a 
supra-additive effect with 
pregnanolone in an animal 
model of anesthesia (Norberg 
1999). 
• 
The use of hypnotics for 
sleep/insomnia such as 
Ambien® and trazodone are 
to be avoided. 
• 
Anticonvulsants and 
atypical antipsychotics are to 
be avoided if possible and are 
not to be initiated at any time 
during active treatment period 
(60 hours).  However, if a 
subject is taking one of these 
medications for at least 30 
days prior to study admission, 
they will be permitted to 
completed.  If clinically 
indicated, new 
antidepressant medications 
may be started or existing 
antidepressant medication 
regimens may be changed 
once the 72-hour 
assessments have been 
completed.  Consideration 
should also be given to 
deferring, starting, or 
changing antidepressant 
medication regimens until 
the Day 7, Day 14, Day 21, 
or Day 30 visits if the HAM-
D score has improved.   
• 
If the subject is taking 
psychotropic medications, 
these must be at a stable 
dose from 14 days prior to 
screening to completion of 
the 72-hour assessments.   
• 
Benzodiazepines are to 
be avoided as much as 
possible owing to the 
potential for a synergistic 
sedative effect.  Eligible 
subjects taking a 
benzodiazepine at the time of 


Protocol 547-PPD-202 
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Version 4 02 February 2017 
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Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
remain on this medication, at 
their current dose (no dose 
adjustments are allowed). 
• 
SAGE-547 has 
demonstrated inhibitory 
effects on cytochrome P-450 
(CYP) 2C9 (CYP2C9).  The 
following medications are 
primarily metabolized by 
CYP2C9 and therefore are 
prohibited during SAGE-547 
administration: fluconazole 
and miconazole (antifungal), 
amentoflavone (constituent of 
Ginkgo biloba and St. John’s 
Wort), sulfaphenazole 
(antibacterial), valproic acid 
(anticonvulsant, mood-
stabilizing), and apigenin.  
See Appendix 10 for a 
complete list. 
study entry will be permitted 
to continue to take their 
current dose of the 
benzodiazepine (to prevent 
acute withdrawal), but no 
new benzodiazepine use will 
be permitted during the 
course of the study.  
Particular attention should be 
paid to assessment of AEs 
and implementation of the 
dose interruption and 
reduction scheme in subjects 
on concomitant 
benzodiazepines since they 
have been shown to have a 
supra-additive effect with 
pregnanolone in an animal 
model of anesthesia (Norberg 
1999).  
• 
The use of hypnotics for 
sleep/insomnia such as 
Ambien® and trazodone are 
to be avoided. 
• 
Anticonvulsants and 
atypical antipsychotics are to 
be avoided if possible and are 
not to be initiated at any time 
during active treatment period 


Protocol 547-PPD-202 
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Version 4 02 February 2017 
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Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
(60 hours).  However, if a 
subject is taking one of these 
medications for at least 30 
days prior to study admission, 
they will be permitted to 
remain on this medication, at 
their current dose (no dose 
adjustments are allowed). 
• 
SAGE-547 has 
demonstrated inhibitory 
effects on cytochrome P-450 
(CYP) 2C9 (CYP2C9).  The 
following medications are 
primarily metabolized by 
CYP2C9 and therefore are 
prohibited during SAGE-547 
administration: fluconazole 
and miconazole (antifungal), 
amentoflavone (constituent of 
Ginkgo biloba and St. John’s 
Wort), sulfaphenazole 
(antibacterial), valproic acid 
(anticonvulsant, mood-
stabilizing), and apigenin.  
See Appendix 10 for a 
complete list. 
 
Section 10.3.4, Restrictions 
 
Added:   
Section 10.3.4, Restrictions 
• 
Electroconvulsive 
 


Protocol 547-PPD-202 
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Version 4 02 February 2017 
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Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
therapy (ECT) is prohibited 
from 14 days prior to 
screening until after the 
Day 7 visit. 
Section 11.1.2.6, Drug of 
Abuse and Alcohol 
Section 11.1.2.6, Drug of 
Abuse and Alcohol 
Alcohol will be assessed in 
plasma at screening and via 
breathalyzer or urine dipstick 
on Day 1. 
A positive urine drug screen 
for any of the tested drugs 
of abuse (except 
benzodiazepines) is 
exclusionary.  Alcohol will 
be assessed in plasma at 
screening and via 
breathalyzer or urine dipstick 
on Day 1. 
Clarified that positive drug 
screen for any tested drug of 
abuse was exclusionary 
except benzodiazepines under 
the specified circumstances. 
Section 11.2.3, Exploratory 
Patient Reported Outcome 
Measures 
Section 11.2.3, Patient 
Reported Outcome Measures 
These will be measured by 
the following clinician- and 
subject-rated outcome 
measures: EPDS, PHQ-9, and 
BIMF. 
These will be measured by 
the following clinician- and 
subject-rated outcome 
measures: EPDS, PHQ-9, 
BIMF, and SF-36. 
Added the SF-36 to the other 
endpoints to measure general 
health status 
(No Section 11.2.3.4) 
Section 11.2.3.4, Short Form-
36 (SF-36) 
 
11.2.3.4  Short Form-36 
(SF-36) 
The Medical Outcomes 
Study Short Form-36 (SF-
36v2) is a 36-item measure 
of health status that has 
undergone validation in 
many different disease 
states (Ware 2007).  The 
Added a description of the 
SF-36 and included a copy in 
Appendix 10 


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Version 4 02 February 2017 
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Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
SF-36 covers eight health 
dimensions including four 
physical health status 
domains (physical 
functioning, role 
participation with physical 
health problems [role-
physical], bodily pain, and 
general health) and four 
mental health status 
domains (vitality, social 
functioning, role 
participation with 
emotional health problems 
[role-emotional], and 
mental health).  In addition, 
two summary scores, 
physical component 
summary (PCS) and mental 
component summary 
(MCS), are produced by 
taking a weighted linear 
combination of the eight 
individual domains.  The 
SF-36v2 is available with 
two recall periods: the 
standard recall period is 4 
weeks and the acute recall 
period is one week.  This 
study will use the acute 


Protocol 547-PPD-202 
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Version 4 02 February 2017 
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Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
version, which asks patients 
to respond to questions as 
they pertain to the past 
week.  Higher SF-36 scores 
indicate a better state of 
health.  The SF-36 requires 
approximately 10 minutes 
to complete, and can be self-
administered or completed 
by interview in person or by 
telephone. 
A copy of the SF-36 is 
provided in Appendix 10. 
(No Section 11.2.3.5) 
Section 11.2.3.5, Healthcare 
Resource Utilization (HCRU) 
and  
Appendix 10 
 
Subject-reported healthcare 
resource utilization data, 
including baseline diagnosis 
history, baseline 
antidepressant treatment 
history, and healthcare 
visits, inpatient visits, and 
medication use, will be 
collected at screening and 
on Day 30 of follow-up (or 
at early termination).  A 
copy of the health resource 
utilization questionnaire is 
provided in Appendix 10. 
Added collection of HCRU 
data and inserted the form to 
be used into Appendix 10 


Protocol 547-PPD-202 
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Version 4 02 February 2017 
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Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Section 11.3.1, Plasma PK 
Samples 
 
Section 11.3.1, Plasma PK 
Samples 
Section 11.3.1, Plasma PK 
Samples 
Deleted the section 
subheading since Section 
11.3.2 was deleted 
Section 11.3.2, Breastmilk 
PK Samples 
 
Women who are actively 
lactating at Screening, and 
who otherwise fulfill all of 
the inclusion and exclusion 
criteria for the study, will be 
asked if they will consent to 
pumping.  Breastmilk will be 
collected and pooled at pre-
defined intervals.  The times 
of the first and last pumping 
of each collection period will 
be recorded.  Breastmilk will 
be pooled within each 
collection period and the total 
volume will be measured.  
Detailed instructions for 
breastmilk PK sampling, 
processing methods, storage 
and shipping will be provided 
in the study PK Manual.  
After Study Day 12, women 
may resume giving 
breastmilk to their infant, per 
Inclusion Criteria 5. 
Women who are actively 
lactating at Screening, and 
who otherwise fulfill all of 
the inclusion and exclusion 
criteria for the study, will be 
asked if they will consent to 
pumping.  Breastmilk will be 
collected and pooled at pre-
defined intervals.  The times 
of the first and last pumping 
of each collection period will 
be recorded.  Breastmilk will 
be pooled within each 
collection period and the total 
volume will be measured.  
Detailed instructions for 
breastmilk PK sampling, 
processing methods, storage 
and shipping will be provided 
in the study PK Manual.  
After Study Day 12, women 
may resume giving 
breastmilk to their infant, per 
Inclusion Criteria 5. 
 


Protocol 547-PPD-202 
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Version 4 02 February 2017 
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Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Section 12, Study Procedures 
Subjects who are evaluated at 
the Day 3 visit of the 
Treatment Period (ie, all Hour 
60 assessments are 
completed, post-infusion) and 
complete the Day 30 (±3 
days) visit during the Follow-
up Period will be defined as 
study completers.   
Section 12, Study Procedures 
Subjects who are evaluated at 
the Day 3 visit of the 
Treatment Period (ie, all Hour 
60 complete the assessments 
are completed, post-infusion) 
at Hour 60 and complete the 
Day 30 (±3 days) visit during 
the Follow-up Period will be 
defined as study completers.   
Clarified the definition of 
study completers 
Section 12.1, Screening 
Period 
Section 12.1, Screening 
Period 
The Screening Period consists 
of a window from Day -5 
through Day -1 prior to 
starting SAGE 547 treatment.   
The Screening Period consists 
of a window from Day -57 
through Day -1 prior to 
starting SAGE 547 treatment 
(up to 5 days [Day -5 to -1; 
Part A] or up to 7 days 
[Day -7 to -1; Parts B and 
C]).   
Clarified the timing of the 
window for the Screening 
Period for Parts A, B, and C. 
Section 12.1, Screening 
Period 
Section 12.1, Screening 
Period 
A full medical and family 
history will be taken 
including recording of all 
depression, other Axis 1 and 
Axis 2 disorders and 
postpartum depression 
episodes in primary probands 
(who may be subject to a 
SCID-I interview). 
A full medical and family 
history will be taken from 
the subject using a SCID-I 
interview, including 
recording of all depression 
(major depressive 
disorders, premenstrual 
dysphoric disorder, 
menstrual migraine, and 
other psychiatric disorders 
per DSM), other Axis I and 
Removed the potential 
SCID-I interview of primary 
probands with depression, 
other Axis II disorders and 
PPD episodes and, instead, 
collected family history for 
primary probands from the 
subject. 


Protocol 547-PPD-202 
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Version 4 02 February 2017 
35 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Axis II disorders, and 
pregnancy history including 
birth complications, and 
postpartum depression 
episodes.  Family history 
will be collected from the 
subject for primary 
probands (who may be 
subject to a SCID-I 
interview), including all 
depression (major 
depressive disorders, 
premenstrual dysphoric 
disorder, menstrual 
migraine, and other 
psychiatric disorders per 
DSM), other Axis I 
disorders, and postpartum 
depression episodes. 
Section 12.1, Screening 
Period 
Section 12.1, Screening 
Period 
• 
Written informed 
consent, with optional 
provision for breast milk 
collection (see Section 5.3 for 
more information)  
• 
Written informed consent 
will be obtained 
• 
Lactation status (ie, 
subject is breastfeeding, 
subject is lactating but not 
breastfeeding, or subject is 
not lactating) will be 
recorded 
Removed the requirement for 
recording informed consent 
for optional breast milk 
collection since breast milk 
was not to be collected. 
Added recording of lactation 
status 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
36 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Section 12.2, Treatment 
Period (Day 1 to Day 3, 
Hours 0-60) 
Section 12.2, Study Drug 
Treatment Period (Day 1 to 
Day 3, Hours 0-72) 
 
Psychiatric follow-up 
outside the study visits will 
be arranged and 
documented, as 
appropriate. 
Added text regarding 
psychiatric follow-up outside 
the study visits 
Section 12.2.1, Day 1 
and 
Section 12.2.2, Day 2 
and 
Section 12.2.3, Day 3 
Section 12.2.1, Day 1 
and 
Section 12.2.2, Day 2 
and 
Section 12.2.3, Day 3 
and 
Section 12.3.1 
 
• 
Breast milk will be 
pumped and discarded by 
subjects who are lactating 
• 
Subjects who are 
lactating will pump and 
discard breast milk and be 
reminded that they must 
continue to pump and 
discard breast milk through 
Day 12 of the study 
Removed collection of breast 
milk as an optional study 
procedure; subjects who were 
lactating were instructed to 
pump and discard breast milk 
through Day 12 of the study 
Section 12.3, Follow-up 
Period (Day 7 through Day 
60 
Section 12.3, Follow-up 
Period (Day 7 through Day 
30 
Section 12.3, Follow-up 
Period (Day 7 through 
Day 60 
Section 12.3, Follow-up 
Period (Day 7 through 
Day 6030 
Corrected the Follow-up 
Period to be through Day 30 
Section 12.3.2, Day 12 
Section 12.3.2, Day 14 (±2 
days) and Day 21 (±3 days) 
(Parts B and C) 
• 
A blood sample for PK 
analysis will be collected at 
the time of the visit  
• 
Per subject consent 
(optional), collection of 
breast milk on the day of the 
visit 
• 
AEs will be monitored 
 
A blood sample for PK 
analysis will be collected at 
the time of the visit  
• 
Per subject consent 
(optional), collection of 
breast milk on the day of the 
visit 
• 
The C-SSRS, HAM-D, 
Removed the visit at Day 12 
and added visits at Days 14 
and 21 for Parts B and C of 
the study; removed the PK 
blood sample and optional 
breast milk sample 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
37 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
• 
Concomitant medications 
will be recorded 
This visit is only applicable to 
those patients who have 
temporarily ceased 
breastfeeding and are 
participating in the optional 
breast milk sampling 
MADRS, CGI-I, EPDS, 
GAD-7, PHQ-9, SF-36, and 
BIMF will be completed 
• 
AEs will be monitored 
• 
Concomitant medications 
will be recorded 
This visit is only applicable to 
those patients who have 
temporarily ceased 
breastfeeding and are 
participating in the optional 
breast milk sampling 
 
Section 12.3.3, Day 30 
• 
Vital signs 
• 
Completion of the C-
SSRS, HAMD, MADRS, 
CGI-I, EPDS, GAD-7, PHQ-
9, and BIMF 
• 
Vital signs 
• 
Completion of the The 
C-SSRS, HAM-D, MADRS, 
CGI-I, EPDS, GAD-7, PHQ-
9, SF-36, and BIMF will be 
completed 
Removed collection of vital 
signs and added the SF-36 
Section 13, Statistical 
Methods and Considerations 
Section 13, Statistical 
Methods and Considerations 
A statistical analysis plan 
(SAP) will be generated and 
approved by a representative 
of Sage Therapeutics prior to 
database lock.   
 
Separate summaries will be 
produced for each part of the 
A separate statistical analysis 
plan (SAP) will be generated 
for each study (Parts A, B, 
and C) and approved by a 
representative of Sage 
Therapeutics prior to the 
respective database lock of 
each study.   
Clarified that, prior to the 
database lock of each study, a 
SAP would be prepared for 
each part of the study (Parts 
A, B, and C). 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
38 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
study. 
 
Separate summaries will be 
produced for each part of the 
study. 
Section 13.1, Data Analysis 
Sets 
Section 13.1, Data Analysis 
Sets 
The Breast Milk Population 
(BMP) will include the subset 
of the Safety Population who 
have at least one evaluable 
breast milk sample.  Subjects 
will be classified according to 
actual treatment received.  
This analysis population will 
be used for all breast milk PK 
analyses. 
The Breast Milk Population 
(BMP) will include the subset 
of the Safety Population who 
have at least one evaluable 
breast milk sample.  Subjects 
will be classified according to 
actual treatment received.  
This analysis population will 
be used for all breast milk PK 
analyses. 
Removed the Breast Milk 
Population since breast milk 
collection was removed from 
the study. 
Section 13.2, Handling of 
Missing Data 
Section 13.2, Handling of 
Missing Data 
Any rules for the imputation 
of missing data will be 
described in the SAP. 
Any rulesA sensitivity 
analysis may be carried out 
to investigate the impact of 
missing data if more than 
5% of subjects are missing 
primary endpoint 
assessments.  Any 
rules/statistical methods for 
the imputation of missing 
data will be described in the 
SAP. 
Clarified the procedure to be 
performed if more than 5% of 
subjects were missing the 
primary endpoint 
assessments. 
Section 13.4, Primary 
Endpoints 
Section 13.4, Primary 
Endpoints 
For Part B, the primary 
comparison will be between 
For efficacy analysis 
purposes, centers with 
Added text to describe 
pooling of centers by region 


Protocol 547-PPD-202 
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Version 4 02 February 2017 
39 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
90 µg SAGE-547 and placebo 
at the 60-hour assessment; if 
this comparison is significant 
at the 0.05 level, then the 60 
µg group will then be 
compared to placebo. 
fewer than 15 subjects for 
Part B or 10 subjects for 
Part C per center will be 
pooled within regions (eg, 
North America region 
centers will be pooled 
separately those in Europe). 
For Part B, the primary 
comparison will be between 
90 µg SAGE-547 and placebo 
at the 60-hour assessment; if 
this comparison is significant 
at the 0.05 level, then the 60 
µg group will then be 
compared to placebo at the 
0.04 level of significance; 
otherwise the comparison 
will be carried out at the 
0.025 level of significance. 
for centers with fewer than 15 
subjects in Part B or 10 
subjects in Part C; clarified 
the significance levels to be 
used when comparing the 60 
µg group to placebo, based on 
whether or not the 90 µg dose 
was significant 
Section 13.5.2, Safety 
Analysis 
Section 13.5.2, Safety 
Analysis 
Sedation will be assessed 
using the SSS.  Safety data 
will be listed by individual 
and summarized by treatment 
group.  In addition, an 
analysis of SSS data will be 
performed comparing the 
treatment groups in the same 
way as for the primary 
In Part A only, sedation will 
be assessed using the 
Stanford Sleepiness Scale 
(SSS) Safety data will be 
listed by individual and 
summarized by treatment 
group. In addition, and an 
analysis of SSS data will be 
performed comparing the 
treatment groups in the same 
Clarified that the SSS would 
be performed and analyzed in 
Part A only.  Switched the 
order of the sentences for 
clarity. 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
40 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
endpoint.   
way as for the primary 
endpoint.  Safety data will 
be listed by individual and 
summarized by treatment 
group. 
Section 13.5.2.8, SSS 
Section 13.5.2.8, SSS (Part A 
only) 
Section 13.5.2.8, SSS 
Section 13.5.2.8, SSS (Part 
A only) 
Clarified that the SSS would 
be analyzed in Part A only.   
Section 13.6, Determination 
of Sample Size 
Section 13.6, Determination 
of Sample Size 
Assuming a two-sided test at 
an alpha level of 0.10, a 
sample size of 10 evaluable 
subjects per group would 
provide 80% power to detect.  
Assuming a two-sided test at 
an alpha level of 0. 1005, a 
sample size of 10 evaluable 
subjects per group would 
provide 8070% power to 
detect 
Changed the alpha level and 
power of the sample size 
determination. 
Section 13.6, Determination 
of Sample Size 
Section 13.6, Determination 
of Sample Size 
For Part B, a sample size of 
18 evaluable subjects per 
group (120 total) would 
provide at least 90% power to 
detect an effect size of 1.2 
between the SAGE-547 and 
placebo groups and a 
common standard deviation 
of 12 points using a two -
sided test at an alpha level of 
0.05.   
For Part C, a sample size of 
16 evaluable subjects per 
group (100 total) would 
For Part B, a sample size of 
1840 evaluable subjects per 
group (120 total) would 
provide at least 90% power to 
detect an effect size of 1.20.9 
between the SAGE-547 and 
placebo groups and a 
common standard deviation 
of 12 points using a two-
sided t-test at an alpha level 
of 0.5.   
For Part C, a sample size of 
1650 evaluable subjects per 
group (100 total) would 
Increased the number of 
subjects to be enrolled into 
Parts B and C and adjusted  
the wording regarding 
standard deviation and alpha 
level. 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
41 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
provide 80% power to detect 
an effect size of 1.0.8 
between the SAGE-547 and 
placebo groups and a 
common standard deviation 
of 12 points using a two-sided 
test at an alpha level of 0.10 
provide 8090% power to 
detect an effect size of 1.0.8 
between the SAGE-547 and 
placebo groups and a 
common standard deviation 
of 12 points using a two-sided 
t-test at an alpha level of 
0.100.5. 
Section 13.6, Determination 
of Sample Size 
Section 13.6, Determination 
of Sample Size 
Assuming a non-evaluability 
rate of 10%, up to 22 subjects 
will be randomized in Part A 
 
Assuming a non-evaluability 
rate of 10%, up to 60 subjects 
will be randomized in Part B. 
 
Assuming a non-evaluability 
rate of 10%, up to 36 subjects 
will be randomized in Part C. 
Assuming a non-evaluability 
rate of 10%, up to 22 subjects 
will be randomized in Part A 
 
Assuming a non-evaluability 
rate of 10%, up to 60 subjects 
will be randomized in Part B. 
 
Assuming a non-evaluability 
rate of 10%, up to 36 subjects 
will be randomized in Part C. 
Since the number of subjects 
to be enrolled into Parts B 
and C was increased, this text 
was deleted. 
Section 13.7, Interim 
Analysis 
Section 13.7, Interim 
Analysis 
A detailed description of the 
interim analysis will be 
included in the SAP. 
A detailed description of the 
interim analysis for sample 
size re-estimation will be 
included in the SAP. 
Clarified that interim analysis 
for sample size re-estimation 
for Part A would be described 
in the SAP. 
Section 13.8, Changes from 
Protocol-Specified Analyses 
Section 13.8, Changes from 
Protocol-Specified Analyses 
Upon the completion of each 
part of the study, the data 
may be unblinded and 
analyzed separately.  The 
Upon the completion of each 
part of the study (547-PPD-
202A, 547-PPD-202B, and 
547 PPD-202C), the data 
Clarified that a separate CSR 
would be provided for each of 
the 3 studies (Parts A, B, and 
C) included in this protocol. 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
42 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
final CSR will report the 
findings of all parts of the 
study. 
maywill be unblinded and 
analyzed separately, and a 
separate final CSR will report 
the findings of all parts of 
theeach study 
Section 14.1.2, Suspected 
Adverse Reaction 
Section 14.1.2, Suspected 
Adverse Reaction 
For the purposes of IND 
safety reporting, “reasonable 
possibility” means there is 
evidence to suggest a causal 
relationship between the drug 
and the AE.   
For the purposes of IND 
safety reporting, 
“rReasonable possibility” 
means there is evidence to 
suggest a causal relationship 
between the drug and the AE.   
Removed the phrase, “for the 
purposes of IND safety 
reporting”  
Section 14.1.5, Unexpected 
Section 14.1.5, Unexpected 
• 
If an Investigator’s 
Brochure is not required or 
available, is not consistent 
with the risk information 
described in the general 
investigational plan or 
elsewhere in the current 
application, as amended 
• 
If an Investigator’s 
Brochure is not required or 
available, is not consistent 
with the risk information 
described in the general 
investigational plan or 
elsewhere in the current 
application, as amended 
Removed this statement from 
the definition of unexpected; 
the correct definition of 
unexpected was an AE not 
listed in the Investigator’s 
Brochure  or at the specificity 
or severity that had been 
observed 
Section 14.2.1, Identification 
and Documentation of 
Adverse Events by 
Investigator 
Section 14.2.1, Identification 
and Documentation of 
Adverse Events by 
Investigator 
AEs will be collected during 
subject preparation, study 
drug administration during 
Screening, after the initiation 
of study drug administration 
through to Day 3, and at the 
Follow-up Visits on Day 7 
(±1 day) and Day 30 (±3 
AEs will be collected during 
subject preparation, study 
drug administration during 
Screeningscreening, after the 
initiation of study drug 
administration through to Day 
3, and at the Follow-up Visits 
on Day 7 (±1 day) 
Clarified that AEs would be 
collected through the Day 30 
visit; added text to describe 
procedures to be performed if 
a female patient became 
pregnant during the study. 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
43 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
days).   
andthrough Day 30 (±3 
days).   
Added: 
Female patients who 
become pregnant during the 
study should be followed to 
determine the outcome of 
the pregnancy. The 
pregnancy must be reported 
to the sponsor within 24 
hours of the site becoming 
aware of the pregnancy. If 
the pregnancy ends for any 
reason before the 
anticipated date, the 
investigator should notify 
the sponsor. At the 
completion of the 
pregnancy, the investigator 
will document the outcome 
of the pregnancy. If the 
outcome of the pregnancy 
meets the criteria for 
immediate classification as 
an SAE (ie, postpartum 
complication, spontaneous 
abortion, stillbirth, neonatal 
death, or congenital 
anomaly), the investigator 
should follow the 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
44 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
procedures for reporting an 
SAE. 
Section 14.2.2.4, Assessment 
of Outcome 
Section 14.2.2.4, Assessment 
of Outcome 
• 
Recovered/Resolved: 
The event has improved or 
recuperated 
• 
Recovering/Resolving: 
The event is improving 
• 
Not Recovered/Not 
Resolved: The event has not 
improved or recuperated 
• 
Recovered/Resolved 
with Sequel: The subject 
recuperated but retained 
pathological conditions 
resulting from the prior 
disease or injury 
• 
Fatal: The termination of 
life as a result of an adverse 
event 
• 
Unknown: Not known, 
not observed, not recorded, or 
refused 
• 
Recovered/Ongoing: At 
the end of the study, the 
event has not resolved or 
stabilized 
• 
Resolved: The event has 
improved or recuperated 
• 
Recovering/Resolving: 
The event is improving 
• 
Not Recovered/Not 
Resolved: The event has not 
improvedresolved or 
recuperatedthe subject 
recovered without sequelae 
• 
Recovered/Resolved 
with Sequel: The subject 
recuperated but retained 
pathological conditions 
resulting from the prior 
disease or injury 
• 
Fatal: The termination of 
life as sequelae: The event 
has at least 1 secondary 
outcome that may result of 
an adverse eventin 
permanent disability and/or 
functional limitation 
• 
Unknown: Not known, 
Revised the former 6 
categories of outcome to be 5 
categories: Ongoing, 
Resolved, Resolved with 
Sequelae, Unknown, or Death 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
45 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
not observed, not recorded, or 
refusedThe status of the 
event is unknown 
• 
Death: The subject has 
expired 
Section 14.2.3, Investigator 
Reporting to Sponsor and 
Sponsor Emergency Contact 
Section 14.2.3, Investigator 
Reporting to Sponsor and 
Sponsor Emergency Contact 
All SAEs that occur during 
the course of the study must 
be reported by the 
Investigator on the designated 
report form (study-specific 
SAE form or 
CIOMS/MedWatch 3500A 
form) and sent by facsimile to 
the medical monitor within 
24 hours from the point in 
time when the Investigator 
becomes aware of the SAE.   
In addition, all SAEs that 
occur up to and including 30 
days after administration of 
study drug must be reported 
within 1 working day from 
when the Investigator 
becomes aware of the SAE. 
All SAEs that occur during 
the course of the study must 
be reported by the 
Investigator immediately, 
with the designated report 
form (study-specific SAE 
form or CIOMS/MedWatch 
3500A form) and sent by 
facsimile to the Medical 
Monitor within 24 hours from 
the point in time when the 
Investigator becomes aware 
of the SAE.   
In addition, all SAEs that 
occur up to and including 30 
days after administration of 
study drug must be reported 
within 1 working day24 
hours from when the 
Investigator becomes aware 
of the SAE. 
Removed description of 
forms to be used to report 
SAEs; removed the method 
of sending SAE forms (ie, by 
facsimile); changed the SAE 
reporting time from “within 1 
working day” to “within 24 
hours” 
Section 14.2.6, Reporting to 
Institutional Review Boards 
Section 14.2.6, Reporting to 
Institutional Review 
Section 14.2.6, Reporting to 
Institutional Review Boards 
Section 14.2.6, Reporting to 
Institutional Review Boards 
Added IECs to the section 
heading since study was to be 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
46 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
(IRBs) 
Boards/Independent Ethics 
Committees 
(IRBs) 
It is the responsibility of the 
Investigator to promptly 
notify the institution’s 
IRB/IEC of all serious and 
unexpected suspected adverse 
reactions (see Section 14.3.2). 
(IRBs)/Independent Ethics 
Committees 
It is the responsibility of the 
Investigator to promptly 
notify the institution’s 
IRB/IEC of all serious and 
unexpected suspected adverse 
reactions (see Section 
14.3.2).SAEs that occur at 
his or her site if applicable 
per the IRB’s/IEC’s 
requirements. 
conducted globally 
Section 14.3.1, Monitoring of 
Adverse Event Data 
Section 14.3.1, Monitoring of 
Adverse Event Data 
The Medical Monitor or 
designee will review AEs on 
an ongoing basis. 
The Medical Monitor or 
designee will review 
SAEs/AEs on an ongoing 
basis. 
Added that the Medical 
Monitor would review SAEs 
on an ongoing basis 
Section 14.3.2, Reporting to 
FDA  
Section 14.3.2, Reporting to 
FDA Regulatory 
Authorities 
The Sponsor must report in 
an IND safety report any 
suspected adverse reaction to 
study treatment that is both 
serious and unexpected (21 
CFR 312.32[c][1][i]).  Before 
submitting an IND safety 
report, the Sponsor will 
ensure the event meets all 3 
of the definitions: (1) 
suspected adverse reaction, 
(2) serious, (3) unexpected.  
The Sponsor must report in 
an IND safety report any 
suspected adverse reaction to 
study treatment that is both 
serious and unexpected (21 
CFR 312.32[c][1][i]).  Before 
submitting an IND safety 
report, the Sponsor will 
ensure the event meets all 3 
of the definitions: (1) 
suspected adverse reaction, 
(2) serious, (3) unexpected.  
Revised text to clarify the 
procedures for reporting 
SUSARs to IRBs/IECs; 
added the requirement for 
providing a annual safety 
report to the relevant parties. 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
47 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
If the AE does not meet all 3 
of the definitions, it should 
not be submitted as an IND 
safety report.  The Sponsor 
should evaluate the available 
information and decide 
whether there is a reasonable 
possibility that the drug 
caused the AE and, therefore, 
that the event meets the 
definition of a suspected 
adverse reaction. 
If there is a serious and 
unexpected suspected adverse 
reaction, the Sponsor will 
notify the appropriate 
regulatory agency(ies) and all 
appropriate parties on an 
expedited basis.  In addition, 
Sponsors must submit 
expedited reports of an 
increased rate of occurrence 
of serious suspected adverse 
reactions over that listed in 
the protocol or Investigator’s 
Brochure. 
If the AE does not meet all 3 
of the definitions, it should 
not be submitted as an IND 
safety report.  The Sponsor 
should evaluate the available 
information and decide 
whether there is a reasonable 
possibility that the drug 
caused the AE and, therefore, 
that the event meets the 
definition of a suspected 
adverse reaction. 
If there is a serious and 
unexpected suspected adverse 
reaction, the Sponsor will 
notify the appropriate 
regulatory agency(ies) and all 
appropriate parties on an 
expedited basis.  In addition, 
Sponsors must submit 
expedited reports of an 
increased rate of occurrence 
of serious suspected adverse 
reactions over that listed in 
the protocol or Investigator’s 
Brochure. 
The Sponsor or its designee 
is responsible for SUSAR 
notification to the relevant 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
48 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
regulatory authorities per 
applicable regulations.  All 
investigators participating 
in the study will also be 
informed as required by 
regulations in order to 
inform their IRBs/IECs. 
In addition to the expedited 
reporting of SUSARs, the 
sponsor will submit, once a 
year throughout the clinical 
trial, a safety report to 
regulatory authorities as 
required by national laws.  
Section 14.4, Emergency 
Identification of Study 
Medication 
Section 14.4, Emergency 
Identification of Study 
Medication 
In exceptional circumstances 
and for the safety of the study 
subject, the Investigator may 
request unblinding of an 
individual subject’s treatment 
from the pharmacist; this 
normally requires prior 
approval by the Medical 
Monitor.  However, if the 
subject is at immediate risk 
and the Investigator believes 
that immediate knowledge of 
the study treatment will alter 
medical management, 
discussion with the Medical 
In exceptional circumstances 
and for the safety of the study 
subject, the Investigator may 
request unblinding of an 
individual subject’s treatment 
from the pharmacist; this 
normally requires prior 
approval by the Medical 
Monitor.  However, if the 
subject is at immediate risk 
and the Investigator believes 
that immediate knowledge of 
the study treatment will alter 
medical management, 
discussion with the Medical 
Clarified the procedure to be 
used for emergency 
unblinding of an individual 
subject. 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
49 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Monitor may take place after 
unblinding.  The Investigator 
will not unblind the Medical 
Monitor during that 
discussion.  The process of 
unblinding will ensure that 
only the investigator is 
unblinded; the Medical 
Monitor, study management 
team, and data management 
team will not be made aware 
of the treatment allocation of 
an individual subject.  All 
cases of emergency 
unblinding will be fully 
documented in a way that 
does not unblind the Medical 
Monitor, study management 
team, and data management 
team. 
Monitor may take place after 
unblinding.  The Investigator 
will not unblind the Medical 
Monitor during that 
discussion.  The process of 
unblinding will ensure that 
only the investigator is 
unblinded; the Medical 
Monitor, study management 
team, and data management 
team will not be made aware 
of the treatment allocation of 
an individual subject.  All 
cases of emergency 
unblinding will be fully 
documenteddescribed in a 
way that does not unblind the 
Medical Monitor, study 
management team, and data 
management team.the Safety 
Management Plan for the 
study. 
Section 16, References 
Section 16, References 
 
Ware JE, Kosinski M, 
Bjorner JB, Turner-Bowker 
DM, Gandek B, Maruish 
ME. User’s Manual for the 
SF-36v2® Health Survey 
(2nd ed). 2007. Lincoln, RI: 
QualityMetric 
Added the reference to the 
User’s Manual for the SF-36 


Protocol 547-PPD-202 
Sage Therapeutics 
Version 4 02 February 2017 
50 
 
Section number and title in 
Protocol (30 Jun 2016) 
Section number and title in 
Amendment 3 (02 Feb 2017) 
Original text: 
Changed to: 
Rationale: 
Incorporated. 
Appendix 2, HAMILTON 
RATING SCALE FOR 
DEPRESSION 
Appendix 2, HAMILTON 
RATING SCALE FOR 
DEPRESSION 
 
Inserted the correct version of 
the HAM-D 
Inserted the most recent, 
correct version of the 
HAM-D 
Appendix 3, 
MONTGOMERY ASBERG 
DEPRESSION RATING 
SCALE (MADRS) 
Appendix 3, 
MONTGOMERY ASBERG 
DEPRESSION RATING 
SCALE (MADRS) 
Included entire journal article 
with MADRS scale 
Deleted journal article; 
inserted correct MADRS 
scale 
Inserted correct MADRS 
scale 
Appendix 5, Stanford 
Sleepiness Scale 
Appendix 6, Edinburgh 
Postnatal Depression Scale 
Appendix 7 Generalized 
Anxiety Disorder 7-Item 
Scale 
Appendix 8, Patient Health 
Questionnaire 
Appendix 9, Barkin Index of 
Maternal Functioning 
Appendix 10, Selected 
Inducers, Inhibitors, and 
Substrates of CYP2C9 
Appendix 5, Edinburgh 
Postnatal Depression Scale 
Appendix 6 Generalized 
Anxiety Disorder 7-Item 
Scale 
Appendix 7, Patient Health 
Questionnaire 
Appendix 8, Barkin Index of 
Maternal Functioning 
Appendix 9, Short-form-36 
Appendix 10, Health 
Resource Utilization 
Questionnaire 
Appendix 5, Stanford 
Sleepiness Scale 
Appendix 6, Edinburgh 
Postnatal Depression Scale 
Appendix 7 Generalized 
Anxiety Disorder 7-Item 
Scale 
Appendix 8, Patient Health 
Questionnaire 
Appendix 9, Barkin Index of 
Maternal Functioning 
Appendix 10, Selected 
Inducers, Inhibitors, and 
Substrates of CYP2C9 
Appendix 5, Edinburgh 
Postnatal Depression Scale 
Appendix 6 Generalized 
Anxiety Disorder 7-Item 
Scale 
Appendix 7, Patient Health 
Questionnaire 
Appendix 8, Barkin Index 
of Maternal Functioning 
Appendix 9, Short-form-36 
Appendix 10, Health 
Resource Utilization 
Questionnaire 
Deleted the SSS, since 
sedation was removed as a 
secondary endpoint (appendix 
numbers changed); added the 
SF-36 and HCRU 
questionnaires as Appendix 9 
and Appendix 10, 
respectively 
 


Protocol 547-PPD-202 Amendment 2
30 June 2016
Confidential
1
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL-
GROUP, PLACEBO-CONTROLLED STUDY EVALUATING THE
EFFICACY, SAFETY, AND PHARMACOKINETICS OF SAGE-547
INJECTION IN THE TREATMENT OF ADULT FEMALE SUBJECTS
WITH SEVERE POSTPARTUM DEPRESSION AND ADULT FEMALE 
SUBJECTS WITH MODERATE POSTPARTUM DEPRESSION
PROTOCOL NUMBER: 547-PPD-202
IND NUMBER: 122279
Investigational Product:
SAGE-547 Injection (allopregnanolone)
Clinical Phase:
2a
Sponsor:
Sage Therapeutics
Sponsor Contact:
, MD, MBA
Sage Therapeutics
215 First Street
Cambridge, MA 02142
Phone:
Medical Monitor:
, MD
Office (9-5 EST):
24/7 Hotline:
Date of Original Protocol:
Date of Amendment 1:
Date of Amendment 2:
Version 1.0, 18 September 2015
Version 2.0, 22 December 2015
Version 3.0, 30 June 2016
Confidentiality Statement
The confidential information in this document is provided to you as an Investigator or consultant for
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee.
Your acceptance of this document constitutes agreement that you will not disclose the information
contained herein to others without written authorization from the Sponsor.




Protocol 547-PPD-202 Amendment 2
30 June 2016
Confidential
3
Investigator Agreement 
By signing this page, I attest that I have read and understand the contents of Clinical Protocol
547-PPD-202 and any current amendments. I agree to adhere to the design, conduct, and
reporting requirements of the study as stated in the clinical protocol and to my obligations to the
Sponsor as described in the protocol and executed contracts between myself, my Institution, and
the Sponsor. I also agree to adhere to any subsequent amendments to the clinical protocol.
Investigator’s Signature: _____________________________________________
Investigator’s Name:
_____________________________________________
Institution:
_____________________________________________
Date (dd/mmm/yyyy):
_____________________________________________


Protocol 547-PPD-202 Amendment 2
30 June 2016
Confidential
4
2.
SYNOPSIS
Name of Sponsor:
Sage Therapeutics
215 First Street
Cambridge, MA 02142
Protocol No. 547-PPD-202
Phase: 2a
Name of Investigational Product:
SAGE-547 Injection
Name of Active Ingredient:
Allopregnanolone
Title of the Protocol:
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study Evaluating the
Efficacy, Safety, and Pharmacokinetics of SAGE-547 Injection in the Treatment of Adult Female
Subjects With Severe Postpartum Depression and Adult Female Subjects with Moderate Postpartum 
Depression
Study Sites: Up to 50 sites in the United States and Canada
Duration of Subject Participation: Up to 35 days
Primary Objective:

To determine if SAGE-547 Injection infused intravenously for 60 hours at up to
90 Κ۷ reduces depressive symptoms in subjects with severe postpartum depression (PPD)
compared to placebo injection as assessed by the change from baseline in Hamilton Rating
Scale for Depression (HAMD) total score.  This objective applies to both Parts A and B.
Secondary Objectives (unless otherwise specified, these objectives apply to Parts A, B, and C):

To determine if SAGE-547 infusion at up to 60 Κ۷۷ for 60 hours reduces depressive
symptoms in subjects with severe PPD compared to placebo injection as assessed by the
change from baseline in HAMD total score.  This objective applies to Part B.

To determine if SAGE-547 Injection infused intravenously for 60 hours reduces depressive
symptoms in subjects with moderate PPD compared to placebo injection as assessed by the
change from baseline in HAMD total score. This objective applies to Part C.

To determine if SAGE-547 Injection infused intravenously for 60 hours reduces depressive
symptoms compared to placebo injection as assessed by HAMD response, HAMD remission,
change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score,
Clinical Global Impression – Improvement (CGI-I) response, and changes from baseline in
HAMD subscale and individual item scores.

To determine if SAGE-547 Injection infused intravenously for 60 hours reduces other mood
symptoms compared to placebo injection as assessed by changes from baseline in the
Generalized Anxiety Disorder 7-Item Scale (GAD-7) total score.


Protocol 547-PPD-202 Amendment 2
30 June 2016
Confidential
5

To determine if SAGE-547 Injection infused intravenously for 60 hours increases sedation
levels compared to placebo injection as assessed by the changes from baseline in Stanford
Sleepiness Scale (SSS) score.

To evaluate the safety and tolerability of SAGE-547 Injection compared with placebo as
assessed by the incidence of adverse events, vital sign measurement, clinical laboratory
evaluations, electrocardiogram (ECG) parameters, and the Columbia Suicide Severity Rating
Scale (C-SSRS).
Exploratory Objective:

To determine if SAGE-547 Injection infused intravenously for 60 hours reduces subject-
reported depressive symptoms compared to placebo injection as assessed by the change from
baseline in Edinburgh Postnatal Depression Scale (EPDS) total score and the change from
baseline in Patient Health Questionnaire (PHQ-9) total score.

To determine if SAGE-547 Injection infused intravenously for 60 hours improves maternal
behaviors compared to placebo injection as assessed by the change from baseline in Barkin
Index of Maternal Functioning (BIMF) total and sub-scale scores.
Pharmacokinetic Objective:

To assess the pharmacokinetic (PK) profile of SAGE-547, metabolites of SAGE-547, and
betadex sulfobutyl ether sodium (SBECD) and the concentration of SAGE-547 in breast milk,
when possible.
Study Design and Methodology:
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of the
efficacy, safety, and pharmacokinetics of SAGE-547 Injection in adult female subjects diagnosed with
severe or moderate PPD. Subjects must remain as in-patients during the study Treatment Period, which
is approximately 60 hours/2.5 days in duration. The Screening Period assessments may be conducted
on an in-patient or an out-patient basis. The Follow-up Period assessments are conducted on an out-
patient basis.
Screening Period: The Screening Period begins with the signature of the informed consent form (ICF).
Eligibility is determined by applying the inclusion/exclusion criteria. The diagnosis of PPD must be by
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). A full medical and family
history will be taken including recording of all depression, other Axis 1 and Axis 2 disorders and
postpartum depression episodes in primary probands (who may be subject to a SCID-I interview).
Treatment Period: In Parts A and C, once subjects are confirmed as eligible for the study, they will be
randomized to one of 2 treatment groups (SAGE-547 or placebo) on a 1:1 basis. Continuous
intravenous infusions of blinded study drug will be administered, with a new bag and line hung every
24 hours during the 60-hour infusion. Infusion rates will increase and then taper, with subjects
receiving 30 μg/kg/hour (0-4 hours), then 60 μg/kg/hour (4-24 hours), then 90 μg/kg/hour
(24-52 hours), followed by 60 μg/kg/hour (52-56 hours), and 30 μg/kg/hour (56-60 hours). Subjects in 
the placebo group will receive infusion rates equivalent to SAGE-547 90 μg/kg/hour. In Part B, once
subjects are confirmed as eligible for the study, they will be randomized to one of 3 treatment groups
(SAGE-547 60 μg/kg/hour, SAGE-547 90 μg/kg/hour, or placebo) on a 1:1:1 basis. For the
60 μg/kg/hour group, subjects will receive 30 μg/kg/hour (0-4 hours), then 60 μg/kg/hour (4-56 hours), 
and 30 μg/kg/hour (56-60 hours). For the 90 μg/kg/hour group, subjects will receive 30 μg/kg/hour 
(0-4 hours), then 60 μg/kg/hour (4-24 hours), then 90 μg/kg/hour (24-52 hours), followed by 
60 μg/kg/hour (52-56 hours), and 30 μg/kg/hour (56-60 hours). Subjects in the placebo group will


Protocol 547-PPD-202 Amendment 2
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randomly receive infusion rates equivalent to either the 60 μg/kg/hour or 90 μg/kg/hour group. Parts B 
and C will run concurrently.
In all parts, subjects may be discharged after the 72-hour assessments have been completed (12 hours
after completion of the study drug infusion). If their clinical condition does not allow discharge,
normal standard of care will be employed in their ongoing management.
Initiation of benzodiazepines, narcotics, antibiotics, neuroleptics, and other anti-anxiety medications
will not be allowed between Screening and completion of the 72-hour assessments. Doses of
psychotropics, which must have been initiated at least 14 days prior to screening, must remain at a
stable dose until completion of the 72-hour assessments. If at the 72-hour assessment there has been no
treatment response (HAMD total score remains above 13), treatment with antidepressant medication
may be optimized prior to discharge, and the subject may remain in the unit or be followed at an out-
patient clinic, as clinically indicated.
Efficacy and safety assessments will be performed periodically during the study, and blood samples
will be collected for analysis of SAGE-547, metabolites of SAGE-547, and SBECD concentrations, as
outlined in the Schedule of Events (Table 1). Blood samples will be collected, and outcome measures
will be obtained at pre-specified times over 60 hours during the Treatment Period.
Follow-up Period: For all parts, follow-up visits will be conducted one week (7±1 day) and one month
(30±3d) after the initiation of the study drug infusion.
Number of Subjects:
Up to 32 subjects will be randomized in Part A, up to 60 subjects will be randomized in Part B, and up
to 36 subjects in Part C.
Inclusion Criteria:
The following inclusion criteria must be met for individuals to be eligible for the trial:
1.
Subject has signed an ICF prior to any study-specific procedures being performed
2.
Subject is an ambulatory female aged between 18 and 45 years of age, inclusive
3.
Subject is in good physical health and has no clinically significant findings, as determined by
the Investigator, on physical examination, 12-lead ECG, or clinical laboratory tests
4.
Subject agrees to adhere to the study requirements
5.
Subject either must have ceased lactating at Screening; or if still lactating or actively breast
feeding at Screening, must agree to temporarily cease giving breastmilk to their infant(s) from
just prior to receiving study drug through 9 days (Study Day 12) after the end of infusion.
6.
Subject must have a negative pregnancy test at Screening and Day 1 prior to the start of study
drug infusion
7.
Subject has had a Major Depressive Episode that began no earlier than the third trimester and
no later than the first 4 weeks following delivery, as diagnosed by Structured Clinical
Interview for DSM-IV Axis I Disorders (SCID-I)
8.
For Part A and B, subject has a HAMD total score of ȑ ҟ at Screening and Day 1 (prior to
randomization). For Part C, subject has a HAMD total score of ȑ ẇand ₢ at Screening and
Day 1 (prior to randomization)
9.
Subject is ₢ҟ months postpartum


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10. Subject is willing to delay start of other antidepressant or anxiety medications and any new
pharmacotherapy regimens, including prn benzodiazepine anxiolytics, until the study drug
infusion and 72-hour assessments have been completed
11. Subject has no detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV),
and human immunodeficiency virus (HIV) antibody at Screening
12. Subject must use one of the following methods of birth control during participation in the study
and for 30 days following the end of the study drug infusion:

Total abstinence (no sexual intercourse)

Hormonal contraceptives (birth control) including birth control pills, implantable or
injectable contraceptives (Norplant® or Depo-Provera®)

A barrier form of contraception such as a condom or occlusive cap with a spermicide

An intrauterine device (IUD)
Exclusion Criteria:
Subjects will be excluded if they meet any of the following exclusion criteria:
1.
Recent history or active clinically significant manifestations of metabolic, hepatic, renal,
hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological,
urogenital, neurological, or eyes, ears, or nose and throat disorders, or any other acute or
chronic condition that, in the Investigator’s opinion, would limit the subject’s ability to
complete or participate in this clinical study
2.
Known allergy to progesterone or allopregnanolone
3.
Active psychosis per Investigator assessment
4.
Attempted suicide associated with index case of postpartum depression
5.
Medical history of seizures
6.
Medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder.
7.
History of active alcoholism or drug addiction (including benzodiazepines) in the 12 months
prior to Screening
8.
Exposure to another investigational medication or device within 30 days prior to Screening
9.
Administration of psychotropics that have been initiated within 14 days prior to Screening and
are not being taken at a stable dose.


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Investigational Product, Dosage, and Mode of Administration:
SAGE-547 Injection, intravenous (IV) administration: SAGE-547 Injection is a sterile, clear, colorless
5 mg/mL solution of SAGE-547 (allopregnanolone) and 250 mg/mL SBECD buffered with 10 mM
citrate at a pH of 6.0, supplied in single-use 20 mL vials for IV administration. As supplied,
SAGE-547 Injection, which is hypertonic, requires further dilution with Sterile Water for Injection
(SWFI) to render it isotonic for IV infusion. The specific infusion dose of SAGE-547 Injection will be
calculated based on weight for each subject at Screening and administered according to the
randomization schedule. Infusion bags will be changed every 24 hours. Details about the preparation
and administration of the study drug infusions will be included in the Pharmacy Manual.
Part A and Part C:
Infusion Rate (μg/kg/hour)
SAGE-547 Dose
Day 1
0-4 hours
Day 1
4-24 hours
Day 2-3
24-52 hours
Day 3
52-56 hours
Day 3
56-60 hours
90 µg
30
60
90
60
30
Part B:
Infusion Rate (μg/kg/hour)
SAGE-547 Dose
Day 1
0-4 hours
Day 1
4-24 hours
Day 2-3
24-52 hours
Day 3
52-56 hours
Day 3
56-60 hours
60 µg
30
60
60
60
30
90 µg
30
60
90
60
30
Reference Therapy, Dosage, and Mode of Administration:
An identical placebo IV infusion will be prepared for IV administration consisting of the same
formulation without allopregnanolone. For each part of the study, the placebo infusion rate will match
that of the SAGE-547 rate(s) used in that part.
Randomization and Stopping Rules:
Subjects will be randomized to receive SAGE-547 Injection or placebo; subjects, clinicians, and study
team will be blinded to treatment allocation. The pharmacist, who will prepare the infusion bags
according to the randomization schedule, will be unblinded. In Parts A and C, the infusion rates are the
same for all subjects within a particular dosing period (0-4 hours, 4-24 hours, etc.) regardless of
randomized treatment. In Part B, the infusion rates will vary according to the dose group randomized
to.
If any subject has an SSS score of ȑ  for 2 or more consecutive assessments or an SSS score of ȑҟ for a
single occurrence during normal waking hours, the infusion rate for this subject will be decreased to the
next lowest infusion dose level (or turned off if this occurs on the 30 μg/kg/hour dose level).


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Criteria for Evaluation:
Primary Endpoint
The primary outcome measure will be the 17-item Hamilton Rating Scale for Depression (HAMD).
The HAMD will be administered before, during, and after the infusion of blinded study drug. The
HAMD total score will be calculated as the sum of the 17 individual item scores. The change from
baseline in HAMD total score at the end of the treatment period (at +60 hours) will be the primary
efficacy endpoint with comparison between the SAGE-547 and placebo treatment groups from Part A
used to evaluate the efficacy of SAGE-547 in treating the depressive symptoms of PPD.
For Parts A and C, the primary comparison will be between 90 μg SAGE-547 and placebo at the 
60-hour assessment.  For Part B, the primary comparison will be between 90 μg SAGE-547 and 
placebo at the 60-hour assessment; if this comparison is significant at the 0.05 level, then the 60 μg 
group will then be compared to placebo.  
Secondary Endpoints
All secondary endpoints apply to Parts A, B and C unless otherwise stated.
Additional measures of depressive symptom severity will be administered before, during, and after the
infusion of study drug, including the Montgomery-Asberg Depression Rating Scale (MADRS), and the
Clinical Global Impression (CGI) scale. Total scores and changes from baseline will be calculated
where applicable. Changes from baseline at the end of the treatment period (at +60 hours) and other
time points will be evaluated as secondary efficacy endpoints with comparisons between the two
treatment groups used to support the efficacy of SAGE-547 in treating the depressive symptoms of
PPD. In addition to the above scales, the individual item scores and subscale scores from the HAMD
scale will also evaluated as secondary efficacy endpoints.
GAD-7 will also be administered before, during, and after the infusion of study drug. As with other
secondary efficacy endpoints, scores from these scales will be evaluated to assess the efficacy in other
mood disorder and anxiety symptoms.
An important safety endpoint will be the assessment of sedation using the SSS. The SSS will be
assessed periodically before, during, and after the infusion of blinded study drug with changes from
baseline over time evaluated similarly to that of efficacy endpoints.
Safety and tolerability of SAGE-547 Injection will be evaluated by summarization of adverse events
(AEs) by frequency, severity, and seriousness; clinical laboratory measures, vital signs, and ECGs
(including changes from baseline); and concomitant medication usage. Suicidality will be monitored
using the C-SSRS.
The doses of all anti-depressant medications will be recorded throughout the study. No changes and/or
additions to antidepressant or anxiolytic medicine will be allowing during the dosing period. An
analysis of time to starting/increasing the dose/decreasing the dose of each different anti-depressant
medication will be undertaken for subjects discharged.
Plasma will be collected to assay for concentrations of SAGE-547, SAGE-547 metabolites, and
SBECD. The following PK parameters will be derived from the plasma concentrations (where
evaluable): area under the concentration-time curve (AUC) from time zero to 60 hours (AUC0-60), AUC
from time zero to infinity (AUCɎ), maximum (peak) plasma concentration (Cmax), time at maximum
(peak) plasma concentration (tmax), steady-state drug concentration in the plasma during constant-rate
infusion (Css), and average drug concentration in the plasma at steady state during a dosing interval


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(Cavg).
Breast milk may be collected as an optional assessment if consent is received from the subject.
Samples will be analyzed for SAGE-547 concentrations.
Exploratory Endpoints
Additional measures of symptoms and function related to the current episode of postpartum depression
severity will be administered before, during, and after the infusion of study drug, including the EPDS,
PHQ-9 and BIMF.
Subscale and total scores and changes from baseline will be calculated where applicable. Changes
from baseline at the end of the treatment period (at +60 hours) and other time points will be evaluated
as secondary efficacy endpoints with comparisons between the two treatment groups used to support
the efficacy of SAGE-547 in treating the depressive symptoms of PPD. In addition to the above scales,
the individual item scores will also be evaluated as exploratory endpoints.
Statistical Methods:
For the purpose of all safety, efficacy, and exploratory analyses where applicable, baseline is defined as
the last measurement prior to the start of blinded study drug infusion.
Interim Analysis
In Part A, an interim analysis will be conducted by an independent statistician for sample size
re-estimation purposes when at least 16 subjects have completed efficacy assessments through
60 hours. Since the sponsor will be kept uninformed of the response rates at the time of the interim
analysis, no statistical adjustment will be made to the level of significance for hypothesis testing at the
end of the study. A detailed description of the interim analysis will be included in the statistical
analysis plan.
There will be no interim analysis for Parts B or C.
Sample Size Calculation
Assuming a two-sided test at an alpha level of 0.10, a sample size of 10 evaluable subjects per group
would provide 80% power to detect an effect size of 1.2 between the SAGE-547 and placebo groups
with regard to the primary outcome variable of change from baseline in HAMD total score. An effect
size of 1.2 corresponds to a placebo adjusted difference of 12 points in the change from baseline in
HAMD total score at 60 hours with an assumed standard deviation of 10 points. By including two
treatment groups and using a 1:1 randomization ratio, a total of 20 evaluable subjects are required for
Part A. Assuming a non-evaluability rate of 10%, up to 22 subjects will be randomized in Part A.
Based on the results of the interim analysis, the sample size in Part A could be increased to a maximum
of 32 randomized subjects. This adjustment to the sample size would allow for an effect size of 1.0 to
be detected.
For Part B, a sample size of 18 evaluable subjects per group would provide at least 90% power to 
detect an effect size of 1.2 between the SAGE-547 and placebo groups using a two-sided test at an 
alpha level of 0.05.  Assuming a non-evaluability rate of 10%, up to 60 subjects will be randomized in 
Part B.
For Part C, a sample size of 16 evaluable subjects per group would provide 80% power to detect an 
effect size of 1.0 between the SAGE-547 and placebo groups using a two-sided test at an alpha level of 


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0.10.  Assuming a non-evaluability rate of 10%, up to 36 subjects will be randomized in Part C.
Efficacy Analysis
The efficacy population will include all subjects who start the infusion of study drug and have a valid
baseline HAMD assessment and at least one post-baseline HAMD assessment. Subjects will be
classified and summarized by randomized treatment. Separate summaries will be produced for each
part of the study.
For each part, the change from baseline in HAMD total score will be analyzed using a mixed effects
repeated measures model including center, treatment, baseline score, time point, and time point-by-
treatment as explanatory variables. Center will be treated as a random effect while all other
explanatory variables will be treated as fixed effects. The primary comparison between each
SAGE-547 dose and placebo will be at the 60-hour time point. Comparisons at other time points will
be conducted to support the findings for the primary comparison. To account for multiple testing in
Part B, the 90 μg group will be compared to placebo first; if this dose is significant at the 0.05 level,
then the 60 μg group will then be compared to placebo.
Changes from baseline in other rating scale scores will be analyzed with methods similar to the primary
endpoint. Any dichotomous response variables will be analyzed using logistic regression methods.
In addition to formal analysis, efficacy rating scale scores (including recorded and change from
baseline values) will be summarized by descriptive statistics, including n, mean, standard deviation
(SD), median, and minimum and maximum values. Categorical efficacy endpoints (including HAMD,
MADRS, and CGI-I response variables) will be summarized by frequency and percentage.
Safety Analysis
The Safety Population (SAF) is defined as all subjects who start the infusion of study drug. Subjects
will be classified and summarized by actual treatment. Separate summaries will be produced for each
part of the study.
Safety will be assessed using SSS, AEs, vital signs, ECG, clinical laboratory tests, C-SSRS, and
concomitant medication data. Continuous safety data (including absolute and change from baseline
values) will be summarized by descriptive statistics, including n, mean, standard deviation (SD),
median, and minimum and maximum values. Categorical endpoints will be summarized by frequency
and percentage. In addition, an analysis of the SSS score will be performed comparing the treatment
groups in the same way as for the primary endpoint.
Safety data will be examined for possible relationships between subject characteristics and plasma
allopregnanolone concentrations, as appropriate.


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Table 1:
Schedule of Events
Screening
Period
Treatment Period
Clinic Period (Day 1 to Day 3)
Follow-up Period 
Visit Days
Screening
D-5 to -1
D1
H0*
D1
H2
D1
H4
D1
H8
D1
H12
D1
H18
D1
H24
D2
H30
D2
H36
D2
H42
D2
H48
D3
H54
D3
H60
D3
H66
D3
H72
D7/ET
(±1d)
D12
(+1d)l
D30
(±3d)
Study Procedure
Informed Consent
X
Inclusion/Exclusion
Criteria
X
X
Demographics
X
Medical/Family
History
X
Physical Examination
X
X
X
Body Weight/Height
X
Clinical Lab
Assessments a
X
X
X
Urinalysis a
X
X
Drug & Alcohol
Screen b
X
X
Pregnancy Test c
X
X
X
Hepatitis & HIV
Screen
X
Genetic Sample d
O
Vital Signs e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulse Oximetry
X
12-Lead ECG f
X
X
X
C-SSRS g
X
X
X
X
X
X
Confinement
X
CGI-I h
X
X
X
X
X
X
X
X
X
X
CGI-S h
X
X
HAMD h
X
X
X
X
X
X
X
X
X
X
X
X
X
MADRS h
X
X
X
X
X
X
X
X
BIMF h
X
X
X
EPDS h
X
X
X
X


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GAD-7 h
X
X
X
X
PHQ-9 h
X
X
X
X
SSS i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma PK j
X
X
X
X
X
X
X
X
X
X
X
Xl
Breast Milk PK k
X
X
X
X
X
X
X
Xl
Xl
Study Drug Infusion
X
Adverse Events
X
Concomitant
Medications
X
O = optional * = All H0 procedures to be completed prior to dosing
a Safety laboratory tests will include hematology, serum chemistry, coagulation, and select hormone parameters. The urine test will include a urinalysis. Lab
assessments are to be completed within ±30 minutes of the scheduled time point.
b Urine for selected drugs of abuse and alcohol (serum or breath)
c Serum at Screening and urine for all other time points
d A blood sample for genetic testing, where consent is given
e Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Vital signs will be obtained within ±30 minutes
of the scheduled time point, unless the subject is asleep between the hours of 23.00h and 06.00h.
f Performed within ±30 minutes of the scheduled time point on Day 2.
g The “Baseline/Screening” C-SSRS form will be completed on Day 1. The “Since Last Visit” C-SSRS form will be completed at all subsequent time points.
h To be completed within ±30 minutes of the scheduled time point.
i To be completed within ±15 minutes of the scheduled time point, unless the subject is asleep between the hours of 23.00h and 06.00h
j Blood samples for PK analysis will be collected at pre-infusion and at 4 (before change in infusion rate), 8, 12, 24 (before change in infusion rate), 30, 36, 48,
60 (before end of infusion), and 72 hours after the start of the infusion. PK blood draws after the start of infusion will have a window of ±10 minutes. In the
event of an unplanned dose adjustment, an unscheduled PK sample should be collected just prior to the infusion rate change.
k Optional assessment per subject consent, breast milk will be collected and pooled over the following time periods of interest: 0, 1-12, 12-24, 24-36, 36-48,
48-60, and 60-72 hours after the start of the infusion.
l Day 7 Breast Milk Samples/Day 12 Visit is only applicable to those patients who have temporarily ceased breastfeeding and are participating in the optional
breast milk sampling.
BIMF = Barkin Index of Maternal Functioning; CGI-I = Clinical Global Impression of Improvement; C-SSRS = Columbia Suicide Severity Rating Scale; ECG =
electrocardiogram; EPDS = Edinburgh Postnatal Depression Scale; GAD-7 = Generalized Anxiety Disorder 7-Item Scale; HAMD = Hamilton Rating Scale for 
Depression, 17-item; MADRS = Montgomery-Asberg Depression Rating Scale; PHQ-9 = Patient Health Questionnaire; PK = pharmacokinetic; SSS = Stanford
Sleepiness Scale.


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3.
TABLE OF CONTENTS
PROTOCOL NUMBER: 547-PPD-202 ...................................................................... 1 
1. 
SIGNATURE PAGE ................................................................................ 2 
2. 
SYNOPSIS ............................................................................................... 4 
3. 
TABLE OF CONTENTS ....................................................................... 14 
LIST OF TABLES..................................................................................................... 19 
LIST OF FIGURES ................................................................................................... 19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................ 20 
4. 
INTRODUCTION AND RATIONALE................................................. 23 
4.1. 
Role of Allopregnanolone in Affective Disturbances ............................ 24 
4.1.1. 
Rationale for Allopregnanolone Treatment of PPD ............................... 24 
4.2. 
SAGE-547 Injection (Allopregnanolone)............................................... 25 
4.3. 
Summary of Nonclinical and Clinical Experience with Allopregnanolone 
or SAGE-547 .......................................................................................... 26 
4.3.1. 
Nonclinical Pharmacology...................................................................... 26 
4.3.2. 
Clinical Experience................................................................................. 26 
4.4. 
Potential Risks and Benefits................................................................... 27 
4.5. 
Study No.  547-PPD-202........................................................................ 27 
4.5.1. 
Study Population..................................................................................... 27 
4.5.2. 
Route of Administration, Dosage, Dosage Regimen, and Treatment 
Period...................................................................................................... 28 
4.5.3. 
Dose Rationale........................................................................................ 28 
5. 
ETHICS .................................................................................................. 30 
5.1. 
Institutional Review Board or Independent Ethics Committee.............. 30 
5.2. 
Ethical Conduct of the Study.................................................................. 30 
5.3. 
Subject Information and Informed Consent ........................................... 30 
6. 
STUDY OBJECTIVES .......................................................................... 31 
6.1. 
Primary Objective................................................................................... 31 
6.2. 
Secondary Objectives ............................................................................. 31 
6.3. 
Exploratory Objectives ........................................................................... 31 
6.4. 
Pharmacokinetic Objective..................................................................... 32 
7. 
INVESTIGATIONAL PLAN................................................................. 33 


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7.1. 
Overview of Study Design...................................................................... 33 
7.2. 
Blinding and Randomization.................................................................. 36 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS.......................... 37 
8.1. 
Inclusion Criteria .................................................................................... 37 
8.2. 
Exclusion Criteria................................................................................... 38 
8.3. 
Subject Withdrawal/Study Termination ................................................. 38 
8.3.1. 
Withdrawal/Discontinuation of Individual Subjects .............................. 38 
8.3.2. 
Subject Withdrawal from the Study ....................................................... 38 
8.3.3. 
Discontinuation of Study Drug by the Investigator................................ 38 
8.3.4. 
Study Termination .................................................................................. 39 
9. 
INVESTIGATIONAL PRODUCT ........................................................ 40 
9.1. 
Identity of Investigational Product ......................................................... 40 
9.2. 
Clinical Supplies..................................................................................... 40 
9.2.1. 
SAGE-547............................................................................................... 40 
9.2.2. 
Placebo.................................................................................................... 40 
9.3. 
Preparation of SAGE-547 Injection or Placebo for Dosing ................... 40 
9.4. 
Administration and Accountability......................................................... 41 
10. 
TREATMENT OF SUBJECTS.............................................................. 42 
10.1. 
Dosing Schedule..................................................................................... 42 
10.1.1. 
Dose Regimen......................................................................................... 43 
10.1.2. 
Route of Administration ......................................................................... 43 
10.1.3. 
Treatment Period .................................................................................... 43 
10.1.4. 
Dosing of Intravenous SAGE-547 in the Case of AEs........................... 43 
10.2. 
Dosing Compliance ................................................................................ 44 
10.3. 
Concomitant Medications and Restrictions............................................ 44 
10.3.1. 
Concomitant Medications....................................................................... 44 
10.3.2. 
Prohibited Medications........................................................................... 44 
11. 
STUDY ASSESSMENTS ...................................................................... 46 
11.1. 
Safety Assessments................................................................................. 46 
11.1.1. 
Adverse Events ....................................................................................... 46 
11.1.2. 
Clinical Laboratory Tests ....................................................................... 46 
11.1.2.1. 
Hematology, Serum Chemistry, Coagulation......................................... 47 
11.1.2.2. 
Hepatitis and HIV................................................................................... 47 


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11.1.2.3. 
Hormones and Exploratory Biochemistry .............................................. 47 
11.1.2.4. 
Pregnancy Test........................................................................................ 47 
11.1.2.5. 
Genetic Testing....................................................................................... 47 
11.1.2.6. 
Urinalysis................................................................................................ 48 
11.1.2.7. 
Drugs of Abuse and Alcohol .................................................................. 48 
11.1.3. 
Physical Examination ............................................................................. 48 
11.1.4. 
Vital Signs .............................................................................................. 48 
11.1.5. 
Pulse Oximetry ....................................................................................... 48 
11.1.6. 
ECG ........................................................................................................ 48 
11.1.7. 
Columbia Suicide Severity Rating Scale (C-SSRS)............................... 49 
11.1.8. 
Stanford Sleepiness Scale (SSS)............................................................. 49 
11.2. 
Efficacy Assessments ............................................................................. 49 
11.2.1. 
Primary Efficacy Outcome Measure ...................................................... 49 
11.2.1.1. 
Hamilton Rating Scale for Depression (HAMD) ................................... 49 
11.2.2. 
Secondary Efficacy Outcome Measures................................................. 50 
11.2.2.1. 
Montgomery Asberg Depression Rating Scale (MADRS)..................... 50 
11.2.2.2. 
Clinical Global Impression (CGI) Scale................................................. 51 
11.2.2.3. 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) ........................... 51 
11.2.3. 
Exploratory Patient Reported Outcome Measures ................................. 51 
11.2.3.1. 
Edinburgh Postnatal Depression Scale (EPDS)...................................... 51 
11.2.3.2. 
Patient Health Questionnaire (PHQ-9) ................................................... 52 
11.2.3.3. 
Barkin Index of Maternal Functioning (BIMF)...................................... 52 
11.3. 
Pharmacokinetics.................................................................................... 52 
11.3.1. 
Plasma PK Samples................................................................................ 52 
11.3.2. 
Breastmilk PK Samples.......................................................................... 53 
12. 
STUDY PROCEDURES........................................................................ 54 
12.1. 
Screening Period..................................................................................... 54 
12.2. 
SAGE-547 Treatment Period (Day 1 to Day 3, Hours 0-60) ................. 55 
12.2.1. 
Day 1....................................................................................................... 55 
12.2.2. 
Day 2....................................................................................................... 56 
12.2.3. 
Day 3....................................................................................................... 56 
12.3. 
Follow-up Period (Day 7 through Day 60)............................................. 57 
12.3.1. 
Day 7 (±1 day)........................................................................................ 57 


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12.3.2. 
Day 12 (+1 day)...................................................................................... 58 
12.3.3. 
Day 30 (±3 days) .................................................................................... 58 
12.3.4. 
Early Termination Visit .......................................................................... 58 
13. 
STATISTICAL METHODS AND CONSIDERATIONS ..................... 59 
13.1. 
Data Analysis Sets .................................................................................. 59 
13.2. 
Handling of Missing Data....................................................................... 60 
13.3. 
Demographics and Baseline Characteristics........................................... 60 
13.4. 
Primary Endpoints .................................................................................. 60 
13.5. 
Secondary Endpoints .............................................................................. 60 
13.5.1. 
Efficacy Analysis.................................................................................... 60 
13.5.2. 
Safety Analysis ....................................................................................... 61 
13.5.2.1. 
Adverse Events ....................................................................................... 61 
13.5.2.2. 
Clinical laboratory evaluations............................................................... 62 
13.5.2.3. 
Physical examinations ............................................................................ 62 
13.5.2.4. 
Vital signs ............................................................................................... 62 
13.5.2.5. 
12-Lead ECG.......................................................................................... 62 
13.5.2.6. 
Concomitant medications ....................................................................... 62 
13.5.2.7. 
C-SSRS................................................................................................... 62 
13.5.2.8. 
SSS.......................................................................................................... 62 
13.5.2.9. 
PK Analysis ............................................................................................ 62 
13.6. 
Determination of Sample Size................................................................ 63 
13.7. 
Interim Analysis...................................................................................... 63 
13.8. 
Changes from Protocol Specified Analyses ........................................... 63 
14. 
ADVERSE EVENTS.............................................................................. 64 
14.1. 
Adverse Event Definitions...................................................................... 64 
14.1.1. 
Adverse Event......................................................................................... 64 
14.1.2. 
Suspected Adverse Reaction................................................................... 64 
14.1.3. 
Life-Threatening..................................................................................... 64 
14.1.4. 
Serious .................................................................................................... 64 
14.1.5. 
Unexpected ............................................................................................. 65 
14.2. 
Investigator Responsibilities................................................................... 65 
14.2.1. 
Identification and Documentation of Adverse Events by Investigator... 65 
14.2.2. 
Adverse Event Classification.................................................................. 66 


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14.2.2.1. 
Relationship to Investigational Drug...................................................... 66 
14.2.2.2. 
Severity................................................................................................... 67 
14.2.2.3. 
Action Taken with Investigational Drug ................................................ 67 
14.2.2.4. 
Assessment of Outcome ......................................................................... 67 
14.2.3. 
Investigator Reporting to Sponsor and Sponsor Emergency Contact .... 67 
14.2.4. 
Medical Monitor and Emergency Contact Information.......................... 68 
14.2.5. 
SAE Reporting Contact Information ...................................................... 68 
14.2.6. 
Reporting to Institutional Review Boards (IRBs) .................................. 68 
14.3. 
Sponsor/Medical Monitor Responsibilities ............................................ 68 
14.3.1. 
Monitoring of Adverse Event Data......................................................... 68 
14.3.2. 
Reporting to FDA ................................................................................... 68 
14.4. 
Emergency Identification of Study Medication...................................... 69 
15. 
STUDY ADMINISTRATION ............................................................... 70 
15.1. 
Quality Control and Quality Assurance.................................................. 70 
15.2. 
Data Handling and Recordkeeping......................................................... 70 
15.2.1. 
Data Handling......................................................................................... 70 
15.2.2. 
Case Report Form Completion............................................................... 70 
15.2.3. 
Retention of Study Records.................................................................... 71 
15.3. 
Confidentiality........................................................................................ 71 
15.4. 
Publication Policy................................................................................... 71 
15.5. 
Protocol Amendments ............................................................................ 72 
16. 
REFERENCES ....................................................................................... 73 
APPENDICES ........................................................................................................... 78 
APPENDIX 1. COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS)79 
APPENDIX 2. HAMILTON RATING SCALE FOR DEPRESSION, 17-ITEM 
(HAMD) ................................................................................................. 86 
APPENDIX 3. MONTGOMERY ASBERG DEPRESSION RATING SCALE
(MADRS) ............................................................................................... 88 
APPENDIX 4. CLINICAL GLOBAL IMPRESSION–IMPROVEMENT SCALE 
(CGI-I) AND SEVERITY SCALE (CGI-S) .......................................... 91 
APPENDIX 5. STANFORD SLEEPINESS SCALE (SSS)................................... 93 
APPENDIX 6. EDINBURGH POSTNATAL DEPRESSION SCALE (EPDS).... 95 
APPENDIX 7. GENERALIZED ANXIETY DISORDER 7-ITEM SCALE (GAD-
7)
97 


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APPENDIX 8. PATIENT HEALTH QUESTIONNAIRE (PHQ-9) ...................... 99 
APPENDIX 9. BARKIN INDEX OF MATERNAL FUNCTIONING (BIMF) .. 101 
APPENDIX 10. SELECTED INDUCERS, INHIBITORS, AND SUBSTRATES 
OF CYP2C9.......................................................................................... 103 
LIST OF TABLES
Table 1: 
Schedule of Events ................................................................................. 12 
Table 2: 
Infusion rates for Part A and C............................................................... 43 
Table 3: 
Infusion Rates for Part B ........................................................................ 43 
LIST OF FIGURES
Figure 1: 
Study Design - Part A and Part C........................................................... 34 
Figure 2: 
Study Design - Part B ............................................................................. 34 
Figure 3: 
Trial Design and Timeline for Dosing – Parts A and C ......................... 42 
Figure 4: 
Trial Design and Timeline for Dosing – Part B ..................................... 42 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
adverse event
ALLO
allopregnanolone
ALT
alanine aminotransferase
AR
androgen receptor
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUCɎ
area under the concentration-time curve from time zero to infinity
AUC0-60
area under the concentration-time curve from time zero to 60 hours
BIMF
Barkin Index of Maternal Functioning
BMI
body mass index
BMP
breast milk population
BUN
blood urea nitrogen
Cavg
average drug concentration in the plasma at steady-state during a dosing
interval
CBC
complete blood count
CFR
Code of Federal Regulations
CGI-I
Clinical Global Impression–Improvement
CGI-S
Clinical Global Impression–Severity
cGMP
Current Good Manufacturing Practice
Cmax
maximum (peak) plasma concentration of the drug
CNS
central nervous system
CRF
case report form
CS
clinically significant
CSF
cerebrospinal fluid
CSR
clinical study report
Css
steady-state drug concentration in the plasma during constant-rate infusion
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
Cytochrome P450 enzyme involved in drug metabolism
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
ECG
electrocardiogram
eCRF
electronic case report form


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EDC
electronic data capture
EEG
electroencephalography
EFF
efficacy population
Ph. Eur.
European Pharmacopeia
EPDS
Edinburgh Postnatal Depression Scale

estrogen receptor alfa
ERß
estrogen receptor beta
ET
early termination
FDA
Food and Drug Administration
GABA
gamma-aminobutyric acid
GABAA
gamma-aminobutyric acid–gated chloride channel
GAD-7
Generalized Anxiety Disorder 7-Item Scale
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
h
hour
HAMD
Hamilton Rating Scale for Depression, 17-item
HBsAg
hepatitis B surface antigen
Hct
hematocrit
HCV
hepatitis C virus
HEENT
head, eyes, ears, nose, and throat
Hgb
hemoglobin
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council on Harmonisation
ID
identification
IEC
Independent Ethics Committee
IND
Investigational New Drug Application
IRB
Institutional Review Board
IV
intravenous
MADRS
Montgomery-Asberg Depression Rating Scale
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MDD
major depressive disorder


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MedDRA
Medical Dictionary for Regulatory Activities
NCS
not clinically significant
PHQ-9
Patient Health Questionnaire
PK
pharmacokinetic
PKP
pharmacokinetic population
PMID
PubMed identification
PP
per-protocol population
PPD
postpartum depression
PR
progesterone receptor
PT/INR
prothrombin time/international normalized ratio
RBC
red blood cell
RSE
refractory status epilepticus
SAE
serious adverse event
SAF
safety population
SAP
statistical analysis plan
SBECD
betadex sulfobutyl ether sodium
SCID-I
Structured Clinical Interview for DSM-IV Axis I Disorders
SD
standard deviation
SOC
system organ class
SOP
standard operating procedure
SRSE
super refractory status epilepticus
SSRI
selective serotonin reuptake inhibitors
SSS
Stanford Sleepiness Scale
SWFI
sterile water for injection
T1/2
half-life
TEAE
treatment-emergent adverse event
Tmax
time to maximum (peak) plasma concentration
TSH
thyroid stimulating hormone
US
United States
USP
United States Pharmacopeia
VAS
visual analogue scale
Vd
volume of distribution
WBC
white blood cell


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4.
INTRODUCTION AND RATIONALE
This study is designed to evaluate the efficacy, safety, and pharmacokinetics (PK) of
SAGE-547 (allopregnanolone) as a treatment for women with severe or moderate postpartum
depression (PPD), an area of high unmet medical need.
PPD is considered to be moderate to severe depression in women who have recently given
birth, otherwise defined as the occurrence of major depressive disorder (MDD) within
4 weeks of delivery (DSM-V 2013) or up to a year after giving birth (Okun 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-V 2013),
although this diagnosis may be confounded by the relative frequency of symptoms such as
sleep disturbance or appetite problems in pregnant and postpartum women. Most women
experience onset of symptoms within the first 3 months following delivery, and PPD is most
prevalent at 10 to 14 weeks following childbirth (Okun 2013).
During pregnancy, estradiol and progesterone levels increase dramatically but then rapidly
decline in the acute postpartum period (Gavin 2005). The onset of PPD symptoms coincides
with the rapid decrease of the gonadal steroids postpartum. The duration of a PPD episode
has been estimated as shorter than depressive episodes in the general population
(approximately 5 months), while other studies indicate time to remission is approximately the
same (Chaudron 2003).
PPD is common and has devastating consequences for the woman and for her family
(Fihrer 2009, Verbeek 2012). Perinatal depression is reported to be the most underdiagnosed
obstetric complication in America (Earls 2010). Furthermore, it is the most common
psychiatric illness to occur in the puerperium (O’Hara 2014). A meta-analysis of 30 studies
(Gaynes 2005) found that the point prevalence of major and minor depression ranged
between 6.5% and 12.9% at different times during the first postpartum year. Overall
incidence is estimated at around 15% to 20% with up to 10% being considered severe
(Edge 2007, O’Hara 2014).
Current standard of care for severe PPD comprises cautious use of pharmacological therapies
in nursing mothers combined with other interventions. Evidence for efficacy of tricyclic
antidepressants and/or selective serotonin reuptake inhibitors (SSRIs) is based on use in the
general population rather than any extensive studies in PPD (Austin 2013), and SSRIs tend to
be preferred due to better data on safety while breastfeeding (Altshuler 2001). Based on the
level of evidence for antidepressants in major depressive disorder (Kirsch 2008, Fournier
2010), there is a considerable need for improved pharmacological therapy for PPD.
Drugs may be combined with a number of counseling, behavioral, and other non-
pharmacological therapy approaches, which are generally used as the first-line therapy in less
severe PPD (Altshuler 2001). Urgent referral and potentially admission are recommended
for mothers at risk of self-harm, with their infants, if such facilities exist (Austin 2013).
Therapeutic options in severe PPD are currently limited, and it is not clear whether the
current standard of care impacts the natural history of the disease, although most women
recover within a year.


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4.1.
Role of Allopregnanolone in Affective Disturbances
The neurosteroid metabolite of progesterone, allopregnanolone, acutely regulates neuronal
function (Gangisetty 2010) and appears to play a significant role in affective disturbances
that occur with changes in reproductive endocrine function, such as during the postpartum
period (Amin 2006, Nappi 2001, Epperson 2006).
Neurosteroids are metabolites of cholesterol-derived steroid hormones that are synthesized in
the brain and nervous system; they modulate the major inhibitory and excitatory central
nervous system (CNS) neurotransmitter systems: ↂ-aminobutyric acid (GABA) and
glutamate, respectively. Neurosteroids are among the most potent and effective modulators
of GABAA receptors and augment GABAergic inhibition (Belelli 2005). The powerful
anxiolysis that accompanies this potentiation of GABAA receptors has led to the speculation
that neurosteroid dysregulation plays a central role in the etiology of affective disorders,
including reproductive mood disorders, such as PPD (Amin 2006).
There is increasing evidence supporting the role of neurosteroids in affective dysregulation.
Allopregnanolone and pregnanolone have been shown to modulate the GABA receptor
positively (Majewska 1986). Several groups have demonstrated decreased allopregnanolone
levels in MDD, with an increase seen in both plasma and cerebrospinal fluid (CSF) following
successful antidepressant treatment (Uzunova 1998, Romeo 1998, Ströhle 1999,
Schüle 2006, Eser 2006, Schüle 2007). In addition, allopregnanolone has demonstrated
anxiolytic effects in several animal anxiety models (Bitran 1991; Wieland 1991;
Bitran 1993).
Allopregnanolone may also exert antidepressant effects by reducing the physiological impact
of stress, promoting neuroprotection, and protecting against the pro-inflammatory immune
activation and cytokine hypersecretion associated with MDD. In animals, allopregnanolone
increases in response to stress, reduces pain sensitivity, and is thought to restore physiologic
homeostasis following stress (Frye 1994, Morrow 1995). Allopregnanolone also exerts
neuroprotective effects by reducing the expression of pro-apoptotic proteins and apoptotic
DNA fragmentation (Djebaili 2005, Sayeed 2009), thereby reducing the cell death and gliosis
associated with depression (Glantz 2010, Shelton 2011). Neuroprotection is mediated by
immune regulation in depression (Licinio 1999), and allopregnanolone reduces the
expression of the pro-inflammatory cytokine TNF- (He 2004), which is elevated in
depressed individuals (Dowlati 2010). Thus, allopregnanolone modulates biological
processes dysregulated in MDD.
4.1.1.
Rationale for Allopregnanolone Treatment of PPD
Genetic susceptibility to affective dysregulation may be unmasked during periods of
reproductive hormone change such as during pregnancy and postpartum (Maguire 2008).
Maguire and Mody demonstrated that a GABA receptor subunit mutation was behaviorally
silent until the animal was exposed to pregnancy and the postpartum state, at which time the
dams showed depressive-like behaviors and cannibalized their offspring (Maguire 2008).
During pregnancy, the expression of the GABAA receptor ꭍ-subunit is down-regulated as
allopregnanolone levels increase, and at parturition, the expression of the GABAA receptor
-subunit is recovered in response to rapidly declining neurosteroid levels (Maguire 2009).
In contrast, the GABAA receptor ꭍ-subunit-deficient mice fail to adapt to the dramatic


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changes in allopregnanolone and experience depression-like and anxiety-like behavior and
abnormal maternal behaviors, which are reversed by administration of allopregnanolone
(Maguire 2008). This model provides compelling support for the hypothesis that changes in
neurosteroid concentrations during pregnancy and postpartum are capable of provoking
affective dysregulation, particularly in those with a genetically-determined susceptibility.
The capacity of changes in neurosteroids, such as allopregnanolone, to function as behavioral
switches suggests a potentially important treatment role of this hormone metabolite in
reproductive endocrine-related mood disorders such as PPD.
The onset of PPD symptoms coincides with the rapid decrease of the gonadal steroids
postpartum and has been reproduced in a pivotal clinical study (Bloch 2000). The authors
investigated the possible role of changes in gonadal steroid levels in PPD by simulating
2 hormonal conditions related to pregnancy and parturition in euthymic women, 8 with and
8 without a history of PPD. They induced hypogonadism with leuprolide, adding back
supra-physiologic doses of estradiol and progesterone for 8 weeks to simulate pregnancy.
They then withdrew both steroids under double-blind conditions to mimic the rapid decrease
of sex steroids upon delivery. Five of the 8 women with a history of postpartum depression
(62.5%) and 0% of the comparison group developed significant mood symptoms typical of
PPD during the withdrawal period.
Although progesterone levels were measured in this study, allopregnanolone was not.
However, since allopregnanolone is the major active metabolite of progesterone, it can be
assumed that the decrease in progesterone would cause a similar precipitate drop in
allopregnanolone levels, as observed in the postpartum period (Gilbert Evans 2005,
Paoletti 2006, Nappi 2001). These data provide direct evidence in support of the
involvement of progesterone and its metabolites in the development of postpartum
depression in a subgroup of women. Further, they suggest that women with a history of
postpartum depression are differentially sensitive to mood-destabilizing effects of gonadal
steroids (Bloch 2000).
Additional details regarding the role of allopregnanolone in the etiology of affective
disorders and its nonclinical pharmacology and pharmacokinetics are presented in the
Investigator’s Brochure.
4.2.
SAGE-547 Injection (Allopregnanolone)
Allopregnanolone is an endogenous, naturally occurring neuroactive steroid formed in the
corpus luteum of the ovary, adrenal cortex, and CNS (Holzbauer 1985, Ottander 2005,
Paul 1992). Allopregnanolone is a metabolite of progesterone created by the actions of 5-
reductase and 3- hydroxy-steroid dehydrogenase. Allopregnanolone is a potent positive
allosteric modulator of both synaptic and extra-synaptic GABAA receptors.
SAGE-547 Injection is a solution of 5 mg/mL allopregnanolone in Sterile Water for Injection
(SWFI), United States Pharmacopeia (USP), and 250 mg/mL betadex sulfobutyl ether
sodium buffered with 10 mM citrate at a pH of 6.0, and will be administered intravenously.
SAGE-547 Injection is also being developed for the treatment of adult patients with
refractory status epilepticus (RSE), inclusive of super refractory status epilepticus (SRSE),
who have not responded to standard treatment regimens, and investigated for the treatment of
adults with essential tremor.


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4.3.
Summary of Nonclinical and Clinical Experience with
Allopregnanolone or SAGE-547
4.3.1.
Nonclinical Pharmacology
The primary pharmacological effects of allopregnanolone or SAGE-547 are described earlier
in the rationale (Section 4.1 and Section 4.1.1). Secondary pharmacologic effects comprise
mainly the binding and consequent increased activity of steroid hormone receptors (androgen
receptor [(AR], progesterone receptor [PR], and estrogen receptor beta [ERß]), with some
evidence of inhibition at the highest doses (AR and estrogen receptor alfa . These
non-target effects may yield some adverse events in the clinic.
Nonclinical toxicology studies largely illustrate the sedative and anesthetic effects of
allopregnanolone and/or SAGE-547 at higher equivalent doses than the proposed dose for the
current study. PK data in animals indicate a short half-life and rapid clearance with a
moderate volume of distribution and cerebral levels higher than plasma. Refer to the
SAGE-547 Investigator’s Brochure for more details.
4.3.2.
Clinical Experience
The clinical PK data with intravenous (IV) administration of allopregnanolone in healthy
women, men, and women on oral contraceptives confirmed the PK observations in animals
of a short half-life (t½ 20-40 mins), Cmax achievable at approximately third trimester levels
(150 nM), rapid clearance and moderate volume of distribution (Vd). Refer to the SAGE-547
Investigator’s Brochure for more details.
There are currently no double-blind, placebo-controlled clinical efficacy data for SAGE-547
in PPD. An open-label, proof-of-concept study (547-PPD-201) evaluating the safety,
tolerability, pharmacokinetics, and efficacy of SAGE-547 Injection in the treatment of adult
female subjects with severe postpartum depression was started in 2014. This was the first 
study in this indication. Four women experienced significant improvement in depressive
symptoms within 24 hours after administration of open-label IV SAGE-547. During the
SAGE-547 treatment period, all 4 subjects rapidly achieved remission, as measured by the
HAMD total score. All 4 subjects also demonstrated consistent improvement as measured by
the CGI-I score. SAGE-547 was well-tolerated in all subjects treated with no serious adverse
events observed during therapy or during the 30-day follow-up period. A total of 14 adverse
events were reported in 4 subjects. The only adverse event reported in more than one subject
was sedation, observed in 2 subjects. This trial was initially planned to enroll 10 women,
however, due to the observed clinical activity, Study 547-PPD-201 was stopped early with
the plan to initiate a placebo-controlled clinical trial as rapidly as possible.
There are 6 reported studies of allopregnanolone, mainly in healthy individuals and none in
PPD (Timby 2006, Timby 2011a and 2011b, van Broekhoven 2007, Kask 2008, Kask 2009,
Navarro 2003). Data indicate that normal physiological allopregnanolone levels in women
vary during the menstrual cycle up to a maximum of 6 to 10 nM, with lower levels present
post-menopause (Genazzani 1998). The highest physiological levels observed are in the
third trimester of pregnancy, up to around 160 nM at time of delivery (Luisi 2000). Levels
drop precipitously to baseline (<10 nM) with removal of the placenta (Klak 2003).


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One study demonstrated subjective improvements in contentedness in women
(van Broekhoven 2007). The clinical safety data are presented below in the Risks and
Benefits section (Section 4.4).
4.4.
Potential Risks and Benefits
In the recently completed open-label clinical trial of SAGE-547 in PPD (547-PPD-201), a
total of 14 adverse events were reported in 4 subjects. The only adverse event reported in
more than one subject was sedation, observed in 2 subjects.
Consistent with these observations, published reports of human administration of exogenous
allopregnanolone indicate that for exposures in men and women up to 150 nM, the most
commonly reported adverse events (AEs) were sedation (recorded as sleepiness or tiredness),
feelings of intoxication (like alcohol), flushing, vertigo, mild nausea, impaired episodic
memory, and mild headache (Timby 2006, 2011a, and 2001b; van Broekhoven 2007). One
subject experienced what was potentially a withdrawal effect, an anxiety attack
(Timby 2011b). No serious AEs (SAEs) were reported in the 6 clinical studies conducted to
date (Timby 2006, Timby 2011a and 2011b, van Broekhoven 2007, Kask 2008, Kask 2009,
Navarro 2003).
There is also a potential risk of supra-additive sedative effects with other drugs interacting
with the GABAA receptor, such as benzodiazepines and anti-epileptic medications
(Norberg 1999); therefore, the Investigator is advised to avoid co-medication if possible and
to exercise caution with these drug classes. As this is one of the first clinical trials of
SAGE-547 in PPD, the potential benefits in this population are unknown, although the risks
are likely to be similar to those mentioned above. Given the nonclinical rationale and the
fact that endogenous allopregnanolone in humans appears to play a role in psychiatric
disorders such as major depression, premenstrual dysphoric disorder, and anxiety disorders, it
is possible that subjects may have a clinical benefit at the exposures selected for this trial. In
view of the limited nature of the demonstrated risks of exogenous allopregnanolone infusion
and the potential for benefit in severe PPD, there is a favorable benefit-risk evaluation for the
conduct of the present study.
4.5.
Study No. 547-PPD-202
4.5.1.
Study Population
This study will evaluate the efficacy, safety, and pharmacokinetics (PK) of SAGE-547
Injection in the treatment of adult female subjects diagnosed with severe or moderate
postpartum depression.
Parts A and B of this study will study women with severe PPD, and Part C will study women
with moderate PPD (Parts B and C will run concurrently). Moderate severity level will be
studied because the pathogenesis of severe postpartum depression may not be generalized to
those patients with a less severe form of illness. For example, outside of postpartum
depression, findings suggest that patient’s treatment-resistant depression may respond more
favorably to certain pharmacotherapy options such as ketamine (Coyle 2015). Therefore, in
order to determine the efficacy of SAGE-547 in women with less severe levels of symptoms,


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a separate group with moderate PPD with the same doses of the study drug used in the severe
group will be investigated.
4.5.2.
Route of Administration, Dosage, Dosage Regimen, and Treatment Period
SAGE-547 Injection or placebo will be administered over a 60 hour period by an IV infusion
according to the dose regimens shown in Table 2 and Table 3 (see Section 10.1.1).
The specific infusion dose of SAGE-547 Injection will be calculated based on weight for
each subject. Infusion bags will be changed every 24 hours. Details about the preparation
and administration of the study drug infusions will be included in the Pharmacy Manual.
4.5.3.
Dose Rationale
The infusion rate of SAGE-547 to be studied in Parts A and C of this study was chosen to
achieve a mean exposure of 150 nM, roughly equivalent to the highest endogenous
concentrations measured in third trimester pregnancy at approximately 157 nM (Luisi 2000).
Since pregnant women tolerate this level without apparent AEs, 150 nM was selected as the
target exposure for this study. This level of exposure has already been achieved in Study 
547-PPD-201 as well at higher levels in a study in subjects with essential tremor (Study 
547-ETD-201) and subjects with super refractory status epilepticus (Study 547-SSE-201),
with no drug-related SAEs reported. Since the most common adverse event in 547-ETD-201
was sedation, dose adjustment rules are included in this protocol to ensure that all subjects
can remain on treatment for 60 hours. A similar Cmax was also achieved in several other
studies conducted with intravenous allopregnanolone (Timby 2011b), with excellent
tolerability (see the current SAGE-547 Investigator’s Brochure for details of safety profile).
The selection of exposure in the current trial is based on a cautious approach adapted to the
anticipated benefit-risk in the PPD patient population, and on previous experience from the
ongoing clinical trials of SAGE-547 in adult subjects with SRSE (Study 547-SSE-201) and
of SAGE-547 in female subjects with PPD (Study 547-PPD-201). In the ongoing SRSE trial,
as determined by simulation, loading and maintenance infusions are required to achieve the
target exposure. In contrast, in the current trial, subjects will instead begin treatment with a
4-hour dose-titration phase. The starting dose is approximately 9- to 18-fold lower than the
NOAEL observed in rats and dogs, although this is not the first in human study. In Parts A
and C, doses will be increased as follows: 30 μg/kg/hour (0-4 hours), then 60 μg/kg/hour
(4-24 hours), then 90 μg/kg/hour (24-52 hours), followed by a decrease to 60 μg/kg/hour
(52-56 hours), and 30 μg/kg/hour (56-60 hours).
In Part B, a lower target dose will also be explored (ie, 60 μg/kg/hour). The use of this dose 
is based on observations in the open-label 547-PPD-201 study in which subjects achieved
substantial improvements in their HAMD scores within the first 12 hours of the SAGE-547
infusion. In this study, subjects received a dose of 21.5 Κ۷۷ for the first 4 hours, then 43
Κ۷ for the next 4 hours, and then 64.5 Κ۷۷ for the following 4 hours before receiving
the target dose of 86 Κ۷Ǒ۷ at 12 hours. Therefore, the 12-hour data from 547-PPD-201
suggests that SAGE-547 at target doses of 60 Κ۷Ǒ۷ may also be efficacious in reducing
depressive symptoms associated with PPD.
Subjects will be treated in an inpatient setting and continually monitored for safety, and if
any severe tolerability issues arise, the infusion will be terminated. The Stanford Sleepiness


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Scale (SSS) will be regularly administered to monitor sedation and allow dose adjustment
based on tolerability, with a formal dose interruption and reduction scheme implemented for
this and other AEs.


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5.
ETHICS
5.1.
Institutional Review Board or Independent Ethics Committee
This trial will be initiated only after the protocol has been reviewed and approved by the
Institutional Review Board (IRB) where the study is to be conducted. The IRB must meet all
US Food and Drug Administration (FDA) requirements governing IRBs (Code of Federal
Regulations [CFR], Title 21, Part 56). The same applies for the implementation of changes
introduced by an amendment.
5.2.
Ethical Conduct of the Study
This study will be conducted according to the principles of the World Medical Association
Declaration of Helsinki and the most recent amendment (2008).
The Sponsor, the Medical Monitor, and the Investigator must comply with all instructions,
regulations, and agreements in this protocol, and must also conduct the study in accordance
with International Council on Harmonisation (ICH) Guidelines on Good Clinical Practice
(GCP) standards as well as local regulations.
5.3.
Subject Information and Informed Consent
Prior to subject participation in the trial, written informed consent must be obtained from
each subject according to ICH GCP and in accordance with local regulations. Written
informed consent is required for each subject prior to any testing under this protocol not
considered standard of care, including screening tests, SAGE-547 infusion, and study
evaluations. Each subject’s signature must be dated by each signatory and the informed
consent form (ICF) retained by the investigator as part of the trial records. As an additional
assessment, the ICF will contain provisions for optional consent for the collection of blood 
for genetic testing during Screening and the collection of breast milk for the duration of the
60-hour SAGE-547 infusion and up to Day 3 for biobanking and PK analysis purposes. The
ICF, as specified by the clinical site’s IRB, must follow the Protection of Human Subjects
regulations listed in the CFR, Title 21, Part 50.
It is the responsibility of the Investigator to obtain consent and to provide the subject a copy
of the signed and dated ICF. The ICF for subject participation must also be available as part
of the subject’s file for review by the site’s dedicated study monitor.
All ICFs used in this study must be approved by the appropriate IRB and by the Sponsor.
The ICF must not be altered without the prior agreement of the relevant IRB and the
Sponsor.


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6.
STUDY OBJECTIVES
6.1.
Primary Objective
The primary objective of this study is to determine if SAGE-547 Injection infused
intravenously for 60 hours at up to 90 Κ۷Ǒ۷ reduces depressive symptoms in subjects with
severe PPD compared to placebo injection as assessed by the change from baseline in
HAMD total score. This objective applies to both Parts A and B.
6.2.
Secondary Objectives
The secondary objectives of the study apply to Parts A, B and C unless otherwise stated, and
are:

To determine if SAGE-547 infusion at up to 60 Κ۷۷ for 60 hours reduces
depressive symptoms in subjects with severe PPD compared to placebo injection
as assessed by the change from baseline in HAMD total score (applies to Part B 
only).

To determine if SAGE-547 Injection infused intravenously for 60 hours reduces
depressive symptoms in subjects with moderate PPD compared to placebo
injection as assessed by the change from baseline in HAMD total score (applies to 
Part C only).

To determine if SAGE-547 Injection infused intravenously for 60 hours reduces
depressive symptoms compared to placebo injection as assessed by HAMD
response, HAMD remission, change from baseline in Montgomery-Asberg
Depression Rating Scale (MADRS) total score, Clinical Global Impression –
Improvement (CGI-I) response, and changes from baseline in HAMD subscale
and individual item scores

To determine if SAGE-547 Injection infused intravenously for 60 hours reduces
other mood symptoms compared to placebo injection as assessed by changes from
baseline in the Generalized Anxiety Disorder 7-Item Scale (GAD-7) total score

To determine if SAGE-547 Injection infused intravenously for 60 hours increases
sedation levels compared to placebo injection as assessed by the changes from
baseline in Stanford Sleepiness Scale (SSS) score

To evaluate the safety and tolerability of SAGE-547 Injection compared with
placebo as assessed by the incidence of adverse events, vital sign measurement,
clinical laboratory evaluations, electrocardiogram (ECG) parameters, and the
Columbia Suicide Severity Rating Scale (C-SSRS)
6.3.
Exploratory Objectives
The exploratory objectives of the study are:

To determine if SAGE-547 Injection infused intravenously for 60 hours reduces
subject-reported depressive symptoms compared to placebo injection as assessed
by the change from baseline in Edinburgh Postnatal Depression Scale (EPDS)


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total score and the change from baseline in Patient Health Questionnaire (PHQ-9)
total score

To determine if SAGE-547 Injection infused intravenously for 60 hours improves
maternal behaviors compared to placebo injection as assessed by the change from
baseline in Barkin Index of Maternal Functioning (BIMF) total and sub-scale
scores
6.4.
Pharmacokinetic Objective
The pharmacokinetics objectives of the study are:

To assess the pharmacokinetic (PK) profile of SAGE-547, metabolites of
SAGE-547, and betadex sulfobutyl ether sodium (SBECD) and the concentration
of SAGE-547 in breast milk, when possible


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7.
INVESTIGATIONAL PLAN
7.1.
Overview of Study Design
This is a 3-part multicenter, randomized, double-blind, parallel-group, placebo-controlled
study of the efficacy, safety, and pharmacokinetics of SAGE-547 Injection in adult female
subjects diagnosed with severe and moderate PPD. The study design for Parts A and C is
presented in Figure 1 and the study design for Part B is presented in Figure 2 (Parts B and C 
will run concurrently). For all parts, the study will consist of an up to 5-day Screening
Period (Day -5 to -1), 3-day (60-hour) Treatment Period, and 30-day Follow-up Period.
Subjects must remain as inpatient during the study Treatment Period, which is approximately
60 hours/2.5 days in duration. The Screening Period assessments may be conducted on an
inpatient or an outpatient basis. The Follow-Up Period assessments are conducted on an
outpatient basis.


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Figure 1:
Study Design - Part A and Part C
Figure 2:
Study Design - Part B
SAGE-547 Injection or placebo will be administered at the study center. Subjects will be
monitored for safety during the Treatment and Follow-up Periods (through Study Day 30
[±3 days]) including monitoring for AEs/SAEs, routine clinical laboratory assessments,
physical examination, vital signs, and ECG.


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All study-related procedures will occur after written informed consent is obtained at the
Screening Visit, which will occur on any one calendar day during the Screening Period
window (Day -5 through Day -1). If applicable, standard of care data collected prior to
obtaining informed consent may also be included as screening data, if appropriate, such as
laboratory tests, ECG, physical examination, and vital signs conducted within the preceding
48 hours, as long as the requirement for the screening assessment to be collected
retrospectively is met in full. If applicable, to ensure protocol compliance, any standard of
care data eligible for inclusion as screening data must include the precise nature and timing
of data collection.
The end of the Screening Period coincides with the beginning of the Treatment Period. The
Treatment Period is the period of Day 1 of SAGE-547 IV infusion through completion of the
infusion on Day 2 and up to Day 3. Subjects will be confined to the study center from Day 1
until after the 60-hour assessments have been conducted on Day 3.
In Parts A and C, once subjects are confirmed as eligible for the study, they will be
randomized to one of 2 treatment groups (SAGE-547 90 μg/kg/hour or placebo) on a 1:1
basis. On the morning of dosing (Day 1), subjects will begin a 4-hour dose titration period of
30 μg/kg/hour (0-4 hours), then 60 μg/kg/hour (4-24 hours), then 90 μg/kg/hour
(24-52 hours); followed by a decrease to 60 μg/kg/hour (52-56 hours), and 30 μg/kg/hour
(56-60 hours). Subjects in the placebo group will receive infusion rates equivalent to the
90 μg/kg/hour group.
In Part B, once subjects are confirmed as eligible for the study, they will be randomized to
one of 3 treatment groups (SAGE-547 60 μg/kg/hour, SAGE-547 90 μg/kg/hour, or placebo)
on a 1:1:1 basis. For the 60 μg/kg/hour group, subjects will receive 30 μg/kg/hour
(0-4 hours), then 60 μg/kg/hour (4-56 hours), followed by 30 μg/kg/hour (56-60 hours). For 
the 90 μg/kg/hour group, subjects will begin a 4-hour dose titration period of 30 μg/kg/hour 
(0-4 hours), then 60 μg/kg/hour (4-24 hours), then 90 μg/kg/hour (24-52 hours); followed by 
a decrease to 60 μg/kg/hour (52-56 hours), and 30 μg/kg/hour (56-60 hours).  Subjects in the 
placebo group will receive infusion rates equivalent to either the 60 μg/kg/hour or
90 μg/kg/hour group. Parts B and C will run concurrently.
See dose regimen presented in Section 10.1.1. Total SAGE-547 Injection or placebo dosing
will occur over 60 hours.
Trial-specific assessments for safety, PK, efficacy, and exploratory outcome measures will be
completed at pre-specified times over a 72-hour period during the Treatment Period:

The safety and tolerability of SAGE-547 Injection will be assessed by AEs,
clinical laboratory measures, physical examinations (including cognitive and
mental health examinations), vital signs, ECG, use of concomitant medication,
and the Columbia Suicide Severity Rating Scale (C-SSRS) during the Screening,
Treatment, and Follow-up Periods (through Study Day 30 [±3 days])

Plasma will be collected to formally assay for SAGE-547, metabolite, and
SBECD levels prior to dosing through the treatment period and up to 12 hours
post infusion on Day 3


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Primary efficacy assessment of the HAMD will be completed as scheduled during
the Screening, Treatment, and Follow-up Periods (through Study Day 30
[±3 days])

Secondary efficacy assessments of MADRS, CGI-I, EPDS, Generalized Anxiety
Disorder 7-Item Scale (GAD-7), PHQ-9 will be completed as scheduled during
the Screening, Treatment, and Follow-up Periods (through Study Day 30
[±3 days])

Concentrations of SAGE-547 in breast milk will be measured for those subjects
who consent to giving breast milk samples
The end of the Treatment Period coincides with the beginning of the Follow-up Period.
Subjects will attend the clinic for safety follow-up assessment at 1 week (7±1d) and 1 month
(30±3d) after the initiation of the study drug infusion.
Scheduled assessments for all safety, PK, efficacy, and exploratory outcome measures
planned for the trial are summarized in Table 1. All subjects who receive treatment with
SAGE-547 are to complete all study assessments through Study Day 30 (±3 days).
The Medical Monitor will review AEs on an ongoing basis.
7.2.
Blinding and Randomization
This is a double-blind study. Subjects will be randomized to SAGE-547 or placebo; subjects,
clinicians, and study team will be blinded to treatment allocation. The pharmacist, who will
prepare the infusion bags according to the randomization schedule, and an unblinded
Monitor, who will perform drug accountability during the study, will be unblinded.
Subjects will be randomly assigned to receive SAGE-547 Injection or placebo according to a
computer-generated randomization schedule.
Only the clinic pharmacist, who is responsible for preparing the infusions, will be given a
copy of the randomization schedule. In the event of a medical emergency, the pharmacist
may reveal actual infusion contents to the primary investigator, who should also alert Sage of
the emergency (see Section 14.4) for more details related to unblinding). In all cases where
the study drug allocation for a subject is unblinded, pertinent information (including the
reason for unblinding) must be documented in the subject’s records and on the electronic
case report form (eCRF). If the subject or study center personnel have been unblinded, the
subject will be terminated from the study.


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8.
SELECTION AND WITHDRAWAL OF SUBJECTS
8.1.
Inclusion Criteria
The following inclusion criteria must be met for individuals to be eligible for the trial:
1. Subject has signed an ICF prior to any study-specific procedures being performed
2. Subject is an ambulatory female aged between 18 and 45 years of age
3. Subject is in good physical health and has no clinically significant findings, as
determined by the Investigator, on physical examination, 12-lead ECG, or clinical
laboratory tests
4. Subject agrees to adhere to the study requirements
5. Subject either must have ceased lactating at Screening; or if still lactating or actively
breastfeeding at Screening, must agree to temporarily cease giving breastmilk to their
infant(s) from just prior to receiving study drug through 9 days (Study Day 12) after
the end of the infusion.
6. Subject must have a negative pregnancy test at Screening and Day 1 prior to the start
of study drug infusion
7. Subject has had a Major Depressive Episode that began no earlier than the third
trimester and no later than the first 4 weeks following delivery, as diagnosed by
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I)
8. For Part A and B, subject has a HAMD total score of ȑ 	 at Screening and Day 1
(prior to randomization). For Part C, subject has a HAMD total score of ȑ ẇand ₢
at Screening and Day 1 (prior to randomization)
9. Subject is 6 months postpartum
10. Subject is willing to delay start of other antidepressant or anxiety medications and
any new pharmacotherapy regimens, including prn benzodiazepine anxiolytics, until
the study drug infusion and 72-hour assessments have been completed
11. Subject has no detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus
(HCV), and human immunodeficiency virus (HIV) antibody at Screening
12. Subject must use one of the following methods of birth control during participation in
the study and for 30 days following the end of the study drug infusion:

Total abstinence (no sexual intercourse)

Hormonal contraceptives (birth control) including birth control pills, implantable
or injectable contraceptives (Norplant® or Depo-Provera®)

A barrier form of contraception such as a condom or occlusive cap with a
spermicide

An intrauterine device (IUD)


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8.2.
Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria:
1. Recent history or active clinically significant manifestations of metabolic, hepatic, renal,
hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal,
dermatological, urogenital, neurological, or eyes, ears, or nose and throat disorders, or
any other acute or chronic condition that, in the Investigator’s opinion, would limit the
subject’s ability to complete or participate in this clinical study
2. Known allergy to progesterone or allopregnanolone
3. Active psychosis per Investigator assessment
4. Attempted suicide associated with index case of postpartum depression
5. Medical history of seizures
6. Medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder.
7. History of active alcoholism or drug addiction (including benzodiazepines) in the
12 months prior to Screening
8. Exposure to another investigational medication or device within 30 days prior to
Screening
9. Administration of psychotropics that have been initiated within 14 days prior to
Screening and are not being taken at a stable dose.
8.3.
Subject Withdrawal/Study Termination
8.3.1.
Withdrawal/Discontinuation of Individual Subjects
The reasons for study drug discontinuation and/or subject withdrawal from the study must be
recorded in the subject’s electronic case report form (eCRF). The Investigator must notify
the Sponsor and/or the Medical Monitor immediately when a subject has been discontinued/
withdrawn for any reason, including withdrawal due to an AE.
Subjects who do not have at least one efficacy observation after 12 hours of SAGE-547
infusion are not considered evaluable for the efficacy assessment and may be replaced.
8.3.2.
Subject Withdrawal from the Study
Subjects may withdraw from the study at any time for any reason without compromising the
subject’s medical care. The Investigator will also withdraw subjects upon the request of
Sage Therapeutics or upon termination of the study.
8.3.3.
Discontinuation of Study Drug by the Investigator
If it is necessary for the Investigator to discontinue the study drug earlier than planned,
subjects should continue to be followed per protocol to capture safety and efficacy
assessments for the duration of the study period.


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The Investigator may withdraw the subject from the study drug for any of the following
reasons:

The subject is unwilling or unable to adhere to the protocol

The subject experiences an intolerable AE

During the course of the study, the subject develops symptoms or conditions
listed in the exclusion criteria

Other medical reason, at the discretion of the Investigator and/or the Medical
Monitor
Subjects who discontinue the study due to an AE, regardless of Investigator-determined
causality, should be followed until the event is resolved, considered stable, or the Investigator
determines the event is no longer clinically significant.
8.3.4.
Study Termination
Sage Therapeutics may terminate this study or any portion of the study at any time for safety
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to
subjects, or for administrative reasons. In the event of study termination, Sage Therapeutics
will provide written notification to the Investigator. Investigational sites must promptly
notify their IRB and initiate withdrawal procedures for participating subjects.


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9.
INVESTIGATIONAL PRODUCT
9.1.
Identity of Investigational Product
SAGE-547 Injection (allopregnanolone)
9.2.
Clinical Supplies
9.2.1.
SAGE-547
SAGE-547 Injection and ancillary supply kits containing IV administration bags, solution
sets, and IV bag labels will be provided to the sites.
SAGE-547 Injection is a preservative-free, sterile, clear, colorless 5 mg/mL solution of
SAGE-547 (allopregnanolone) and 250 mg/mL betadex sulfobutyl ether sodium buffered
with 10 mM citrate at a pH of 6.0, intended for IV injection. All inactive excipients used in
the formulation are compendial grade and conform to current United States Pharmacopeia
(USP) and European Pharmacopeia (Ph. Eur.) standards. The product is aseptically
processed, sterile filtered, and filled into 20 mL Type 1 parenteral glass vials with West
FluroTec® coated stopper container closure systems, under current Good Manufacturing
Practice (cGMP) conditions. SAGE-547 Injection is intended to be used as a single-use vial.
An appropriate number of single-use vials to support the dosing duration of the study are
packaged and delivered to the site. SAGE-547 Injection vials should be stored under
refrigerated conditions (2–8°C). Ancillary supply kits should be stored at controlled room
temperature (20–25°C).
All study drug labels will contain information to meet the applicable regulatory requirements.
9.2.2.
Placebo
Placebo will be identical to SAGE-547 and presented in identical vials. Placebo will be
manufactured in a similar way to SAGE-547 and consisting of the same formulation without
allopregnanolone. Placebo vials should be stored under refrigerated conditions (2–8°C).
9.3.
Preparation of SAGE-547 Injection or Placebo for Dosing
The pharmacy will be responsible for preparing SAGE-547 Injection or placebo for subject
dosing. The prepared admixture will be administered at room temperature. The prepared
admixture will be assigned a room temperature (20–25 °C) storage shelf life of 30 hours from
time of compounding.
SAGE-547 Injection or placebo is not intended to be administered to subjects undiluted.
Each single-use vial of SAGE-547 Injection, which is hypertonic, will require dilution with
an appropriate volume of Sterile Water for Injection (SWFI) to render it isotonic. Refer to
the Pharmacy Manual for specific instructions regarding infusion preparation and
administration instructions.


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9.4.
Administration and Accountability
The pharmacy will maintain accurate records of all investigational drug product supplies
received, stored, dispensed, and discarded. Accurate records will be kept regarding the
volume of SAGE-547 Injection or placebo used for each IV preparation, as well as the
required infusion rate (or rates), and the date and time of preparation. Reasons for departure
from the expected dosing regimen must be recorded. To satisfy regulatory requirements
regarding drug accountability, all study medication needs to be reconciled in full.
Refer to the Pharmacy Manual for complete details on preparation and administration.


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10.
TREATMENT OF SUBJECTS
10.1.
Dosing Schedule
This is a double-blind study. Subjects will be randomized to receive 60 hours of intravenous
treatment with either SAGE-547 Injection or placebo. In Parts A and C, subjects randomized
to SAGE-547 will receive the target dose of 90 μg/kg/hour; in Part B, SAGE-547 subjects
will receive target doses of either 60 or 90 μg/kg/hour.
The timing of infusion relative to the overall trial designs are shown in Figure 3 and Figure 4.
Figure 3:
Trial Design and Timeline for Dosing – Parts A and C
Figure 4:
Trial Design and Timeline for Dosing – Part B
Clinical supply and preparation of SAGE-547 Injection for dosing is described Section 9.2
and Section 9.3, respectively.


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10.1.1.
Dose Regimen
The specific infusion dose of SAGE-547 Injection will be calculated based on weight
(obtained at screening) for each subject and administered according to dose regimen shown
in Table 2 and Table 3). The infusion rates are the same for all subjects within a particular
dosing period (0-4 hours, 4-24 hours, etc.).
Table 2:
Infusion rates for Part A and C
Infusion Rate (µg/kg/hour)
SAGE-547 Dose
Day 1
0-4 hours
Day 1
4-24 hours
Day 2-3
24-52 hours
Day 3
52-56 hours
Day 3
56-60 hours
90 µg
30
60
90
60
30
Table 3:
Infusion Rates for Part B
Infusion Rate (µg/kg/hour)
SAGE-547 Dose
Day 1
0-4 hours
Day 1
4-24 hours
Day 2-3
24-52 hours
Day 3
52-56 hours
Day 3
56-60 hours
60 µg
30
60
60
60
30
90 µg
30
60
90
60
30
Dosing is to begin in the morning (on Day 1) to avoid awakening subjects during the night
for completion of study assessments.
If any subject has an SSS score of ȑ  for 2 or more consecutive assessments or an SSS score
of ȑҟ for a single occurrence during normal waking hours, the infusion rate for this subject
will be decreased to the next lowest infusion dose level (or turned off if this occurs on the
30 μg/kg/hour dose level). Please refer to Section 11.1.8 for more details.
10.1.2.
Route of Administration
SAGE-547 Injection is intended for IV administration only. The compatibility of SAGE-547
with other drugs is unknown, and the product should be administered via a dedicated
peripheral IV line with the supplied study-specific IV administration bags and lines.
10.1.3.
Treatment Period
Total dosing with SAGE-547 or placebo will occur over 60 hours, including a 24-hour dose
titration, a 28-hour maintenance infusion, and an 8-hour taper.
10.1.4.
Dosing of Intravenous SAGE-547 in the Case of AEs
Since allopregnanolone levels in the proposed clinical trial are similar to physiological levels
seen in the third trimester of pregnancy, and all the AEs reported with SAGE-547 or
allopregnanolone to date in healthy volunteers and subjects with postpartum depression were


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mild and non-serious, it is anticipated that the AEs associated with SAGE-547 in this study 
will be mild and manageable without dose interruption or reduction. Based on the safety data 
in subjects with PPD collected to date, no subjects reported events that were serious or severe 
and none led to discontinuation of study drug (2 subjects reported sedation that lead to a dose 
reduction, one of these subjects also reported dizziness; one subject reported rash that lead to 
a dose reduction; refer to the current Investigator’s Brochure for more information).
However, in the case of severe or life-threatening AEs occurring, the investigator is advised
to stop study treatment until the AE resolves and only resume study treatment if it is
considered to be in the best interest of the subject based on the Investigator’s assessment.
Resumption of infusion at the next lowest dose (or turned off if this event occurs on the
30 μg/kg/hour dose level) for one hour, followed by re-escalation to the maintenance rate,
may be considered to address potential recurrence of the AE. If the AE recurs, study 
treatment should be permanently discontinued.
10.2.
Dosing Compliance
Investigational product will be prepared in the site pharmacy, administered as a continuous
IV infusion by the study staff, and will be documented in the study record. There should be
no adjustments in dosing except those described in Section 10.1.4.
10.3.
Concomitant Medications and Restrictions
10.3.1.
Concomitant Medications
Subjects will receive standard of care for adult female patients diagnosed with PPD. Any
concomitant medication determined necessary for the welfare of the subject may be given at
the discretion of the Investigator at any time during the study under the guidance outlined in
Section 10.3. All concomitant medications should be documented throughout the study from
Screening through Day 30 (±3 days) and recorded on the eCRF. Prior medications (ie, those
taken prior to signing of informed consent) that required wash-out for study entry will also be
documented.
10.3.2.
Prohibited Medications
Restrictions on specific classes of medications include the following:

Initiation of new antidepressant therapy is prohibited upon admission to the study
center for those eligible subjects who desire study participation. Those subjects
already taking an antidepressant at the time of study entry (and meeting all study
inclusion criteria) will be permitted to remain on the pre-existing antidepressant at
their current dose if they were on this medication for at least 30 days prior to study
enrollment.


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Benzodiazepines are to be avoided as much as possible. Eligible subjects taking a
benzodiazepine at the time of study entry will be permitted to continue to take their
current dose of the benzodiazepine (to prevent acute withdrawal), but no new
benzodiazepine use will be permitted during the course of the study. Particular
attention should be paid to assessment of AEs and implementation of the dose
interruption and reduction scheme in subjects on concomitant benzodiazepines since
they have been shown to have a supra-additive effect with pregnanolone in an animal
model of anesthesia (Norberg 1999).

The use of hypnotics for sleep/insomnia such as Ambien® and trazodone are to be
avoided.

Anticonvulsants and atypical antipsychotics are to be avoided if possible and are not
to be initiated at any time during active treatment period (60 hours). However, if a
subject is taking one of these medications for at least 30 days prior to study
admission, they will be permitted to remain on this medication, at their current dose
(no dose adjustments are allowed).

SAGE-547 has demonstrated inhibitory effects on cytochrome P-450 (CYP) 2C9
(CYP2C9). The following medications are primarily metabolized by CYP2C9 and
therefore are prohibited during SAGE-547 administration: fluconazole and
miconazole (antifungal), amentoflavone (constituent of Ginkgo biloba and St. John’s
Wort), sulfaphenazole (antibacterial), valproic acid (anticonvulsant, mood-
stabilizing), and apigenin. See Appendix 10 for a complete list.


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11.
STUDY ASSESSMENTS
11.1.
Safety Assessments
The safety and tolerability of SAGE-547 Injection will be evaluated by summarization of
AEs by frequency, severity and seriousness, mean changes from baseline in clinical
laboratory measures, physical examination, vital signs, ECGs, and concomitant medication
usage. Suicidality will be monitored using the C-SSRS. All safety assessments should be
performed per the study center’s standard of care and will be collected according to the
Schedule of Events (Table 1). All safety assessments are to be completed within
±30 minutes of the scheduled time point.
In addition to the schedule outlined in Table 1, completion of safety assessments including
physical examination, vital signs, and clinical laboratory tests should occur in the event of an
emergency or SAE, when possible.
11.1.1.
Adverse Events
Adverse events will be collected after the ICF has been signed through the end of the study
(see Section 14.2.1 for additional details). Medical conditions or adverse events that occur
after the ICF has been signed and prior to completion of Screening will be captured on the
Medical History eCRF.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA™) coding system (version 17.0 or higher).
11.1.2.
Clinical Laboratory Tests
Blood samples will be collected for hematology, serum chemistry, coagulation, and specific
hormone parameters, hepatitis, human immunodeficiency virus (HIV), pregnancy and genetic
analysis. Urine samples for urinalysis and selected drugs of abuse will also be collected. All
samples will be analyzed at the central laboratory. Patients may be considered eligible for
the study based on local laboratory results, however screening samples must also be sent to
the central laboratory. Both local and central Screening labs must adhere to the visit window
provided in the Schedule of Events (Table 1).
These assessments will be performed in accordance with the Schedule of Events (Table 1)
and as outlined individually below.
All clinical laboratory test results outside the reference range will be interpreted by the
Investigator as Abnormal; not clinically significant (NCS) or Abnormal; clinically significant
(CS). Screening results considered Abnormal; CS will be recorded as medical history.
Clinical laboratory results that are Abnormal; CS during the study and indicate a worsening
from baseline will be considered AEs, assessed according to Section 14, and recorded in the
eCRF.


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11.1.2.1.
Hematology, Serum Chemistry, Coagulation
Blood samples will be collected for analysis of the following:

Hematology: complete blood count (CBC) including white blood cell (WBC) count
with differential (basophils, eosinophils, lymphocytes, monocytes, and neutrophils)
platelet count, red blood cell (RBC) count, hemoglobin (Hgb) and hematocrit (Hct),
mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH)

Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT),
aspartate aminotransferase (AST), bilirubin (total), blood urea nitrogen (BUN),
calcium, chloride, creatinine, gamma glutamyl transferase (GGT), glucose phosphate,
potassium, sodium, total protein, and triglycerides (Screening only)

Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT),
and international normalized ratio (INR)
11.1.2.2.
Hepatitis and HIV
Blood samples will be collected for analysis of the following:

Hepatitis: hepatitis B virus surface antigen (HBsAg), antibody against hepatitis C
virus (anti-HCV)

HIV: antibody against human immunodeficiency virus type 1/2 (anti-HIV 1/2)
11.1.2.3.
Hormones and Exploratory Biochemistry
Blood samples will be collected and may be analyzed for thyroid stimulating hormone
(TSH), estrogen, progesterone, progesterone metabolites, oxytocin, tryptophan, kynurenine,
and markers of inflammation.
11.1.2.4.
Pregnancy Test
All subjects will be tested for pregnancy by serum hCG at Screening and urine hCG on
Day 1 prior to administration of study drug. Subjects with a positive pregnancy test at
Screening or Day 1will be ineligible for study participation.
11.1.2.5.
Genetic Testing
A blood sample for genetic testing will be collected at screening, where consent is given.
The objective of this research is to collect and store blood samples for possible DNA
extraction and exploratory research into how genes or specific genetic variation may
influence response (ie, distribution, safety, tolerability, and efficacy) to SAGE-547. Specific
genetic variations of interest include but are not limited to: classes of metabolizing enzymes
(eg, Cytochrome P450 supra-family genes), genes encoding enzymes involved in the
production and metabolism of allopregnanolone (eg, AKR1C4 (3a-hydroxysteroid
dehydrogenase)), genes associated with the GABA receptor (eg, GABRA1-A6,
GABRB1-B3, GABRD, GABRE, GABRG1-3) and genes associated with the production and
degradation of GABA.


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Future research may suggest other genes or gene categories as candidates for influencing not
only response to SAGE-547 but also susceptibility to disorders for which SAGE-547 may be
evaluated. Thus, the genetic research may involve study of additional unnamed genes or
gene categories, but only as related to disease susceptibility and drug action.
11.1.2.6.
Urinalysis
Urinalysis will include assessment of bilirubin, glucose, ketones, leukocytes, nitrite, pH,
protein, and specific gravity.
11.1.2.7.
Drugs of Abuse and Alcohol
Urine assessment for selected drugs of abuse (including amphetamines, barbiturates,
benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine and propoxyphene). Use of
benzodiazepines at screening is not necessarily exclusionary, as subjects will be allowed to
take psychotropics that have been initiated at least 14 days prior to admission to the study
center at a stable dose (see Section 10.3.2). Alcohol will be assessed in plasma at Screening
and in serum, via breathalyzer or urine dipstick on Day 1.
11.1.3.
Physical Examination
Body weight and height will be measured at Screening. Body mass index (BMI) will be
programmatically calculated in the eCRF.
Any condition present at the post-treatment physical examination that was not present at or
worsened since the baseline examination is to be documented as an AE. Whenever possible,
the same individual is to perform all physical examinations. Physical examinations will
include assessment of body systems (eg, HEENT, heart, lungs, abdomen, and extremities) as
well as cognitive and neurological examination and mental status examination.
11.1.4.
Vital Signs
Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure
(supine and standing). A full set of vital signs will be obtained at all specified time points
(±30 minutes), unless the subject is asleep between the hours of 23.00h and 06.00h each day.
11.1.5.
Pulse Oximetry
Pulse oximetry will be monitored continuously from H0 until H60, and checked
approximately every 2 hours, including during the overnight hours, or at the alarm. If there
is an indication of oxygen desaturation, this should be recorded as an adverse event at the
discretion of the Investigator. No pulse oximetry data will be recorded in the eCRF.
11.1.6.
ECG
A baseline 12-lead ECG will be performed during Screening to assess the presence of any
current or historical cardiovascular conditions. The following ECG parameters will be
recorded: heart rate, PR, QRS, QT, and QTc. Subjects with clinically significant
abnormalities should not be entered into the study.


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11.1.7.
Columbia Suicide Severity Rating Scale (C-SSRS)
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale
consists of a pre-dose evaluation that assesses the lifetime and recent experience of the
subject with suicidal ideation and behavior, and a post-baseline evaluation that focuses on
suicidality since the last study visit. The C-SSRS includes “yes” or “no” responses for
assessment of suicidal ideation and behavior as well as numeric ratings for severity of
ideation, if present (from 1 to 5, with 5 being the most severe). The “Baseline/Screening”
C-SSRS form will be completed on Day 1 prior to dosing. The “Since Last Visit” C-SSRS
form will be completed for all subsequent assessments.
Copies of the C-SSRS are provided in Appendix 1.
11.1.8.
Stanford Sleepiness Scale (SSS)
The Stanford Sleepiness Scale is patient-rated scale designed to quickly assess how sedated
or sleepy a patient is feeling. The degree of sleepiness is rated on a scale of 1 to 7, where the
lowest score of 1 indicates that the patient is “feeling active, vital, alert, or wide awake” and
the highest score of 7 indicates that the patient is “no longer fighting sleep, sleep onset soon;
having dream-like thoughts.” The SSS will be administered unless the subject is asleep
between the hours of 23.00h and 06.00h each day. If the SSS is not scored due to a subject
being asleep, a score of X will be reported in the CRF to indicate that the subject was asleep.
All SSS assessments are to be completed within ±15 minutes of the scheduled time point.
A copy of the SSS is provided in Appendix 5.
11.2.
Efficacy Assessments
For all efficacy assessments, the baseline values will be calculated as the last recorded value
prior to the start of infusion of randomized treatment. Change from baseline values will be
calculated as the assessment score minus the baseline value. Change from baseline values
will be calculated for each item and total score.
11.2.1.
Primary Efficacy Outcome Measure
The primary outcome measure is the HAMD. The HAMD will be administered before,
during, and after the infusion of blinded study drug.
11.2.1.1.
Hamilton Rating Scale for Depression (HAMD)
The 17-item HAMD will be used to rate the severity of depression in subjects who are
already diagnosed as depressed (Hamilton 1960). The 17-item HAMD is comprised of
individual ratings related to the following symptoms: depressed mood (sadness, hopeless,
helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and
activities, retardation (slowness of thought and speech; impaired ability to concentrate;
decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms
(gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and
insight. The HAMD assessments are to be completed within ±30 minutes of the scheduled
time point, but prior to starting dosing on D1 H0. Every effort should be made for the same
rater to perform all HAMD assessments for a single patient.


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The HAMD total score will be calculated as the sum of the 17 individual item scores. Item
16 can be rated according to history (item 16A) or actual weight change (item 16B). The
item 16 score is calculated as the item 16 response that is not equal to 3 (ie, “Not assessed”).
In addition to the primary efficacy endpoint of change from baseline in HAMD total score,
several secondary efficacy endpoints will be derived for the HAMD. HAMD subscale scores
will be calculated as the sum of the items comprising each subscale. HAMD response will
be defined as having a 50% or greater reduction from baseline in HAMD total score. HAMD
remission will be defined as having a HAMD total score of7.
A copy of the HAMD is provided in Appendix 2.
11.2.2.
Secondary Efficacy Outcome Measures
Secondary efficacy assessments include evaluation of depressive symptom severity by the
MADRS (Section 11.2.2.1) and CGI (Section 11.2.2.2). Additional assessments of
depressive symptom severity and reproductive mood disorders will be measured by the
following clinician- and subject-rated outcome measures: EPDS (Section 11.2.3.1), GAD-7
(Section 11.2.2.3), and PHQ-9 (Section 11.2.3.2).
11.2.2.1.
Montgomery Asberg Depression Rating Scale (MADRS)
The MADRS is a 10-item diagnostic questionnaire which psychiatrists use to measure the
severity of depressive episodes in patients with mood disorders. It was designed as an
adjunct to the HAMD which would be more sensitive to the changes brought on by
antidepressants and other forms of treatment than the Hamilton Scale was.
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to
6. The overall score ranges from 0 to 60 (McDowell 2006, Müller-Thomsen 2005).
The questionnaire includes questions on the following symptoms
1. Apparent sadness
2. Reported sadness
3. Inner tension
4. Reduced sleep
5. Reduced appetite
6. Concentration difficulties
7. Lassitude
8. Inability to feel
9. Pessimistic thoughts
10. Suicidal thoughts
The MADRS total score will be calculated as the sum of the 10 individual item scores.
A copy of the MADRS is provided in Appendix 3.


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11.2.2.2.
Clinical Global Impression (CGI) Scale
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate
several sources of information into a single rating of the patient’s condition. The CGI scale
is comprised of 3 items. Only the first 2 items are being used in this study.
The CGI-Severity (CGI-S) item uses a 7-point Likert scale to rate the severity of the patient’s
illness at the time of assessment, relative to the clinician’s past experience with patients who
have the same diagnosis. Considering total clinical experience, a patient is assessed on
severity of mental illness at the time of rating 1=normal, not at all ill, 2=borderline mentally
ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7=extremely ill. The
CGI-S will be rated by the clinician at screening and on Day 1 (prior to dosing).
The CGI-Improvement (CGI-I) item employs a 7-point Likert scale to measure the overall
improvement in the patient’s condition post-treatment. The investigator will rate the
patient’s total improvement whether or not it is due entirely to drug treatment. Response
choices include: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally
improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. The
CGI-I is only rated at post-treatment assessments. By definition, all CGI-I assessments are
evaluated against baseline conditions. CGI-I response will be defined as having a CGI-I
score of “very much improved” or “much improved.”
A copy of the CGI is provided in Appendix 4.
11.2.2.3.
Generalized Anxiety Disorder 7-Item Scale (GAD-7)
The GAD-7 is a patient-rated generalized anxiety symptom severity scale (Spitzer 2006).
Scoring for GAD-7 generalized anxiety is calculated by assigning scores of 0, 1, 2, and 3 to
the response categories, respectively, of “not at all sure,” “several days,” “over half the
days,” and “nearly every day.” GAD-7 total score for the seven items ranges from 0 to 21,
where a score of 0 to 4=minimal anxiety, 5 to 9=mild anxiety, 10 to 14=moderate anxiety,
and 15 to 21=severe anxiety. All assessments are to be completed within ±30 minutes of the
scheduled time point.
The GAD-7 total score will be calculated as the sum of the 7 individual item scores.
A copy of the GAD-7 is provided in Appendix 7.
11.2.3.
Exploratory Patient Reported Outcome Measures
Exploratory efficacy assessments include evaluation of depressive symptom severity and
reproductive mood disorders. These will be measured by the following clinician- and
subject-rated outcome measures: EPDS, PHQ-9, and BIMF.
11.2.3.1.
Edinburgh Postnatal Depression Scale (EPDS)
The EPDS is a patient-rated depressive symptom severity scale specific to the perinatal
period (Cox 1987). The EPDS total score will be calculated as the sum of the 10 individual
item scores.
A copy of the EPDS is provided in Appendix 6.


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11.2.3.2.
Patient Health Questionnaire (PHQ-9)
The PHQ-9 is a patient-rated depressive symptom severity scale. To monitor severity over
time for newly diagnosed patients or patients in current treatment for depression, patients
may complete questionnaires at baseline and at regular intervals thereafter. Scoring is total
based on responses to specific questions, as follows: not at all=0; several days=1; more than
half the days=2; and nearly every day=3. All assessments are to be completed within
±30 minutes of the scheduled time point.
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores. The
PHQ-9 total score will be categorized as follows: 1-4=minimal depression, 5-9=mild
depression, 10-14=moderate depression, 15-19=moderately severe depression; and
20-27=severe depression.
A copy of the PHQ-9 is provided in Appendix 8.
11.2.3.3.
Barkin Index of Maternal Functioning (BIMF)
The BIMF is a patient reported outcome scale BIMF covers a broad range of functional areas
(self-care, infant care, mother-child interaction, psychological well-being of mother, social
support, management, adjustment). This new application of maternal functional status is a
robust construct where the physical and mental health of the mother is essential to optimal
functioning. Each item is rated on a scale of 0 (strongly disagree) to 6 (strongly agree).
A copy of the BIMF is provided in Appendix 9.
11.3.
Pharmacokinetics
11.3.1.
Plasma PK Samples
Blood samples for PK analysis will be collected in accordance with the Schedule of Events
(Table 1). Scheduled time points for PK blood draws after the start of infusion will have a
window of ±10 minutes. Samples will be processed according to the PK Manual, and may be 
analyzed for concentrations of SAGE-547, metabolites of SAGE-547, and SBECD.
Additionally, PK samples may be obtained outside the planned collection times if issues
administering study drug are encountered, such as incorrect infusion rate, interrupted
infusion, or other administration deviations where PK level assessment may be important in
understanding subject state. In the event of an unplanned dose adjustment, an unscheduled
PK sample should be collected just prior to the infusion rate change.
The following PK parameters will be derived from the plasma concentrations (where
evaluable): area under the concentration-time curve (AUC) from time zero to 60 hours
(AUC0-60), AUC from time zero to infinity (AUCɎ), maximum (peak) plasma concentration
(Cmax), time at maximum (peak) plasma concentration (tmax), steady-state drug concentration
in the plasma during constant-rate infusion (Css), and average drug concentration in the
plasma at steady state during a dosing interval (Cavg). Each PK parameter will be derived
separately for each part of the study.
The plasma samples will be drawn from the arm contralateral to that used for drug
administration. Subject-specific plasma PK kits for sampling including instructions on


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sample collection, processing methods, storage and shipping conditions, will be provided in
the study PK Manual.
11.3.2.
Breastmilk PK Samples
Women who are actively lactating at Screening, and who otherwise fulfill all of the inclusion
and exclusion criteria for the study, will be asked if they will consent to pumping.
Breastmilk will be collected and pooled at pre-defined intervals. The times of the first and
last pumping of each collection period will be recorded. Breastmilk will be pooled within
each collection period and the total volume will be measured. Detailed instructions for
breastmilk PK sampling, processing methods, storage and shipping will be provided in the
study PK Manual. After Study Day 12, women may resume giving breastmilk to their infant,
per Inclusion Criteria 5.


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12.
STUDY PROCEDURES
The study procedures listed below by study day reflect the data collection times for this
protocol.
Scheduled assessments for all safety, efficacy, PK, and exploratory outcome measures
planned for the trial are summarized in Table 1 (Schedule of Events). All subjects who
receive treatment with SAGE-547 should complete all study assessments through Study
Day 30 (±3 days).
Subjects who are evaluated at the Day 3 visit of the Treatment Period (ie, all Hour 60
assessments are completed, post-infusion) and complete the Day 30 (±3 days) visit during the
Follow-up Period will be defined as study completers.
12.1.
Screening Period
The Screening Period consists of a window from Day -5 through Day -1 prior to starting
SAGE-547 treatment. The Screening Period begins with the signature of the ICF. Eligibility
is determined by applying the inclusion/exclusion criteria. The diagnosis of PPD must be by
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). A full medical and
family history will be taken including recording of all depression, other Axis 1 and Axis 2
disorders and post-partum depression episodes in primary probands (who may be subject to a
SCID-I interview).
The following assessments/procedures will be conducted at the Screening Visit, which will
occur on any one calendar day of the Screening Period. Standard of care data collected prior
to obtaining informed consent may also be included as screening data, if appropriate, such as
laboratory tests, ECG, physical examinations, and vital signs conducted within the preceding
48 hours, as long as the requirement for the screening assessment to be collected
retrospectively is met in full, and all screening assessments are completed, reviewed and
approved by the Investigator prior to administration of SAGE-547.
Subjects will be confined to the study center from Day 1 until after the 60-hour assessments
have been conducted on Day 3.

Written informed consent, with optional provision for breast milk collection (see
Section 5.3 for more information)

Review of inclusion/exclusion criteria to determine subject eligibility

Demographic information and medical/family history collected

Blood will be collected for a pregnancy test

Blood will be collected to screen for hepatitis and HIV

Completion of physical examination, including body weight. Height should be
recorded. BMI will be calculated.

Vital signs

Blood and urine samples collected for clinical laboratory testing, including drug
and alcohol screening


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Blood sample will be taken for genetic analysis with subject consent

An ECG reading taken

Completion of the HAMD, CGI-S, and MADRS

Recording of concomitant medications
12.2.
SAGE-547 Treatment Period (Day 1 to Day 3, Hours 0-60)
All safety, efficacy, pharmacokinetic and other outcome assessments described in this section
are to be completed within ±30 minutes of the scheduled time points, unless otherwise stated.
Windows for PK collection time points are specified by respective time point for Study
Days 1 to 3 in Section 12.2.1 to Section 12.2.3, respectively (see Section 11.3 for additional
details). Subjects will be confined to the study center from the Screening Visit until after the
60-hour assessments have been conducted on Day 3.
12.2.1.
Day 1

Review of inclusion/exclusion criteria to determine subject eligibility

Randomization (on a 1:1 basis: one group will receive SAGE-547 and one group
will receive placebo)

Urine will be collected for a pregnancy test

Begin study drug administration for dose titration in the morning followed by
maintenance infusion

Vital signs will be recorded prior to infusion and at 2, 4, 8, 12, 18, and 24 hours
on Day 1 (±30 minutes), unless the subject is asleep between the hours of 23.00h
and 06.00h each day

Pulse oximetry will be monitored continuously (from H0 until H60), and checked 
approximately every 2 hours, including during the overnight hours, or at the alarm

Blood and urine samples collected for drug and alcohol screening

A blood sample for PK analysis will be collected prior to infusion (ie, morning of
Day 1 prior to dosing), and at Hours 4 (before change in infusion rate), 8, 12, and
24 (before change in infusion rate) after the start of the infusion. PK blood draws
after the start of infusion will have a window of ±10 minutes. In the event of an
unplanned dose adjustment, an unscheduled PK sample should be collected just
prior to the infusion rate change.

Completion of the HAMD prior to dosing and at Hours 2, 4, 8, 12, and 24 on
Day 1 (±30 minutes)

Completion of the MADRS prior to dosing and at Hour 24 on Day 1
(±30 minutes)

Completion of the CGI-S prior to dosing and the CGI-I at Hours 2, 4, 12, and 24
on Day 1 (±30 minutes)


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Completion of the following questionnaires prior to dosing: BIMF, EPDS,
GAD-7, and PHQ-9 (±30 minutes)

Completion of the SSS prior to dosing and at Hours 2, 4, 8, 12, 18, and 24 on
Day 1 (±15 minutes) unless the subject is asleep between the hours of 23.00h and
06.00h each day

AEs will be monitored

Concomitant medications will be recorded

Completion of the “Baseline/Screening” C-SSRS form prior to dosing.
Completion of the “Since Last Visit” C-SSRS form at Hour 24 (± 30 minutes)

Per subject consent (optional), collection of breast milk at pre-infusion and at the
following time periods of interest: 0, 1-12, 12-24, 24-36, 36-48, 48-60, and
60-72 hours after the start of the infusion
12.2.2.
Day 2

Ongoing SAGE-547 maintenance infusion administration

Vital signs will be recorded at Hours 30, 36, 42, and 48 (±30 minutes), unless the
subject is asleep between the hours of 23.00h and 06.00h each day

Pulse oximetry will be monitored continuously (from H0 until H60), and checked 
approximately every 2 hours, including during the overnight hours, or at the alarm

A blood sample for PK analysis will be collected at Hours 30, 36, and 48. PK
blood draws will have a window of ±10 minutes. In the event of an unplanned
dose adjustment, an unscheduled PK sample should be collected just prior to the
infusion rate change

Completion of the HAMD at Hour 36 and Hour 48 (±30 minutes)

Completion of the CGI-I at Hour 36 and Hour 48 (±30 minutes)

Completion of the MADRS at Hour 48 (±30 minutes)

Completion of the SSS at Hours 30, 36, 42, and 48 on Day 2 (±15 minutes) unless
the subject is asleep between the hours of 23.00h and 06.00h each day

An ECG reading taken at Hour 48

AEs will be monitored

Concomitant medications will be recorded

Per subject consent (optional), ongoing collection of breast milk during the
maintenance phase of infusion
12.2.3.
Day 3

Ongoing SAGE-547 maintenance infusion administration until Hour 60

Completion of physical examination at Hour 72


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Vital signs will be recorded at Hours 54, 60, 66, and 72 (±30 minutes)

Pulse oximetry will be monitored continuously (from H0 until H60), and checked 
approximately every 2 hours, including during the overnight hours, or at the alarm

A blood sample for PK analysis will be collected at Hours 60 and
72 (±10 minutes). In the event of an unplanned dose adjustment, an unscheduled
PK sample should be collected just prior to the infusion rate change

Blood sample collected for clinical laboratory testing at Hour 72

Completion of the HAMD and MADRS at Hour 60 and 72 (±30 minutes)

Completion of the CGI-I at Hours 60 and 72 (±30 minutes)

Completion of the following questionnaires at Hour 60: EPDS, GAD-7, and
PHQ-9 (±30 minutes)

Completion of the SSS at Hours 54, 60, 66, and 72 on Day 3 (±15 minutes) unless
the subject is asleep between the hours of 23.00h and 06.00h each day

AEs will be monitored

Concomitant medications will be recorded

Completion of the C-SSRS at Hours 60 and 72

Per subject consent (optional), ongoing collection of breast milk
12.3.
Follow-up Period (Day 7 through Day 60)
12.3.1.
Day 7 (±1 day)
The following assessments should be completed:

Completion of physical examination

Vital signs

Blood and urine samples collected for clinical laboratory testing

An ECG reading taken

Completion of the C-SSRS, HAMD, MADRS, CGI-I, EPDS, GAD-7, PHQ-9,
and BIMF

A blood sample for PK analysis will be collected at the time of the visit

Per subject consent (optional), collection of breast milk on the day of the visit*

AEs will be monitored

Concomitant medications will be recorded
*Assessment is only applicable to those patients who have temporarily ceased breastfeeding
and are participating in the optional breast milk sampling.


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12.3.2.
Day 12 (+1 day)

A blood sample for PK analysis will be collected at the time of the visit

Per subject consent (optional), collection of breast milk on the day of the visit

AEs will be monitored

Concomitant medications will be recorded
This visit is only applicable to those patients who have temporarily ceased breastfeeding
and are participating in the optional breast milk sampling.
12.3.3.
Day 30 (±3 days)
The following assessments should be completed:

Urine will be collected for a pregnancy test

Vital signs

Completion of the C-SSRS, HAMD, MADRS, CGI-I, EPDS, GAD-7, PHQ-9,
and BIMF

AEs will be monitored

Concomitant medications will be recorded
12.3.4.
Early Termination Visit
The following assessments should be completed if the patient discontinues from the study
prior to the Day 7 Visit:

Completion of physical examination

Vital signs

Blood and urine samples collected for clinical laboratory testing

An ECG reading taken

Completion of the C-SSRS, HAMD, MADRS, CGI-I, EPDS, GAD-7, PHQ-9,
and BIMF

AEs will be monitored

Concomitant medications will be recorded
The visit should occur within 3 days of notification of the patient discontinuing.


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13.
STATISTICAL METHODS AND CONSIDERATIONS
In general, summary statistics for all study endpoints will be presented as mean, standard
deviation (SD), median, and ranges for continuous endpoints, and as counts and percentages
for categorical endpoints. For the purpose of all safety, efficacy, and exploratory analyses
where applicable, baseline is defined as the last pre-dose measurement closest to the start of
blinded study drug infusion.
A statistical analysis plan (SAP) will be generated and approved by a representative of Sage
Therapeutics prior to database lock. All statistical analyses will be conducted using SAS for
Windows (version 9.1.3, or higher; Cary, NC), unless otherwise specified.
Any deviations from the planned analyses will be described and justified in the final clinical
study report (CSR).
Separate summaries will be produced for each part of the study.
13.1.
Data Analysis Sets
The All Enrolled Population will include all subjects who have given written informed
consent. This population will be used for subject disposition and demographic characteristic
summaries.
The All Randomized Population will include the subset of subjects from the All Enrolled
Population who have been randomized. Subjects will be classified according to randomized
treatment. This population will be used for subject disposition, demographic characteristic,
and baseline characteristic summaries.
The Safety Population will include all randomized subjects who start the infusion of study
drug. Subjects will be classified according to actual treatment received. This analysis
population will be used for all safety analyses.
The Efficacy Population (EFF) will include the subset of the Safety Population who have a
valid baseline HAMD assessment and at least one post-baseline HAMD assessment.
Subjects will be classified according to randomized treatment. This analysis population will
be used for all efficacy analyses.
The Per Protocol Population (PP) will include the subset of the Efficacy Population who
complete the full infusion without significant protocol violations or deviations. Subjects will
be classified according to randomized treatment. This analysis population will be used for
sensitivity analyses of the primary and select secondary endpoints.
The PK Population (PKP) will include the subset of the Safety Population who have at least
one evaluable PK sample. Subjects will be classified according to actual treatment received.
This analysis population will be used for all PK analyses.
The Breast Milk Population (BMP) will include the subset of the Safety Population who
have at least one evaluable breast milk sample. Subjects will be classified according to
actual treatment received. This analysis population will be used for all breast milk PK
analyses.


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The number and percentage of subjects who receive SAGE-547 Injection or placebo,
prematurely discontinue, and complete the study will be summarized. The number and
percentage of subjects will also be summarized for each reason for premature
discontinuation. In addition, the number of subjects whose data should be used for the
planned analyses will be identified for each respective analysis population (ie, SAF, EFF,
PKP, PP, and BMP).
13.2.
Handling of Missing Data
Every attempt will be made to avoid missing data. All subjects will be used in the analyses,
as per the analysis populations, using all non-missing data available. Any rules for the
imputation of missing data will be described in the SAP.
13.3.
Demographics and Baseline Characteristics
Demographics such as age, race, and ethnicity will be summarized. In addition, baseline
characteristics such as height, weight, and BMI will be summarized. Categorical summaries,
such as race and ethnicity, will be summarized by frequency and percentage. Continuous
summaries, such as age, height, weight, BMI and baseline vital signs, will be summarized
using descriptive statistics such as n, mean, SD, median, minimum, and maximum.
Drug, alcohol, and pregnancy screening results will be collected and listed but not
summarized, as they are considered part of the inclusion/exclusion criteria.
Medical/family history will be collected and listed by subject.
13.4.
Primary Endpoints
Change from baseline to each assessment in HAMD total score will be analyzed using a
mixed effects repeated measures model (MMRM) including center, treatment, baseline
HAMD total score, assessment time point, and time point-by-treatment. Center will be
treated as a random effect while all other explanatory variables will be treated as fixed
effects. Separate models will be fit for each part of the study. For Parts A and C, the
primary comparison will be between 90 μg SAGE-547 and placebo at the 60-hour
assessment. For Part B, the primary comparison will be between 90 μg SAGE-547 and
placebo at the 60-hour assessment; if this comparison is significant at the 0.05 level, then the
60 μg group will then be compared to placebo. Comparisons at other time points will be
conducted to support the findings for the primary comparison. Model based point estimates
(ie, LS means), 95% confidence intervals, and p-values will be reported for each assessment.
Summaries of HAMD total scores and changes from baseline values will include n, mean,
SD, median, minimum, and maximum.
13.5.
Secondary Endpoints
13.5.1.
Efficacy Analysis
MMRM methods similar to those described in Section 13.4 will be used for the analysis of
the following variables: MADRS total score, EPDS total score, GAD-7 total score, PHQ-9
total score, and select individual item and subscale scores. Separate models will be fit for


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each part of the study. For each model, the comparison of interest will be between each
SAGE-547 dose and placebo at the 60-hour assessment. Model based point estimates
(ie, LS means), 95% confidence intervals, and p-values will be reported.
Logistic regression methods will be used for the analysis of the following response variables:
HAMD response, HAMD remission, and CGI-I response. Logistic regression models will
include terms for center, treatment, and baseline score. Separate models will be fit for each
part of the study. The comparison of interest will be the difference between each SAGE-547
dose and placebo at the 60-hour assessment. Model based point estimates (ie, odds ratios),
95% confidence intervals, and p-values will be reported. For the CGI-I response analysis,
baseline CGI-S score will be included in the model.
Descriptive statistics for all scores, change from baseline values, and response variables will
be presented by treatment and assessment time point. Summaries will include n, mean, SD,
median, minimum, and maximum.
13.5.2.
Safety Analysis
Safety and tolerability of SAGE-547 Injection will be evaluated by AEs, concomitant
medications, changes from baseline in physical examination, vital signs, CBC, serum
chemistry, urinalysis, and 12-lead ECG. Suicidality will be monitored by the C-SSRS.
Sedation will be assessed using the SSS. Safety data will be listed by individual and
summarized by treatment group. In addition, an analysis of SSS data will be performed
comparing the treatment groups in the same way as for the primary endpoint. All safety
summaries will be performed on the SAF population.
Safety data will be examined for possible relationships between subject characteristics and
plasma allopregnanolone concentrations, as appropriate.
Scheduled visits for all safety assessments are described in Section 12 and summarized in
Table 1.
13.5.2.1.
Adverse Events
The analysis of AEs will be based on the concept of treatment-emergent AEs (TEAEs). A
TEAE is defined as an AE with onset after the start of SAGE-547 infusion, or any worsening
of a pre-existing medical condition/AE with onset after the start of SAGE-547 infusion and
until 7 days after the end of infusion. The incidence of TEAEs will be summarized overall
and by MedDRA System Organ Class (SOC) and preferred term (PT). Incidences will be
presented in order of decreasing frequency. In addition, summaries will be provided by
severity (mild, moderate, severe) and by causality (related, not related) to study drug (see
Section 14.2.2.1).
TEAEs leading to discontinuation and SAEs (see Section 14.1.4 for definition) with onset
after the start of randomized infusion will also be summarized.
All AEs and SAEs (including those with onset or worsening before the start of randomized
infusion) through the Day 30 follow-up visit (±3 days) will be listed.


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13.5.2.2.
Clinical laboratory evaluations
Results will be listed by Subject ID and timing of collection. Mean changes from baseline in
clinical laboratory measures will be evaluated.
13.5.2.3.
Physical examinations
Physical examinations will be evaluated at Screening and Day 7. Any clinically significant
change in physical examination compared to those observed at Screening should be noted as
an AE.
13.5.2.4.
Vital signs
Vital signs, including oral temperature (°C), respiratory rate, heart rate, and blood pressure
(supine and standing) will be obtained at the scheduled time points described in
Section 11.1.4. Mean changes from baseline (pre-infusion) in vital signs will be evaluated.
13.5.2.5.
12-Lead ECG
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, and
QTc. Any clinically significant abnormalities or changes in ECGs should be listed as an AE.
ECG findings will be listed by subject and visit.
13.5.2.6.
Concomitant medications
A summary of all concomitant medications taken during the course of the study will be
presented in tabular form by therapeutic drug class and generic drug name using the WHO
Collaborating Centre for Drug Statistics Methodology Norwegian Institute of Public Health
(http://www.whocc.no).
13.5.2.7.
C-SSRS
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period
will be listed for all subjects. Listings will include behavior type and/or category for Suicidal
Ideation and Suicidal Behavior of the C-SSRS.
13.5.2.8.
SSS
Changes in score over time will be represented graphically, and change from baseline will be
measured.
13.5.2.9.
PK Analysis
Plasma will be collected to assay for concentrations of SAGE-547, metabolites of
SAGE-547, and SBECD. The following PK parameters will be derived from the plasma
concentrations (where evaluable): AUC0-60, AUCɎ, Cmax, time at maximum (peak) plasma
concentration (tmax), steady-state drug concentration in the plasma during constant-rate
infusion (Css), and average drug concentration in the plasma at steady state during a dosing
interval (Cavg).
Plasma concentrations will be listed by subject and summarized by nominal collection time
point. PK parameters will be listed by subject and summarized by collection time point.


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Correlations between concentrations and AEs or tolerability measures may be performed as
deemed necessary.
In addition to typical descriptive statistics, summaries should include geometric mean,
coefficient of variation, and geometric coefficient of variation.
13.6.
Determination of Sample Size
Assuming a two-sided test at an alpha level of 0.10, a sample size of 10 evaluable subjects
per group would provide 80% power to detect an effect size of 1.2 between the SAGE-547
and placebo groups with regard to the primary outcome variable of change from baseline in
HAMD total score. An effect size of 1.2 corresponds to a placebo adjusted difference of
12 points in the change from baseline in HAMD total score at 60 hours with an assumed
standard deviation of 10 points. By including 2 treatment groups and using a 1:1
randomization ratio, a total of 20 evaluable subjects are required for Part A. Assuming a
non-evaluability rate of 10%, up to 22 subjects will be randomized in Part A.
Based on the results of the interim analysis (Section 13.7), the sample size for Part A could
be increased to a maximum of 32 randomized subjects. This adjustment to the sample size
would allow for an effect size of 1.0 to be detected.
For Part B, a sample size of 18 evaluable subjects per group would provide at least 90%
power to detect an effect size of 1.2 between the SAGE-547 and placebo groups using a
two-sided test at an alpha level of 0.05.  Assuming a non-evaluability rate of 10%, up to 
60 subjects will be randomized in Part B.
For Part C, a sample size of 16 evaluable subjects per group would provide 80% power to 
detect an effect size of 1.0 between the SAGE-547 and placebo groups using a two-sided test 
at an alpha level of 0.10.  Assuming a non-evaluability rate of 10%, up to 36 subjects will be 
randomized in Part C.  
13.7.
Interim Analysis
In Part A, an interim analysis will be conducted by an independent statistician for sample size
re-estimation purposes when at least 16 subjects have completed efficacy assessments
through 60 hours in Part A. Since the Sponsor will be kept uninformed of the response rates
at the time of the interim analysis, no statistical adjustment will be made to the level of
significance for hypothesis testing of Part A of the study. A detailed description of the
interim analysis will be included in the SAP.
No interim analyses are planned for Parts B and C of the study.
13.8.
Changes from Protocol Specified Analyses
Any changes from the analytical methods outlined in the protocol will be documented in the
final SAP.
Upon the completion of each part of the study, the data may be unblinded and analyzed
separately. The final CSR will report the findings of all parts of the study.


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14.
ADVERSE EVENTS
Section 14.1 lists important AE definitions.
Section 14.2 summarizes Investigator responsibilities regarding the identification and
documentation of AEs, the classification of AEs for relationship to study drug and severity,
and the reporting of AE information to the Sponsor and the IRB.
Section 14.3 summarizes Sponsor/Medical Monitor Responsibilities regarding monitoring of
AE data and reporting relevant safety information to FDA.
14.1.
Adverse Event Definitions
14.1.1.
Adverse Event
An AE is any untoward medical occurrence associated with the use of a drug in humans,
whether or not considered drug related.
14.1.2.
Suspected Adverse Reaction
A suspected adverse reaction is any AE for which there is a reasonable possibility that the
drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility”
means there is evidence to suggest a causal relationship between the drug and the AE.
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse
reaction, which means any AE caused by a drug.
14.1.3.
Life-Threatening
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either
the Investigator or Sponsor, its occurrence places the subject at immediate risk of death. It
does not include an AE or suspected adverse reaction that, had it occurred in a more severe
form, might have caused death.
14.1.4.
Serious
An AE or suspected adverse reaction is considered “serious” if, in the view of either the
Investigator or Sponsor, it results in any of the following outcomes:

Death

A life-threatening AE (see definition in Section 14.1.3)

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant disability or incapacity

A congenital anomaly or birth defect

Other medically important condition (as described below)
Important medical events that may not result in death, be life-threatening, or require
hospitalization may be considered serious when, based upon appropriate medical judgment,
they may jeopardize the subject and may require medical or surgical intervention to prevent
one of the outcomes listed in this definition. Examples of such medical events include


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allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of
drug dependency or drug abuse.
14.1.5.
Unexpected
An AE or suspected adverse reaction is considered “unexpected:”

If it is not listed in the Investigator’s Brochure or is not listed at the specificity or
severity that has been observed, or

If an Investigator’s Brochure is not required or available, is not consistent with the
risk information described in the general investigational plan or elsewhere in the
current application, as amended
For example, under this definition, hepatic necrosis would be unexpected (by virtue of
greater severity) if the Investigator’s Brochure referred only to elevated hepatic enzymes or
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected
(by virtue of greater specificity) if the Investigator’s Brochure listed only cerebral vascular
accidents.
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions
that are mentioned in the Investigator’s Brochure as occurring with a class of drugs or as
anticipated from the pharmacological properties of the drug, but are not specifically
mentioned as occurring with the particular drug under investigation.
In the clinical trial setting, the term “expected” would not mean “anticipated” for the 
condition being treated or population being studied since “expected” would indicate being 
“listed in the Investigator’s Brochure.”  For example, some adverse events can be anticipated 
to occur as a result of a disease or condition or in a certain population (eg, cancer-related 
deaths in a cancer trial, strokes or acute myocardial infarctions in an older population).  
However, for reporting purposes, these anticipated events are not considered “expected” if 
they are not listed in the Investigator’s Brochure (ie, the investigational drug is not suspected 
or known to cause them). 
14.2.
Investigator Responsibilities
14.2.1.
Identification and Documentation of Adverse Events by Investigator
Subjects will be evaluated and questioned generally (if possible) to identify AEs during the
course of the study. AEs will be collected during subject preparation, study drug
administration during Screening, after the initiation of study drug administration through to
Day 3, and at the Follow-up Visits on Day 7 (±1 day) and Day 30 (±3 days). SAEs will also
be collected until the Day 30 (±3 days) follow-up visit. Medical conditions that occur prior
to completion of the Screening Visit will be captured on the Medical History eCRF. Adverse
events that occur after completion of the Screening Visit will be recorded on the AE page of
the eCRF (AE eCRF).
All AEs revealed by observation, physical examinations, other diagnostic procedures, or
spontaneously reported by the subject and/or in response to an open question from study
personnel will be recorded on the AE eCRF. Any clinically significant deterioration from


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baseline in laboratory assessments or other clinical findings is considered an AE and must be
recorded on the AE eCRF, unless otherwise stated. AE information recorded on AE eCRF
will be entered into the database on an ongoing basis. The database, including AE
information, will be transferred to the Sponsor on a pre-defined schedule for review.
All AEs, regardless of investigator-determined causality, should be followed until the event
is resolved or the Investigator determines the event is stable or no longer clinically
significant.
For all SAEs, an SAE report form must be completed with as much information as possible
and submitted in the time frame described in Section 14.2.3. When new significant
information is obtained as well as when the outcome of an event is known, the SAE report
form should be updated on a follow-up report. If the subject was an outpatient at the time of
the SAE and was re-hospitalized due to the SAE, a copy of relevant hospital records
(eg, admission report, laboratory test results, discharge summary, etc.) may be requested to
be included as part of the subject’s medical file.
All SAEs will be followed until the events are resolved or improved and a stable status has
been achieved, or the subject is lost to follow-up.
14.2.2.
Adverse Event Classification
Definitions for the categories of AE classification are included in this section.
14.2.2.1.
Relationship to Investigational Drug
Not Related:
No relationship between the experience and the administration of study
drug; related to other etiologies such as concomitant medications or
subject’s clinical state.
Possibly Related:
A reaction that follows a plausible temporal sequence from
administration of the study drug and follows a known response pattern to
the suspected study drug.
The reaction might have been produced by the subject’s clinical state or
other modes of therapy administered to the subject, but this is not known
for sure.
Probably Related:
A reaction that follows a plausible temporal sequence from
administration of the study drug and follows a known response pattern to
the suspected study drug.
The reaction cannot be reasonably explained by the known
characteristics of the subject’s clinical state or other modes of therapy
administered to the subject


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14.2.2.2.
Severity
The severity of an adverse experience will be defined as follows and reported as indicated on
the AE eCRF:
Mild:
Discomfort noticed, but no disruption to daily activity.
Moderate:
Discomfort sufficient to reduce or affect normal daily activity, but is
not hazardous to health; prescription drug therapy may be employed to
treat the AE.
Severe:
Inability to work or perform normal daily activity and represented a
definite hazard to health; prescription drug therapy and/or
hospitalization may be employed to treat the AE.
14.2.2.3.
Action Taken with Investigational Drug
Action taken with regard to administration of SAGE-547 Injection for this trial will be
recorded using the one of following categories (the category “dose increased” does not apply
to this trial):

Drug withdrawn: An indication that a medication schedule was modified through
termination of a prescribed regimen of medication

Dose not changed: An indication that a medication schedule was maintained

Drug interrupted: An indication that a medication schedule was modified by
temporarily terminating a prescribed regimen of medication

Dose reduced: An indication that a medication schedule was modified to a
reduced rate/dose

Unknown: Unknown, not known, not observed, not recorded, or refused

Not applicable: Determination of a value is not relevant in the current context
14.2.2.4.
Assessment of Outcome
Assessment of outcome of AEs will be categorized as one of the following:

Recovered/Resolved: The event has improved or recuperated

Recovering/Resolving: The event is improving

Not Recovered/Not Resolved: The event has not improved or recuperated

Recovered/Resolved with Sequel: The subject recuperated but retained
pathological conditions resulting from the prior disease or injury

Fatal: The termination of life as a result of an adverse event

Unknown: Not known, not observed, not recorded, or refused
14.2.3.
Investigator Reporting to Sponsor and Sponsor Emergency Contact
All SAEs that occur during the course of the study must be reported by the Investigator on
the designated report form (study-specific SAE form or MedWatch 3500A form) and sent by


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facsimile to the medical monitor within 24 hours from the point in time when the Investigator
becomes aware of the SAE. Investigators must report any SAE, whether or not considered
drug related. The initial report must be as complete as possible, including assessment of the
causal relationship (ie, assessment of whether there is a reasonable possibility that the drug
caused the event). The medical monitor will contact the investigator via telephone for
follow-up information regarding the SAE, as appropriate.
Information not available at the time of the initial report must be documented on a follow-up
report. As additional information becomes available, the designated report form must be
updated and supporting information, including hospital records, laboratory and diagnostic
testing results, etc. All supporting documentation must be de-identified. In addition, all
SAEs that occur up to and including 30 days after administration of study drug must be
reported within 1 working day from when the Investigator becomes aware of the SAE. A
final report to document resolution of all SAEs is required.
In a medical emergency (ie, an event that requires immediate attention regarding the
treatment of a subject, operation of the clinical study, and/or the use of investigational drug),
study site staff will apply appropriate medical intervention according to current standards of
care and contact the Medical Monitor.
14.2.4.
Medical Monitor and Emergency Contact Information
, MD
Office (9-5 EST):
24/7 Hotline:
14.2.5.
SAE Reporting Contact Information
Contact information and reporting instructions are provided in the Safety Management Plan.
14.2.6.
Reporting to Institutional Review Boards (IRBs)
It is the responsibility of the Investigator to promptly notify the institution’s IRB of all
serious and unexpected suspected adverse reactions (see Section 14.3.2).
14.3.
Sponsor/Medical Monitor Responsibilities
14.3.1.
Monitoring of Adverse Event Data
The Medical Monitor or designee will review AEs on an ongoing basis.
14.3.2.
Reporting to FDA
The Sponsor must report in an IND safety report any suspected adverse reaction to study
treatment that is both serious and unexpected (21 CFR 312.32[c][1][i]). Before submitting
an IND safety report, the Sponsor will ensure the event meets all 3 of the definitions:


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(1) suspected adverse reaction, (2) serious, (3) unexpected. If the AE does not meet all 3 of
the definitions, it should not be submitted as an IND safety report. The Sponsor should
evaluate the available information and decide whether there is a reasonable possibility that
the drug caused the AE and, therefore, that the event meets the definition of a suspected
adverse reaction.
If there is a serious and unexpected suspected adverse reaction, the Sponsor will notify the
appropriate regulatory agency(ies) and all appropriate parties on an expedited basis. In
addition, Sponsors must submit expedited reports of an increased rate of occurrence of
serious suspected adverse reactions over that listed in the protocol or Investigator’s Brochure.
14.4.
Emergency Identification of Study Medication
In exceptional circumstances and for the safety of the study subject, the Investigator may
request unblinding of an individual subject’s treatment from the pharmacist; this normally
requires prior approval by the Medical Monitor. However, if the subject is at immediate risk
and the Investigator believes that immediate knowledge of the study treatment will alter
medical management, discussion with the Medical Monitor may take place after unblinding.
The Investigator will not unblind the Medical Monitor during that discussion. The process of
unblinding will ensure that only the investigator is unblinded; the Medical Monitor, study
management team, and data management team will not be made aware of the treatment
allocation of an individual subject. All cases of emergency unblinding will be fully
documented in a way that does not unblind the Medical Monitor, study management team,
and data management team.


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15.
STUDY ADMINISTRATION
15.1.
Quality Control and Quality Assurance
The Investigators and institutions will permit trial-related monitoring, audits, IRB review,
and regulatory inspections as requested by FDA, the Sponsor, or the Sponsor’s designee,
including direct access to source data/documents (ie, original medical records, laboratory
reports, hospital documents, progress reports, signed ICFs, etc.) in addition to CRFs.
Quality assurance and quality control systems with written standard operating procedures
(SOPs) will be followed to ensure that this trial will be conducted and data will be generated,
documented (recorded), and reported in compliance with the protocol, GCP, and the
applicable regulatory requirements.
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals
during the study. The monitoring visits must be conducted according to the applicable ICH
and GCP guidelines to ensure protocol adherence, quality of data, drug accountability,
compliance with regulatory requirements, and continued adequacy of the investigational site
and its facilities. During these visits, CRFs and other data related to the study will be
reviewed and any discrepancies or omissions will be identified and resolved. The study
monitor will be given access to study-relevant source documents (including medical records)
for purposes of source data verification.
During and/or after completion of the study, quality assurance officers named by Sage
Therapeutics or the regulatory authorities may wish to perform on-site audits. The
Investigator is expected to cooperate with any audit and provide assistance and
documentation (including source data) as requested.
Quality control will be applied to each stage of data handling to ensure that all data are
reliable and have been processed correctly.
Agreements made by the Sponsor with the Investigator/institution and any other parties
involved with the clinical trial will be in writing in a separate agreement.
15.2.
Data Handling and Recordkeeping
15.2.1.
Data Handling
Procedures for data handling (including electronic data) used in this protocol will be
documented in a Data Management Plan.
15.2.2.
Case Report Form Completion
Electronic CRFs (eCRFs) will be completed for each study subject. It is the Investigator’s
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the
subject’s eCRF. Source documentation supporting the eCRF data should indicate the
subject’s participation in the study and should document the dates and details of study
procedures, AEs, and subject status.
The Investigator will have access to the electronic data capture (EDC) system and will
receive a copy of the subject eCRF data at the end of the study. For subjects who discontinue


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or terminate from the study, the eCRFs will be completed as much as possible, and the reason
for the discontinuation or termination clearly and concisely specified on the appropriate
eCRF.
15.2.3.
Retention of Study Records
The Investigator will maintain all study records according to ICH-GCP and applicable
regulatory requirements. Records will be retained for at least two years after the last
marketing application approval and until there are no pending or contemplated marketing
applications or two years after formal discontinuation of the clinical development of the
investigational product or according to applicable regulatory requirements. If the
Investigator withdraws from the responsibility of keeping the study records, custody must be
transferred to an appropriate person willing to accept the responsibility. The Sponsor must
be notified in writing if a custodial change occurs.
15.3.
Confidentiality
To maintain subject privacy, all eCRFs, study drug accountability records, study reports, and
communications will identify the subject by the assigned subject number. The Investigator
will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory
authority(ies) access to the subject’s original medical records for verification of data gathered
on the CRFs and to audit the data collection process. The subject’s confidentiality will be
maintained and will not be made publicly available to the extent permitted by the applicable
laws and regulations.
Subjects will be notified that registration information, results, and other information about
this study will be submitted to ClinicalTrials.gov, a publicly available trial registry database;
however, protected health information of individual subjects will not be used.
All information regarding the investigational product supplied by Sage Therapeutics to the
Investigator is privileged and confidential information. The Investigator agrees to use this
information to accomplish the study and will not use it for other purposes without consent
from the Sponsor. It is understood that there is an obligation to provide the Sponsor with
complete data obtained during the study. The information obtained from the clinical study
will be used towards the development of the investigational product and may be disclosed to
regulatory authority(ies), other Investigators, corporate partners, or consultants as required.
15.4.
Publication Policy
All information concerning SAGE-547 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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15.5.
Protocol Amendments
Changes to the conduct of the study should be prepared as a protocol amendment by the
Sponsor. Protocol amendments should receive written IRB/IEC approval prior to
implementation at the investigative site, except when necessary to eliminate immediate
hazards to the subjects or when the changes involve only logistical or administrative aspects
of the trial (eg, change of monitor, telephone numbers). In this case, Sage Therapeutics will
amend and implement the protocol change and subsequently notify the regulatory authorities
and the Investigative sites who will notify the respective IRB, as appropriate.


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16.
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severity—a patient-level meta-analysis. JAMA 2010;303:47-53. PMID: 20051569.
Frye CA, Duncan JE. Progesterone metabolites, effective at the GABAA receptor complex,
attenuate pain sensitivity in rats. Brain Res 1994;643(1-2):194-203. PMID: 8032914.
Gangisetty O and Reddy DS. Neurosteroid withdrawal regulates GABA-A receptor -
subunit expression and seizure susceptibility by activation of progesterone receptor-
independent early growth response factor-3 pathway. Neuroscience 2010; 170:865-880.
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Gaynes BN, Gavin N, Meltzer-Brody S, Lohr KN, Swinson T, Gartlehner G, et al. Perinatal
depression: prevalence, screening accuracy, and screening outcomes. Evid Rep Technol
Assess (Summ) 2005;(119):1-8. PMID: 15760246.
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precursors during pregnancy and the postpartum period. Gynecol Endocrinol 2005 21, 268-
279. PMID: 16373246.
Genazzani AR, Petraglia F, Bernardi F, Casarosa E, Salvestroni C, Tonetti A, et al.
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Clin Endocrinol Metab 1998;83(6):2099-103. PubMed PMID: 9626145.
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[Article in Chinese]. PMID: 15553820.


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Holzbauer M, Birmingham MK, De Nicola AF, Oliver JT. In vivo secretion of 3 alpha-
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Kask K, Bäckström T, Lundgren P, Sundström Poromaa I. Allopregnanolone has no effect
on startle response and prepulse inhibition of startle response in patients with premenstrual
dysphoric disorder or healthy controls. Pharmacol Biochem Behav 2009;92(4):608-13.
PubMed PMID: 19268499.
Kask K, Bäckström T, Nilsson LG, Sundström-Poromaa I. Allopregnanolone impairs
episodic memory in healthy women. Psychopharmacology (Berl) 2008;199(2):161-8.
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A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Med 2008;
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Klak J, Hill M, Parízek A, Havlíková H, et al. Pregnanolone isomers, pregnenolone and their
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Nappi RE, Petraglia F, Luisi S et al. Serum allopregnanolone in women with postpartum
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Navarro PA, Kaddouz D, de Ziegler D, Silva de Sá MF, Ferriani RA. Vaginal administration
of allopregnanolone to postmenopausal women undergoing estrogen replacement therapy:
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10.1007/978-1-4419-1005-9_826.
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Sayeed I, Parvez S, Wali B, Siemen D, Stein DG. Direct inhibition of the mitochondrial
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Shelton RC, Trivedi MH. Moderators of antidepressant response in major depression. J Clin
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Spitzer RL, Kroenke K, Williams JBW, Löwe B. A Brief Measure for Assessing
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Timby E, Balgård M, Nyberg S, Spigset O, Andersson A, Porankiewicz-Asplund J, et al.
Pharmacokinetic and behavioral effects of allopregnanolone in healthy women.
Psychopharmacology (Berl) 2006 Jun;186(3):414-24. PMID: 16177884.
Timby E, Hedström H, Bäckström T, Sundström-Poromaa I, Nyberg S, Bixo M.
Allopregnanolone, a GABAA receptor agonist, decreases gonadotropin levels in women A
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Timby E. Allopregnanolone effects in women. Clinical studies in relation to the menstrual
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van Broekhoven F, Bäckström T, van Luijtelaar G, Buitelaar JK, Smits P, Verkes RJ. Effects
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Verbeek T, Bockting CL, van Pampus MG et al. Postpartum depression predicts offspring
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J Affect Disord 2012;136(3):948-54. doi: 10.1016/j.jad.2011.08.035.
Wieland S, Lan NC, Mirasedeghi S, Gee KW. Anxiolytic activity of the progesterone
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APPENDICES
Copies of the rating scales and questionnaires included in Appendix 1 through Appendix 9
are for reference only.
 


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Appendix 1.
COLUMBIA SUICIDE SEVERITY RATING SCALE
(C-SSRS)
The “Baseline/Screening” and “Since Last Visit” versions of the C-SSRS begin on the next
full page (Posner 2011).
 


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Appendix 2.
HAMILTON RATING SCALE FOR DEPRESSION,
17-ITEM (HAMD)
The HAMD presents on the next full page (Hamilton 1960).
The HAMD total score will be calculated as the sum of the 17 individual item scores. Item
16 can be rated according to history (item 16A) or actual weight change (item 16B). The
item 16 score is calculated as the item 16 response that is not equal to 3 (ie, “Not assessed).
 


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Appendix 3.
MONTGOMERY ASBERG DEPRESSION RATING
SCALE (MADRS)
The MADRS presents on the next full page (McDowell 2006, Müller-Thomsen 2005).


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Appendix 4.
CLINICAL GLOBAL IMPRESSION–IMPROVEMENT
SCALE (CGI-I) AND SEVERITY SCALE (CGI-S)
The CGI-I and CGI-S presents on the next full page. For the purposes of Protocol 547-PPD-
202, only Items 1 and 2, Severity of Illness and Global Improvement, will be assessed in
subjects enrolled in the study.


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Appendix 5.
STANFORD SLEEPINESS SCALE (SSS)
The SSS presents on the next full page.
 


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Stanford Sleepiness Scale
This is a quick way to assess how alert you are feeling. If it is during the day when you go about your
business, ideally you would want a rating of a one. Take into account that most people have two peak
times of alertness daily, at about 9 a.m. and 9 p.m. Alertness wanes to its lowest point at around 3
p.m.; after that it begins to build again. Rate your alertness at different times during the day. If you
go below a three when you should be feeling alert, this is an indication that you have a serious sleep
debt and you need more sleep.
An Introspective Measure of Sleepiness
The Stanford Sleepiness Scale (SSS)
Degree of Sleepiness
Scale
Rating
Feeling active, vital, alert, or wide awake
1
Functioning at high levels, but not at peak;
able to concentrate
2
Awake, but relaxed; responsive but not fully
alert
3
Somewhat foggy, let down
4
Foggy; losing interest in remaining awake;
slowed down
5
Sleepy, woozy, fighting sleep; prefer to lie
down
6
No longer fighting sleep, sleep onset soon;
having dream-like thoughts
7
Asleep
X


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Appendix 6.
EDINBURGH POSTNATAL DEPRESSION SCALE
(EPDS)
The EPDS presents on the next full page (Cox 1987).


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Appendix 7.
GENERALIZED ANXIETY DISORDER 7-ITEM
SCALE (GAD-7)
The GAD-7 presents on the next full page (Spitzer 2006).
 


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APPENDIX 8.
PATIENT HEALTH QUESTIONNAIRE (PHQ-9)
The PHQ-9 presents on the next full page.
Developed by Drs. Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke, and colleagues
with an educational grant from Pfizer Inc. No permission required to reproduce, translate,
display or distribute.
 


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APPENDIX 9.
BARKIN INDEX OF MATERNAL FUNCTIONING
(BIMF)
The BIMF is presented on the next full page.
 
 


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APPENDIX 10. SELECTED INDUCERS, INHIBITORS, AND
SUBSTRATES OF CYP2C9
Inhibitors of CYP2C9 can be classified by their potency, such as:

Strong being one that causes at least a 5-fold increase in the plasma AUC values, or more
than 80% decrease in clearance.

Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or
50-80% decrease in clearance.

Weak being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma
AUC values, or 20-50% decrease in clearance.
Substrates
Inhibitors
Inducers

NSAIDs (analgesic, antipyretic,
anti-inflammatory)
o
celecoxib
o
lornoxicam
o
diclofenac
o
ibuprofen
o
naproxen
o
ketoprofen
o
piroxicam
o
meloxicam
o
suprofen

phenytoin (antiepileptic)

fluvastatin (statin)

sulfonylureas (antidiabetic)
o
glipizide
o
glibenclamide
o
glimepiride
o
tolbutamide
o
glyburide

angiotensin II receptor
antagonists (in hypertension,
diabetic nephropathy, CHF)
o
irbesartan
o
losartan

S-warfarin (anticoagulant)

sildenafil (in erectile dysfunction)

terbinafine (antifungal)

amitriptyline (tricyclic
antidepressant)

fluoxetine (SSRI antidepressant)

nateglinide (antidiabetic)

rosiglitazone (antidiabetic)

tamoxifen (SERM)

torasemide (loop diuretic)

ketamine

THC

JWH-018

AM-2201
Strong

fluconazole (antifungal)

miconazole (antifungal)

amentoflavone
(constituent of Ginkgo biloba
and St. John’s Wort)

sulfaphenazole (antibacterial)

valproic acid (anticonvulsant,
mood-stabilizing)

apigenin
Moderate

amiodarone (antiarrhythmic)
Unspecified potency

antihistamines (H1 receptor
antagonists)
o
cyclizine
o
promethazine

chloramphenicol

fenofibrate (fibrate)

flavones

flavonols

fluvastatin (statin)

fluvoxamine (SSRI)

isoniazid (in tuberculosis)

lovastatin (statin)

phenylbutazone (NSAID)

probenecid (uricosuric)

sertraline (SSRI)

sulfamethoxazole (antibiotic)

teniposide (chemotherapeutic)

voriconazole (antifungal)

zafirlukast (leukotriene
antagonist)

quercetin (anti-inflammatory)
Strong

rifampicin (bactericidal)

secobarbital
(barbiturate)
 


 
Protocol 547-PPD-202   Amendment 2                                   Page 1 of 18  
 
                             Date: 30 Jun 2016 
 
Protocol 547-PPD-202 Amendment 2, Version 3.0 
 
Summary of Changes 
Protocol-547-PPD-202 
Dated 30 June 2016 
 
The following changes were made to the attached protocol in this amendment.  Minor typographical/editorial errors throughout the 
document were also corrected. The Synopsis, Tables, Figures and Abbreviations were corrected to be consistent with the changes in 
the main body of the protocol.  
 
Section number 
and title in 
Protocol 
Version 2.0 (22 
December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
Global 
Global 
N/A 
Protocol amended to include 
Parts A, B, and C. Part A is the 
existing completed part. Part A and 
Part B will study women with 
severe postpartum depression 
(PPD).  Part C will study women 
with moderate PPD.  
Addition of 
Part B to 
evaluate 
women with 
severe PPD at 
lower target 
doses of 
SAGE-547. 
Addition of 
Part C to 
evaluate 
women with 
moderate 
PPD.   
Title Page, 1. 
Signature Page, 
2. Synopsis 
Title Page, 1. 
Signature Page, 2. 
Synopsis 
A MULTICENTER, 
RANDOMIZED, DOUBLE-
BLIND, PARALLEL-GROUP, 
PLACEBO-CONTROLLED 
STUDY EVALUATING THE 
EFFICACY, SAFETY, AND 
A MULTICENTER, 
RANDOMIZED, DOUBLE-
BLIND, PARALLEL-GROUP, 
PLACEBO-CONTROLLED 
STUDY EVALUATING THE 
EFFICACY, SAFETY, AND 
Inclusion of 
subjects with 
moderate 
postpartum 
depression. 


 
Protocol 547-PPD-202   Amendment 2                                   Page 2 of 18  
 
                             Date: 30 Jun 2016 
 
Protocol 547-PPD-202 Amendment 2, Version 3.0 
 
Section number 
and title in 
Protocol 
Version 2.0 (22 
December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
PHARMACOKINETICS OF 
SAGE-547 INJECTION IN THE 
TREATMENT OF ADULT 
FEMALE SUBJECTS WITH 
SEVERE POSTPARTUM 
DEPRESSION 
PHARMACOKINETICS OF 
SAGE-547 INJECTION IN THE 
TREATMENT OF ADULT 
FEMALE SUBJECTS WITH 
SEVERE POSTPARTUM 
DEPRESSION AND ADULT 
FEMALE SUBJECTS WITH 
MODERATE POSTPARTUM 
DEPRESSION 
1. Signature 
Page 
1. Signature Page 
N/A 
, PhD 
 
 
Sage Therapeutics 
, MPH 
 
Sage Therapeutics 
  
 
 
 
Sage Therapeutics 
Addition of 
signatories for 
Sponsor 
Approval 
2. Synopsis 
2. Synopsis 
Approximately 15 sites in the 
United States 
Up to 50 sites in the United States 
and Canada 
Additional 
sites and 
country added 
to support 
enrollment in 
Parts B and C. 


 
Protocol 547-PPD-202   Amendment 2                                   Page 3 of 18  
 
                             Date: 30 Jun 2016 
 
Protocol 547-PPD-202 Amendment 2, Version 3.0 
 
Section number 
and title in 
Protocol 
Version 2.0 (22 
December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
5. Introduction 
and Rationale  
4. Introduction and 
Rationale 
This study is designed to evaluate 
the efficacy, safety, and 
pharmacokinetics (PK) of 
SAGE-547 (allopregnanolone) as 
a treatment for women with 
severe postpartum depression 
(PPD), an area of high unmet 
medical need. 
 
This study is designed to evaluate 
the efficacy, safety, and 
pharmacokinetics (PK) of 
SAGE-547 (allopregnanolone) as a 
treatment for women with severe or 
moderate postpartum depression 
(PPD), an area of high unmet 
medical need. 
 
 
5.5.1 Study 
Population 
4.5.1 Study 
Population 
This study will evaluate the 
efficacy, safety, and 
pharmacokinetics (PK) of SAGE-
547 Injection in the treatment of 
adult female subjects diagnosed 
with severe postpartum 
depression.   
This study will evaluate the 
efficacy, safety, and 
pharmacokinetics (PK) of 
SAGE-547 Injection in the 
treatment of adult female subjects 
diagnosed with severe or moderate 
postpartum depression.   
Inclusion of 
subjects with 
moderate 
postpartum 
depression 
5.5.1 Study 
Population 
4.5.1 Study 
Population 
N/A 
Part A of this study will study 
women with severe PPD, and 
Part C will study women with 
moderate PPD (Part B and C will 
run concurrently).  Moderate 
severity level will be studied 
because the pathogenesis of severe 
postpartum depression may not be 
generalized to those patients with a 
less severe form of illness.  For 
example, outside of postpartum 
Addition of 
Parts A and C 
study 
population.  


 
Protocol 547-PPD-202   Amendment 2                                   Page 4 of 18  
 
                             Date: 30 Jun 2016 
 
Protocol 547-PPD-202 Amendment 2, Version 3.0 
 
Section number 
and title in 
Protocol 
Version 2.0 (22 
December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
depression, findings suggest that 
patient’s treatment-resistant 
depression may respond more 
favorably to certain 
pharmacotherapy options such as 
ketamine (Coyle 2015).  Therefore, 
in order to determine the efficacy of 
SAGE-547 in women with less 
severe levels of symptoms, a 
separate group with moderate PPD 
with the same doses of the study 
drug used in the severe group will 
be investigated. 
5.5.3 Dose 
Rationale 
4.5.3 Dose Rationale The infusion rate of SAGE-547 to 
be studied in this trial was chosen 
to achieve a mean exposure of 
150 nM, roughly equivalent to the 
highest endogenous 
concentrations measured in third 
trimester pregnancy at 
approximately 157 nM (Luisi 
2000).   
The infusion rate of SAGE-547 to 
be studied in Parts A and C of this 
study was chosen to achieve a mean 
exposure of 150 nM, roughly 
equivalent to the highest 
endogenous concentrations 
measured in third trimester 
pregnancy at approximately 
157 nM (Luisi 2000).   
Addition of 
Parts A and C.  
5.5.3 Dose 
Rationale 
4.5.3 Dose Rationale Doses will be increased as 
follows: 30 µg /kg/hour [(0-4 
hours],), then 60 µg/kg/hour [(4- 
24 hours],), then 90 µg/kg/hour 
[(24-52 hours],), followed by a 
decrease to 60 µg/kg/hour (52- 56 
In Parts A and C, doses will be 
increased as follows: 30 µg/kg/hour 
[(0-4 hours],), then 60 µg/kg/hour 
[(4- 24 hours],), then 90 µg/kg/hour 
[(24-52 hours],), followed by a 
decrease to 60 µg/kg/hour 
Addition of 
Parts A and C. 


 
Protocol 547-PPD-202   Amendment 2                                   Page 5 of 18  
 
                             Date: 30 Jun 2016 
 
Protocol 547-PPD-202 Amendment 2, Version 3.0 
 
Section number 
and title in 
Protocol 
Version 2.0 (22 
December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
hours), and 30 µg/kg/hour (56-60 
hours).   
(52-56 hours), and 30 µg/kg/hour 
(56-60 hours).   
5.5.3 Dose 
Rationale 
4.5.3 Dose Rationale N/A 
In Part B, lower target doses will be 
explored (ie, 30 and 
60 µg/kg/hour).  These doses are 
based on observations in the open-
label 547-PPD-201 study in which 
subjects achieved substantial 
improvements in their HAMD 
scores within the first 12 hours of 
the SAGE-547 infusion.  In this 
study, subjects received a dose of 
21.5 μg/kg/h for the first 4 hours, 
then 43 μg/kg/h for the next 
4 hours, and then 64.5 μg/kg/h for 
the following 4 hours before 
receiving the target dose of 
86 μg/kg/h at 12 hours.  Therefore, 
the 12-hour data from 547-PPD-201 
suggests that SAGE-547 at target 
doses of 60 μg/kg/h or less may 
also be efficacious in reducing 
depressive symptoms associated 
with PPD.   
Addition of 
Part B.  
5.3 Subject 
Information and 
Informed 
Consent 
5.3 Subject 
Information and 
Informed Consent 
As an additional assessment, the 
ICF will contain a provision for 
optional consent for the collection 
of breast milk for the duration of 
As an additional assessment, the 
ICF will contain provisions for 
optional consent for the collection 
of blood for genetic testing during 
Addition of 
language to 
clarify that 
there will be 


 
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Version 2.0 (22 
December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
the 60-hour SAGE-547 infusion 
and up to Day 3 for biobanking 
and PK analysis purposes 
Screening and the collection of 
breast milk for the duration of the 
60-hour SAGE-547 infusion and up 
to Day 3 for biobanking and PK 
analysis purposes. 
an optional 
consent for 
genetic testing.  
7.1 Primary 
Objective 
6.1 Primary 
Objective 
The primary objective of this 
study is to determine if SAGE-
547 Injection infused 
intravenously for 60 hours 
reduces depressive symptoms in 
subjects with postpartum 
depression (PPD) compared to 
placebo injection as assessed by 
the change from baseline in 
Hamilton Rating Scale for 
Depression (HAMD) total score. 
The primary objective of this study 
is to determine if SAGE-547 
Injection infused intravenously for 
60 hours at up to 90 μg/kg/h 
reduces depressive symptoms in 
subjects with severe PPD compared 
to placebo injection as assessed by 
the change from baseline in HAMD 
total score. This objective applies 
to both Parts A and B. 
Addition of 
infusion rate 
associated 
with the 
timeframe. 
Addition of 
language to 
specify the 
Parts included 
in the 
objective.  
7.2 Secondary 
Objective 
6.2 Secondary 
Objective 
The secondary objectives of the 
study are: 
The secondary objectives of the 
study apply to Parts A, B and C 
unless otherwise stated, and are: 
 
Additional of 
language to 
specify the 
Parts included 
in the 
objective.  
7.2 Secondary 
Objective 
6.2 Secondary 
Objective 
N/A 
• To determine if SAGE-547 
infusion at up to 60 μg/kg/h for 
60 hours reduces depressive 
symptoms in subjects with severe 
PPD compared to placebo injection 
as assessed by the change from 
Addition of 
secondary 
objectives. 


 
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December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
baseline in HAMD total score 
(applies to Part B only). 
 
• To determine if SAGE-547 
Injection infused intravenously for 
60 hours reduces depressive 
symptoms in subjects with 
moderate PPD compared to placebo 
injection as assessed by the change 
from baseline in HAMD total score 
(applies to Part C only). 
8.1 Overview of 
Study Design 
7.1 Overview of 
Study Design 
This is a multicenter, randomized, 
double-blind, parallel-group, 
placebo-controlled study of the 
efficacy, safety, and 
pharmacokinetics of SAGE-547 
Injection in adult female subjects 
diagnosed with severe PPD.  The 
study design is presented in 
Figure 1. The study will consist of 
an up to 5 day Screening Period 
(Day -5 to -1), 3- day (60-hour) 
Treatment Period, and 30-day 
Follow-up Period.    
This is a 3-part multicenter, 
randomized, double-blind, parallel-
group, placebo-controlled study of 
the efficacy, safety, and 
pharmacokinetics of SAGE-547 
Injection in adult female subjects 
diagnosed with severe and 
moderate PPD.  The study design 
for Parts A and C is presented in 
Figure 1 and the study design for 
Part B is presented in Figure 2 
(Parts B and C will run 
concurrently).  For all parts, the 
study will consist of an up to 5-day 
Screening Period (Day -5 to -1), 3- 
day (60-hour) Treatment Period, 
and 30-day Follow-up Period.  
Addition of 
language to 
specify three 
parts. 
 Addition of 
Figure 2.  


 
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December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
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Changed to: 
 
 
Rationale 
8.1 Overview of 
Study Design 
7.1 Overview of 
Study Design 
Subjects will be confined to the 
study center from the Screening 
Visit until after the 60-hour 
assessments have been conducted 
on Day 3. 
Subjects will be confined to the 
study center from Screening Visit 
Day 1 until after the 60-hour 
assessments have been conducted 
on Day 3. 
Start time of 
subject 
confinement 
corrected to be 
consistent with 
SOE.  
8.1 Overview of 
Study Design 
7.1 Overview of 
Study Design 
N/A 
In Parts A and C, once subjects are 
confirmed as eligible for the study, 
they will be randomized to one of 2 
treatment groups (SAGE-547 90 
µg/kg/hour or placebo) on a 1:1 
basis.   
Addition of 
language for 
design of Parts 
A and C. 
8.1 Overview of 
Study Design 
7.1 Overview of 
Study Design 
N/A 
Subjects in the placebo group will 
receive infusion rates equivalent to 
the 90 µg/kg/hour group. 
 Language to 
clarify infusion 
rates for 
placebo group.  
8.1 Overview of 
Study Design 
7.1 Overview of 
Study Design 
N/A 
In Part B, once subjects are 
confirmed as eligible for the study, 
they will be randomized to one of 3 
treatment groups (SAGE-547 
60 µg/kg/hour, SAGE-547 
90 µg/kg/hour, or placebo) on a 
1:1:1 basis.  For the 60 µg/kg/hour 
group, subjects will receive 
30 µg/kg/hour (0-4 hours), then 
60 µg/kg/hour (4-56 hours), 
followed by 30 µg/kg/hour 
Addition of 
language for 
design of Part 
B.  


 
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3.0 (30 June 2016) 
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Changed to: 
 
 
Rationale 
(56-60 hours).  For the 90 
µg/kg/hour group, subjects will 
begin a 4-hour dose titration period 
of 30 µg/kg/hour (0-4 hours), then 
60 µg/kg/hour (4-24 hours), then 
90 µg/kg/hour (24-52 hours); 
followed by a decrease to 
60 µg/kg/hour (52-56 hours), and 
30 µg/kg/hour (56-60 hours).  
Subjects in the placebo group will 
receive infusion rates equivalent to 
either the 60 µg/kg/hour or 
90 µg/kg/hour group.  Parts B and 
C will run concurrently. 
See dose regimen presented in 
Section 10.1.1.  Total SAGE-547 
Injection or placebo dosing will 
occur over 60 hours. 
 
9.1 Inclusion 
Criteria, 8 
8.1 Inclusion 
Criteria, 8 
8. Subject has a HAMD total 
score of ≥26 at Screening and Day 
1 (prior to randomization). 
8. For Part A and B, subject has a 
HAMD total score of ≥26 at 
Screening and Day 1 (prior to 
randomization).  For Part C, 
subject has a HAMD total score 
of ≥20 and ≤25 at Screening and 
Day 1 (prior to randomization). 
Addition of 
criteria 
language for 
Parts A, B, and 
C. 
11.1 Dosing 
10.1 Dosing 
N/A 
In Parts A and C, subjects 
Addition of 


 
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and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
Schedule 
Schedule 
randomized to SAGE-547 will 
receive the target dose of 
90 µg/kg/hour; in Part B, SAGE-
547 subjects will receive target 
doses of either 60 or 90 µg/kg/hour.   
dosing 
schedule for 
Parts A, B and 
C. 
11.1 Dosing 
Schedule 
10.1 Dosing 
Schedule 
Figure 3. Trial Design and 
Timeline for Dosing 
Figure 3. Trial Design and Timeline 
for Dosing - Parts A and C 
 
Figure 4. Trial Design and 
Timeline for Dosing – Part B 
Language 
added to 
specify Figure 
3 relates to 
Parts A and C.  
 
Addition of 
Figure 4 for 
addition of 
Part B 
11.1.1 Dose 
Regimen 
10.1.1. Dose 
Regimen 
Table 2. Infusion Rates 
Table 2: Infusion rates for Part A 
and C 
 
Table 3: Infusion Rates for Part 
B 
Language 
added to 
specify Figure 
3 relates to 
Parts A and C.  
 
Addition of 
Figure 4 for 
addition of 
Part B 
11.1.4 Dosing of 
Intravenous 
SAGE-547 in 
10.1.4 Dosing of 
Intravenous SAGE-
547 in Case of AEs 
Since allopregnanolone levels in 
the proposed clinical trial are 
Since allopregnanolone levels in the 
proposed clinical trial are similar to 
physiological levels seen in the 
Addition of 
safety data. 


 
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December 2015) 
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and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
Case of AEs 
similar to physiological levels 
seen in the third trimester of 
pregnancy, and all the AEs 
reported with SAGE-547 or 
allopregnanolone to date were 
mild and non-serious, it is 
anticipated that the AEs 
associated with SAGE-547 will be 
mild and manageable without 
dose interruption or reduction.  
Based on the observed adverse 
events to date, the adverse events 
most likely to result in AE are 
sedation with or without 
hypotension.   
 
third trimester of pregnancy, and all 
the AEs reported with SAGE-547 
or allopregnanolone to date in 
healthy volunteers and subjects 
with postpartum depression were 
mild and non-serious, it is 
anticipated that the AEs associated 
with SAGE-547 in this study will 
be mild and manageable without 
dose interruption or reduction.  
Based on the safety data in 
subjects with PPD collected to 
date, no subjects reported events 
that were serious or severe and 
none led to discontinuation of 
study drug (2 subjects reported 
sedation that lead to a dose 
reduction, one of these subjects 
also reported dizziness; one 
subject reported rash that lead to 
a dose reduction; refer to the 
current Investigator’s Brochure 
for more information).   
12.1.2.3 
Hormones and 
Exploratory 
Biochemistry 
11.1.2.3. Hormones 
and Exploratory 
Biochemistry 
Blood samples will be collected 
for analysis of thyroid stimulating 
hormone (TSH), estrogen, 
progesterone, progesterone 
Blood samples will be collected 
and may be analyzed for thyroid 
stimulating hormone (TSH), 
estrogen, progesterone, 
Language 
added to 
clarify the 
potential 
analysis of 


 
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Protocol 
Version 2.0 (22 
December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
metabolites, oxytocin, tryptophan, 
kynurenine, and markers of 
inflammation. 
progesterone metabolites, oxytocin, 
tryptophan, kynurenine, and 
markers of inflammation. 
samples. 
12.1.5 Pulse 
Oximetry 
11.1.5 Pulse 
Oximetry 
Pulse oximetry will be monitored 
continuously from H0 until H60 
on Day 1, and checked 
approximately every 2 hours, 
including during the overnight 
hours, or at the alarm.   
Pulse oximetry will be monitored 
continuously from H0 until H60 
and checked approximately every 
2 hours, including during the 
overnight hours, or at the alarm.   
“Day 1” 
removed for 
clarification. 
12.3.1 Plasma 
PK Samples 
11.3.1. Plasma PK 
Samples 
N/A 
Each PK parameter will be derived 
separately for each part of the 
study. 
Language 
added to 
clarify how the 
specified 
parameters 
will be 
derived.  
13.1 Screening 
Period 
12.1 Screening 
Period 
Subjects will be confined to the 
study center from the Screening 
Visit until after the 60-hour 
assessments have been conducted 
on Day 3. 
Subjects will be confined to the 
study center from Day 1 until after 
the 60-hour assessments have been 
conducted on Day 3. 
Clarification 
of confinement 
to be 
consistent with 
the SOE.  
13.2.1 Day 1 
12.2.1 Day 1 
N/A 
 
• Pulse oximetry will be 
monitored continuously 
from H0 until H60 on Day 
1, and checked 
approximately every 
Language 
added to 
clarify the 
monitoring 
and collection 


 
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December 2015) 
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and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
2 hours, including during 
the overnight hours, or at 
the alarm 
of pulse 
oximetry on 
Day 1.  
13.2.2 Day 2 
12.2.2 Day 2 
N/A 
 
 
 
• Pulse oximetry will be 
monitored continuously 
(from H0 until H60), and 
checked approximately 
every 2 hours, including 
during the overnight hours, 
or at the alarm 
Language 
added to 
clarify the 
monitoring 
and collection 
of pulse 
oximetry on 
Day 2. 
13.2.2 Day 2 
12.2.2 Day 2 
• Additional measures of 
pulse oximetry will be 
collected during sleeping 
hours 
 
• Additional measures of 
pulse oximetry will be 
collected during sleeping 
hours 
 
Language 
deleted as 
assessment 
clarified in 
Day 2 
description. 
13.2.3 Day 3 
12.2.3 Day 3 
• Completion of physical 
examination 
• Completion of physical 
examination at Hour 72 
Clarification 
of timing of 
assessment. 
13.2.3 Day 3 
12.2.3 Day 3 
N/A 
• Pulse oximetry will be 
monitored continuously 
(from H0 until H60), and 
checked approximately 
every 2 hours, including 
during the overnight hours, 
or at the alarm 
Addition of 
assessment on 
Day 3. 
14.  Statistical 
13. Statistical 
N/A 
Separate summaries will be 
Addition of 


 
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Protocol 547-PPD-202 Amendment 2, Version 3.0 
 
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Protocol 
Version 2.0 (22 
December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
Methods and 
Considerations 
Methods and 
Considerations 
produced for each part of the study. 
language 
explaining 
production of 
separate 
summaries for 
each study 
part. 
14. 4. Primary 
Endpoints 
13.4. Primary 
Endpoints 
The primary comparison will be 
between SAGE-547 and placebo 
at the 60-hour assessment.  
Separate models will be fit for 
each part of the study.  For Parts 
A and C, the primary comparison 
will be between 90 µg SAGE-547 
and placebo at the 60-hour 
assessment.  For Part B, the 
primary comparison will be 
between 90 µg SAGE-547 and 
placebo at the 60-hour 
assessment; if this comparison is 
significant at the 0.05 level, then 
the 60 µg group will then be 
compared to placebo.  
Comparisons at other time points 
will be conducted to support the 
findings for the primary 
comparison.   
To redefine the 
primary 
endpoints 
based on the 
additions of 
Parts A, B, and 
C. 
14.5 Secondary 
Endpoints 
13.5 Secondary 
Endpoints 
For each model, the comparison 
of interest will be between SAGE-
547 and placebo at the 48-hour 
assessment.  Model based point 
Separate models will be fit for 
each part of the study.  For each 
model, the comparison of interest 
will be between each SAGE-547 
Language 
added to 
specify used of 
separate 


 
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Protocol 
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December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
estimates (ie, LS means), 95% 
confidence intervals, and p-values 
will be reported. 
dose and placebo at the 60-hour 
assessment.  Model based point 
estimates (ie, LS means), 95% 
confidence intervals, and p-values 
will be reported. 
models for 
comparison 
and time point 
change from 
the 48 hour to 
the 60 hour. 
14.5 Secondary 
Endpoints, 
Efficacy 
Analysis 
13.5.1 Efficacy 
Analysis 
N/A 
Separate models will be fit for each 
part of the study.   
Additional 
language for 
analysis of 
each study 
part.  
14.5 Secondary 
Endpoints, 
Efficacy 
Analysis 
13.5.1 Efficacy 
Analysis 
For each model, the comparison 
of interest will be between each 
SAGE-547 and placebo at the 48 -
hour assessment.   
For each model, the comparison of 
interest will be between each 
SAGE-547 dose and placebo at the 
60-hour assessment.   
Change of 
comparison 
time point.  
14.5 Secondary 
Endpoints, 
Efficacy 
Analysis 
13.5.1 Efficacy 
Analysis 
N/A 
Separate models will be fit for each 
part of the study.   
Additional 
language for 
analysis of 
each study 
part. 
14.6 
Determination of 
Sample Size 
13.6 Determination 
of Sample Size 
By including two treatment 
groups and using a 1:1 
randomization ratio, a total of 20 
evaluable subjects are required. 
Assuming a non-evaluability rate 
of 10%, at least 22 subjects will 
be randomized. 
 
By including 2 treatment groups 
and using a 1:1 randomization ratio, 
a total of 20 evaluable subjects are 
required for Part A.  Assuming a 
non-evaluability rate of 10%, up to 
22 subjects will be randomized in 
Part A. 
 
Additional 
language 
added to 
specify Part A 
requirements. 


 
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Protocol 547-PPD-202 Amendment 2, Version 3.0 
 
Section number 
and title in 
Protocol 
Version 2.0 (22 
December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
Based on the results of the interim 
analysis (see Section 14.7), the 
sample size could be increased to 
a maximum of 32 randomized 
subjects. 
Based on the results of the interim 
analysis (see Section 14.7), the 
sample size for Part A could be 
increased to a maximum of 
32 randomized subjects. 
14.6 
Determination of 
Sample Size 
13.6 Determination 
of Sample Size 
N/A 
For Part B, a sample size of 
18 evaluable subjects per group 
would provide at least 90% power 
to detect an effect size of 1.2 
between the SAGE-547 and 
placebo groups using a two-sided 
test at an alpha level of 0.05.  
Assuming a non-evaluability rate of 
10%, up to 60 subjects will be 
randomized in Part B. 
For Part C, a sample size of 
16 evaluable subjects per group 
would provide 80% power to detect 
an effect size of 1.0 between the 
SAGE-547 and placebo groups 
using a two-sided test at an alpha 
level of 0.10.  Assuming a non-
evaluability rate of 10%, up to 
36 subjects will be randomized in 
Part C.   
Addition of 
language for 
Parts B and C. 
14.7 Interim 
Analysis 
13.7 Interim 
Analysis 
An interim analysis will be 
conducted by an independent 
An interim analysis will be 
conducted by an independent 
Addition of 
language to 


 
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and title in 
Protocol 
Version 2.0 (22 
December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
statistician for sample size re- 
estimation purposes when at least 
16 subjects have completed 
efficacy assessments through 60 
hours. Since the sponsor will be 
kept uninformed of the response 
rates at the time of the interim 
analysis, no statistical adjustment 
will be made to the level of 
significance for hypothesis testing 
at the end of the study.   
statistician for sample size re- 
estimation purposes when at least 
16 subjects have completed efficacy 
assessments through 60 hours in 
Part A.  Since the Sponsor will be 
kept uninformed of the response 
rates at the time of the interim 
analysis, no statistical adjustment 
will be made to the level of 
significance for hypothesis testing 
Part A of the study. 
specify 
analysis for 
Part A.  
14.8 Changes 
from Protocol 
Specified 
Analyses 
13.8 Changes from 
Protocol Specified 
Analyses 
N/A 
Upon the completion of each part of 
the study, the data may be 
unblinded and analyzed separately.  
The final CSR will report the 
findings of all parts of the study.   
Addition of 
language for 
analysis of 
each part. 
14.1.5 
Unexpected 
14.1.5 Unexpected 
N/A 
In the clinical trial setting, the term 
“expected” would not mean 
“anticipated” for the condition 
being treated or population being 
studied since “expected” would 
indicate being “listed in the 
Investigator’s Brochure.”  For 
example, some adverse events can 
be anticipated to occur as a result of 
a disease or condition or in a certain 
population (eg, cancer-related 
Language 
added to 
clarify the 
term 
“expected” in 
a clinical 
setting.  


 
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and title in 
Protocol 
Version 2.0 (22 
December 2015) 
Section number 
and title in Version 
3.0 (30 June 2016) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
deaths in a cancer trial, strokes or 
acute myocardial infarctions in an 
older population).  However, for 
reporting purposes, these 
anticipated events are not 
considered “expected” if they are 
not listed in the Investigator’s 
Brochure (ie, the investigational 
drug is not suspected or known to 
cause them).  
 


Protocol 547-PPD-202 
Sage Therapeutics 
 
22 Dec 2015 
Confidential 
      1   
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL-
GROUP, PLACEBO-CONTROLLED STUDY EVALUATING THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS OF SAGE-547 
INJECTION IN THE TREATMENT OF ADULT FEMALE SUBJECTS 
WITH SEVERE POSTPARTUM DEPRESSION 
 
PROTOCOL NUMBER: 547-PPD-202 
 
IND NUMBER: 122279 
 
Investigational Product: 
SAGE-547 Injection (allopregnanolone) 
Clinical Phase: 
2a 
Sponsor: 
Sage Therapeutics 
Sponsor Contact: 
, MDMBA 
  
 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Phone: 
 
 
 
 
Medical Monitor: 
 
, MD  
 
Office (9-5 EST): 
  
24/7 Hotline: 
 
Date of Original Protocol: 
Date of Amendment One: 
Version 1.0 18 September 2015 
Version 2.0 22 December 2015 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without written authorization from the Sponsor. 




Protocol 547-PPD-202 
Sage Therapeutics 
 
22 Dec 2015 
Confidential 
      3   
 
2 SYNOPSIS 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
Name of Investigational Product: 
SAGE-547 Injection 
Name of Active Ingredient: 
Allopregnanolone 
Title of the Protocol: 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study Evaluating the 
Efficacy, Safety, and Pharmacokinetics of SAGE-547 Injection in the Treatment of Adult Female 
Subjects With Severe Postpartum Depression 
Study Sites: Approximately 15 sites in the United States 
Duration of Subject Participation: Up to 35 days 
Primary Objective: 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces depressive 
symptoms in subjects with postpartum depression (PPD) compared to placebo injection as 
assessed by the change from baseline in Hamilton Rating Scale for Depression (HAMD) total 
score 
Secondary Objectives: 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces depressive 
symptoms compared to placebo injection as assessed by HAMD response, HAMD remission, 
change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score, 
Clinical Global Impression – Improvement (CGI-I) response, and changes from baseline in 
HAMD subscale and individual item scores.   
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces other mood 
symptoms compared to placebo injection as assessed by changes from baseline in the 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) total score. 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours increases sedation 
levels compared to placebo injection as assessed by the changes from baseline in Stanford 
Sleepiness Scale (SSS) score. 
• 
To evaluate the safety and tolerability of SAGE-547 Injection compared with placebo as 
assessed by the incidence of adverse events, vital sign measurement, clinical laboratory 


Protocol 547-PPD-202 
Sage Therapeutics 
 
22 Dec 2015 
Confidential 
      4   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
evaluations, electrocardiogram (ECG) parameters, and the Columbia Suicide Severity Rating 
Scale (C-SSRS). 
Exploratory Objective: 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces subject-
reported depressive symptoms compared to placebo injection as assessed by the change from 
baseline in Edinburgh Postnatal Depression Scale (EPDS) total score and the change from 
baseline in Patient Health Questionnaire (PHQ-9) total score. 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours improves maternal 
behaviors compared to placebo injection as assessed by the change from baseline in Barkin 
Index of Maternal Functioning (BIMF) total and sub-scale scores.  
Pharmacokinetic Objective: 
• 
To assess the pharmacokinetic (PK) profile of SAGE-547, metabolites of SAGE-547, and 
betadex sulfobutyl ether sodium (SBECD) and the concentration of SAGE-547 in breast milk, 
when possible. 
Study Design and Methodology:  
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of the 
efficacy, safety, and pharmacokinetics of SAGE-547 Injection in adult female subjects diagnosed with 
severe PPD. Subjects must remain as in-patients during the study Treatment Period, which is 
approximately 60 hours/2.5 days in duration. The Screening Period assessments may be conducted on 
an in-patient or an out-patient basis. The Follow-up Period assessments are conducted on an out-patient 
basis. 
Screening Period: The Screening Period begins with the signature of the informed consent form (ICF). 
Eligibility is determined by applying the inclusion/exclusion criteria. The diagnosis of PPD must be by 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). A full medical and family history 
will be taken including recording of all depression, other Axis 1 and Axis 2 disorders and postpartum 
depression episodes in primary probands (who may be subject to a SCID-I interview). 
Treatment Period: Once subjects are confirmed as eligible for the study, they will be randomized to 
one of two treatment groups (SAGE-547 or placebo) on a 1:1 basis. Continuous intravenous infusions 
of blinded study drug will be administered, with a new bag and line hung every 24 hours during the 60-
hour infusion. Infusion rates will increase and then taper, with subjects receiving 30 µg/kg/hour (0-4 
hours), then 60 µg/kg/hour (4-24 hours), then 90 µg/kg/hour (24-52 hours), followed by 60 µg/kg/hour 
(52-56 hours), and 30 µg/kg/hour (56-60 hours). Subjects may be discharged after the 72-hour 
assessments have been completed (12 hours after completion of the study drug infusion). If their 
clinical condition does not allow discharge, normal standard of care will be employed in their ongoing 
management. 


Protocol 547-PPD-202 
Sage Therapeutics 
 
22 Dec 2015 
Confidential 
      5   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
Initiation of benzodiazepines, narcotics, antibiotics, neuroleptics, and other anti-anxiety medications 
will not be allowed between Screening and completion of the 72-hour assessments. Doses of 
psychotropics, which must have been initiated at least 14 days prior to screening, must remain at a 
stable dose until completion of the 72-hour assessments. If at the 72-hour assessment there has been no 
treatment response (HAMD total score remains above 13), treatment with antidepressant medication 
may be optimized prior to discharge, and the subject may remain in the unit or be followed at an out-
patient clinic, as clinically indicated. 
Efficacy and safety assessments will be performed periodically during the study, and blood samples 
will be collected for analysis of SAGE-547, metabolites of SAGE-547, and SBECD concentrations, as 
outlined in the Schedule of Events (Table 1). Blood samples will be collected, and outcome measures 
will be obtained at pre-specified times over 60 hours during the Treatment Period.  
Follow-up Period: Follow-up visits will be conducted one week (7±1 day) and one month (30±3d) 
after the initiation of the study drug infusion. 
Number of Subjects: 
Up to 32 subjects will be randomized   
Inclusion Criteria:  
The following inclusion criteria must be met for individuals to be eligible for the trial: 
1. Subject has signed an ICF prior to any study-specific procedures being performed 
2. Subject is an ambulatory female aged between 18 and 45 years of age, inclusive 
3. Subject is in good physical health and has no clinically significant findings, as determined by 
the Investigator, on physical examination, 12-lead ECG, or clinical laboratory tests 
4. Subject agrees to adhere to the study requirements 
5. Subject either must have ceased lactating at Screening; or if still lactating or actively breast 
feeding at Screening, must agree to temporarily cease giving breastmilk to their infant(s) from 
just prior to receiving study drug through 9 days (Study Day 12) after the end of infusion.  
6. Subject must have a negative pregnancy test at Screening and Day 1 prior to the start of study 
drug infusion 
7. Subject has had a Major Depressive Episode that began no earlier than the third trimester and 
no later than the first 4 weeks following delivery, as diagnosed by Structured Clinical 
Interview for DSM-IV Axis I Disorders (SCID-I) 
8. Subject has a HAMD total score of ≥26 at Screening and Day 1 (prior to randomization) 
9. Subject is ≤ six months postpartum 


Protocol 547-PPD-202 
Sage Therapeutics 
 
22 Dec 2015 
Confidential 
      6   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
10. Subject is willing to delay start of other antidepressant or anxiety medications and any new 
pharmacotherapy regimens, including prn benzodiazepine anxiolytics, until the study drug 
infusion and 72-hour assessments have been completed 
11. Subject has no detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), 
and human immunodeficiency virus (HIV) antibody at Screening 
12. Subject must use one of the following methods of birth control during participation in the study 
and for 30 days following the end of the study drug infusion: 
• 
Total abstinence (no sexual intercourse) 
• 
Hormonal contraceptives (birth control) including birth control pills, implantable or 
injectable contraceptives (Norplant® or Depo-Provera® ) 
• 
A barrier form of contraception such as a condom or occlusive cap with a spermicide 
• 
An intrauterine device (IUD) 
 
Exclusion Criteria: 
Subjects will be excluded if they meet any of the following exclusion criteria: 
1. Recent history or active clinically significant manifestations of metabolic, hepatic, renal, 
hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, 
urogenital, neurological, or eyes, ears, or nose and throat disorders, or any other acute or 
chronic condition that, in the Investigator’s opinion, would limit the subject’s ability to 
complete or participate in this clinical study 
2. Known allergy to progesterone or allopregnanolone 
3. Active psychosis per Investigator assessment 
4. Attempted suicide associated with index case of postpartum depression 
5. Medical history of seizures 
6. Medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder. 
7. History of active alcoholism or drug addiction (including benzodiazepines) in the 12 months 
prior to Screening 
8. Exposure to another investigational medication or device within 30 days prior to Screening 
9. Administration of psychotropics that have been initiated within 14 days prior to Screening and 
are not being taken at a stable dose. 


Protocol 547-PPD-202 
Sage Therapeutics 
 
22 Dec 2015 
Confidential 
      7   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
Investigational Product, Dosage, and Mode of Administration:  
SAGE-547 Injection, intravenous (IV) administration: SAGE-547 Injection is a sterile, clear, colorless 
5 mg/mL solution of SAGE-547 (allopregnanolone) and 250 mg/mL SBECD buffered with 10 mM 
citrate at a pH of 6.0, supplied in single-use 20 mL vials for IV administration. As supplied, SAGE-547 
Injection, which is hypertonic, requires further dilution with Sterile Water for Injection (SWFI) to 
render it isotonic for IV infusion. The specific infusion dose of SAGE-547 Injection will be calculated 
based on weight for each subject at Screening and administered according to the randomization 
schedule. Infusion bags will be changed every 24 hours. Details about the preparation and 
administration of the study drug infusions will be included in the Pharmacy Manual. 
Timepoint 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2-3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
Infusion Rate 
30 µg/kg/hour 
60 µg /kg/hour 
90 µg /kg/hour 
60 µg /kg/hour 
30 µg/kg/hour 
 
Reference Therapy, Dosage, and Mode of Administration:  
An identical placebo IV infusion will be prepared for IV administration consisting of the same 
formulation without allopregnanolone. 
Randomization and Stopping Rules: 
Subjects will be randomized to receive SAGE-547 Injection or placebo; subjects, clinicians, and study 
team will be blinded to treatment allocation. The pharmacist, who will prepare the infusion bags 
according to the randomization schedule, will be unblinded. The infusion rates are the same for all 
subjects within a particular dosing period (0-4 hours, 4-24 hours, etc.). 
If any subject has an SSS score of ≥5 for two or more consecutive assessments or an SSS score of ≥6 
for a single occurrence during normal waking hours, the infusion rate for this subject will be decreased 
to the next lowest infusion dose level (or turned off if this occurs on the 30 µg/kg/hour dose level). 


Protocol 547-PPD-202 
Sage Therapeutics 
 
22 Dec 2015 
Confidential 
      8   
 
Criteria for Evaluation: 
Primary Endpoint 
The primary outcome measure will be the 17-item Hamilton Rating Scale for Depression (HAMD). 
The HAMD will be administered before, during, and after the infusion of blinded study drug. The 
HAMD total score will be calculated as the sum of the 17 individual item scores. The change from 
baseline in HAMD total score at the end of the treatment period (at +60 hours) will be the primary 
efficacy endpoint with comparison between the two treatment groups used to evaluate the efficacy of 
SAGE-547 in treating the depressive symptoms of PPD. 
Secondary Endpoints 
Additional measures of depressive symptom severity will be administered before, during, and after the 
infusion of study drug, including the Montgomery-Asberg Depression Rating Scale (MADRS), and the 
Clinical Global Impression (CGI) scale. Total scores and changes from baseline will be calculated 
where applicable. Changes from baseline at the end of the treatment period (at +60 hours) and other 
time points will be evaluated as secondary efficacy endpoints with comparisons between the two 
treatment groups used to support the efficacy of SAGE-547 in treating the depressive symptoms of 
PPD. In addition to the above scales, the individual item scores and subscale scores from the HAMD 
scale will also evaluated as secondary efficacy endpoints. 
GAD-7 will also be administered before, during, and after the infusion of study drug.  As with other 
secondary efficacy endpoints, scores from these scales will be evaluated to assess the efficacy in other 
mood disorder and anxiety symptoms.   
An important safety endpoint will be the assessment of sedation using the SSS. The SSS will be 
assessed periodically before, during, and after the infusion of blinded study drug with changes from 
baseline over time evaluated similarly to that of efficacy endpoints.   
Safety and tolerability of SAGE-547 Injection will be evaluated by summarization of adverse events 
(AEs) by frequency, severity, and seriousness; clinical laboratory measures, vital signs, and ECGs 
(including changes from baseline); and concomitant medication usage. Suicidality will be monitored 
using the C-SSRS. 
The doses of all anti-depressant medications will be recorded throughout the study.  No changes and/or 
additions to antidepressant or anxiolytic medicine will be allowing during the dosing period. An 
analysis of time to starting/increasing the dose/decreasing the dose of each different anti-depressant 
medication will be undertaken for subjects discharged. 
Plasma will be collected to assay for concentrations of SAGE-547, SAGE-547 metabolites, and 
SBECD. The following PK parameters will be derived from the plasma concentrations (where 
evaluable): area under the concentration-time curve (AUC) from time zero to 60 hours (AUC0-60), AUC 
from time zero to infinity (AUCinf), maximum (peak) plasma concentration (Cmax), time at maximum 
(peak) plasma concentration (Tmax), steady-state drug concentration in the plasma during constant-rate 
infusion (Css), and average drug concentration in the plasma at steady state during a dosing interval 
(Cavg). 
Breast milk may be collected as an optional assessment if consent is received from the subject. Samples 


Protocol 547-PPD-202 
Sage Therapeutics 
 
22 Dec 2015 
Confidential 
      9   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
will be analyzed for SAGE-547 concentrations. 
Exploratory Endpoints 
Additional measures of symptoms and function related to the current episode of postpartum depression 
severity will be administered before, during, and after the infusion of study drug, including the EPDS, 
PHQ-9 and BIMF. 
Subscale and total scores and changes from baseline will be calculated where applicable.  Changes 
from baseline at the end of the treatment period (at +60 hours) and other time points will be evaluated 
as secondary efficacy endpoints with comparisons between the two treatment groups used to support 
the efficacy of SAGE-547 in treating the depressive symptoms of PPD.  In addition to the above scales, 
the individual item scores will also be evaluated as exploratory endpoints. 
Statistical Methods: 
For the purpose of all safety, efficacy, and exploratory analyses where applicable, baseline is defined as 
the last measurement prior to the start of blinded study drug infusion. 
Interim Analysis 
An interim analysis will be conducted by an independent statistician for sample size re-estimation 
purposes when at least 16 subjects have completed efficacy assessments through 60 hours.  Since the 
sponsor will be kept uninformed of the response rates at the time of the interim analysis, no statistical 
adjustment will be made to the level of significance for hypothesis testing at the end of the study.  A 
detailed description of the interim analysis will be included in the statistical analysis plan. 
Sample Size Calculation 
Assuming a two-sided test at an alpha level of 0.10, a sample size of 10 evaluable subjects per group 
would provide 80% power to detect an effect size of 1.2 between the SAGE-547 and placebo groups 
with regard to the primary outcome variable of change from baseline in HAMD total score. An effect 
size of 1.2 corresponds to a placebo adjusted difference of 12 points in the change from baseline in 
HAMD total score at 60 hours with an assumed standard deviation of 10 points. By including two 
treatment groups and using a 1:1 randomization ratio, a total of 20 evaluable subjects are required. 
Assuming a non-evaluability rate of 10%, at least 22 subjects will be randomized. 
Based on the results of the interim analysis, the sample size could be increased to a maximum of 32 
randomized subjects. This adjustment to the sample size would allow for an effect size of 1.0 to be 
detected.   
Efficacy Analysis 


Protocol 547-PPD-202 
Sage Therapeutics 
 
22 Dec 2015 
Confidential 
      10   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
The efficacy population will include all subjects who start the infusion of study drug and have a valid 
baseline HAMD assessment and at least one post-baseline HAMD assessment.  Subjects will be 
classified and summarized by randomized treatment.   
The change from baseline in HAMD total score will be analyzed using a mixed effects repeated 
measures model including center, treatment, baseline score, timepoint, and timepoint-by-treatment as 
explanatory variables. Center will be treated as a random effect while all other explanatory variables 
will be treated as fixed effects.  The primary comparison between SAGE-547 and placebo will be at the 
60 hour timepoint.  Comparisons at other timepoints will be conducted to support the findings for the 
primary comparison.   
Changes from baseline in other rating scale scores will be analyzed with methods similar to the primary 
endpoint. Any dichotomous response variables will be analyzed using logistic regression methods.   
In addition to formal analysis, efficacy rating scale scores (including recorded and change from 
baseline values) will be summarized by descriptive statistics, including n, mean, standard deviation 
(SD), median, and minimum and maximum values. Categorical efficacy endpoints (including HAMD, 
MADRS, and CGI-I response variables) will be summarized by frequency and percentage. 
Safety Analysis 
The Safety Population (SAF) is defined as all subjects who start the infusion of study drug. Subjects 
will be classified and summarized by actual treatment.   
Safety will be assessed using SSS, AEs, vital signs, ECG, clinical laboratory tests, C-SSRS, and 
concomitant medication data. Continuous safety data (including absolute and change from baseline 
values) will be summarized by descriptive statistics, including n, mean, standard deviation (SD), 
median, and minimum and maximum values.  Categorical endpoints will be summarized by frequency 
and percentage. In addition, an analysis of the SSS score will be performed comparing the treatment 
groups in the same way as for the primary endpoint. 
Safety data will be examined for possible relationships between subject characteristics and plasma 
allopregnanolone concentrations, as appropriate. 


Protocol 547-PPD-202 
Sage Therapeutics 
 
22 Dec 2015 
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      11   
 
TABLE 1: SCHEDULE OF EVENTS 
 
Screening 
Period 
Treatment Period 
Clinic Period (Day 1 to Day 3) 
Follow-up Period 
Visit Days  
Screening 
D-5 to -1 
D1 
H0* 
D1 
H2 
D1 
H4 
D1 
H8 
D1 
H12 
D1 
H18 
D1 
H24 
D2 
H30 
D2 
H36 
D2 
H42 
D2 
H48 
D3 
H54 
D3 
H60 
D3 
H66 
D3 
H72 
D7/ET 
(±1d) 
D12 
(+1d)l 
D30 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Lab Assessments a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Urinalysis a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Drug & Alcohol Screen b 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic Sample d 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pulse Oximetry 
 
X 
 
 
 
 
 
12-Lead ECG f 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
C-SSRS g 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
Confinement 
 
X 
 
 
 
CGI-I h 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
CGI-S h 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAMD h 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
MADRS h 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
X 
BIMF h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
EPDS h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
GAD-7 h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
PHQ-9 h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
SSS i 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


Protocol 547-PPD-202 
Sage Therapeutics 
 
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      12   
 
 
Screening 
Period 
Treatment Period 
Clinic Period (Day 1 to Day 3) 
Follow-up Period 
Visit Days  
Screening 
D-5 to -1 
D1 
H0* 
D1 
H2 
D1 
H4 
D1 
H8 
D1 
H12 
D1 
H18 
D1 
H24 
D2 
H30 
D2 
H36 
D2 
H42 
D2 
H48 
D3 
H54 
D3 
H60 
D3 
H66 
D3 
H72 
D7/ET 
(±1d) 
D12 
(+1d)l 
D30 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK j 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Xl 
 
Breast Milk PK k 
 
X 
X 
X 
X 
X 
X 
X 
Xl 
Xl 
 
Study Drug Infusion 
 
X 
 
 
 
 
 
Adverse Events 
X 
Concomitant Medications 
X 
O = optional 
* = All H0 procedures to be completed prior to dosing 
a  Safety laboratory tests will include hematology, serum chemistry, coagulation,  and select hormone parameters. The urine test will include a urinalysis. Lab 
assessments are to be completed within ± 30 minutes of the scheduled timepoint. 
b  Urine for selected drugs of abuse and alcohol (serum or breath) 
c  Serum at Screening and urine for all other timepoints 
d A blood sample for genetic testing, where consent is given 
e  Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Vital signs will be obtained within ± 30 minutes 
of the scheduled timepoint, unless the subject is asleep between the hours of 23.00h and 06.00h. 
f  Performed within ± 30 minutes of the scheduled time point on Day 2. 
g  The “Baseline/Screening” C-SSRS form will be completed on Day 1. The “Since Last Visit” C-SSRS form will be completed at all subsequent timepoints. 
h  To be completed within ± 30 minutes of the scheduled timepoint. 
i  To be completed within ± 15 minutes of the scheduled timepoint, unless the subject is asleep between the hours of 23.00h and 06.00h  
j  Blood samples for PK analysis will be collected at pre-infusion and at 4 (before change in infusion rate), 8, 12, 24 (before change in infusion rate), 30, 36, 48 
60 (before end of infusion) and 72 hours after the start of the infusion. PK blood draws after the start of infusion will have a window of ± 10 minutes. In the 
event of an  unplanned dose adjustment, an unscheduled PK sample should be collected just prior to the infusion rate change. 
k  Optional assessment per subject consent, breast milk will be collected and pooled over the following time periods of interest: 0, 1-12, 12-24, 24-36, 36-48, 48-
60 and 60-72 hours after the start of the infusion. 
l  Day 7 Breast Milk Samples/Day 12 Visit is only applicable to those patients who have temporarily ceased breastfeeding and are participating in the optional 
breast milk sampling.  
BIMF = Barkin Index of Maternal Functioning; CGI-I = Clinical Global Impression of Improvement; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = 
electrocardiogram; EPDS = Edinburgh Postnatal Depression Scale; GAD-7 = Generalized Anxiety Disorder 7-Item Scale; HAMD = Hamilton Rating Scale 
forDepression, 17-item; MADRS = Montgomery-Asberg Depression Rating Scale; PHQ-9 = Patient Health Questionnaire; PK = pharmacokinetic; SSS = 
Stanford Sleepiness Scale. 


Protocol 547-PPD-202 
Sage Therapeutics 
 
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      13   
 
3 TABLE OF CONTENTS, LIST OF TABLES, FIGURES AND 
APPENDICES 
Table of Contents 
1 
SIGNATURE PAGE ................................................................................ 2 
2 
SYNOPSIS ............................................................................................... 3 
3 
TABLE OF CONTENTS, LIST OF TABLES, FIGURES AND 
APPENDICES ........................................................................................ 13 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS......... 18 
5 
INTRODUCTION AND RATIONALE ................................................. 21 
5.1 
Role of Allopregnanolone in Affective Disturbances ............................ 22 
5.1.1 
Rationale for Allopregnanolone Treatment of PPD ............................... 22 
5.2 
SAGE-547 Injection (Allopregnanolone) ............................................... 23 
5.3 
Summary of Nonclinical and Clinical Experience With 
Allopregnanolone or SAGE-547 ............................................................ 24 
5.3.1 
Nonclinical Pharmacology ...................................................................... 24 
5.3.2 
Clinical Experience ................................................................................. 24 
5.4 
Potential Risks and Benefits ................................................................... 25 
5.5 
Study No. 547-PPD-202 ......................................................................... 25 
5.5.1 
Study Population ..................................................................................... 25 
5.5.2 
Route of Administration, Dosage, Dosage Regimen, and Treatment 
Period ...................................................................................................... 25 
5.5.3 
Dose Rationale ........................................................................................ 26 
6 
ETHICS .................................................................................................. 27 
6.1 
Institutional Review Board or Independent Ethics Committee .............. 27 
6.2 
Ethical Conduct of the Study .................................................................. 27 
6.3 
Subject Information and Informed Consent ........................................... 27 
7 
STUDY OBJECTIVES .......................................................................... 28 
7.1 
Primary Objective ................................................................................... 28 
7.2 
Secondary Objectives ............................................................................. 28 
7.3 
Exploratory Objectives ........................................................................... 28 
7.4 
Pharmacokinetic Objective ..................................................................... 28 
8 
INVESTIGATIONAL PLAN ................................................................. 29 


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8.1 
Overview of Study Design ...................................................................... 29 
8.2 
Blinding and Randomization .................................................................. 30 
9 
SELECTION AND WITHDRAWAL OF SUBJECTS .......................... 32 
9.1 
Inclusion Criteria .................................................................................... 32 
9.2 
Exclusion Criteria ................................................................................... 32 
9.3 
Subject Withdrawal/Study Termination ................................................. 33 
9.3.1 
Withdrawal/Discontinuation of Individual Subjects .............................. 33 
9.3.2 
Subject Withdrawal From the Study ....................................................... 33 
9.3.3 
Discontinuation of Study Drug by the Investigator ................................ 33 
9.3.4 
Study Termination .................................................................................. 34 
10 
INVESTIGATIONAL PRODUCT ........................................................ 35 
10.1 
Identity of Investigational Product ......................................................... 35 
10.2 
Clinical Supplies ..................................................................................... 35 
10.2.1 
SAGE-547 ............................................................................................... 35 
10.2.2 
Placebo .................................................................................................... 35 
10.3 
Preparation of SAGE-547 Injection or Placebo for Dosing ................... 35 
10.4 
Administration and Accountability ......................................................... 36 
11 
TREATMENT OF SUBJECTS .............................................................. 37 
11.1 
Dosing Schedule ..................................................................................... 37 
11.1.1 
Dose Regimen ......................................................................................... 37 
11.1.2 
Route of Administration ......................................................................... 38 
11.1.3 
Treatment Period .................................................................................... 38 
11.1.4 
Dosing of Intravenous SAGE-547 in the Case of AEs ........................... 38 
11.2 
Dosing Compliance ................................................................................ 38 
11.3 
Concomitant Medications and Restrictions ............................................ 39 
11.3.1 
Concomitant Medications ....................................................................... 39 
11.3.2 
Prohibited Medications ........................................................................... 39 
12 
STUDY ASSESSMENTS ...................................................................... 40 
12.1 
Safety Assessments ................................................................................. 40 
12.1.1 
Adverse Events ....................................................................................... 40 
12.1.2 
Clinical Laboratory Tests ....................................................................... 40 
12.1.2.1 
Hematology, Serum Chemistry, Coagulation ......................................... 40 
12.1.2.2 
Hepatitis and HIV ................................................................................... 41 


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      15   
 
12.1.2.3 
Hormones and Exploratory Biochemistry .............................................. 41 
12.1.2.4 
Pregnancy Test ........................................................................................ 41 
12.1.2.5 
Genetic Testing ....................................................................................... 41 
12.1.2.6 
Urinalysis ................................................................................................ 42 
12.1.2.7 
Drugs of Abuse and Alcohol .................................................................. 42 
12.1.3 
Physical Examination ............................................................................. 42 
12.1.4 
Vital Signs .............................................................................................. 42 
12.1.5 
Pulse Oximetry ....................................................................................... 42 
12.1.6 
ECG ........................................................................................................ 42 
12.1.7 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................... 43 
12.1.8 
Stanford Sleepiness Scale (SSS) ............................................................. 43 
12.2 
Efficacy Assessments ............................................................................. 43 
12.2.1 
Primary Efficacy Outcome Measure ...................................................... 43 
12.2.1.1 
Hamilton Rating Scale for Depression (HAMD) ................................... 43 
12.2.2 
Secondary Efficacy Outcome Measures ................................................. 44 
12.2.2.1 
Montgomery Asberg Depression Rating Scale (MADRS) ..................... 44 
12.2.2.2 
Clinical Global Impression (CGI) Scale ................................................. 44 
12.2.2.3 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) ........................... 45 
12.2.3 
Exploratory Patient Reported Outcome Measures ................................. 45 
12.2.3.1 
Edinburgh Postnatal Depression Scale (EPDS) ...................................... 45 
12.2.3.2 
Patient Health Questionnaire (PHQ-9) ................................................... 45 
12.2.3.3 
Barkin Index of Maternal Functioning (BIMF) ...................................... 46 
12.3 
Pharmacokinetics .................................................................................... 46 
12.3.1 
Plasma PK Samples ................................................................................ 46 
12.3.2 
Breastmilk PK Samples .......................................................................... 46 
13 
STUDY PROCEDURES ........................................................................ 47 
13.1 
Screening Period ..................................................................................... 47 
13.2 
SAGE-547 Treatment Period (Day 1 to Day 3, Hours 0-60) ................. 48 
13.2.1 
Day 1 ....................................................................................................... 48 
13.2.2 
Day 2 ....................................................................................................... 49 
13.2.3 
Day 3 ....................................................................................................... 49 
13.3 
Follow-up Period (Day 7 through Day 60) ............................................. 50 
13.3.1 
Day 7 (± 1 day) ....................................................................................... 50 


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13.3.2 
Day12 (+1 day) ....................................................................................... 50 
13.3.3 
Day 30 (± 3 days) ................................................................................... 51 
13.3.4 
Early Termination Visit .......................................................................... 51 
14 
STATISTICAL METHODS AND CONSIDERATIONS ..................... 52 
14.1 
Data Analysis Sets .................................................................................. 52 
14.2 
Handling of Missing Data ....................................................................... 53 
14.3 
Demographics and Baseline Characteristics ........................................... 53 
14.4 
Primary Endpoints .................................................................................. 53 
14.5 
Secondary Endpoints .............................................................................. 53 
14.6 
Determination of Sample Size ................................................................ 55 
14.7 
Interim Analysis ...................................................................................... 56 
14.8 
Changes From Protocol Specified Analyses ........................................... 56 
15 
ADVERSE EVENTS.............................................................................. 57 
15.1 
Adverse Event Definitions ...................................................................... 57 
15.1.1 
Adverse Event ......................................................................................... 57 
15.1.2 
Suspected Adverse Reaction ................................................................... 57 
15.1.3 
Life-Threatening ..................................................................................... 57 
15.1.4 
Serious .................................................................................................... 57 
15.1.5 
Unexpected ............................................................................................. 58 
15.2 
Investigator Responsibilities ................................................................... 58 
15.2.1 
Identification and Documentation of Adverse Events by Investigator ... 58 
15.2.2 
Adverse Event Classification .................................................................. 59 
15.2.2.1 
Relationship to Investigational Drug ...................................................... 59 
15.2.2.2 
Severity ................................................................................................... 59 
15.2.2.3 
Action Taken With Investigational Drug ............................................... 60 
15.2.2.4 
Assessment of Outcome ......................................................................... 60 
15.2.3 
Investigator Reporting to Sponsor and Sponsor Emergency Contact .... 60 
15.2.4 
Medical Monitor and Emergency Contact Information.......................... 61 
15.2.5 
SAE Reporting Contact Information ...................................................... 61 
15.2.6 
Reporting to Institutional Review Boards (IRBs) .................................. 61 
15.3 
Sponsor/Medical Monitor Responsibilities ............................................ 61 
15.3.1 
Monitoring of Adverse Event Data ......................................................... 61 
15.3.2 
Reporting to FDA ................................................................................... 61 


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15.4 
Emergency Identification of Study Medication ...................................... 62 
16 
STUDY ADMINISTRATION ............................................................... 63 
16.1 
Quality Control and Quality Assurance .................................................. 63 
16.2 
Data Handling and Recordkeeping ......................................................... 63 
16.2.1 
Data Handling ......................................................................................... 63 
16.2.2 
Case Report Form Completion ............................................................... 63 
16.2.3 
Retention of Study Records .................................................................... 64 
16.3 
Confidentiality ........................................................................................ 64 
16.4 
Publication Policy ................................................................................... 64 
16.5 
Protocol Amendments ............................................................................ 65 
17 
REFERENCES ....................................................................................... 66 
18 
APPENDICES ........................................................................................ 71 
APPENDIX 1. Columbia Suicide Severity Rating Scale (C-SSRS) ....................... 72 
APPENDIX 2. Hamilton Rating Scale for Depression, 17-Item (HAMD) ............ 79 
APPENDIX 3. Montgomery Asberg Depression Rating Scale (MADRS) ............ 81 
APPENDIX 4. Clinical Global Impression–Improvement Scale (CGI-I) and 
Severity Scale (CGI-S) ........................................................................... 84 
APPENDIX 5. Stanford Sleepiness Scale (SSS) .................................................... 86 
APPENDIX 6. Edinburgh Postnatal Depression Scale (EPDS) ............................. 88 
APPENDIX 7. Generalized Anxiety Disorder 7-Item Scale (GAD-7) ................... 90 
APPENDIX 8. Patient Health Questionnaire (PHQ-9) ........................................... 92 
APPENDIX 9. Barkin Index of Maternal Functioning (BIMF).............................. 94 
APPENDIX 10. Selected Inducers, Inhibitors, and Substrates of CYP2C9 ........... 96 
 
List of Tables 
Table 1: 
Schedule of Events ................................................................................. 11 
Table 2:  
Infusion rates .......................................................................................... 38 
 
List of Figures 
Figure 1: 
Study Design ........................................................................................... 29 
Figure 2: 
Trial Design and Timeline for Dosing .................................................... 37 
 


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4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term 
Definition of Terms 
AE 
adverse event 
ALLO 
allopregnanolone 
ALT 
alanine aminotransferase 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUCinf 
area under the concentration-time curve from time 
zero to infinity 
AUC0-60 
area under the concentration-time curve from time 
zero to 60 hours 
BIMF 
Barkin Index of Maternal Functioning 
BMI 
body mass index 
BMP 
breast milk population 
BUN 
blood urea nitrogen 
Cavg 
average drug concentration in the plasma at steady-
state during a dosing interval 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression–Improvement 
CGI-S 
Clinical Global Impression–Severity 
cGMP 
Current Good Manufacturing Practice 
Cmax 
maximum (peak) plasma concentration of the drug 
CMO 
Chief Medical Officer 
CNS 
central nervous system 
CRF 
case report form 
CS 
clinically significant 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
Css 
Steady-state drug concentration in the plasma 
during constant-rate infusion 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
Cytochrome P450 enzyme involved in drug 
metabolism 
DSM-IV 
Diagnostic and Statistical Manual of Mental 
Disorders, Fourth Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture  
EEG 
electroencephalography 
EFF 
efficacy population 
Ph. Eur. 
European Pharmacopeia  
EPDS 
Edinburgh Postnatal Depression Scale 
ERα 
estrogen receptor alfa 
ERß 
estrogen receptor beta 


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Abbreviation or Specialist Term 
Definition of Terms 
ET  
Early Termination 
FDA 
Food and Drug Administration 
GABA 
gamma-aminobutyric acid  
GABAA 
gamma-aminobutyric acid–gated chloride channel 
GAD-7 
Generalized Anxiety Disorder 7-Item Scale  
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
h 
hour 
HAMD 
Hamilton Rating Scale for Depression, 17-item 
HBsAg 
hepatitis B surface antigen  
Hct 
hematocrit 
HCV 
hepatitis C virus 
HEENT 
head, eyes, ears, nose, and throat 
Hgb 
hemoglobin 
HPLC MS/MS 
High-performance liquid chromatography tandem 
mass spectrometry 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
intention-to-treat population 
IV 
intravenous 
LFT 
liver function test 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
NF 
National Formulary 
NIMH 
National Institute of Mental Health  
PHQ-9 
Patient Health Questionnaire  
PK 
pharmacokinetic 
PKP 
pharmacokinetic population 
PMID 
PubMed identification 
PP 
per-protocol population 
PPD 
postpartum depression 
PR 
progesterone receptor 
PT/INR 
prothrombin time/international normalized ratio 
RBC 
red blood cell 
RSE 
refractory status epilepticus 
SAE 
serious adverse event 


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Abbreviation or Specialist Term 
Definition of Terms 
SAF 
safety population 
SAP 
statistical analysis plan 
SBECD 
betadex sulfobutyl ether sodium 
SCID-I 
Structured Clinical Interview for DSM-IV Axis I 
Disorders 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
SRSE 
super refractory status epilepticus 
SSRI 
selective serotonin reuptake inhibitors 
SSS 
Stanford Sleepiness Scale 
SWFI 
sterile water for injection 
T1/2 
half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum (peak) plasma concentration 
TSH 
thyroid stimulating hormone 
US 
United States 
USP 
United States Pharmacopeia 
VAS 
Visual analogue scale 
Vd 
volume of distribution 
WBC 
white blood cell 


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5 INTRODUCTION AND RATIONALE 
This study is designed to evaluate the efficacy, safety, and pharmacokinetics (PK) of SAGE-
547 (allopregnanolone) as a treatment for women with severe postpartum depression (PPD), 
an area of high unmet medical need. 
PPD is considered to be moderate to severe depression in women who have recently given 
birth, otherwise defined as the occurrence of major depressive disorder (MDD) within 4 
weeks of delivery (DSM V 2013) or up to a year after giving birth (Okun 2013). There are 
two entry criteria for the diagnosis of depression (depressed mood and/or loss of interest) and 
seven 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 five symptoms of depression (DSM 
V 2013), although this diagnosis may be confounded by the relative frequency of symptoms 
such as sleep disturbance or appetite problems in pregnant and postpartum women. Most 
women experience onset of symptoms within the first three months following delivery, and 
PPD is most prevalent at 10 to 14 weeks following childbirth (Okun 2013). 
During pregnancy, estradiol and progesterone levels increase dramatically but then rapidly 
decline in the acute postpartum period (Gavin 2005). The onset of PPD symptoms coincides 
with the rapid decrease of the gonadal steroids postpartum. The duration of a PPD episode 
has been estimated as shorter than depressive episodes in the general population (approx. 5 
months), while other studies indicate time to remission is approximately the same (Chaudron 
2003). 
PPD is common and has devastating consequences for the woman and for her family (Fihrer 
2009; Verbeek 2012). Perinatal depression is reported to be the most underdiagnosed 
obstetric complication in America (Earls 2010). Furthermore, it is the most common 
psychiatric illness to occur in the puerperium (O’Hara 2014). A meta-analysis of 30 studies 
(Gaynes 2005) found that the point prevalence of major and minor depression ranged 
between 6.5% and 12.9% at different times during the first postpartum year. Overall 
incidence is estimated at around 15–20% with up to 10% being considered severe (Edge 
2007, O’Hara 2014). 
Current standard of care for severe PPD comprises cautious use of pharmacological therapies 
in nursing mothers combined with other interventions. Evidence for efficacy of tricyclic 
antidepressants and/or selective serotonin reuptake inhibitors (SSRIs) is based on use in the 
general population rather than any extensive studies in PPD (Austin 2013), and SSRIs tend to 
be preferred due to better data on safety while breastfeeding (Altshuler 2001). Based on the 
level of evidence for antidepressants in major depressive disorder (Kirsch 2008, Fournier 
2010), there is a considerable need for improved pharmacological therapy for PPD. 
Drugs may be combined with a number of counseling, behavioral, and other non-
pharmacological therapy approaches, which are generally used as the first-line therapy in less 
severe PPD (Altshuler 2001). Urgent referral and potentially admission are recommended for 
mothers at risk of self-harm, with their infants, if such facilities exist (Austin 2013). 
Therapeutic options in severe PPD are currently limited, and it is not clear whether the 
current standard of care impacts the natural history of the disease, although most women 
recover within a year. 


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5.1 Role of Allopregnanolone in Affective Disturbances 
The neurosteroid metabolite of progesterone, allopregnanolone, acutely regulates neuronal 
function (Gangisetty 2010) and appears to play a significant role in affective disturbances 
that occur with changes in reproductive endocrine function, such as during the postpartum 
period (Amin 2006, Nappi 2001, Epperson 2006). 
Neurosteroids are metabolites of cholesterol-derived steroid hormones that are synthesized in 
the brain and nervous system; they modulate the major inhibitory and excitatory central 
nervous system (CNS) neurotransmitter systems: γ-aminobutyric acid (GABA) and 
glutamate, respectively. Neurosteroids are among the most potent and effective modulators 
of GABAA receptors and augment GABAergic inhibition (Belelli 2005). The powerful 
anxiolysis that accompanies this potentiation of GABAA receptors has led to the speculation 
that neurosteroid dysregulation plays a central role in the etiology of affective disorders, 
including reproductive mood disorders, such as PPD (Amin 2006). 
There is increasing evidence supporting the role of neurosteroids in affective dysregulation. 
Allopregnanolone and pregnanolone have been shown to modulate the GABA receptor 
positively (Majewska 1986). Several groups have demonstrated decreased allopregnanolone 
levels in MDD, with an increase seen in both plasma and cerebrospinal fluid (CSF) following 
successful antidepressant treatment (Uzunova 1998; Romeo 1998; Ströhle 1999; Schüle 
2006; Eser 2006; Schüle 2007). In addition, allopregnanolone has demonstrated anxiolytic 
effects in several animal anxiety models (Bitran 1991; Wieland 1991; Bitran 1993).  
Allopregnanolone may also exert antidepressant effects by reducing the physiological impact 
of stress, promoting neuroprotection, and protecting against the pro-inflammatory immune 
activation and cytokine hypersecretion associated with MDD. In animals, allopregnanolone 
increases in response to stress, reduces pain sensitivity, and is thought to restore physiologic 
homeostasis following stress (Frye 1994; Morrow 1995). Allopregnanolone also exerts 
neuroprotective effects by reducing the expression of pro-apoptotic proteins and apoptotic 
DNA fragmentation (Djebaili 2005; Sayeed 2009), thereby reducing the cell death and gliosis 
associated with depression (Glantz 2010; Shelton 2011). Neuroprotection is mediated by 
immune regulation in depression (Licinio 1999), and allopregnanolone reduces the 
expression of the pro-inflammatory cytokine TNF-α (He 2004), which is elevated in 
depressed individuals (Dowlati 2010). Thus, allopregnanolone modulates biological 
processes dysregulated in major depressive disorder. 
5.1.1 Rationale for Allopregnanolone Treatment of PPD 
Genetic susceptibility to affective dysregulation may be unmasked during periods of 
reproductive hormone change such as during pregnancy and postpartum (Maguire 2008). 
Maguire and Mody demonstrated that a GABA receptor subunit mutation was behaviorally 
silent until the animal was exposed to pregnancy and the postpartum state, at which time the 
dams showed depressive-like behaviors and cannibalized their offspring (Maguire 2008). 
During pregnancy, the expression of the GABAA receptor δ-subunit is down-regulated as 
allopregnanolone levels increase, and at parturition, the expression of the GABAA receptor δ-
subunit is recovered in response to rapidly declining neurosteroid levels (Maguire 2009). In 
contrast, the GABAA receptor δ-subunit-deficient mice fail to adapt to the dramatic changes 
in allopregnanolone and experience depression-like and anxiety-like behavior and abnormal 


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maternal behaviors, which are reversed by administration of allopregnanolone (Maguire 
2008). This model provides compelling support for the hypothesis that changes in 
neurosteroid concentrations during pregnancy and postpartum are capable of provoking 
affective dysregulation, particularly in those with a genetically-determined susceptibility. 
The capacity of changes in neurosteroids, such as allopregnanolone, to function as behavioral 
switches suggests a potentially important treatment role of this hormone metabolite in 
reproductive endocrine-related mood disorders such as PPD. 
The onset of PPD symptoms coincides with the rapid decrease of the gonadal steroids 
postpartum and has been reproduced in a pivotal clinical study (Bloch 2000). The authors 
investigated the possible role of changes in gonadal steroid levels in PPD by simulating two 
hormonal conditions related to pregnancy and parturition in euthymic women, 8 with and 8 
without a history of PPD. They induced hypogonadism with leuprolide, adding back supra-
physiologic doses of estradiol and progesterone for 8 weeks to simulate pregnancy. They 
then withdrew both steroids under double-blind conditions to mimic the rapid decrease of sex 
steroids upon delivery. Five of the eight women with a history of postpartum depression 
(62.5%) and 0% of the comparison group developed significant mood symptoms typical of 
PPD during the withdrawal period. 
Although progesterone levels were measured in this study, allopregnanolone was not. 
However, since allopregnanolone is the major active metabolite of progesterone, it can be 
assumed that the decrease in progesterone would cause a similar precipitate drop in 
allopregnanolone levels, as observed in the postpartum period (Gilbert Evans 2005, Paoletti 
2006, Nappi 2001).These data provide direct evidence in support of the involvement of 
progesterone and its metabolites in the development of postpartum depression in a subgroup 
of women. Further, they suggest that women with a history of postpartum depression are 
differentially sensitive to mood-destabilizing effects of gonadal steroids (Bloch 2000). 
Additional details regarding the role of allopregnanolone in the etiology of affective 
disorders and its nonclinical pharmacology and pharmacokinetics are presented in the 
Investigational Brochure. 
5.2 SAGE-547 Injection (Allopregnanolone) 
Allopregnanolone is an endogenous, naturally occurring neuroactive steroid formed in the 
corpus luteum of the ovary, adrenal cortex, and CNS (Holzbauer 1985; Ottander 2005; Paul 
1992). It is a metabolite of progesterone created by the actions of 5-α reductase and 3-α 
hydroxy-steroid dehydrogenase. Allopregnanolone is a potent positive allosteric modulator of 
both synaptic and extra-synaptic GABAA receptors. 
SAGE-547 Injection is a solution of 5 mg/mL allopregnanolone in Sterile Water for Injection 
(SWFI), United States Pharmacopeia (USP), and 250 mg/mL betadex sulfobutyl ether 
sodium buffered with 10 mM citrate at a pH of 6.0, and will be administered intravenously. 
SAGE-547 Injection is also being developed for the treatment of adult patients with 
refractory status epilepticus (RSE), inclusive of super refractory status epilepticus (SRSE), 
who have not responded to standard treatment regimens, and investigated for the treatment of 
adults with essential tremor. 


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5.3 Summary of Nonclinical and Clinical Experience With 
Allopregnanolone or SAGE-547 
5.3.1 Nonclinical Pharmacology 
The primary pharmacological effects of allopregnanolone or SAGE-547 are described earlier 
in the rationale (Sections 5.1 and 5.1.1). Secondary pharmacologic effects comprise mainly 
the binding and consequent increased activity of steroid hormone receptors (androgen 
receptor [(AR], progesterone receptor [PR], and estrogen receptor beta [ERß]), with some 
evidence of inhibition at the highest doses (AR and estrogen receptor alfa [ERα]). These non-
target effects may yield some adverse events in the clinic. 
Nonclinical toxicology studies largely illustrate the sedative and anesthetic effects of 
allopregnanolone and/or SAGE-547 at higher equivalent doses than the proposed dose for the 
current study. PK data in animals indicate a short half-life and rapid clearance with a 
moderate volume of distribution and cerebral levels higher than plasma. See SAGE-547 
Investigational Brochure for more details. 
5.3.2 Clinical Experience 
The clinical PK data with intravenous (IV) administration of allopregnanolone in healthy 
women, men, and women on oral contraceptives confirmed the PK observations in animals 
of a short half-life (T1/2 20-40 mins), Cmax achievable at approximately 3rd trimester levels 
(150 nM), rapid clearance and moderate volume of distribution (Vd). See SAGE-547 
Investigational Brochure for more details. 
There are currently no double-blind, placebo-controlled clinical efficacy data for SAGE-547 
in PPD. An open-label, proof-of-concept study (547-PPD-201) evaluating the safety, 
tolerability, pharmacokinetics, and efficacy of SAGE-547 Injection in the treatment of adult 
female subjects with severe postpartum depression was started in 2014. This was the first-
ever study in this indication. Four women experienced significant improvement in depressive 
symptoms within 24 hours after administration of open-label intravenous SAGE-547. During 
the SAGE-547 treatment period, all four subjects rapidly achieved remission, as measured by 
the HAMD total score. All four subjects also demonstrated consistent improvement as 
measured by the CGI-I score. SAGE-547 was well-tolerated in all subjects treated with no 
serious adverse events observed during therapy or during the 30-day follow-up period. A 
total of 14 adverse events were reported in four subjects. The only adverse event reported in 
more than one subject was sedation, observed in two subjects. This trial was initially planned 
to enroll 10 women, however, due to the observed clinical activity, the 547-PPD-201 trial 
was stopped early with the plan to initiate a placebo-controlled clinical trial as rapidly as 
possible.  
There are six reported studies of allopregnanolone, mainly in healthy individuals and none in 
PPD (Timby 2006; Timby 2011a and 2011b; van Broekhoven 2007; Kask 2008; Kask 2009; 
Navarro 2003). Data indicate that normal physiological allopregnanolone levels in women 
vary during the menstrual cycle up to a maximum of 6-10 nM, with lower levels present 
post-menopause (Genazzani 1998). The highest physiological levels observed are in the third 
trimester of pregnancy, up to around 160 nM at time of delivery (Luisi 2000). Levels drop 
precipitously to baseline (<10 nM) with removal of the placenta (Klak 2003).  


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One study demonstrated subjective improvements in contentedness in women (van 
Broekhoven 2007). The clinical safety data are presented below in the Risks and Benefits 
section (Section 5.4). 
5.4 Potential Risks and Benefits 
In the recently completed open-label clinical trial of SAGE-547 in PPD (547-PPD-201), a 
total of 14 adverse events were reported in four subjects. The only adverse event reported in 
more than one subject was sedation, observed in two subjects.  
Consistent with these observations, published reports of human administration of exogenous 
allopregnanolone indicate that for exposures in men and women up to 150 nM, the most 
commonly reported adverse events (AEs) were sedation (recorded as sleepiness or tiredness), 
feelings of intoxication (like alcohol), flushing, vertigo, mild nausea, impaired episodic 
memory, and mild headache (Timby 2006 and 2011a and 2001b; van Broekhoven 2007). 
One subject experienced what was potentially a withdrawal effect, an anxiety attack (Timby 
2011b). No serious AEs (SAEs) were reported in the six clinical studies conducted to date 
(Timby 2006; Timby 2011a and 2011b; van Broekhoven 2007; Kask 2008; Kask 2009; 
Navarro 2003). There is also a potential risk of supra-additive sedative effects with other 
drugs interacting with the GABAA receptor, such as benzodiazepines and anti-epileptic 
medications (Norberg 1999); therefore, the Investigator is advised to avoid co-medication if 
possible and to exercise caution with these drug classes. As this is one of the first clinical 
trials of SAGE-547 in PPD, the potential benefits in this population are unknown, although 
the risks are likely to be similar to those mentioned above. Given the nonclinical rationale 
and the fact that endogenous allopregnanolone in humans appears to play a role in psychiatric 
disorders such as major depression, premenstrual dysphoric disorder, and anxiety disorders, it 
is possible that subjects may have a clinical benefit at the exposures selected for this trial. In 
view of the limited nature of the demonstrated risks of exogenous allopregnanolone infusion 
and the potential for benefit in severe PPD, there is a favorable benefit-risk evaluation for the 
conduct of the present study. 
5.5 Study No. 547-PPD-202 
5.5.1 Study Population 
This study will evaluate the efficacy, safety, and pharmacokinetics (PK) of SAGE-547 
Injection in the treatment of adult female subjects diagnosed with severe postpartum 
depression. 
5.5.2 Route of Administration, Dosage, Dosage Regimen, and Treatment Period 
SAGE-547 Injection or placebo will be administered over a 60 hour period by an IV infusion 
according to the dose regimen shown in Table 2 (see Section 11.1.1). 
The specific infusion dose of SAGE-547 Injection will be calculated based on weight for 
each subject. Infusion bags will be changed every 24 hours. Details about the preparation and 
administration of the study drug infusions will be included in the Pharmacy Manual. 


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5.5.3 Dose Rationale 
The infusion rate of SAGE-547 to be studied in this trial was chosen to achieve a mean 
exposure of 150 nM, roughly equivalent to the highest endogenous concentrations measured 
in third trimester pregnancy at approximately 157 nM (Luisi 2000). Since pregnant women 
tolerate this level without apparent AEs, 150 nM was selected as the target exposure for this 
study. This level of exposure has already been achieved in 547-PPD-201 as well at higher 
levels in a study in subjects with essential tremor (547-ETD-201) and subjects with super 
refractory status epilepticus (547-SSE-201), with no drug-related SAEs reported. Since the 
most common adverse event in 547-ETD-201 was sedation, dose adjustment rules are 
included in this protocol to ensure that all subjects can remain on treatment for 60 hours. A 
similar Cmax was also achieved in several other studies conducted with intravenous 
allopregnanolone (Timby 2011b), with excellent tolerability (see SAGE-547 IB 2014 for 
details of safety profile). 
The selection of exposure in the current trial is based on a cautious approach adapted to the 
anticipated benefit-risk in the PPD patient population, and on previous experience from the 
ongoing clinical trials of SAGE-547 in adult subjects with SRSE (Protocol 547-SSE-201) 
and of SAGE-547 in female subjects with PPD (Protocol 547-PPD-201). In the ongoing 
SRSE trial, as determined by simulation, loading and maintenance infusions are required to 
achieve the target exposure. In contrast, in the current trial, subjects will instead begin 
treatment with a four-hour dose-titration phase. The starting dose is approximately 9- to 18-
fold lower than the NOAEL observed in rats and dogs, although this is not the first in human 
study. Doses will be increased as follows: 30 µg /kg/hour [0-4 hours], then 60 µg/kg/hour [4-
24 hours], then 90 µg/kg/hour [24-52 hours], followed by a decrease to 60 µg/kg/hour (52-56 
hours), and 30 µg/kg/hour (56-60 hours). 
Subjects will be treated in an inpatient setting and continually monitored for safety, and if 
any severe tolerability issues arise, the infusion will be terminated. The Stanford Sleepiness 
Scale (SSS) will be regularly administered to monitor sedation and allow dose adjustment 
based on tolerability, with a formal dose interruption and reduction scheme implemented for 
this and other adverse events. 


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6 ETHICS 
6.1 Institutional Review Board or Independent Ethics Committee 
This trial will be initiated only after the protocol has been reviewed and approved by the 
Institutional Review Board (IRB) where the study is to be conducted. The IRB must meet all 
US Food and Drug Administration (FDA) requirements governing IRBs (Code of Federal 
Regulations [CFR], Title 21, Part 56). The same applies for the implementation of changes 
introduced by an amendment. 
6.2 Ethical Conduct of the Study 
This study will be conducted according to the principles of the World Medical Association 
Declaration of Helsinki and the most recent amendment (2008).  
The Sponsor, the Medical Monitor, and the Investigator must comply with all instructions, 
regulations, and agreements in this protocol, and must also conduct the study in accordance 
with International Conference on Harmonisation (ICH) Guidelines on Good Clinical Practice 
(GCP) standards as well as local regulations.  
6.3 Subject Information and Informed Consent 
Prior to subject participation in the trial, written informed consent must be obtained from 
each subject according to ICH GCP and in accordance with local regulations. Written 
informed consent is required for each subject prior to any testing under this protocol not 
considered standard of care, including screening tests, SAGE-547 infusion, and study 
evaluations. Each subject’s signature must be dated by each signatory and the informed 
consent form (ICF) retained by the investigator as part of the trial records. As an additional 
assessment, the ICF will contain a provision for optional consent for the collection of breast 
milk for the duration of the 60-hour SAGE-547 infusion and up to Day 3 for biobanking and 
PK analysis purposes. The ICF, as specified by the clinical site’s IRB, must follow the 
Protection of Human Subjects regulations listed in the CFR, Title 21, Part 50. 
It is the responsibility of the Investigator to obtain consent and to provide the subject a copy 
of the signed and dated ICF. The ICF for subject participation must also be available as part 
of the subject’s file for review by the site’s dedicated study monitor. 
All ICFs used in this study must be approved by the appropriate IRB and by the Sponsor. The 
ICF must not be altered without the prior agreement of the relevant IRB and the Sponsor.  
 


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7 STUDY OBJECTIVES 
7.1 Primary Objective 
The primary objective of this study is to determine if SAGE-547 Injection infused 
intravenously for 60 hours reduces depressive symptoms in subjects with postpartum 
depression (PPD) compared to placebo injection as assessed by the change from baseline in 
Hamilton Rating Scale for Depression (HAMD) total score 
7.2 Secondary Objectives 
The secondary objectives of the study are: 
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
depressive symptoms compared to placebo injection as assessed by HAMD response, 
HAMD remission, change from baseline in Montgomery-Asberg Depression Rating 
Scale (MADRS) total score, Clinical Global Impression – Improvement (CGI-I) 
response, and changes from baseline in HAMD subscale and individual item scores.   
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces other 
mood symptoms compared to placebo injection as assessed by changes from baseline 
in the Generalized Anxiety Disorder 7-Item Scale (GAD-7) total score. 
• To determine if SAGE-547 Injection infused intravenously for 60 hours increases 
sedation levels compared to placebo injection as assessed by the changes from 
baseline in Stanford Sleepiness Scale (SSS) score. 
• To evaluate the safety and tolerability of SAGE-547 Injection compared with placebo 
as assessed by the incidence of adverse events, vital sign measurement, clinical 
laboratory evaluations, electrocardiogram (ECG) parameters, and the Columbia 
Suicide Severity Rating Scale (C-SSRS). 
7.3 Exploratory Objectives 
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
subject-reported depressive symptoms compared to placebo injection as assessed by 
the change from baseline in Edinburgh Postnatal Depression Scale (EPDS) total score 
and the change from baseline in Patient Health Questionnaire (PHQ-9) total score. 
• To determine if SAGE-547 Injection infused intravenously for 60 hours improves 
maternal behaviors compared to placebo injection as assessed by the change from 
baseline in Barkin Index of Maternal Functioning (BIMF) total and sub-scale scores.  
7.4 Pharmacokinetic Objective 
• To assess the pharmacokinetic (PK) profile of SAGE-547, metabolites of SAGE-547, 
and betadex sulfobutyl ether sodium (SBECD) and the concentration of SAGE-547 in 
breast milk, when possible. 


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8 INVESTIGATIONAL PLAN 
8.1 Overview of Study Design 
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of 
the efficacy, safety, and pharmacokinetics of SAGE-547 Injection in adult female subjects 
diagnosed with severe PPD. The study design is presented in Figure 1. The study will consist 
of an up to 5-day Screening Period (Day -5 to -1), 3-day (60-hour) Treatment Period, and 30-
day Follow-up Period; see Figure 2. Subjects must remain as in-patient during the study 
Treatment Period, which is approximately 60 hours/2.5 days in duration. The Screening 
Period assessments may be conducted on an in-patient or an out-patient basis. The Follow-
Up Period assessments are conducted on an out-patient basis. 
 
FIGURE 1: STUDY DESIGN 
 
SAGE-547 Injection or placebo will be administered at the study center. Subjects will be 
monitored for safety during the Treatment and Follow-up Periods (through Study Day 30 ± 3 
days) including monitoring for AEs/SAEs, routine clinical laboratory assessments, physical 
examination, vital signs, and ECG. 
All study-related procedures will occur after written informed consent is obtained at the 
Screening Visit, which will occur on any one calendar day during the Screening Period 
window (Day -5 through Day -1). If applicable, standard of care data collected prior to 
obtaining informed consent may also be included as screening data, if appropriate, such as 
laboratory tests, ECG, physical examination, and vital signs conducted within the preceding 
48 hours, as long as the requirement for the screening assessment to be collected 


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retrospectively is met in full. If applicable, to ensure protocol compliance, any standard of 
care data eligible for inclusion as screening data must include the precise nature and timing 
of data collection. 
The end of the Screening Period coincides with the beginning of the Treatment Period. The 
Treatment Period is the period of Day 1 of SAGE-547 IV infusion through completion of the 
infusion on Day 2 and up to Day 3. Subjects will be confined to the study center from the 
Screening Visit until after the 60-hour assessments have been conducted on Day 3. On the 
morning of dosing (Day 1), subjects will begin a 4-hour dose titration period of 30 
µg/kg/hour [0-4 hours], then 60 µg/kg/hour [4-24 hours], then 90 µg/kg/hour [24-52 hours]); 
followed by a decrease to 60 µg/kg/hour (52-56 hours), and 30 µg/kg/hour (56-60 hours). See 
dose regimen presented in Section 11.1.1. Total SAGE-547 Injection or placebo dosing will 
occur over 60 hours. 
Trial-specific assessments for safety, PK, efficacy, and exploratory outcome measures will be 
completed at pre-specified times over a 72-hour period during the Treatment Period: 
• The safety and tolerability of SAGE-547 Injection will be assessed by AEs, clinical 
laboratory measures, physical examinations (including cognitive and mental health 
examinations), vital signs, ECG, use of concomitant medication, and the Columbia 
Suicide Severity Rating Scale (C-SSRS) during the Screening, Treatment, and 
Follow-up Periods (through Study Day 30 ± 3 days). 
• Plasma will be collected to formally assay for SAGE-547, metabolite, and SBECD 
levels prior to dosing through the treatment period and up to 12 hours post infusion 
on Day 3.  
• Primary efficacy assessment of the HAMD will be completed as scheduled during the 
Screening, Treatment, and Follow-up Periods (through Study Day 30). 
• Secondary efficacy assessments of MADRS, CGI-I, EPDS, Generalized Anxiety 
Disorder 7-Item Scale (GAD-7), PHQ-9 will be completed as scheduled during the 
Screening, Treatment, and Follow-up Periods (through Study Day 30).  
• Concentrations of SAGE-547 in breast milk will be measured for those subjects who 
consent to giving breast milk samples. 
The end of the Treatment Period coincides with the beginning of the Follow-up Period. 
Subjects will attend the clinic for safety follow-up assessment at one week (7±1d) and one 
month (30±3d) after the initiation of the study drug infusion. 
Scheduled assessments for all safety, PK, efficacy, and exploratory outcome measures 
planned for the trial are summarized in Table 1. All subjects who receive treatment with 
SAGE-547 are to complete all study assessments through Study Day 30 (±3d). 
The Medical Monitor will review AEs on an ongoing basis. 
8.2 Blinding and Randomization 
This is a double-blind study. Subjects will be randomized to SAGE-547 or placebo; subjects, 
clinicians, and study team will be blinded to treatment allocation. The pharmacist, who will 


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prepare the infusion bags according to the randomization schedule, and an unblinded 
Monitor, who will perform drug accountability during the study, will be unblinded.  
Subjects will be randomly assigned to receive SAGE-547 Injection or placebo according to a 
computer-generated randomization schedule.  
Only the clinic pharmacist, who is responsible for preparing the infusions, will be given a 
copy of the randomization schedule. In the event of a medical emergency, the pharmacist 
may reveal actual infusion contents to the primary investigator, who should also alert Sage of 
the emergency (see Section 15.4 for more details related to unblinding). In all cases where 
the study drug allocation for a subject is unblinded, pertinent information (including the 
reason for unblinding) must be documented in the subject’s records and on the electronic 
case report form (eCRF). If the subject or study center personnel have been unblinded, the 
subject will be terminated from the study. 


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9 SELECTION AND WITHDRAWAL OF SUBJECTS 
9.1 Inclusion Criteria 
The following inclusion criteria must be met for individuals to be eligible for the trial: 
1. Subject has signed an ICF prior to any study-specific procedures being performed 
2. Subject is an ambulatory female aged between 18 and 45 years of age 
3. Subject is in good physical health and has no clinically significant findings, as 
determined by the Investigator, on physical examination, 12-lead ECG, or clinical 
laboratory tests 
4. Subject agrees to adhere to the study requirements 
5. Subject either must have ceased lactating at Screening; or if still lactating or actively 
breastfeeding at Screening, must agree to temporarily cease giving breastmilk to their 
infant(s) from just prior to receiving study drug through 9 days (Study Day 12) after the 
end of the infusion.  
6. Subject must have a negative pregnancy test at Screening and Day 1 prior to the start of 
study drug infusion 
7. Subject has had a Major Depressive Episode that began no earlier than the third trimester 
and no later than the first 4 weeks following delivery, as diagnosed by Structured Clinical 
Interview for DSM-IV Axis I Disorders (SCID-I) 
8. Subject has a HAMD total score of ≥26 at Screening and Day 1 (prior to randomization) 
9. Subject is ≤ six months postpartum 
10. Subject is willing to delay start of other antidepressant or anxiety medications and any 
new pharmacotherapy regimens, including prn benzodiazepine anxiolytics, until the study 
drug infusion and 72-hour assessments have been completed  
11. Subject has no detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus 
(HCV), and human immunodeficiency virus (HIV) antibody at Screening 
12. Subject must use one of the following methods of birth control during participation in the 
study and for 30 days following the end of the study drug infusion: 
• Total abstinence (no sexual intercourse) 
• Hormonal contraceptives (birth control) including birth control pills, implantable or 
injectable contraceptives (Norplant® or Depo-Provera® ) 
• A barrier form of contraception such as a condom or occlusive cap with a spermicide 
• An intrauterine device (IUD) 
9.2 Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria: 
1. Recent history or active clinically significant manifestations of metabolic, hepatic, renal, 
hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 


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dermatological, urogenital, neurological, or eyes, ears, or nose and throat disorders, or 
any other acute or chronic condition that, in the Investigator’s opinion, would limit the 
subject’s ability to complete or participate in this clinical study 
2. Known allergy to progesterone or allopregnanolone 
3. Active psychosis per Investigator assessment 
4. Attempted suicide associated with index case of postpartum depression 
5. Medical history of seizures 
6. Medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder. 
7. History of active alcoholism or drug addiction (including benzodiazepines) in the 12 
months prior to Screening 
8. Exposure to another investigational medication or device within 30 days prior to 
Screening 
9. Administration of psychotropics that have been initiated within 14 days prior to 
Screening and are not being taken at a stable dose. 
9.3 Subject Withdrawal/Study Termination 
9.3.1 Withdrawal/Discontinuation of Individual Subjects  
The reasons for study drug discontinuation and/or subject withdrawal from the study must be 
recorded in the subject’s electronic case report form (eCRF). The Investigator must notify the 
Sponsor and/or the Medical Monitor immediately when a subject has been discontinued/ 
withdrawn for any reason, including withdrawal due to an AE. 
Subjects who do not have at least one efficacy observation after 12 hours of SAGE-547 
infusion are not considered evaluable for the efficacy assessment and may be replaced.  
9.3.2 Subject Withdrawal From the Study 
Subjects may withdraw from the study at any time for any reason without compromising the 
subject’s medical care. The Investigator will also withdraw subjects upon the request of Sage 
Therapeutics or upon termination of the study. 
9.3.3 Discontinuation of Study Drug by the Investigator 
If it is necessary for the Investigator to discontinue the study drug earlier than planned, 
subjects should continue to be followed per protocol to capture safety and efficacy 
assessments for the duration of the study period.  
The Investigator may withdraw the subject from the study drug for any of the following 
reasons:  
• The subject is unwilling or unable to adhere to the protocol 
• The subject experiences an intolerable AE 


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• During the course of the study, the subject develops symptoms or conditions listed in 
the exclusion criteria 
• Other medical reason, at the discretion of the Investigator and/or the Medical Monitor 
Subjects who discontinue the study due to an AE, regardless of Investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the Investigator 
determines the event is no longer clinically significant.  
9.3.4 Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
subjects, or for administrative reasons. In the event of study termination, Sage Therapeutics 
will provide written notification to the Investigator. Investigational sites must promptly 
notify their IRB and initiate withdrawal procedures for participating subjects.  


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10 INVESTIGATIONAL PRODUCT 
10.1 Identity of Investigational Product 
SAGE-547 Injection (allopregnanolone) 
10.2 Clinical Supplies 
10.2.1 SAGE-547 
SAGE-547 Injection and ancillary supply kits containing IV administration bags, solution 
sets, and IV bag labels will be provided to the sites. 
SAGE-547 Injection is a preservative-free, sterile, clear, colorless 5 mg/mL solution of 
SAGE-547 (allopregnanolone) and 250 mg/mL betadex sulfobutyl ether sodium buffered 
with 10 mM citrate at a pH of 6.0, intended for IV injection. All inactive excipients used in 
the formulation are compendial grade and conform to current United States Pharmacopeia 
(USP) and European Pharmacopeia (Ph. Eur.) standards. The product is aseptically 
processed, sterile filtered, and filled into 20 mL Type 1 parenteral glass vials with West 
FluroTec® coated stopper container closure systems, under current Good Manufacturing 
Practice (cGMP) conditions. SAGE-547 Injection is intended to be used as a single-use vial. 
An appropriate number of single-use vials to support the dosing duration of the study are 
packaged and delivered to the site. SAGE-547 Injection vials should be stored under 
refrigerated conditions (2–8 °C). Ancillary supply kits should be stored at controlled room 
temperature (20–25 °C). 
All study drug labels will contain information to meet the applicable regulatory requirements. 
10.2.2 Placebo 
Placebo will be identical to SAGE-547 and presented in identical vials. Placebo will be 
manufactured in a similar way to SAGE-547 and consisting of the same formulation without 
allopregnanolone.  Placebo vials should be stored under refrigerated conditions (2–8 °C).   
10.3 Preparation of SAGE-547 Injection or Placebo for Dosing 
The pharmacy will be responsible for preparing SAGE-547 Injection or placebo for subject 
dosing. The prepared admixture will be administered at room temperature. The prepared 
admixture will be assigned a room temperature (20–25 °C) storage shelf life of 30 hours from 
time of compounding.  
SAGE-547 Injection or placebo is not intended to be administered to subjects undiluted. Each 
single-use vial of SAGE-547 Injection, which is hypertonic, will require dilution with an 
appropriate volume of Sterile Water for Injection (SWFI) to render it isotonic. Refer to the 
Pharmacy Manual for specific instructions regarding infusion preparation and administration 
instructions. 


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10.4 Administration and Accountability 
The pharmacy will maintain accurate records of all investigational drug product supplies 
received, stored, dispensed, and discarded. Accurate records will be kept regarding the 
volume of SAGE-547 Injection or placebo used for each IV preparation, as well as the 
required infusion rate (or rates), and the date and time of preparation. Reasons for departure 
from the expected dosing regimen must be recorded. To satisfy regulatory requirements 
regarding drug accountability, all study medication needs to be reconciled in full.  
Refer to the Pharmacy Manual for complete details on preparation and administration. 


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11 TREATMENT OF SUBJECTS 
11.1 Dosing Schedule 
This is a double-blind study. Subjects will be randomized to receive 60 hours of intravenous 
treatment with either SAGE-547 Injection or placebo.  
The timing of infusion relative to the overall trial design is shown in Figure 2. 
 
FIGURE 2: TRIAL DESIGN AND TIMELINE FOR DOSING 
 
Clinical supply and preparation of SAGE-547 Injection for dosing is described Section 10.2 
and Section 10.3, respectively. 
11.1.1 Dose Regimen 
The specific infusion dose of SAGE-547 Injection will be calculated based on weight 
(obtained at screening) for each subject and administered according to dose regimen shown 
in Table 2). The infusion rates are the same for all subjects within a particular dosing period 
(0-4 hours, 4-24 hours, etc.) (Table 2).   
 
 


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TABLE 2: INFUSION RATES 
Timepoint 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2/3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
Infusion rates 
30 µg/kg/hour 
60 µg/kg/hour 
90 µg/kg/hour 
60 µg/kg/hour 
30 µg/kg/hour 
Dosing is to begin in the morning (on Day 1) to avoid awakening subjects during the night 
for completion of study assessments. 
If any subject has an SSS score of ≥5 for two or more consecutive assessments or an SSS 
score of ≥6 for a single occurrence during normal waking hours, the infusion rate for this 
subject will be decreased to the next lowest infusion dose level (or turned off if this occurs on 
the 30 µg/kg/hour dose level). Please refer to Section 11.1.4 for more details. 
11.1.2 Route of Administration 
SAGE-547 Injection is intended for IV administration only. The compatibility of SAGE-547 
with other drugs is unknown, and the product should be administered via a dedicated 
peripheral IV line with the supplied study-specific IV administration bags and lines. 
11.1.3 Treatment Period 
Total dosing with SAGE-547 or placebo will occur over 60 hours, including a 24-hour dose 
titration, a 28-hour maintenance infusion, and an 8-hour taper. 
11.1.4 Dosing of Intravenous SAGE-547 in the Case of AEs 
Since allopregnanolone levels in the proposed clinical trial are similar to physiological levels 
seen in the third trimester of pregnancy, and all the AEs reported with SAGE-547 or 
allopregnanolone to date were mild and non-serious, it is anticipated that the AEs associated 
with SAGE-547 will be mild and manageable without dose interruption or reduction. Based 
on the observed adverse events to date, the adverse events most likely to result in AE are 
sedation with or without hypotension.  
However, in the case of severe or life-threatening AEs occurring, the investigator is advised 
to interrupt infusion until regression of the AE to mild or resolution and only resume infusion 
if it is deemed in the best interest of the subject. Resumption of infusion at the next lowest 
dose (or turned off if this event occurs on the 30 µg/kg/hour dose level) for one hour, 
followed by re-escalation to the maintenance rate, may be considered to address potential 
recurrence of the AE. If the AE recurs infusion should be definitively discontinued. 
11.2 Dosing Compliance 
Investigational product will be prepared in the site pharmacy, administered as a continuous 
IV infusion by the study staff, and will be documented in the study record.  There should be 
no adjustments in dosing except those described in Section 11.1.4. 


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11.3 Concomitant Medications and Restrictions 
11.3.1 Concomitant Medications 
Subjects will receive standard of care for adult female patients diagnosed with PPD. Any 
concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 11.3.2. All concomitant medications should be documented throughout the study 
from Screening through Day 30 (± 3 days) and recorded on the eCRF. Prior medications (i.e., 
those taken prior to signing of informed consent) that required wash-out for study entry will 
also be documented. 
11.3.2 Prohibited Medications 
Restrictions on specific classes of medications include the following: 
• 
Initiation of new antidepressant therapy is prohibited upon admission to the study 
center for those eligible subjects who desire study participation. Those subjects 
already taking an antidepressant at the time of study entry (and meeting all study 
inclusion criteria) will be permitted to remain on the pre-existing antidepressant at 
their current dose if they were on this medication for at least 30 days prior to study 
enrollment. 
• 
Benzodiazepines are to be avoided as much as possible. Eligible subjects taking a 
benzodiazepine at the time of study entry will be permitted to continue to take their 
current dose of the benzodiazepine (to prevent acute withdrawal), but no new 
benzodiazepine use will be permitted during the course of the study. Particular 
attention should be paid to assessment of AEs and implementation of the dose 
interruption and reduction scheme in subjects on concomitant benzodiazepines since 
they have been shown to have a supra-additive effect with pregnenolone in an animal 
model of anesthesia (Norberg 1999). 
• 
The use of hypnotics for sleep/insomnia such as Ambien® and trazodone are to be 
avoided. 
• 
Anticonvulsants and atypical antipsychotics are to be avoided if possible and are not 
to be initiated at any time during active treatment period (60 hours).  However, if a 
subject is taking one of these medications for at least 30 days prior to study 
admission, they will be permitted to remain on this medication, at their current dose 
(no dose adjustments are allowed). 
• 
SAGE-547 has demonstrated inhibitory effects on cytochrome P-450 (CYP) 2C9 
(CYP2C9). The following medications are primarily metabolized by CYP2C9 and 
therefore are prohibited during SAGE-547 administration: fluconazole and 
miconazole (antifungal), amentoflavone (constituent of Ginkgo biloba and St. John’s 
Wort), sulfaphenazole (antibacterial), valproic acid (anticonvulsant, mood-
stabilizing), and apigenin. See Appendix 10 for a more complete list. 


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12 STUDY ASSESSMENTS 
12.1 Safety Assessments 
The safety and tolerability of SAGE-547 Injection will be evaluated by summarization of 
AEs by frequency, severity and seriousness, mean changes from baseline in clinical 
laboratory measures, physical examination, vital signs, ECGs, and concomitant medication 
usage. Suicidality will be monitored using the C-SSRS. All safety assessments should be 
performed per the study center’s standard of care and will be collected according to the 
Schedule of Events (Table 1). All safety assessments are to be completed within 
± 30 minutes of the scheduled time point. 
In addition to the schedule outlined in Table 1, completion of safety assessments including 
physical examination, vital signs, and clinical laboratory tests should occur in the event of an 
emergency or SAE, when possible.  
12.1.1 Adverse Events 
Adverse events will be collected after the ICF has been signed through the end of the study 
(see Section 15.2.1 for additional details). Medical conditions or adverse events that occur 
after the ICF has been signed and prior to completion of Screening will be captured on the 
Medical History eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA™) coding system (version 17.0 or higher).  
12.1.2 Clinical Laboratory Tests 
Blood samples will be collected for hematology, serum chemistry, coagulation, and specific 
hormone parameters, hepatitis, human immunodeficiency virus (HIV), pregnancy and genetic 
analysis. Urine samples for urinalysis and selected drugs of abuse will also be collected. All 
samples will be analyzed at the central laboratory. Patients may be considered eligible for the 
study based on local laboratory results, however screening samples must also be sent to the 
central laboratory. Both local and central Screening labs must adhere to the visit window 
provided in the Schedule of Events (Table 1). 
These assessments will be performed in accordance with the Schedule of Events (Table 1) 
and as outlined individually below. 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as Abnormal; not clinically significant (NCS) or Abnormal; clinically significant 
(CS). Screening results considered Abnormal; CS will be recorded as medical history. 
Clinical laboratory results that are Abnormal; CS during the study and indicate a worsening 
from baseline will be considered AEs, assessed according to Section 15, and recorded in the 
eCRF.  
12.1.2.1 Hematology, Serum Chemistry, Coagulation 
Blood samples will be collected for analysis of the following:  


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• Hematology: complete blood count (CBC) including white blood cell (WBC) count 
with differential (basophils, eosinophils, lymphocytes, monocytes, and neutrophils) 
platelet count, red blood cell (RBC) count, hemoglobin (Hgb) and hematocrit (Hct), 
mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) 
• Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin (total), blood urea nitrogen (BUN), 
calcium, chloride, creatinine, gamma glutamyl transferase (GGT), glucose phosphate, 
potassium, sodium, total protein and triglycerides (Screening only) 
• Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT), 
international normalized ratio (INR) 
12.1.2.2 Hepatitis and HIV 
Blood samples will be collected for analysis of the following: 
• Hepatitis: hepatitis B virus surface antigen (HBsAg), antibody against hepatitis C 
virus (anti-HCV) 
• HIV: antibody against human immunodeficiency virus type 1/2 (anti-HIV 1/2) 
12.1.2.3 Hormones and Exploratory Biochemistry 
Blood samples will be collected for analysis of thyroid stimulating hormone (TSH), estrogen, 
progesterone, progesterone metabolites, oxytocin, tryptophan, kynurenine, and markers of 
inflammation. 
12.1.2.4 Pregnancy Test 
All subjects will be tested for pregnancy by serum hCG at Screening and urine hGC on Day 
1 prior to administration of study drug.  Subjects with a positive pregnancy test at Screening 
or Day 1will be ineligible for study participation. 
12.1.2.5 Genetic Testing 
A blood sample for genetic testing will be collected at screening, where consent is given.  
The objective of this research is to collect and store blood samples for possible DNA 
extraction and exploratory research into how genes or specific genetic variation may 
influence response (i.e. distribution, safety, tolerability, and efficacy) to SAGE-547. Specific 
genetic variations of interest include but are not limited to: classes of metabolizing enzymes 
(e.g. Cytochrome P450 supra-family genes), genes encoding enzymes involved in the 
production and metabolism of allopregnanolone (e.g. AKR1C4 (3a-hydroxysteroid 
dehydrogenase)), genes associated with the GABA receptor (e.g. GABRA1-A6, GABRB1-
B3, GABRD, GABRE, GABRG1-3) and genes associated with the production and 
degradation of GABA.    
  
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to SAGE-547 but also susceptibility to disorders for which SAGE-547 may be 


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evaluated. Thus, the genetic research my involve study of additional unnamed genes or gene 
categories, but only as related to disease susceptibility and drug action. 
12.1.2.6 Urinalysis 
Urinalysis will include assessment of bilirubin, glucose, ketones, leukocytes, nitrite, pH, 
protein and specific gravity.  
12.1.2.7 Drugs of Abuse and Alcohol 
Urine assessment for selected drugs of abuse (including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine and propoxyphene). Use of 
benzodiazepines at screening is not necessarily exclusionary, as subjects will be allowed to 
take psychotropics that have been initiated at least 14 days prior to admission to the study 
center at a stable dose (see Section 11.3). Alcohol will be assessed in plasma at Screening 
and in serum, via breathalyzer or urine dipstick on Day 1. 
12.1.3 Physical Examination 
Body weight and height will be measured at Screening. Body mass index (BMI) will be 
programmatically calculated in the eCRF. 
Any condition present at the post-treatment physical examination that was not present at or 
worsened since the baseline examination is to be documented as an AE. Whenever possible, 
the same individual is to perform all physical examinations. Physical examinations will 
include assessment of body systems (e.g., HEENT, heart, lungs, abdomen, and extremities) 
as well as cognitive and neurological examination and mental status examination.  
12.1.4 Vital Signs 
Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure 
(supine and standing). A full set of vital signs will be obtained at all specified timepoints 
(± 30 minutes), unless the subject is asleep between the hours of 23.00h and 06.00h each day.  
12.1.5 Pulse Oximetry 
Pulse oximetry will be monitored continuously from H0 until H60 on Day 1, and checked 
approximately every 2 hours, including during the overnight hours, or at the alarm. If there is 
an indication of oxygen desaturation, this should be recorded as an adverse event at the 
discretion of the Investigator. No pulse oximetry data will be recorded in the eCRF. 
12.1.6 ECG 
A baseline 12-lead ECG will be performed during Screening to assess the presence of any 
current or historical cardiovascular conditions. The following ECG parameters will be 
recorded: heart rate, PR, QRS, QT, and QTc. Subjects with clinically significant 
abnormalities should not be entered into the study. 


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12.1.7 Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a pre-dose evaluation that assesses the lifetime and recent experience of the 
subject with suicidal ideation and behavior, and a post-baseline evaluation that focuses on 
suicidality since the last study visit. The C-SSRS includes “yes” or “no” responses for 
assessment of suicidal ideation and behavior as well as numeric ratings for severity of 
ideation, if present (from 1 to 5, with 5 being the most severe). The “Baseline/Screening” C-
SSRS form will be completed on Day 1 prior to dosing. The “Since Last Visit” C-SSRS form 
will be completed for all subsequent assessments.   
Copies of the C-SSRS are provided in APPENDIX 1. 
12.1.8 Stanford Sleepiness Scale (SSS) 
The Stanford Sleepiness Scale is patient-rated scale designed to quickly assess how sedated 
or sleepy a patient is feeling. The degree of sleepiness is rated on a scale of 1 to 7, where the 
lowest score of 1 indicates that the patient is “feeling active, vital, alert, or wide awake” and 
the highest score of 7 indicates that the patient is “no longer fighting sleep, sleep onset soon; 
having dream-like thoughts.” The SSS will be administered unless the subject is asleep 
between the hours of 23.00h and 06.00h each day. If the SSS is not scored due to a subject 
being asleep, a score of X will be reported in the CRF to indicate that the subject was asleep. 
All SSS assessments are to be completed within ± 15 minutes of the scheduled time point. 
A copy of the SSS is provided in APPENDIX 5. 
12.2 Efficacy Assessments 
For all efficacy assessments, the baseline values will be calculated as the last recorded value 
prior to the start of infusion of randomized treatment.  Change from baseline values will be 
calculated as the assessment score minus the baseline value.  Change from baseline values 
will be calculated for each item and total score.   
12.2.1 Primary Efficacy Outcome Measure 
The primary outcome measure is the HAMD. The HAMD will be administered before, 
during, and after the infusion of blinded study drug.  
12.2.1.1 Hamilton Rating Scale for Depression (HAMD)  
The 17-item HAMD will be used to rate the severity of depression in subjects who are 
already diagnosed as depressed (Hamilton 1960). The 17-item HAMD is comprised of 
individual ratings related to the following symptoms: depressed mood (sadness, hopeless, 
helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and 
activities, retardation (slowness of thought and speech; impaired ability to concentrate; 
decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms 
(gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and 
insight. The HAMD assessments are to be completed within ± 30 minutes of the scheduled 
time point, but prior to starting dosing on D1 H0. Every effort should be made for the same 
rater to perform all HAMD assessments for a single patient. 


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The HAMD total score will be calculated as the sum of the 17 individual item scores.  Item 
16 can be rated according to history (item 16A) or actual weight change (item 16B).  The 
item 16 score is calculated as the item 16 response that is not equal to 3 (i.e., “Not assessed”).   
In addition to the primary efficacy endpoint of change from baseline in HAMD total score, 
several secondary efficacy endpoints will be derived for the HAMD.  HAMD subscale scores 
will be calculated as the sum of the items comprising each subscale.  HAMD response will 
be defined as having a 50% or greater reduction from baseline in HAMD total score. HAMD 
remission will be defined as having a HAMD total score of ≤7.   
A copy of the HAMD is provided in APPENDIX 2. 
12.2.2 Secondary Efficacy Outcome Measures 
Secondary efficacy assessments include evaluation of depressive symptom severity by the 
MADRS and CGI, as described in Section 9. Additional assessments of depressive symptom 
severity and reproductive mood disorders will be measured by the following clinician- and 
subject-rated outcome measures: EPDS, GAD-7 and PHQ-9, as described in Sections 
12.2.3.1 through 13. 
12.2.2.1 Montgomery Asberg Depression Rating Scale (MADRS) 
The MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the 
severity of depressive episodes in patients with mood disorders. It was designed as an adjunct 
to the HAMD which would be more sensitive to the changes brought on by antidepressants 
and other forms of treatment than the Hamilton Scale was. 
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 
6. The overall score ranges from 0 to 60 (McDowell 2006, Müller-Thomsen 2005). 
The questionnaire includes questions on the following symptoms 1. Apparent sadness 2. 
Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration 
difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts. 
The MADRS total score will be calculated as the sum of the 10 individual item scores. 
A copy of the MADRS is provided in APPENDIX 3. 
12.2.2.2 Clinical Global Impression (CGI) Scale 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the patient’s condition. The CGI scale is 
comprised of 3 items. Only the first two items are being used in this study.   
The CGI-Severity (CGI-S) item uses a 7-point Likert scale to rate the severity of the patient’s 
illness at the time of assessment, relative to the clinician’s past experience with patients who 
have the same diagnosis. Considering total clinical experience, a patient is assessed on 
severity of mental illness at the time of rating 1 = normal, not at all ill, 2 = borderline 
mentally ill, 3 = mildly ill, 4 = moderately ill, 5 = markedly ill, 6 = severely ill, and 7 = 
extremely ill. The CGI-S will be rated by the clinician at screening and on Day 1 (prior to 
dosing). 


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The CGI-Improvement (CGI-I) item employs a 7-point Likert scale to measure the overall 
improvement in the patient’s condition post-treatment. The investigator will rate the patient’s 
total improvement whether or not it is due entirely to drug treatment. Response choices 
include: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally 
improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. 
The CGI-I is only rated at post-treatment assessments.  By definition, all CGI-I assessments 
are evaluated against baseline conditions.  CGI-I response will be defined as having a CGI-I 
score of “very much improved” or “much improved”.   
A copy of the CGI is provided in APPENDIX 4. 
12.2.2.3 Generalized Anxiety Disorder 7-Item Scale (GAD-7) 
The GAD-7 is a patient-rated generalized anxiety symptom severity scale (Spitzer 2006). 
Scoring for GAD-7 generalized anxiety is calculated by assigning scores of 0, 1, 2, and 3 to 
the response categories, respectively, of “not at all sure,” “several days,” “over half the 
days,” and “nearly every day.” GAD-7 total score for the seven items ranges from 0 to 21, 
where a score of 0 to 4 = minimal anxiety, 5 to 9 = mild anxiety, 10 to 14 = moderate 
anxiety, and 15 to 21 = severe anxiety. All assessments are to be completed within ± 30 
minutes of the scheduled time point. 
The GAD-7 total score will be calculated as the sum of the 7 individual item scores. 
A copy of the GAD-7 is provided in APPENDIX 7. 
12.2.3 Exploratory Patient Reported Outcome Measures 
Exploratory efficacy assessments include evaluation of depressive symptom severity and 
reproductive mood disorders. These will be measured by the following clinician- and subject-
rated outcome measures: EPDS, PHQ-9, and BIMF. 
12.2.3.1 Edinburgh Postnatal Depression Scale (EPDS) 
The EPDS is a patient-rated depressive symptom severity scale specific to the perinatal 
period (Cox 1987). The EPDS total score will be calculated as the sum of the 10 individual 
item scores. 
A copy of the EPDS is provided in APPENDIX 6. 
12.2.3.2 Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is a patient-rated depressive symptom severity scale. To monitor severity over 
time for newly diagnosed patients or patients in current treatment for depression, patients 
may complete questionnaires at baseline and at regular intervals thereafter. Scoring is total 
based on responses to specific questions, as follows: “not at all” = 0; “several days” = 1; 
“more than half the days” = 2; and “nearly every day = 3.” All assessments are to be 
completed within ± 30 minutes of the scheduled time point. 
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores.  The 
PHQ-9 total score will be categorized as follows: 1-4 = minimal depression, 5-9 = mild 
depression, 10-14 = moderate depression, 15-19 = moderately severe depression; and 20-27 
= severe depression. 


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A copy of the PHQ-9 is provided in APPENDIX 8. 
12.2.3.3 Barkin Index of Maternal Functioning (BIMF)  
The BIMF is a patient reported outcome scale BIMF covers a broad range of functional areas 
(self-care, infant care, mother-child interaction, psychological well-being of mother, social 
support, management, adjustment). This new application of maternal functional status is a 
robust construct where the physical and mental health of the mother is essential to optimal 
functioning. Each item is rated on a scale of 0 (strongly disagree) to 6 (strongly agree).  
A copy of the BIMF is provided in APPENDIX 9. 
12.3 Pharmacokinetics 
12.3.1 Plasma PK Samples 
Blood samples for PK analysis will be collected in accordance with the Schedule of Events 
(Table 1). Scheduled time points for PK blood draws after the start of infusion will have a 
window of ± 10 minutes. Samples will be processed according to the PK Manual, and 
analyzed for concentrations of SAGE-547, metabolites of SAGE-547, and SBECD. 
Additionally, PK samples may be obtained outside the planned collection times if issues 
administering study drug are encountered, such as incorrect infusion rate, interrupted 
infusion, or other administration deviations where PK level assessment may be important in 
understanding subject state. In the event of an unplanned dose adjustment, an unscheduled 
PK sample should be collected just prior to the infusion rate change. 
The following PK parameters will be derived from the plasma concentrations (where 
evaluable): area under the concentration-time curve (AUC) from time zero to 60 hours 
(AUC0-60), AUC from time zero to infinity (AUCinf), maximum (peak) plasma concentration 
(Cmax), time at maximum (peak) plasma concentration (Tmax), steady-state drug concentration 
in the plasma during constant-rate infusion (Css), and average drug concentration in the 
plasma at steady state during a dosing interval (Cavg). 
The plasma samples will be drawn from the arm contralateral to that used for drug 
administration. Subject-specific plasma PK kits for sampling including instructions on 
sample collection, processing methods, storage and shipping conditions, will be provided in 
the study PK Manual. 
12.3.2 Breastmilk PK Samples 
Women who are actively lactating at Screening, and who otherwise fulfill all of the inclusion 
and exclusion criteria for the study, will be asked if they will consent to pumping. Breastmilk 
will be collected and pooled at pre-defined intervals. The times of the first and last pumping 
of each collection period will be recorded. Breastmilk will be pooled within each collection 
period and the total volume will be measured. Detailed instructions for breastmilk PK 
sampling, processing methods, storage and shipping will be provided in the study PK 
Manual. After Study Day 12, women may resume giving breastmilk to their infant, per 
Inclusion Criteria 5. 


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13 STUDY PROCEDURES 
The study procedures listed below by study day reflect the data collection times for this 
protocol.  
Scheduled assessments for all safety, efficacy, PK and exploratory outcome measures 
planned for the trial are summarized in Table 1 (Schedule of Events). All subjects who 
receive treatment with SAGE-547 should complete all study assessments through Study Day 
30 (± 3 days). 
Subjects who are evaluated at the Day 3 visit of the Treatment Period (i.e., all Hour 60 
assessments are completed, post-infusion) and complete the Day 30 (± 3 days) visit during 
the Follow-up Period will be defined as study completers.  
13.1 Screening Period 
The Screening Period consists of a window from Day -5 through Day -1 prior to starting 
SAGE-547 treatment. The Screening Period begins with the signature of the ICF. Eligibility 
is determined by applying the inclusion/exclusion criteria. The diagnosis of PPD must be by 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). A full medical and 
family history will be taken including recording of all depression, other Axis 1 and Axis 2 
disorders and post-partum depression episodes in primary probands (who may be subject to a 
SCID-I interview). 
The following assessments/procedures will be conducted at the Screening Visit, which will 
occur on any one calendar day of the Screening Period. Standard of care data collected prior 
to obtaining informed consent may also be included as screening data, if appropriate, such as 
laboratory tests, ECG, physical examinations, and vital signs conducted within the preceding 
48 hours, as long as the requirement for the screening assessment to be collected 
retrospectively is met in full, and all screening assessments are completed, reviewed and 
approved by the Investigator prior to administration of SAGE-547. 
Subjects will be confined to the study center from the Screening Visit until after the 60-hour 
assessments have been conducted on Day 3. 
• Written informed consent, with optional provision for breast milk collection (see 
Section 6.3 for more information). 
• Review of inclusion/exclusion criteria to determine subject eligibility. 
• Demographic information and medical/family history collected.  
• Blood will be collected for a pregnancy test. 
• Blood will be collected to screen for hepatitis and HIV. 
• Completion of physical examination, including body weight. Height should be 
recorded. BMI will be calculated. 
• Vital signs. 
• Blood and urine samples collected for clinical laboratory testing, including drug and 
alcohol screening. 


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• Blood sample will be taken for genetic analysis with subject consent. 
• An ECG reading taken. 
• Completion of the HAMD, CGI-S, and MADRS.  
• Recording of concomitant medications.  
13.2 SAGE-547 Treatment Period (Day 1 to Day 3, Hours 0-60) 
All safety, efficacy, pharmacokinetic and other outcome assessments described in this section 
are to be completed within ± 30 minutes of the scheduled time points, unless otherwise 
stated. Windows for PK collection time points are specified by respective time point for 
Study Days 1 to 3 in Section 13.2.1 to Section 13.2.3, respectively (see Section 12.3 for 
additional details). Subjects will be confined to the study center from the Screening Visit 
until after the 60-hour assessments have been conducted on Day 3. 
13.2.1 Day 1 
• Review of inclusion/exclusion criteria to determine subject eligibility. 
• Randomization (on a 1:1 basis: one group will receive SAGE-547 and one group will 
receive placebo). 
• Urine will be collected for a pregnancy test. 
• Begin study drug administration for dose titration in the morning followed by 
maintenance infusion. 
• Vital signs and pulse oximetry will be recorded prior to infusion and at 2, 4, 8, 12, 18, 
and 24 hours on Day 1 (± 30 minutes), unless the subject is asleep between the hours 
of 23.00h and 06.00h each day.  Additional measures of pulse oximetry will be 
collected during sleeping hours. 
• Blood and urine samples collected for drug and alcohol screening. 
• A blood sample for PK analysis will be collected prior to infusion (i.e., morning of 
Day 1 prior to dosing), and at Hours 4 (before change in infusion rate), 8, 12, and 24 
(before change in infusion rate) after the start of the infusion. PK blood draws after 
the start of infusion will have a window of ± 10 minutes. In the event of an unplanned 
dose adjustment, an unscheduled PK sample should be collected just prior to the 
infusion rate change. 
• Completion of the HAMD prior to dosing and at Hours 2, 4, 8, 12, and 24 on Day 1 
(± 30 minutes). 
• Completion of the MADRS prior to dosing and at Hour 24 on Day 1 (± 30 minutes). 
• Completion of the CGI-S prior to dosing and the CGI-I at Hours 2, 4, 12, and 24 on 
Day 1 (± 30 minutes). 
• Completion of the following questionnaires prior to dosing: BIMF, EPDS, GAD-7, 
and PHQ-9 (± 30 minutes). 


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• Completion of the SSS prior to dosing and at Hours 2, 4, 8, 12, 18, and 24 on Day 1 
(± 15 minutes) unless the subject is asleep between the hours of 23.00h and 06.00h 
each day. 
• AEs will be monitored. 
• Concomitant medications will be recorded. 
• Completion of the “Baseline/Screening” C-SSRS form prior to dosing. Completion of 
the “Since Last Visit” C-SSRS form at Hour 24 (± 30 minutes). 
• Per subject consent (optional), collection of breast milk at pre-infusion and at the 
following time periods of interest: 0, 1-12, 12-24, 24-36, 36-48, 48-60, and 60-72 
hours after the start of the infusion. 
13.2.2 Day 2 
• Ongoing SAGE-547 maintenance infusion administration. 
• Vital signs and pulse oximetry will be recorded at Hours 30, 36, 42, and 48 
(± 30 minutes), unless the subject is asleep between the hours of 23.00h and 06.00h 
each day. 
• Additional measures of pulse oximetry will be collected during sleeping hours. 
• A blood sample for PK analysis will be collected at Hours 30, 36, and 48. PK blood 
draws will have a window of ± 10 minutes. In the event of an unplanned dose 
adjustment, an unscheduled PK sample should be collected just prior to the infusion 
rate change. 
• Completion of the HAMD at Hour 36 and Hour 48 (± 30 minutes). 
• Completion of the CGI-I at Hour 36 and Hour 48 (± 30 minutes). 
• Completion of the MADRS at Hour 48 (± 30 minutes). 
• Completion of the SSS at Hours 30, 36, 42, and 48 on Day 2 (± 15 minutes) unless 
the subject is asleep between the hours of 23.00h and 06.00h each day. 
• An ECG reading taken at Hour 48. 
• AEs will be monitored. 
• Concomitant medications will be recorded. 
• Per subject consent (optional), ongoing collection of breast milk during the 
maintenance phase of infusion. 
13.2.3 Day 3 
• Ongoing SAGE-547 maintenance infusion administration until Hour 60. 
• Completion of physical examination. 
• Vital signs will be recorded at Hours 54, 60, 66, and 72 (± 30 minutes). 


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• A blood sample for PK analysis will be collected at Hours 60 and 72 (± 10 minutes). 
In the event of an unplanned dose adjustment, an unscheduled PK sample should be 
collected just prior to the infusion rate change. 
• Blood sample collected for clinical laboratory testing at Hour 72. 
• Completion of the HAMD and MADRS at Hour 60 and 72 (± 30 minutes). 
• Completion of the CGI-I at Hours 60 and 72 (± 30 minutes). 
• Completion of the following questionnaires at Hour 60: EPDS, GAD-7, and PHQ-9 
(± 30 minutes). 
• Completion of the SSS at Hours 54, 60, 66, and 72 on Day 3 (± 15 minutes) unless 
the subject is asleep between the hours of 23.00h and 06.00h each day. 
• AEs will be monitored.  
• Concomitant medications will be recorded. 
• Completion of the C-SSRS at Hours 60 and 72. 
• Per subject consent (optional), ongoing collection of breast milk. 
13.3 Follow-up Period (Day 7 through Day 60) 
13.3.1 Day 7 (± 1 day) 
The following assessments should be completed: 
• Completion of physical examination. 
• Vital signs. 
• Blood and urine samples collected for clinical laboratory testing. 
• An ECG reading taken. 
• Completion of the C-SSRS, HAMD, MADRS, CGI-I, EPDS, GAD-7, PHQ-9 and 
BIMF. 
• A blood sample for PK analysis will be collected at the time of the visit 
• Per subject consent (optional), collection of breast milk on the day of the visit* 
• AEs will be monitored.  
• Concomitant medications will be recorded.  
*Assessment is only applicable to those patients who have temporarily ceased breastfeeding 
and are participating in the optional breast milk sampling. 
13.3.2 Day12 (+1 day) 
• A blood sample for PK analysis will be collected at the time of the visit  
• Per subject consent (optional), collection of breast milk on the day of the visit 


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• AEs will be monitored.  
• Concomitant medications will be recorded.  
This visit is only applicable to those patients who have temporarily ceased breastfeeding 
and are participating in the optional breast milk sampling. 
13.3.3 Day 30 (± 3 days) 
The following assessments should be completed: 
• Urine will be collected for a pregnancy test. 
• Vital signs. 
• Completion of the C-SSRS, HAMD, MADRS, CGI-I, EPDS, GAD-7, PHQ-9 and 
BIMF. 
• AEs will be monitored.  
• Concomitant medications will be recorded.  
 
13.3.4 Early Termination Visit 
The following assessments should be completed if the patient discontinues from the study 
prior to the Day 7 Visit: 
• Completion of physical examination. 
• Vital signs. 
• Blood and urine samples collected for clinical laboratory testing. 
• An ECG reading taken. 
• Completion of the C-SSRS, HAMD, MADRS, CGI-I, EPDS, GAD-7, PHQ-9 and 
BIMF. 
• AEs will be monitored.  
• Concomitant medications will be recorded.  
 
The visit should occur within 3 days of notification of the patient discontinuing. 
 


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14 STATISTICAL METHODS AND CONSIDERATIONS 
In general, summary statistics for all study endpoints will be presented as mean, standard 
deviation (SD), median, and ranges for continuous endpoints, and as counts and percentages 
for categorical endpoints. For the purpose of all safety, efficacy, and exploratory analyses 
where applicable, baseline is defined as the last pre-dose measurement closest to the start of 
blinded study drug infusion. 
A statistical analysis plan (SAP) will be generated and approved by a representative of Sage 
Therapeutics prior to database lock. All statistical analyses will be conducted using SAS for 
Windows (version 9.1.3, or higher; Cary, NC), unless otherwise specified.  
Any deviations from the planned analyses will be described and justified in the final clinical 
study report (CSR). 
14.1 Data Analysis Sets 
The All Enrolled Population will include all subjects who have given written informed 
consent. This population will be used for subject disposition and demographic characteristic 
summaries. 
The All Randomized Population will include the subset of subjects from the All Enrolled 
Population who have been randomized. Subjects will be classified according to randomized 
treatment.  This population will be used for subject disposition, demographic characteristic, 
and baseline characteristic summaries. 
The Safety Population will include all randomized subjects who start the infusion of study 
drug.  Subjects will be classified according to actual treatment received. This analysis 
population will be used for all safety analyses. 
The Efficacy Population (EFF) will include the subset of the Safety Population who have a 
valid baseline HAMD assessment and at least one post-baseline HAMD assessment. Subjects 
will be classified according to randomized treatment.  This analysis population will be used 
for all efficacy analyses. 
The Per Protocol Population (PP) will include the subset of the Efficacy Population who 
complete the full infusion without significant protocol violations or deviations.  Subjects will 
be classified according to randomized treatment.  This analysis population will be used for 
sensitivity analyses of the primary and select secondary endpoints. 
The PK Population (PKP) will include the subset of the Safety Population who have at least 
one evaluable PK sample. Subjects will be classified according to actual treatment received. 
This analysis population will be used for all PK analyses. 
The Breast Milk Population (BMP) will include the subset of the Safety Population who 
have at least one evaluable breast milk sample. Subjects will be classified according to actual 
treatment received. This analysis population will be used for all breast milk PK analyses. 
The number and percentage of subjects who receive SAGE-547 Injection or placebo, 
prematurely discontinue, and complete the study will be summarized. The number and 
percentage of subjects will also be summarized for each reason for premature 
discontinuation. In addition, the number of subjects whose data should be used for the 


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planned analyses will be identified for each respective analysis population (i.e., SAF, EFF, 
PKP, PP, and BMP). 
14.2 Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, 
as per the analysis populations, using all non-missing data available. Any rules for the 
imputation of missing data will be described in the SAP. 
14.3 Demographics and Baseline Characteristics 
Demographics such as age, race, and ethnicity will be summarized. In addition, baseline 
characteristics such as height, weight, and BMI will be summarized. Categorical summaries, 
such as race and ethnicity, will be summarized by frequency and percentage. Continuous 
summaries, such as age, height, weight, BMI and baseline vital signs, will be summarized 
using descriptive statistics such as n, mean, SD, median, minimum, and maximum. 
Drug, alcohol, and pregnancy screening results will be collected and listed but not 
summarized, as they are considered part of the inclusion/exclusion criteria.  
Medical/family history will be collected and listed by subject. 
14.4 Primary Endpoints 
Change from baseline to each assessment in HAMD total score will be analyzed using a 
mixed effects repeated measures model (MMRM) including center, treatment, baseline 
HAMD total score, assessment timepoint, and timepoint-by-treatment.  Center will be treated 
as a random effect while all other explanatory variables will be treated as fixed effects. The 
primary comparison will be between SAGE-547 and placebo at the 60 hour assessment.  
Model based point estimates (i.e., LS means), 95% confidence intervals, and p-values will be 
reported for each assessment.   
Summaries of HAMD total scores and changes from baseline values will include n, mean, 
SD, median, minimum, and maximum.  
14.5 Secondary Endpoints 
Efficacy Analysis 
MMRM methods similar to those described in Section 14.4 will be used for the analysis of 
the following variables: MADRS total score, EPDS total score, GAD-7 total score, PHQ-9 
total score, and select individual item and subscale scores. For each model, the comparison of 
interest will be between SAGE-547 and placebo at the 48 hour assessment. Model based 
point estimates (i.e., LS means), 95% confidence intervals, and p-values will be reported.   
Logistic regression methods will be used for the analysis of the following response variables: 
HAMD response, HAMD remission, and CGI-I response.  Logistic regression models will 
include terms for center, treatment, and baseline score. The comparison of interest will be the 
difference between SAGE-547 and placebo at the 60-hour assessment. Model based point 
estimates (i.e., odds ratios), 95% confidence intervals, and p-values will be reported. For the 
CGI-I response analysis, baseline CGI-S score will be included in the model.   


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Descriptive statistics for all scores, change from baseline values, and response variables will 
be presented by treatment and assessment timepoint.  Summaries will include n, mean, SD, 
median, minimum, and maximum.  
Safety Analysis 
Safety and tolerability of SAGE-547 Injection will be evaluated by AEs, concomitant 
medications, changes from baseline in physical examination, vital signs, CBC, serum 
chemistry, urinalysis, and 12-lead ECG. Suicidality will be monitored by the C-SSRS. 
Sedation will be assessed using the SSS. Safety data will be listed by individual and 
summarized by treatment group. In addition, an analysis of SSS data will be performed 
comparing the treatment groups in the same way as for the primary endpoint. All safety 
summaries will be performed on the SAF population. 
Safety data will be examined for possible relationships between subject characteristics and 
plasma allopregnanolone concentrations, as appropriate. 
Scheduled visits for all safety assessments are described in Section 12.1 and summarized in 
Table 1. 
Adverse events: The analysis of AEs will be based on the concept of treatment-emergent AEs 
(TEAEs). A TEAE is defined as an AE with onset after the start of SAGE-547 infusion, or 
any worsening of a pre-existing medical condition/AE with onset after the start of SAGE-547 
infusion and until 7 days after the end of infusion. The incidence of TEAEs will be 
summarized overall and by MedDRA® System Organ Class (SOC) and preferred term (PT).  
Incidences will be presented in order of decreasing frequency. In addition, summaries will be 
provided by severity (mild, moderate, severe) and by causality (related, not related) to study 
drug (see Section 15.2.2). 
TEAEs leading to discontinuation and serious adverse events (SAEs; see Section 15.1.4 for 
definition) with onset after the start of randomized infusion will also be summarized. 
All AEs and SAEs (including those with onset or worsening before the start of randomized 
infusion) through the Day 30 follow-up visit will be listed. 
 
Clinical laboratory evaluations: Results will be listed by Subject ID and timing of collection. 
Mean changes from baseline in clinical laboratory measures will be evaluated. 
Physical examinations: Physical examinations will be evaluated at Screening and Day 7. Any 
clinically significant change in physical examination compared to those observed at 
Screening should be noted as an AE.  
Vital signs: Vital signs, including oral temperature (°C), respiratory rate, heart rate, and 
blood pressure (supine and standing) will be obtained at the scheduled time points described 
in Section 12.1.4. Mean changes from baseline (pre-infusion) in vital signs will be evaluated.  
12-Lead ECG: The following ECG parameters will be listed for each subject: heart rate, PR, 
QRS, QT, and QTc. Any clinically significant abnormalities or changes in ECGs should be 
listed as an AE. ECG findings will be listed by subject and visit. 


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Concomitant medications: A summary of all concomitant medications taken during the 
course of the study will be presented in tabular form by therapeutic drug class and generic 
drug name using the WHO Collaborating Centre for Drug Statistics Methodology Norwegian 
Institute of Public Health (http://www.whocc.no). 
C-SSRS: Suicidality data collected on the C-SSRS at baseline and by visit during the 
Treatment Period will be listed for all subjects. Listings will include behavior type and/or 
category for Suicidal Ideation and Suicidal Behavior of the C-SSRS. 
SSS: Changes in score over time will be represented graphically, and change from baseline 
will be measured. 
PK Analysis: Plasma will be collected to assay for concentrations of SAGE-547, metabolites 
of SAGE-547, and SBECD. The following PK parameters will be derived from the plasma 
concentrations (where evaluable): AUC0-60, AUCinf, Cmax, time at maximum (peak) plasma 
concentration (Tmax), steady-state drug concentration in the plasma during constant-rate 
infusion (Css), and average drug concentration in the plasma at steady state during a dosing 
interval (Cavg). 
Plasma concentrations will be listed by subject and summarized by nominal collection 
timepoint. PK parameters will be listed by subject and summarized by collection timepoint. 
Correlations between concentrations and AEs or tolerability measures may be performed as 
deemed necessary. 
In addition to typical descriptive statistics, summaries should include geometric mean, 
coefficient of variation, and geometric coefficient of variation. 
14.6 Determination of Sample Size 
Assuming a two-sided test at an alpha level of 0.10, a sample size of 10 evaluable subjects 
per group would provide 80% power to detect an effect size of 1.2 between the SAGE-547 
and placebo groups with regard to the primary outcome variable of change from baseline in 
HAMD total score. An effect size of 1.2 corresponds to a placebo adjusted difference of 12 
points in the change from baseline in HAMD total score at 60 hours with an assumed 
standard deviation of 10 points. By including two treatment groups and using a 1:1 
randomization ratio, a total of 20 evaluable subjects are required. Assuming a non-
evaluability rate of 10%, at least 22 subjects will be randomized. 
Based on the results of the interim analysis (see Section 14.7), the sample size could be 
increased to a maximum of 32 randomized subjects. This adjustment to the sample size 
would allow for an effect size of 1.0 to be detected.   
 


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14.7 Interim Analysis 
An interim analysis will be conducted by an independent statistician for sample size re-
estimation purposes when at least 16 subjects have completed efficacy assessments through 
60 hours. Since the sponsor will be kept uninformed of the response rates at the time of the 
interim analysis, no statistical adjustment will be made to the level of significance for 
hypothesis testing at the end of the study. A detailed description of the interim analysis will 
be included in the SAP. 
14.8 Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the 
final SAP.  


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15 ADVERSE EVENTS 
Section 15.1 lists important AE definitions. 
Section 15.2 summarizes Investigator responsibilities regarding the identification and 
documentation of AEs, the classification of AEs for relationship to study drug and severity, 
and the reporting of AE information to the Sponsor and the IRB. 
Section 15.3 summarizes Sponsor/Medical Monitor Responsibilities regarding monitoring of 
AE data and reporting relevant safety information to FDA. 
15.1 Adverse Event Definitions 
15.1.1 Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  
15.1.2 Suspected Adverse Reaction  
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
15.1.3 Life-Threatening  
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either 
the Investigator or Sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death. 
15.1.4 Serious  
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
• Death 
• A life-threatening AE (see definition in Section 15.1.3) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability or incapacity  
• A congenital anomaly or birth defect 
• Other medically important condition (as described below)  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 


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allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
15.1.5 Unexpected  
An AE or suspected adverse reaction is considered “unexpected”:  
• If it is not listed in the Investigational Brochure or is not listed at the specificity or 
severity that has been observed, or  
• If an Investigational Brochure is not required or available, is not consistent with the 
risk information described in the general investigational plan or elsewhere in the 
current application, as amended.  
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the Investigational Brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the Investigational Brochure listed only cerebral vascular 
accidents.  
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the Investigational Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.  
15.2 Investigator Responsibilities 
15.2.1 Identification and Documentation of Adverse Events by Investigator 
Subjects will be evaluated and questioned generally (if possible) to identify AEs during the 
course of the study. AEs will be collected during subject preparation, study drug 
administration during Screening, after the initiation of study drug administration through to 
Day 3, and at the Follow-up Visits on Day 7 (± 1 day) and Day 30 (± 3 days). SAEs will also 
be collected until the Day 30 (± 3 days) follow-up visit. Medical conditions that occur prior 
to completion of the Screening Visit will be captured on the Medical History eCRF. Adverse 
events that occur after completion of the Screening Visit will be recorded on the AE page of 
the eCRF (AE eCRF).  
All AEs revealed by observation, physical examinations, other diagnostic procedures, or 
spontaneously reported by the subject and/or in response to an open question from study 
personnel will be recorded on the AE eCRF. Any clinically significant deterioration from 
baseline in laboratory assessments or other clinical findings is considered an AE and must be 
recorded on the AE eCRF, unless otherwise stated. AE information recorded on AE eCRF 
will be entered into the database on an ongoing basis. The database, including AE 
information, will be transferred to the Sponsor on a pre-defined schedule for review.  
All AEs, regardless of investigator-determined causality, should be followed until the event 
is resolved or the Investigator determines the event is stable or no longer clinically 
significant.  


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For all SAEs, an SAE report form must be completed with as much information as possible 
and submitted in the time frame described in Section 15.2.3. When new significant 
information is obtained as well as when the outcome of an event is known, the SAE report 
form should be updated on a follow-up report. If the subject was an outpatient at the time of 
the SAE and was re-hospitalized due to the SAE, a copy of relevant hospital records (e.g., 
admission report, laboratory test results, discharge summary, etc.) may be requested to be 
included as part of the subject’s medical file.  
All SAEs will be followed until the events are resolved or improved, a stable status has been 
achieved, or the subject is lost to follow-up.  
15.2.2 Adverse Event Classification 
Definitions for the categories of AE classification are included in this section.  
15.2.2.1 Relationship to Investigational Drug 
Not Related:  
No relationship between the experience and the administration of study 
drug; related to other etiologies such as concomitant medications or 
subject’s clinical state. 
Possibly Related:  A reaction that follows a plausible temporal sequence from 
administration of the study drug and follows a known response pattern to 
the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or 
other modes of therapy administered to the subject, but this is not known 
for sure.  
Probably Related:  A reaction that follows a plausible temporal sequence from 
administration of the study drug and follows a known response pattern to 
the suspected study drug.  
The reaction cannot be reasonably explained by the known 
characteristics of the subject’s clinical state or other modes of therapy 
administered to the subject  
15.2.2.2 Severity 
The severity of an adverse experience will be defined as follows and reported as indicated on 
the AE eCRF: 
Mild: 
 
Discomfort noticed, but no disruption to daily activity.  
Moderate: 
Discomfort sufficient to reduce or affect normal daily activity, but is 
not hazardous to health; prescription drug therapy may be employed to 
treat the AE. 
Severe: 
Inability to work or perform normal daily activity and represented a 
definite hazard to health; prescription drug therapy and/or 
hospitalization may be employed to treat the AE. 


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15.2.2.3 Action Taken With Investigational Drug 
Action taken with regard to administration of SAGE-547 Injection for this trial will be 
recorded using the one of following categories (the category “dose increased” does not apply 
to this trial):  
• Drug withdrawn: An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication.  
• Dose not changed: An indication that a medication schedule was maintained.  
• Drug interrupted: An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication.  
• Dose reduced: An indication that a medication schedule was modified to a reduced 
rate/dose.  
• Unknown: Unknown, not known, not observed, not recorded, or refused. 
• Not applicable: Determination of a value is not relevant in the current context.  
15.2.2.4 Assessment of Outcome 
Assessment of outcome of AEs will be categorized as one of the following:  
• Recovered/Resolved: The event has improved or recuperated.  
• Recovering/Resolving: The event is improving.  
• Not Recovered/Not Resolved: The event has not improved or recuperated.  
• Recovered/Resolved with Sequel: The subject recuperated but retained pathological 
conditions resulting from the prior disease or injury.  
• Fatal: The termination of life as a result of an adverse event.  
• Unknown: Not known, not observed, not recorded, or refused.  
15.2.3 Investigator Reporting to Sponsor and Sponsor Emergency Contact 
All SAEs that occur during the course of the study must be reported by the Investigator on 
the designated report form (study-specific SAE form or MedWatch 3500A form) and sent by 
facsimile to the medical monitor within 24 hours from the point in time when the Investigator 
becomes aware of the SAE. Investigators must report any SAE, whether or not considered 
drug related. The initial report must be as complete as possible, including assessment of the 
causal relationship (i.e., assessment of whether there is a reasonable possibility that the drug 
caused the event). The medical monitor will contact the investigator via telephone for follow-
up information regarding the SAE, as appropriate. 
Information not available at the time of the initial report must be documented on a follow-up 
report. As additional information becomes available, the designated report form must be 
updated and supporting information, including hospital records, laboratory and diagnostic 
testing results, etc. All supporting documentation must be de-identified. In addition, all SAEs 
that occur up to and including 30 days after administration of study drug must be reported 
within 1 working day from when the Investigator becomes aware of the SAE. A final report 
to document resolution of all SAEs is required. 


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In a medical emergency (i.e., an event that requires immediate attention regarding the 
treatment of a subject, operation of the clinical study, and/or the use of investigational drug), 
study site staff will apply appropriate medical intervention according to current standards of 
care and contact the Medical Monitor. 
15.2.4 Medical Monitor and Emergency Contact Information 
 
, MD  
Office (9-5 EST): 
  
24/7 Hotline: 
  
 
15.2.5 SAE Reporting Contact Information 
Contact information and reporting instructions are provided in the Safety Management Plan. 
15.2.6 Reporting to Institutional Review Boards (IRBs) 
It is the responsibility of the Investigator to promptly notify the institution’s IRB of all 
serious and unexpected suspected adverse reactions (see Section 15.3.2). 
15.3 Sponsor/Medical Monitor Responsibilities 
15.3.1 Monitoring of Adverse Event Data 
The Medical Monitor or designee will review AEs on an ongoing basis. 
15.3.2 Reporting to FDA 
The Sponsor must report in an IND safety report any suspected adverse reaction to study 
treatment that is both serious and unexpected (21 CFR 312.32[c][1][i]). Before submitting an 
IND safety report, the Sponsor will ensure the event meets all three of the definitions: (1) 
suspected adverse reaction, (2) serious, (3) unexpected. If the AE does not meet all three of 
the definitions, it should not be submitted as an IND safety report. The Sponsor should 
evaluate the available information and decide whether there is a reasonable possibility that 
the drug caused the AE and, therefore, that the event meets the definition of a suspected 
adverse reaction. 
If there is a serious and unexpected suspected adverse reaction, the Sponsor will notify the 
appropriate regulatory agency(ies) and all appropriate parties on an expedited basis. In 
addition, Sponsors must submit expedited reports of an increased rate of occurrence of 
serious suspected adverse reactions over that listed in the protocol or Investigational 
Brochure. 


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15.4 Emergency Identification of Study Medication 
In exceptional circumstances and for the safety of the study subject, the Investigator may 
request unblinding of an individual subject’s treatment from the pharmacist; this normally 
requires prior approval by the Medical Monitor. However, if the subject is at immediate risk 
and the Investigator believes that immediate knowledge of the study treatment will alter 
medical management, discussion with the Medical Monitor may take place after unblinding. 
The Investigator will not unblind the Medical Monitor during that discussion. The process of 
unblinding will ensure that only the investigator is unblinded; the Medical Monitor, study 
management team, and data management team will not be made aware of the treatment 
allocation of an individual subject. All cases of emergency unblinding will be fully 
documented in a way that does not unblind the Medical Monitor, study management team, 
and data management team. 
 


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16 STUDY ADMINISTRATION 
16.1 Quality Control and Quality Assurance 
The Investigators and institutions will permit trial-related monitoring, audits, IRB review, 
and regulatory inspections as requested by FDA, the Sponsor, or the Sponsor’s designee, 
including direct access to source data/documents (i.e., original medical records, laboratory 
reports, hospital documents, progress reports, signed ICFs, etc.) in addition to CRFs. 
Quality assurance and quality control systems with written standard operating procedures 
(SOPs) will be followed to ensure that this trial will be conducted and data will be generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements.  
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals 
during the study. The monitoring visits must be conducted according to the applicable ICH 
and GCP guidelines to ensure protocol adherence, quality of data, drug accountability, 
compliance with regulatory requirements, and continued adequacy of the investigational site 
and its facilities. During these visits, CRFs and other data related to the study will be 
reviewed and any discrepancies or omissions will be identified and resolved. The study 
monitor will be given access to study-relevant source documents (including medical records) 
for purposes of source data verification. 
During and/or after completion of the study, quality assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The 
Investigator is expected to cooperate with any audit and provide assistance and 
documentation (including source data) as requested.  
Quality control will be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties 
involved with the clinical trial will be in writing in a separate agreement. 
16.2 Data Handling and Recordkeeping 
16.2.1 Data Handling 
Procedures for data handling (including electronic data) used in this protocol will be 
documented in a Data Management Plan.  
16.2.2 Case Report Form Completion 
Electronic CRFs (eCRFs) will be completed for each study subject. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
subject’s eCRF. Source documentation supporting the eCRF data should indicate the 
subject’s participation in the study and should document the dates and details of study 
procedures, AEs, and subject status. 
The Investigator will have access to the electronic data capture (EDC) system and will 
receive a copy of the subject eCRF data at the end of the study. For subjects who discontinue 


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or terminate from the study, the eCRFs will be completed as much as possible, and the reason 
for the discontinuation or termination clearly and concisely specified on the appropriate 
eCRF. 
16.2.3 Retention of Study Records 
The Investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirements. Records will be retained for at least two years after the last 
marketing application approval and until there are no pending or contemplated marketing 
applications or two years after formal discontinuation of the clinical development of the 
investigational product or according to applicable regulatory requirements. If the Investigator 
withdraws from the responsibility of keeping the study records, custody must be transferred 
to an appropriate person willing to accept the responsibility. The Sponsor must be notified in 
writing if a custodial change occurs.  
16.3 Confidentiality 
To maintain subject privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the subject by the assigned subject number. The Investigator 
will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authority(ies) access to the subject’s original medical records for verification of data gathered 
on the CRFs and to audit the data collection process. The subject’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable 
laws and regulations. 
Subjects will be notified that registration information, results, and other information about 
this study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used. 
All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information. The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent 
from the Sponsor. It is understood that there is an obligation to provide the Sponsor with 
complete data obtained during the study. The information obtained from the clinical study 
will be used towards the development of the investigational product and may be disclosed to 
regulatory authority(ies), other Investigators, corporate partners, or consultants as required. 
16.4 Publication Policy 
All information concerning SAGE-547 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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16.5 Protocol Amendments 
Changes to the conduct of the study should be prepared as a protocol amendment by the 
Sponsor. Protocol amendments should receive written IRB/IEC approval prior to 
implementation at the investigative site, except when necessary to eliminate immediate 
hazards to the subjects or when the changes involve only logistical or administrative aspects 
of the trial (e.g., change of monitor, telephone numbers). In this case, Sage Therapeutics will 
amend and implement the protocol change and subsequently notify the regulatory authorities 
and the Investigative sites who will notify the respective IRB, as appropriate. 


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Gellman MD and Turner JR; Springer Science and Business Media, New York: 1518-1520. 
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Ottander U, Poromaa IS, Bjurulf E, Skytt A, Bäckström T, Olofsson JI. Allopregnanolone 
and pregnanolone are produced by the human corpus luteum. Mol Cell Endocrinol 2005 Jul 
15;239(1-2):37-44. PubMed PMID: 15935549. 
Paoletti AM, Romagnino S, Contu R, et al. Observational study on the stability of the 
psychological status during normal pregnancy and increased blood levels of neuroactive 
steroids with GABA-A receptor agonist activity. Psychoneuroendocrinology 2006; 31(4): 
485-492. PMID: 16406349. 
Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992;6(6):2311-22. PMID: 1347506. 
Posner K, Brown GK, Stanley B, et al. The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry 2011;168(12):1266-77. doi: 10.1176/appi.ajp.2011.10111704. 
Romeo E, Ströhle A, Spalletta G, di Michele F, Hermann B, Holsboer F, Pasini A, Rupprecht 
R. Effects of antidepressant treatment on neuroactive steroids in major depression. Am J 
Psychiatry 1998;155(7):910-3. PMID: 9659856. 
Sayeed I, Parvez S, Wali B, Siemen D, Stein DG. Direct inhibition of the mitochondrial 
permeability transition pore: a possible mechanism for better neuroprotective effects of 
allopregnanolone over progesterone. Brain Res 2009;1263:165-73. PMID: 19368823. 
Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, et al. Influence of 
mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3α-
hydroxysteroid dehydrogenase activity. Mol Psychiatry 2006;11(3):261-72. PMID: 
16344854. 
Schüle C, Baghai TC, di Michele F, Eser D, Pasini A, Schwarz M. Effects of combination 
treatment with mood stabilizers and mirtazapine on plasma concentrations of neuroactive 
steroids in depressed patients. Psychoneuroendocrinology 2007;32(6):669-80. PMID: 
17560730. 
Shelton RC, Trivedi MH. Moderators of antidepressant response in major depression. J Clin 
Psychiatry 2011;72(10):e32. PMID: 22075105. 
Spitzer RL, Kroenke K, Williams JBW, Löwe B. A Brief Measure for Assessing Generalized 
Anxiety Disorder: The GAD-7. Arch Intern Med 2006; 166(10):1092-1097. doi: 
10.1001/archinte.166.10.1092. 


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Ströhle A, Romeo E, Hermann B, Pasini A, Spalletta G, di Michele F, et al. Concentrations 
of 3α-reduced neuroactivesteroids and their precursors in plasma of patients with major 
depression and after clinical recovery. Biol Psychiatry 1999;45(3):274-77. PMID: 10023501. 
Timby E, Balgård M, Nyberg S, Spigset O, Andersson A, Porankiewicz-Asplund J, et al. 
Pharmacokinetic and behavioral effects of allopregnanolone in healthy women. 
Psychopharmacology (Berl) 2006 Jun;186(3):414-24. PMID: 16177884. 
Timby E, Hedström H, Bäckström T, Sundström-Poromaa I, Nyberg S, Bixo M. 
Allopregnanolone, a GABAA receptor agonist, decreases gonadotropin levels in women A 
preliminary study. Gynecol Endocrinol 2011 Dec;27(12):1087-93. PMID: 21190418. (Timby 
2011a) 
Timby E. Allopregnanolone effects in women. Clinical studies in relation to the menstrual 
cycle, premenstrual dysphoric disorder and oral contraceptive use. Umea University Medical 
Dissertation 2011; New Series No. 1459. (Timby 2011b) 
Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, et al. Increase in the 
cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who 
are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci 1998;95(6):3239-44. PMID: 
9501247. 
van Broekhoven F, Bäckström T, van Luijtelaar G, Buitelaar JK, Smits P, Verkes RJ. Effects 
of allopregnanolone on sedation in men, and in women on oral contraceptives. 
Psychoneuroendocrinology. 2007 Jun;32(5):555-64. PMID: 17470385. 
Verbeek T, Bockting CL, van Pampus MG et al. Postpartum depression predicts offspring 
mental health problems in adolescence independently of parental lifetime psychopathology. J 
Affect Disord 2012;136(3):948-54. doi: 10.1016/j.jad.2011.08.035. 
Wieland S, Lan NC, Mirasedeghi S, Gee KW. Anxiolytic activity of the progesterone 
metabolite 5α-pregnan-3α-ol-20-one. Brain Res 1991;565(2):263-8. PMID: 1688192. 
 
 
 


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18 APPENDICES 
Copies of the rating scales and questionnaires included in APPENDIX 1 through APPENDIX 
9 are for reference only. 
 
 
APPENDIX 1. Columbia Suicide Severity Rating Scale (C-SSRS) ....................... 72 
APPENDIX 2. Hamilton Rating Scale for Depression, 17-Item (HAMD) ............ 79 
APPENDIX 3. Montgomery Asberg Depression Rating Scale (MADRS) ............ 81 
APPENDIX 4. Clinical Global Impression–Improvement Scale (CGI-I) and Severity 
Scale (CGI-S) ..................................................................................... 84 
APPENDIX 5. Stanford Sleepiness Scale (SSS) .................................................... 86 
APPENDIX 6. Edinburgh Postnatal Depression Scale (EPDS) ............................. 88 
APPENDIX 7. Generalized Anxiety Disorder 7-Item Scale (GAD-7) ................... 90 
APPENDIX 8. Patient Health Questionnaire (PHQ-9) ........................................... 92 
APPENDIX 9. Barkin Index of Maternal Functioning (BIMF).............................. 94 
APPENDIX 10. Selected Inducers, Inhibitors, and Substrates of CYP2C9 ........... 96 
   
 
 
 


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APPENDIX 1. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The “Baseline/Screening” and “Since Last Visit” versions of the C-SSRS begin on the next 
full page (Posner et al. 2011). 
 
 


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APPENDIX 2. 
Hamilton Rating Scale for Depression, 17-Item (HAMD) 
The HAMD presents on the next full page (Hamilton 1960). 
The HAMD total score will be calculated as the sum of the 17 individual item scores. Item 16 
can be rated according to history (item 16A) or actual weight change (item 16B). The item 16 
score is calculated as the item 16 response that is not equal to 3 (i.e., “Not assessed). 
 
 


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APPENDIX 3. 
Montgomery Asberg Depression Rating Scale (MADRS) 
The MADRS presents on the next full page. (McDowell 2006, Müller-Thomsen 2005). 
 
 


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APPENDIX 4. 
Clinical Global Impression–Improvement Scale (CGI-I) 
and Severity Scale (CGI-S) 
 
The CGI-I and CGI-S presents on the next full page. For the purposes of Protocol 547-PPD-202, only 
Items 1 and 2, Severity of Illness and Global Improvement, will be assessed in subjects enrolled in the 
study. 
 


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APPENDIX 5. 
Stanford Sleepiness Scale (SSS) 
The SSS presents on the next full page. 
 
 


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Stanford Sleepiness Scale 
This is a quick way to assess how alert you are feeling. If it is during the day when you go about your 
business, ideally you would want a rating of a one. Take into account that most people have two peak 
times of alertness daily, at about 9 a.m. and 9 p.m. Alertness wanes to its lowest point at around 3 
p.m.; after that it begins to build again. Rate your alertness at different times during the day. If you go 
below a three when you should be feeling alert, this is an indication that you have a serious sleep debt 
and you need more sleep. 
An Introspective Measure of Sleepiness 
The Stanford Sleepiness Scale (SSS) 
Degree of Sleepiness 
Scale 
Rating 
Feeling active, vital, alert, or wide awake 
1 
Functioning at high levels, but not at peak; 
able to concentrate 
2 
Awake, but relaxed; responsive but not fully 
alert 
3 
Somewhat foggy, let down 
4 
Foggy; losing interest in remaining awake; 
slowed down 
5 
Sleepy, woozy, fighting sleep; prefer to lie 
down 
6 
No longer fighting sleep, sleep onset soon; 
having dream-like thoughts 
7 
Asleep 
X 
 


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APPENDIX 6. 
Edinburgh Postnatal Depression Scale (EPDS) 
 
The EPDS presents on the next full page (Cox et al. 1987). 
 


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APPENDIX 7. 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) 
The GAD-7 presents on the next full page (Spitzer 2006). 
 
 


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APPENDIX 8. 
Patient Health Questionnaire (PHQ-9) 
The PHQ-9 presents on the next full page. 
Developed by Drs. Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke, and colleagues 
with an educational grant from Pfizer Inc. No permission required to reproduce, translate, 
display or distribute. 
 
 
 


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APPENDIX 9. 
Barkin Index of Maternal Functioning (BIMF) 
 
The BIMF is presented on the next full page. 
 
 


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APPENDIX 10. Selected Inducers, Inhibitors, and Substrates of CYP2C9 
Inhibitors of CYP2C9 can be classified by their potency, such as: 
• 
Strong being one that causes at least a 5-fold increase in the plasma AUC values, or more 
than 80% decrease in clearance. 
• 
Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or 50-
80% decrease in clearance. 
• 
Weak being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma 
AUC values, or 20-50% decrease in clearance. 
Substrates 
Inhibitors 
Inducers 
• 
NSAIDs 
(analgesic, antipyretic, anti-
inflammatory) 
o 
celecoxib  
o 
lornoxicam  
o 
diclofenac  
o 
ibuprofen  
o 
naproxen  
o 
ketoprofen 
o 
piroxicam  
o 
meloxicam  
o 
suprofen 
• 
phenytoin (antiepileptic) 
• 
fluvastatin (statin) 
• 
sulfonylureas (antidiabetic) 
o 
glipizide  
o 
glibenclamide  
o 
glimepiride  
o 
tolbutamide  
o 
glyburide 
• 
angiotensin II receptor 
antagonists (in 
hypertension, diabetic 
nephropathy, CHF) 
o 
irbesartan  
o 
losartan  
• 
S-warfarin (anticoagulant) 
• 
sildenafil (in erectile dysfunction) 
• 
terbinafine (antifungal) 
• 
amitriptyline (tricyclic 
antidepressant) 
• 
fluoxetine (SSRI antidepressant) 
• 
nateglinide (antidiabetic) 
• 
rosiglitazone (antidiabetic) 
• 
tamoxifen (SERM) 
• 
torasemide (loop diuretic) 
• 
ketamine 
• 
THC 
• 
JWH-018 
• 
AM-2201 
Strong 
• 
fluconazole (antifungal) 
• 
miconazole (antifungal) 
• 
amentoflavone 
(constituent of Ginkgo 
biloba and St. John’s Wort) 
• 
sulfaphenazole (antibacterial) 
• 
valproic acid (anticonvulsant, 
mood-stabilizing) 
• 
apigenin 
 
Moderate 
• 
amiodarone (antiarrhythmic) 
 
Unspecified potency 
• 
antihistamines (H1 receptor 
antagonists) 
o 
cyclizine 
o 
promethazine 
• 
chloramphenicol 
• 
fenofibrate (fibrate) 
• 
flavones 
• 
flavonols 
• 
fluvastatin (statin) 
• 
fluvoxamine (SSRI) 
• 
isoniazid (in tuberculosis) 
• 
lovastatin (statin) 
• 
phenylbutazone (NSAID) 
• 
probenecid (uricosuric) 
• 
sertraline (SSRI) 
• 
sulfamethoxazole (antibiotic) 
• 
teniposide (chemotherapeutic) 
• 
voriconazole (antifungal) 
• 
zafirlukast (leukotriene 
antagonist) 
• 
quercetin (anti-inflammatory) 
Strong 
• 
rifampicin (bactericidal) 
• 
secobarbital 
(barbiturate) 
 
 
 


 
Protocol 547-PPD-202                                     
 
  Page 1 of 23  
 
                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
Summary of Changes 
Protocol-547-PPD-202 
Dated 22 Dec 2015 
 
The following changes were made to the attached protocol in this amendment.  Minor typographical/editorial errors throughout the 
document were also corrected. The Synopsis, Tables, and Figures were corrected to be consistent with the changes in the main body of 
the protocol.  
 
Section number and 
title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
Title Page  
Title page 
, MD PhD 
 
 
, MD, MBA 
 
 
 
Change in 
Medical Monitor 
12.2.3 Exploratory 
Patient Reported 
Outcome Measures 
/15 Interactive Voice 
Response (IVR) 
HAMD/13 Study 
Procedures 
Global/12.2.3 
Exploratory Patient 
Reported Outcome 
Measures/13 Study 
Procedures 
The IVR HAMD is a validated 
patient reported version of the 
clinician rated HAMD.  Similar 
total and subscale scores as 
described in Section 12.2.1.1 will 
be calculated for the IVR HAMD. 
 
Removed all references throughout 
the document, including references 
in endpoints, and 12.2.3 Exploratory 
Patient Reported Outcome 
Measures 
IVR HAMD will 
not be 
implemented in 
this study. 
Table 1: Schedule of 
Events 
Table 1: Schedule of 
Events 
D7(±1d) 
 D7/ ET (±1d) 
Additional 
requirement for 
an Early 
Termination Visit 
Table 1: Schedule of 
Events/ 13.3.1 Day 7 
( ±1day) 
Table 1: Schedule of 
Events/ 13.3.1 Day 7 
( ±1day) 
N/A 
A blood sample for PK analysis 
will be collected at the time of the 
visit 
Addition of Day 7 
plasma sample to 
evaluate 


 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
Section number and 
title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
 
pharmacokinetics 
of SAGE-547 
Table 1: Schedule of 
Events/ 13.3.1 Day 7 
( ±1day) 
Table 1: Schedule of 
Events/ 13.3.1 Day 7 
( ±1day) 
N/A 
Per subject consent (optional), 
collection of breast milk on the day 
of the visit* 
*Assessment is only applicable to 
those patients who have temporarily 
ceased breastfeeding and are 
participating in the optional breast 
milk sampling. 
Table 1:Schedule of Events updated 
Addition of 
optional Day 7 
breastmilk sample 
to evaluate 
breastmilk 
Table 1: Schedule of 
Events 
Table 1: Schedule of 
Events/Section 
13.3.2 Day 12 
(+1day) 
N/A 
• A blood sample for PK 
analysis will be collected at 
the time of the visit  
• Per subject consent 
(optional), collection of 
breast milk on the day of the 
visit 
• AEs will be monitored.  
• Concomitant medications 
will be recorded.  
This visit is only applicable to those 
patients who have temporarily 
Addition of 
optional Day 12 
visit for purposes 
of collecting PK 
Samples at the 
end of the 
temporary 
ceasing of 
breastfeeding 
timepoint 


 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
Section number and 
title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
ceased breastfeeding and are 
participating in the optional breast 
milk sampling. 
 
Table 1: 
Day 12 (+1d) 
Footnote: 
l Day 7 PK plasma and Breast Milk 
Samples/Day 12 Visit is only 
applicable to those patients who 
have temporarily ceased 
breastfeeding and are 
participating in the optional breast 
milk sampling. 
 
Table 1: Schedule of 
Events/Global 
Change 
Table 1: Schedule of 
Events/Global 
Change 
g  The “Baseline” C-SSRS form 
will be completed on Day 1. 
The “Since Last Visit” C-SSRS 
form will be completed at all 
subsequent timepoints. 
 
g  The “Baseline/Screening” C-
SSRS form will be completed on 
Day 1. The “Since Last Visit” C-
SSRS form will be completed at 
all subsequent timepoints. 
 
 
 
Clarification of 
the version of the 
C-SSRS 
throughout the 
document 


 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
Section number and 
title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
5.5.3 Dose Rationale 
5.5.3 Dose Rationale Doses will be increased as 
follows: 30 µg /kg/hour [0-4 
hours], then 60 µg/kg/hour [4-
24 hours], then 90 µg/kg/hour 
[24-60 hours]. 
Doses will be increased as follows: 
30 µg /kg/hour [0-4 hours], then 
60 µg/kg/hour [4-24 hours], then 
90 µg/kg/hour [24-52 hours], 
followed by a decrease to 
60 µg/kg/hour (52-56 hours), 
and 30 µg/kg/hour (56-60 
hours). 
The addition of a 
taper the last 8 
hours of the 
infusion to 
minimize the 
possibility of any 
withdrawal at the 
end of the 
infusion. 
7.2 Secondary 
Objectives 
7.2 Secondary 
Objectives 
• To determine if SAGE-
547 Injection infused 
intravenously for 60 hours 
reduces depressive 
symptoms compared to 
placebo injection as 
assessed by HAMD 
response, HAMD 
remission, change from 
baseline in Montgomery-
Asberg Depression Rating 
Scale (MADRS) total 
score, change from 
baseline in Clinical Global 
Impression – Severity 
(CGI-S) score, Clinical 
Global Impression – 
• To determine if SAGE-547 
Injection infused 
intravenously for 60 hours 
reduces depressive 
symptoms compared to 
placebo injection as 
assessed by HAMD 
response, HAMD remission, 
change from baseline in 
Montgomery-Asberg 
Depression Rating Scale 
(MADRS) total score, 
Clinical Global Impression 
– Improvement (CGI-I) 
response, and changes from 
baseline in HAMD subscale 
Removal of the 
change from 
baseline objective 
for CGI-S 


 
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Protocol 547-PPD-202 Amendment One, Version 2.0 
 
Section number and 
title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
Improvement (CGI-I) 
response, and changes 
from baseline in HAMD 
subscale and individual 
item scores.   
 
and individual item scores.   
 
7.3 Exploratory 
Objectives 
7.3 Exploratory 
Objectives 
• To determine if SAGE-
547 Injection infused 
intravenously for 60 hours 
reduces subject-reported 
depressive symptoms 
compared to placebo 
injection as assessed by 
the change from baseline 
in Edinburgh Postnatal 
Depression Scale (EPDS) 
total score, change from 
baseline in Patient Health 
Questionnaire (PHQ-9) 
total score, and change 
from baseline in 
Interactive Voice 
Response (IVR) HAMD 
total score. 
 
• To determine if SAGE-547 
Injection infused 
intravenously for 60 hours 
reduces subject-reported 
depressive symptoms 
compared to placebo 
injection as assessed by the 
change from baseline in 
Edinburgh Postnatal 
Depression Scale (EPDS) 
total score, and the change 
from baseline in Patient 
Health Questionnaire (PHQ-
9) total score. 
 
IVR HAMD will 
not be 
implemented in 
this study. 


 
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Protocol 547-PPD-202 Amendment One, Version 2.0 
 
Section number and 
title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
8.1 Overview of 
Study Design 
8.1 Overview of 
Study Design 
On the morning of dosing (Day 
1), subjects will begin a 4-hour 
dose titration period 
30µg/kg/hour [0-4 hours], then 
60 µg/kg/hour [4-24 hours], 
then 90 µg/kg/hour [24-60 
hours]); see dose regimen 
presented in Section 11.1.1.  
On the morning of dosing (Day 1), 
subjects will begin a 4-hour dose 
titration period 30µg/kg/hour [0-4 
hours], then 60 µg/kg/hour [4-24 
hours], then 90 µg/kg/hour [24-52 
hours]); followed by a decrease 
to 60 µg/kg/hour (52-56 hours), 
and 30 µg/kg/hour (56-60 
hours). See dose regimen 
presented in Section 11.1.1.  
 
Table 2 and Figure 2 also revised 
to reflect addition of taper. 
The addition of a 
taper the last 8 
hours of the 
infusion to 
minimize the 
possibility of any 
withdrawal 
symptoms at the 
end of the 
infusion. 
8.2 Blinding and 
Randomization 
8.2 Blinding and 
Randomization 
Subjects will be randomly 
assigned to receive SAGE-547 
Injection followed by placebo 
according to a computer-
generated randomization 
schedule.  
 
Subjects will be randomly assigned 
to receive SAGE-547 Injection or 
placebo according to a computer-
generated randomization schedule.  
 
Correction of 
inaccurate 
description of 
design. 
9.1 Inclusion Criteria 9.1 Inclusion 
Criteria 
5. Subject either must have ceased 
lactating at Screening; or if still 
lactating at Screening, must have 
already fully and permanently 
weaned their infant(s) from 
5. Subject either must have ceased 
lactating at Screening; or if still 
lactating or actively 
breastfeeding at Screening, 
must agree to temporarily 
Allowance to 
resume 
breastfeeding 
after a period of 
cessation based 


 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
Section number and 
title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
breastmilk; or if still actively 
breastfeeding at Screening, must 
agree to cease giving breastmilk 
to their infant(s) prior to receiving 
study drug. For the avoidance of 
doubt, subjects who are 
breastfeeding and do not agree to 
permanently wean their infant(s) 
from breastmilk at Screening are 
not eligible for the study. 
 
cease giving breastmilk to 
their infant(s) from just prior 
to receiving study drug 
through 9 days (Study Day 
12) after the end of the 
infusion.  
 
on PK modeling  
9.1 Inclusion Criteria 9.1 Inclusion 
Criteria 
N/A  
12. Subject must use one of the 
following methods of birth 
control during participation in 
the study and for 30 days 
following the end of the study 
drug infusion: 
• Total abstinence (no sexual 
intercourse) 
• Hormonal contraceptives 
(birth control) including 
birth control pills, 
implantable or injectable 
contraceptives (Norplant® 
Contraception 
requirements 
were 
inadvertently 
omitted out of the 
original protocol.  


 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
Section number and 
title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
or Depo-Provera® ) 
• A barrier form of 
contraception such as a 
condom or occlusive cap 
with a spermicide 
• An intrauterine device 
(IUD) 
 
9.2 Exclusion 
Criteria 
9.2 Exclusion 
Criteria  
6. Medical history of bipolar 
disorder 
6. Medical history of bipolar 
disorder, schizophrenia, 
and/or schizoaffective 
disorder. 
 
To further clarify 
what disorders 
are excluded from 
the patient 
population  
10.3 Preparation of 
SAGE-547 Injection 
or Placebo for 
Dosing 
10.3 Preparation of 
SAGE-547 Injection 
or Placebo for 
Dosing 
The prepared admixture will be 
assigned a room temperature (20–
25 °C) storage shelf life of 
24 hours from time of 
compounding.  
 
The prepared admixture will be 
assigned a room temperature (20–
25 °C) storage shelf life of 30 hours 
from time of compounding.  
 
To update shelf 
life of admixture 
to current data. 


 
Protocol 547-PPD-202                                     
 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
11.1.1 Dose Regimen  11.1.1 Dose 
Regimen 
If any subject has an SSS score of 
≥5 for two or more consecutive 
assessments or an SSS score of 
≥6 for a single occurrence 
during normal waking hours, the 
infusion rate will be decreased to 
the next lowest infusion dose (or 
turned off if this occurs on the 
30 µg/kg/hour dose level) for the 
remainder of the study. 
If any subject has an SSS score of 
≥5 for two or more consecutive 
assessments or an SSS score of ≥6 
for a single occurrence during 
normal waking hours, the infusion 
rate for this subject will be 
decreased to the next lowest 
infusion dose level (or turned off if 
this occurs on the 30 µg/kg/hour 
dose level). 
Clarification of 
infusion rate 
decreases for 
subjects taking 
into consideration 
of the addition of 
the taper. 
12.1.2 Clinical 
Laboratory Tests 
12.1.2 Clinical 
Laboratory Tests 
Blood samples will be collected 
for hematology, serum 
chemistry, coagulation, and 
specific hormone parameters, 
hepatitis, human 
immunodeficiency virus (HIV), 
pregnancy and genetic analysis. 
Urine samples for urinalysis and 
selected drugs of abuse will also 
be collected. 
Blood samples will be collected for 
hematology, serum chemistry, 
coagulation, and specific hormone 
parameters, hepatitis, human 
immunodeficiency virus (HIV), 
pregnancy and genetic analysis. 
Urine samples for urinalysis and 
selected drugs of abuse will also be 
collected. All samples will be 
analyzed at the central 
laboratory. Patients may be 
considered eligible for the study 
based on local laboratory results, 
however screening samples must 
also be sent to the central 
laboratory. Both local and central 
To clarify 
operational 
activities during 
the Screening 
window. 


 
Protocol 547-PPD-202                                     
 
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                             Date: 22 Dec 2015 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
Screening labs must adhere to the 
visit window provided in the 
Schedule of Events (Table 1). 
3. Hormones 
12.1.2.3 Hormones 
and Exploratory 
Biochemistry 
Blood samples will be collected 
for analysis of thyroid stimulating 
hormone (TSH), estrogen, 
progesterone, progesterone 
metabolites and oxytocin. 
 
Blood samples will be collected for 
analysis of thyroid stimulating 
hormone (TSH), estrogen, 
progesterone, progesterone 
metabolites, oxytocin, tryptophan, 
kynurenine, and markers of 
inflammation. 
 
Addition and 
clarification of 
testing for 
exploratory 
purposes 
5. Genetic Testing 
12.1.2.5  Genetic 
Testing 
This sample will be used to test 
for the GABAA receptor δ-
subunit. Genetic susceptibility to 
affective dysregulation may be 
unmasked during periods of 
reproductive hormone change 
such as during pregnancy and 
postpartum (Maguire 2008). 
Maguire and Mody 
demonstrated that a GABA 
receptor subunit mutation was 
behaviorally silent until the 
The objective of this research is to 
collect and store blood samples for 
possible DNA extraction and 
exploratory research into how genes 
or specific genetic variation may 
influence response (i.e. distribution, 
safety, tolerability, and efficacy) to 
SAGE-547. Specific genetic 
variations of interest include but are 
not limited to: classes of 
metabolizing enzymes (e.g. 
Clarification and 
more detail of the 
genetic testing 
that will be 
performed. 


 
Protocol 547-PPD-202                                     
 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
animal was exposed to 
pregnancy and the postpartum 
state, at which time the dams 
showed depressive-like 
behaviors and cannibalized their 
offspring (Maguire 2008). 
Cytochrome P450 supra-family 
genes), genes encoding enzymes 
involved in the production and 
metabolism of allopregnanolone 
(e.g. AKR1C4 (3a-hydroxysteroid 
dehydrogenase)), genes associated 
with the GABA receptor (e.g. 
GABRA1-A6, GABRB1-B3, 
GABRD, GABRE, GABRG1-3) 
and genes associated with the 
production and degradation of 
GABA.    
  
Future research may suggest other 
genes or gene categories as 
candidates for influencing not only 
response to SAGE-547 but also 
susceptibility to disorders for which 
SAGE-547 may be evaluated. Thus, 
the genetic research my involve 
study of additional unnamed genes 
or gene categories, but only as 
related to disease susceptibility and 
drug action. 


 
Protocol 547-PPD-202                                     
 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
12.1.4 Vital Signs 
12.1.4 Vital Signs 
Vital signs include oral 
temperature (°C), respiratory rate, 
heart rate, and blood pressure 
(supine and standing) and pulse 
oximetry A full set of vital signs 
will be obtained at all specified 
timepoints (± 30 minutes), unless 
the subject is asleep between the 
hours of 23.00h and 06.00h each 
day. Additional measures of pulse 
oximetry will be collected during 
sleeping hours. 
 
Vital signs include oral temperature 
(°C), respiratory rate, heart rate, and 
blood pressure (supine and 
standing).A full set of vital signs 
will be obtained at all specified 
timepoints (± 30 minutes), unless 
the subject is asleep between the 
hours of 23.00h and 06.00h each 
day.  
 
Removal of Pulse 
Oximetry from 
Vital sign 
assessment 
description 
N/A 
12.1.5 Pulse 
Oximetry 
N/A 
Pulse oximetry will be monitored 
continuously from H0 until H60 on 
Day 1, and checked approximately 
every 2 hours, including during the 
overnight hours, or at the alarm. If 
there is an indication of oxygen 
desaturation, this should be 
recorded as an adverse event at the 
discretion of the Investigator. No 
pulse oximetry data will be 
recorded in the eCRF. 
Further 
clarification and 
description of the 
Pulse oximetry 
monitoring and 
data collection. 


 
Protocol 547-PPD-202                                     
 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
12.2.1 Primary 
Efficacy Outcome 
Measure /8. 
Hamilton Rating 
Scale for Depression 
(HAMD) 
12.2.1 Primary 
Efficacy Outcome 
Measure /12.2.1.1 
Hamilton Rating 
Scale for Depression 
(HAMD) 
N/A 
Addition of: 
Every effort should be made for the 
same rater to perform all HAMD 
assessments for a single patient. 
Provide guidance 
on raters for 
consistency within 
a patient 
12.2.2 Secondary 
Efficacy Outcome 
Measures/11. 
Generalized Anxiety 
Disorder 7-Item 
Scale (GAD-7) 
12.2.2 Secondary 
Efficacy Outcome 
Measures/12.2.2.3 
Generalized Anxiety 
Disorder 7-Item 
Scale (GAD-7) 
The GAD-7 is a patient-rated 
depressive symptom severity 
scale (Spitzer 2006). 
The GAD-7 is a patient-rated 
generalized anxiety symptom 
severity scale (Spitzer 2006). 
Correction of the 
description of the 
scale 
12.3.2 Breastmilk PK 
Samples 
 
12.3.2 Breastmilk 
PK Samples 
 
After collection of the last 
breastmilk sample, women will 
reduce pumping to comfortably 
curtail breast milk production. 
After Study Day 12, women may 
resume giving breastmilk to their 
infant, per Inclusion Criteria 5. 
Description of 
resuming 
breastfeeding per 
new Inclusion 
Criteria 
14. Barkin Index of 
Maternal 
Functioning (BIMF) 
12.2.3.3 Barkin 
Index of Maternal 
Functioning (BIMF) 
Each item is rated on a scale of 0 
(strongly disagree) to 6 (strongly 
agree), and subscales are drawn 
from these items. 
Each item is rated on a scale of 0 
(strongly disagree) to 6 (strongly 
agree). 
Removal of 
description of 
subscales. 
Further details 
will be in the 
SAP. 


 
Protocol 547-PPD-202                                     
 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
N/A 
 
13.3.4 Early 
Termination Visit 
N/A 
The following assessments should 
be completed if the patient 
discontinues from the study prior to 
the Day 7 Visit: 
• Completion of physical 
examination. 
• Vital signs. 
• Blood and urine samples 
collected for clinical 
laboratory testing. 
• An ECG reading taken. 
• Completion of the C-SSRS, 
HAMD, MADRS, CGI-I, 
EPDS, GAD-7, PHQ-9 and 
BIMF. 
• AEs will be monitored.  
• Concomitant medications 
will be recorded.  
The visit should occur within 3 
days of notification of the patient 
discontinuing. 
Addition of the 
Early 
Termination Visit  


 
Protocol 547-PPD-202                                     
 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
14.1 Data Analysis 
Sets  
14.1 Data Analysis 
Sets 
 
The All Enrolled Population will 
include all subjects who have given 
written informed consent. This 
population will be used for subject 
disposition and demographic 
characteristic summaries. 
The All Randomized Population 
will include the subset of subjects 
from the All Enrolled Population 
who have been randomized. 
Subjects will be classified 
according to randomized treatment.  
This population will be used for 
subject disposition, demographic 
characteristic, and baseline 
characteristic summaries. 
 
 
Addition of New 
Populations to the 
protocol 
14.1 Data Analysis 
Sets 
14.1 Data Analysis 
Sets 
 
The intent-to-treat (ITT) subject 
population in this study is adult 
female subjects who meet all 
eligibility criteria and who sign an 
 
 
 
 
To redefine the 
populations based 
on the additions 
of the all enrolled 
and all 
randomized 


 
Protocol 547-PPD-202                                     
 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
informed consent to participate in 
this trial regardless whether or not 
study drug is administered. 
Safety Population (SAF): All 
ITT subjects who begin receiving 
a study drug infusion will be 
included in the safety population.  
Subjects will be classified 
according to actual treatment 
received. This analysis population 
will be used for all safety 
analyses.   
 
 
 
The Safety Population will include 
all randomized subjects who start 
the infusion of study drug infusion.  
Subjects will be classified 
according to actual treatment 
received. This analysis population 
will be used for all safety analyses. 
 
population. 
14.1 Data Analysis 
Sets 
14.1 Data Analysis 
Sets 
Efficacy Population (EFF): All 
SAF subjects who complete at 
least 12 hours of infusion and 
have efficacy evaluations through 
the 12-hour timepoint on Day 1.  
Subjects will be classified 
according to randomized 
treatment.  This analysis 
population will be used for all 
efficacy analyses. 
 
The Efficacy Population (EFF) 
will include the subset of the Safety 
Population who have a valid 
baseline HAMD assessment and at 
least one post-baseline HAMD 
assessment. Subjects will be 
classified according to randomized 
treatment.  This analysis population 
will be used for all efficacy 
analyses. 
 
To redefine the 
populations based 
on the additions 
of the all enrolled 
and all 
randomized 
population. 


 
Protocol 547-PPD-202                                     
 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
Section number and 
title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
14.1 Data Analysis 
Sets 
14.1 Data Analysis 
Sets 
Per Protocol Population (PP): 
All EFF subjects who complete 
the full infusion with all efficacy 
assessments through hour 60, and 
without significant protocol 
violations or deviations.  Subjects 
will be classified according to 
randomized treatment.  This 
analysis population will be used 
for select sensitivity analyses of 
the primary and key secondary 
endpoints. 
 
The Per Protocol Population (PP) 
will include the subset of the 
Efficacy Population who complete 
the full infusion without significant 
protocol violations or deviations.  
Subjects will be classified 
according to randomized treatment.  
This analysis population will be 
used for sensitivity analyses of the 
primary and select secondary 
endpoints. 
 
To redefine the 
populations based 
on the additions 
of the all enrolled 
and all 
randomized 
population. 
14.1 Data Analysis 
Sets 
14.1 Data Analysis 
Sets 
PK Population (PKP): All SAF 
subjects treated with SAGE-547 
for whom at least one evaluable 
PK sample is available. 
The PK Population (PKP) will 
include the subset of the Safety 
Population who have at least one 
evaluable PK sample. Subjects will 
be classified according to actual 
treatment received. This analysis 
population will be used for all PK 
analyses. 
 
To redefine the 
populations based 
on the additions 
of the all enrolled 
and all 
randomized 
population. 


 
Protocol 547-PPD-202                                     
 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
 
 
Breast Milk Population (BMP): 
All SAF subjects who begin 
receiving a study drug infusion 
and have at least one breast milk 
sample taken. 
 
The Breast Milk Population 
(BMP) will include the subset of 
the Safety Population who have at 
least one evaluable breast milk 
sample. Subjects will be classified 
according to actual treatment 
received. This analysis population 
will be used for all breast milk PK 
analyses. 
 
To redefine the 
populations based 
on the additions 
of the all enrolled 
and all 
randomized 
population. 
14.5 Secondary 
Endpoints 
14.5 Secondary 
Endpoints 
Adverse events: The analysis of 
AEs will be based on the concept 
of treatment-emergent AEs 
(TEAEs). A TEAE is defined as 
an AE with onset after the start of 
SAGE-547 infusion, or any 
worsening of a pre-existing 
medical condition/AE with onset 
after the start of SAGE-547 
infusion and until 7 days after the 
end of infusion (i.e., Day 10). A 
treatment-emergent serious AE 
(TESAE) is defined as an AE with 
onset after the start of SAGE-547 
infusion, or any worsening of a 
Adverse events: The analysis of 
AEs will be based on the concept of 
treatment-emergent AEs (TEAEs). 
A TEAE is defined as an AE with 
onset after the start of SAGE-547 
infusion, or any worsening of a pre-
existing medical condition/AE with 
onset after the start of SAGE-547 
infusion and until 7 days after the 
end of infusion The incidence of 
TEAEs will be summarized overall 
and by MedDRA® System Organ 
Class (SOC) and preferred term 
(PT).  Incidences will be presented 
in order of decreasing frequency. In 
Revision of the 
analysis and 
presentation of 
AEs and SAEs. 


 
Protocol 547-PPD-202                                     
 
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Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
pre-existing medical condition/AE 
with onset after the start of 
SAGE-547 infusion and until 30 
days after the end of infusion (i.e., 
Day 33). All TEAEs will be 
summarized and grouped by 
MedDRA® System Organ Class 
(SOC) and specific AE preferred 
term (PT). Results will be 
displayed in order of decreasing 
frequency by SOC and PT. For 
presentation, AE verbatim text 
will be coded into a MedDRA 
term and classified by SOC and 
PT using MedDRA® version 17.0 
or higher. In addition, summaries 
will be provided by severity 
(mild, moderate, severe) and by 
causality (related, not related) to 
study drug (see Section 15.2.2). 
TEAEs and TESAEs leading to 
discontinuation will be 
summarized and listed. 
 
addition, summaries will be 
provided by severity (mild, 
moderate, severe) and by causality 
(related, not related) to study drug 
(see Section 15.2.2). 
TEAEs leading to discontinuation 
and serious adverse events (SAEs; 
see 15.1.4 for definition) with onset 
after the start of randomized 
infusion will also be summarized  
All AEs and SAEs (including those 
with onset or worsening before the 
start of randomized infusion) 
through the Day 30 follow-up visit 
will be listed. 
 
 


 
Protocol 547-PPD-202                                     
 
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Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
14.7 Interim 
Analysis 
14.7 Interim 
Analysis 
An interim analysis will be 
conducted by an independent 
DSMB for sample size re-
estimation purposes when at least 
16 subjects have completed 
efficacy assessments through 60 
hours. Since the sponsor will be 
kept uninformed of the response 
rates at the time of the interim 
analysis, no statistical adjustment 
will be made to the level of 
significance for hypothesis testing 
at the end of the study. A detailed 
description of the interim analysis 
plan will be included in an interim 
analysis plan. 
 
An interim analysis will be 
conducted by an independent 
statistician for sample size re-
estimation purposes when at least 
16 subjects have completed efficacy 
assessments through 60 hours. 
Since the sponsor will be kept 
uninformed of the response rates at 
the time of the interim analysis, no 
statistical adjustment will be made 
to the level of significance for 
hypothesis testing at the end of the 
study. A detailed description of the 
interim analysis will be included in 
the SAP. 
 
Clarify the 
conduct of the 
interim analysis. 
The original 
protocol referred 
to a DSMB in 
error. 
15.2.2 Adverse Event 
Classification/16 
Relationship to 
Investigational Drug 
15.2.2 Adverse 
Event Classification/ 
15.2.2.1 
Relationship to 
Investigational Drug 
Not Related:  
The temporal 
relationship 
of the clinical 
event to 
study drug 
administratio
n makes 
causal 
Related:  
No relationship 
between the 
experience and 
the 
administration 
of study drug; 
related to other 
etiologies such 
Revision of 
definition of 
relationship of the 
AE to drug, to be 
consistent with 
other studies 
evaluating Sage-
547; previously 


 
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Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
relationship 
unlikely 
AND other 
drugs, 
therapeutic 
interventions, 
or underlying 
conditions 
provide a 
plausible 
explanation 
for the 
observed 
event. 
Related:  
Reasonable 
temporal 
relationship 
of the clinical 
event to 
study drug 
administratio
n AND 
cannot be 
reasonably 
explained by 
other factors 
as concomitant 
medications or 
subject’s 
clinical state. 
Possibly Related:  A reaction that 
follows a 
plausible 
temporal 
sequence from 
administration 
of the study 
drug and 
follows a 
known 
response 
pattern to the 
suspected 
study drug.  
The reaction 
might have 
been produced 
by the subject’s 
clinical state or 
other modes of 
therapy 
described in an 
Administrative 
Letter  


 
Protocol 547-PPD-202                                     
 
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                             Date: 22 Dec 2015 
 
Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
(such as the 
subject’s 
clinical state, 
concomitant 
therapy, 
and/or other 
interventions)
.  
Possibly Related:  The temporal 
relationship 
of the clinical 
event to 
study drug 
administratio
n makes 
causal 
relationship 
possible but 
not unlikely 
AND other 
drugs, 
therapeutic 
interventions, 
or underlying 
conditions do 
not provide a 
administered to 
the subject, but 
this is not 
known for 
sure.  
 
Probably Related:   A reaction that 
follows a 
plausible 
temporal 
sequence from 
administration 
of the study 
drug and 
follows a 
known 
response 
pattern to the 
suspected 
study drug.  
The reaction 
cannot be 
reasonably 
explained by 
the known 


 
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Protocol 547-PPD-202 Amendment One, Version 2.0 
 
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title in Protocol 
Version 1.0 (18 
September 2015) 
Section number 
and title in Version 
2.0 (22 December 
2015) 
Original text: 
 
 
Changed to: 
 
 
Rationale 
sufficient 
explanation 
for the 
observed 
event.  
 
characteristics 
of the subject’s 
clinical state or 
other modes of 
therapy 
administered to 
the subject  
 


Protocol 547-PPD-202 
Sage Therapeutics 
 
18 Sep 2015 
Confidential 
      1   
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL-
GROUP, PLACEBO-CONTROLLED STUDY EVALUATING THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS OF SAGE-547 
INJECTION IN THE TREATMENT OF ADULT FEMALE SUBJECTS 
WITH SEVERE POSTPARTUM DEPRESSION 
PROTOCOL NUMBER: 547-PPD-202 
 
IND NUMBER: 122279 
Investigational Product: 
SAGE-547 Injection (allopregnanolone) 
Clinical Phase: 
2a 
Sponsor: 
Sage Therapeutics 
Sponsor Contact: 
, MD, PhD 
 
 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Phone: 
 
 
 
Medical Monitor: 
 
, MD  
Office (9-5 EST): 
  
24/7 Hotline: 
 
 
 
Date of Original Protocol: 
18 September 2015 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee. Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without 
written authorization from the Sponsor. 


Protocol 547-PPD-202 
Sage Therapeutics 
18 Sep 2015 
1 SIGNATURE PAGE 
Title of protocol: 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-
Controlled Study Evaluating the Efficacy, Safety, and 
Pharmacokinetics of SAGE-547 Injection in the Treatment of Adult 
Female Subjects With Severe Postpartum Depression 
Protocol No: 
547-PPD-202 
, MD, PhD 
 
Sage Therapeutics 
Investigator Agreement 
Q 1- Sef- 201-5' 
Date ( dd/mmm/yyyy) 
By signing this page I attest that I have read and understand the contents of Clinical Protocol 
547-PPD-202 and any current amendments. I agree to adhere to the design, conduct, and 
reporting requirements of the study as stated in the clinical protocol and to my obligations to 
the Sponsor as described in the protocol and executed contracts between myself, my 
Institution, and the Sponsor. I also agree to adhere to any subsequent amendments to the 
clinical protocol. 
Investigator's Signature: 
Investigator's Name: 
Institution: 
Date (dd/mmm/yyyy): 
Confidential 
2 


Protocol 547-PPD-202 
Sage Therapeutics 
 
18 Sep 2015 
Confidential 
      3   
 
2 SYNOPSIS 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
Name of Investigational Product: 
SAGE-547 Injection 
Name of Active Ingredient: 
Allopregnanolone 
Title of the Protocol: 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study Evaluating the 
Efficacy, Safety, and Pharmacokinetics of SAGE-547 Injection in the Treatment of Adult Female 
Subjects With Severe Postpartum Depression 
Study Sites: Approximately 15 sites in the United States 
Duration of Subject Participation: Up to 35 days 
Primary Objective: 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces depressive 
symptoms in subjects with postpartum depression (PPD) compared to placebo injection as 
assessed by the change from baseline in Hamilton Rating Scale for Depression (HAMD) total 
score 
Secondary Objectives: 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces depressive 
symptoms compared to placebo injection as assessed by HAMD response, HAMD remission, 
change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score, 
change from baseline in Clinical Global Impression – Severity (CGI-S) score, Clinical Global 
Impression – Improvement (CGI-I) response, and changes from baseline in HAMD subscale 
and individual item scores.   
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces other mood 
symptoms compared to placebo injection as assessed by changes from baseline in the 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) total score. 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours increases sedation 
levels compared to placebo injection as assessed by the changes from baseline in Stanford 
Sleepiness Scale (SSS) score. 


Protocol 547-PPD-202 
Sage Therapeutics 
 
18 Sep 2015 
Confidential 
      4   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
• 
To evaluate the safety and tolerability of SAGE-547 Injection compared with placebo as 
assessed by the incidence of adverse events, vital sign measurement, clinical laboratory 
evaluations, electrocardiogram (ECG) parameters, and the Columbia Suicide Severity Rating 
Scale (C-SSRS). 
Exploratory Objective: 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours reduces subject-
reported depressive symptoms compared to placebo injection as assessed by the change from 
baseline in Edinburgh Postnatal Depression Scale (EPDS) total score, change from baseline in 
Patient Health Questionnaire (PHQ-9) total score, and change from baseline in Interactive 
Voice Response (IVR) HAMD total score. 
• 
To determine if SAGE-547 Injection infused intravenously for 60 hours improves maternal 
behaviors compared to placebo injection as assessed by the change from baseline in Barkin 
Index of Maternal Functioning (BIMF) total and sub-scale scores.  
Pharmacokinetic Objective: 
• 
To assess the pharmacokinetic (PK) profile of SAGE-547, metabolites of SAGE-547, and 
betadex sulfobutyl ether sodium (SBECD) and the concentration of SAGE-547 in breast milk, 
when possible. 
Study Design and Methodology:  
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of the 
efficacy, safety, and pharmacokinetics of SAGE-547 Injection in adult female subjects diagnosed with 
severe PPD. Subjects must remain as in-patients during the study Treatment Period, which is 
approximately 60 hours/2.5 days in duration. The Screening Period assessments may be conducted on 
an in-patient or an out-patient basis. The Follow-up Period assessments are conducted on an out-patient 
basis. 
Screening Period: The Screening Period begins with the signature of the informed consent form (ICF). 
Eligibility is determined by applying the inclusion/exclusion criteria. The diagnosis of PPD must be by 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). A full medical and family history 
will be taken including recording of all depression, other Axis 1 and Axis 2 disorders and postpartum 
depression episodes in primary probands (who may be subject to a SCID-I interview). 
Treatment Period: Once subjects are confirmed as eligible for the study, they will be randomized to 
one of two treatment groups (SAGE-547 or placebo) on a 1:1 basis. Continuous intravenous infusions 
of blinded study drug will be administered, with a new bag and line hung every 24 hours during the 60-
hour infusion. Infusion rates will increase, with subjects receiving 30 µg/kg/hour (0-4 hours), then 
60 µg/kg/hour (4-24 hours), then 90 µg/kg/hour (24-60 hours). Subjects may be discharged after the 
72-hour assessments have been completed (12 hours after completion of the study drug infusion). If 


Protocol 547-PPD-202 
Sage Therapeutics 
 
18 Sep 2015 
Confidential 
      5   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
their clinical condition does not allow discharge, normal standard of care will be employed in their 
ongoing management. 
Initiation of benzodiazepines, narcotics, antibiotics, neuroleptics, and other anti-anxiety medications 
will not be allowed between Screening and completion of the 72-hour assessments. Doses of 
psychotropics, which must have been initiated at least 14 days prior to screening, must remain at a 
stable dose until completion of the 72-hour assessments. If at the 72-hour assessment there has been no 
treatment response (HAMD total score remains above 13), treatment with antidepressant medication 
may be optimized prior to discharge, and the subject may remain in the unit or be followed at an out-
patient clinic, as clinically indicated. 
Efficacy and safety assessments will be performed periodically during the study, and blood samples 
will be collected for analysis of SAGE-547, metabolites of SAGE-547, and SBECD concentrations, as 
outlined in the Schedule of Events (Table 1). Blood samples will be collected, and outcome measures 
will be obtained at pre-specified times over 60 hours during the Treatment Period.  
Follow-up Period: Follow-up visits will be conducted one week (7±1 day) and one month (30±3d) 
after the initiation of the study drug infusion. 
Number of Subjects: 
Up to 32 subjects will be randomized   
Inclusion Criteria:  
The following inclusion criteria must be met for individuals to be eligible for the trial: 
1. Subject has signed an ICF prior to any study-specific procedures being performed 
2. Subject is an ambulatory female aged between 18 and 45 years of age, inclusive 
3. Subject is in good physical health and has no clinically significant findings, as determined by 
the Investigator, on physical examination, 12-lead ECG, or clinical laboratory tests 
4. Subject agrees to adhere to the study requirements 
5. Subject either must have ceased lactating at Screening; or if still lactating at Screening, must 
have already fully and permanently weaned their infant(s) from breastmilk; or if still actively 
breastfeeding at Screening, must agree to cease giving breastmilk to their infant(s) prior to 
receiving study drug. For the avoidance of doubt, subjects who are breastfeeding and do not 
agree to permanently wean their infant(s) from breastmilk at Screening are not eligible for the 
study. 
6. Subject must have a negative pregnancy test at Screening and Day 1 prior to the start of study 
drug infusion 


Protocol 547-PPD-202 
Sage Therapeutics 
 
18 Sep 2015 
Confidential 
      6   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
7. Subject has had a Major Depressive Episode that began no earlier than the third trimester and 
no later than the first 4 weeks following delivery, as diagnosed by Structured Clinical 
Interview for DSM-IV Axis I Disorders (SCID-I) 
8. Subject has a HAMD total score of ≥26 at Screening and Day 1 (prior to randomization) 
9. Subject is ≤ six months postpartum 
10. Subject is willing to delay start of other antidepressant or anxiety medications and any new 
pharmacotherapy regimens, including prn benzodiazepine anxiolytics, until the study drug 
infusion and 72-hour assessments have been completed 
11. Subject has no detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), 
and human immunodeficiency virus (HIV) antibody at Screening 
Exclusion Criteria: 
Subjects will be excluded if they meet any of the following exclusion criteria: 
1. Recent history or active clinically significant manifestations of metabolic, hepatic, renal, 
hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, 
urogenital, neurological, or eyes, ears, or nose and throat disorders, or any other acute or 
chronic condition that, in the Investigator’s opinion, would limit the subject’s ability to 
complete or participate in this clinical study 
2. Known allergy to progesterone or allopregnanolone 
3. Active psychosis per Investigator assessment 
4. Attempted suicide associated with index case of postpartum depression 
5. Medical history of seizures 
6. Medical history of bipolar disorder 
7. History of active alcoholism or drug addiction (including benzodiazepines) in the 12 months 
prior to Screening 
8. Exposure to another investigational medication or device within 30 days prior to Screening 
9. Administration of psychotropics that have been initiated within 14 days prior to Screening and 
are not being taken at a stable dose. 


Protocol 547-PPD-202 
Sage Therapeutics 
 
18 Sep 2015 
Confidential 
      7   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
Investigational Product, Dosage, and Mode of Administration:  
SAGE-547 Injection, intravenous (IV) administration: SAGE-547 Injection is a sterile, clear, colorless 
5 mg/mL solution of SAGE-547 (allopregnanolone) and 250 mg/mL SBECD buffered with 10 mM 
citrate at a pH of 6.0, supplied in single-use 20 mL vials for IV administration. As supplied, SAGE-547 
Injection, which is hypertonic, requires further dilution with Sterile Water for Injection (SWFI) to 
render it isotonic for IV infusion. The specific infusion dose of SAGE-547 Injection will be calculated 
based on weight for each subject at Screening and administered according to the randomization 
schedule. Infusion bags will be changed every 24 hours. Details about the preparation and 
administration of the study drug infusions will be included in the Pharmacy Manual. 
Timepoint 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2/3 
24-60 hours 
Infusion Rate 
30 µg/kg/hour 
60 µg /kg/hour 
90 µg /kg/hour 
 
Reference Therapy, Dosage, and Mode of Administration:  
An identical placebo IV infusion will be prepared for IV administration consisting of the same 
formulation without allopregnanolone. 
Randomization and Stopping Rules: 
Subjects will be randomized to receive SAGE-547 Injection or placebo; subjects, clinicians, and study 
team will be blinded to treatment allocation. Only the pharmacist, who will prepare the infusion bags 
according to the randomization schedule, will be unblinded. The infusion rates are the same for all 
subjects within a particular dosing period (0-4 hours, 4-24 hours, etc.). 
If any subject has an SSS score of ≥5 for two or more consecutive assessments or an SSS score of ≥6 
for a single occurrence during normal waking hours, the infusion rate will be decreased to the next 
lowest infusion dose (or turned off if this occurs on the 30 µg/kg/hour dose level) for the remainder of 
the study. 


Protocol 547-PPD-202 
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18 Sep 2015 
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      8   
 
Criteria for Evaluation: 
Primary Endpoint 
The primary outcome measure will be the 17-item Hamilton Rating Scale for Depression (HAMD). 
The HAMD will be administered before, during, and after the infusion of blinded study drug. The 
HAMD total score will be calculated as the sum of the 17 individual item scores. The change from 
baseline in HAMD total score at the end of the treatment period (at +60 hours) will be the primary 
efficacy endpoint with comparison between the two treatment groups used to evaluate the efficacy of 
SAGE-547 in treating the depressive symptoms of PPD. 
Secondary Endpoints 
Additional measures of depressive symptom severity will be administered before, during, and after the 
infusion of study drug, including the Montgomery-Asberg Depression Rating Scale (MADRS), and the 
Clinical Global Impression (CGI) scale. Total scores and changes from baseline will be calculated 
where applicable. Changes from baseline at the end of the treatment period (at +60 hours) and other 
time points will be evaluated as secondary efficacy endpoints with comparisons between the two 
treatment groups used to support the efficacy of SAGE-547 in treating the depressive symptoms of 
PPD. In addition to the above scales, the individual item scores and subscale scores from the HAMD 
scale will also evaluated as secondary efficacy endpoints. 
GAD-7 will also be administered before, during, and after the infusion of study drug.  As with other 
secondary efficacy endpoints, scores from these scales will be evaluated to assess the efficacy in other 
mood disorder and anxiety symptoms.   
An important safety endpoint will be the assessment of sedation using the SSS. The SSS will be 
assessed periodically before, during, and after the infusion of blinded study drug with changes from 
baseline over time evaluated similarly to that of efficacy endpoints.   
Safety and tolerability of SAGE-547 Injection will be evaluated by summarization of adverse events 
(AEs) by frequency, severity, and seriousness; clinical laboratory measures, vital signs, and ECGs 
(including changes from baseline); and concomitant medication usage. Suicidality will be monitored 
using the C-SSRS. 
The doses of all anti-depressant medications will be recorded throughout the study.  No changes and/or 
additions to antidepressant or anxiolytic medicine will be allowing during the dosing period. An 
analysis of time to starting/increasing the dose/decreasing the dose of each different anti-depressant 
medication will be undertaken for subjects discharged. 
Plasma will be collected to assay for concentrations of SAGE-547, SAGE-547 metabolites, and 
SBECD. The following PK parameters will be derived from the plasma concentrations (where 
evaluable): area under the concentration-time curve (AUC) from time zero to 60 hours (AUC0-60), AUC 
from time zero to infinity (AUCinf), maximum (peak) plasma concentration (Cmax), time at maximum 
(peak) plasma concentration (Tmax), steady-state drug concentration in the plasma during constant-rate 
infusion (Css), and average drug concentration in the plasma at steady state during a dosing interval 
(Cavg). 
Breast milk may be collected as an optional assessment if consent is received from the subject. Samples 


Protocol 547-PPD-202 
Sage Therapeutics 
 
18 Sep 2015 
Confidential 
      9   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
will be analyzed for SAGE-547 concentrations. 
Exploratory Endpoints 
Additional measures of symptoms and function related to the current episode of postpartum depression 
severity will be administered before, during, and after the infusion of study drug, including the EPDS, 
PHQ-9 and BIMF. 
Subscale and total scores and changes from baseline will be calculated where applicable.  Changes 
from baseline at the end of the treatment period (at +60 hours) and other time points will be evaluated 
as secondary efficacy endpoints with comparisons between the two treatment groups used to support 
the efficacy of SAGE-547 in treating the depressive symptoms of PPD.  In addition to the above scales, 
the individual item scores will also be evaluated as exploratory endpoints. 
Statistical Methods: 
For the purpose of all safety, efficacy, and exploratory analyses where applicable, baseline is defined as 
the last measurement prior to the start of blinded study drug infusion. 
Interim Analysis 
An interim analysis will be conducted by an independent DSMB for sample size re-estimation purposes 
when at least 16 subjects have completed efficacy assessments through 60 hours.  Since the sponsor 
will be kept uninformed of the response rates at the time of the interim analysis, no statistical 
adjustment will be made to the level of significance for hypothesis testing at the end of the study.  A 
detailed description of the interim analysis will be included in an interim analysis plan. 
Sample Size Calculation 
Assuming a two-sided test at an alpha level of 0.10, a sample size of 10 evaluable subjects per group 
would provide 80% power to detect an effect size of 1.2 between the SAGE-547 and placebo groups 
with regard to the primary outcome variable of change from baseline in HAMD total score. An effect 
size of 1.2 corresponds to a placebo adjusted difference of 12 points in the change from baseline in 
HAMD total score at 60 hours with an assumed standard deviation of 10 points. By including two 
treatment groups and using a 1:1 randomization ratio, a total of 20 evaluable subjects are required. 
Assuming a non-evaluability rate of 10%, at least 22 subjects will be randomized. 
Based on the results of the interim analysis, the sample size could be increased to a maximum of 32 
randomized subjects. This adjustment to the sample size would allow for an effect size of 1.0 to be 
detected.   
Efficacy Analysis 


Protocol 547-PPD-202 
Sage Therapeutics 
 
18 Sep 2015 
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      10   
 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 547-PPD-202 
Phase: 2a 
The efficacy population will include all subjects who complete at least 12 hours of infusion and have 
efficacy evaluations through the 12-hour time point on Day 1.  Subjects will be classified and 
summarized by randomized treatment.   
The change from baseline in HAMD total score will be analyzed using a mixed effects repeated 
measures model including center, treatment, baseline score, timepoint, and timepoint-by-treatment as 
explanatory variables. Center will be treated as a random effect while all other explanatory variables 
will be treated as fixed effects.  The primary comparison between SAGE-547 and placebo will be at the 
60 hour timepoint.  Comparisons at other timepoints will be conducted to support the findings for the 
primary comparison.   
Changes from baseline in other rating scale scores will be analyzed with methods similar to the primary 
endpoint. Any dichotomous response variables will be analyzed using logistic regression methods.   
In addition to formal analysis, efficacy rating scale scores (including recorded and change from 
baseline values) will be summarized by descriptive statistics, including n, mean, standard deviation 
(SD), median, and minimum and maximum values. Categorical efficacy endpoints (including HAMD, 
MADRS, and CGI-I response variables) will be summarized by frequency and percentage. 
Safety Analysis 
The Safety Population (SAF) is defined as all subjects who begin an infusion of study drug. Subjects 
will be classified and summarized by actual treatment.   
Safety will be assessed using SSS, AEs, vital signs, ECG, clinical laboratory tests, C-SSRS, and 
concomitant medication data. Continuous safety data (including absolute and change from baseline 
values) will be summarized by descriptive statistics, including n, mean, standard deviation (SD), 
median, and minimum and maximum values.  Categorical endpoints will be summarized by frequency 
and percentage. In addition, an analysis of the SSS score will be performed comparing the treatment 
groups in the same way as for the primary endpoint. 
Safety data will be examined for possible relationships between subject characteristics and plasma 
allopregnanolone concentrations, as appropriate. 


Protocol 547-PPD-202 
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      11   
 
TABLE 1: SCHEDULE OF EVENTS 
 
Screening 
Period 
Treatment Period 
Clinic Period (Day 1 to Day 3) 
Follow-up 
Period 
Visit Days  
Screening 
D-5 to -1 
D1 
H0* 
D1 
H2 
D1 
H4 
D1 
H8 
D1 
H12 
D1 
H18 
D1 
H24 
D2 
H30 
D2 
H36 
D2 
H42 
D2 
H48 
D3 
H54 
D3 
H60 
D3 
H66 
D3 
H72 
D7 
(±1d) 
D30 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Lab Assessments a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Urinalysis a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug & Alcohol Screen b 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic Sample d 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetry 
 
X 
 
 
 
 
12-Lead ECG f 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
C-SSRS g 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Confinement 
 
X 
 
 
CGI-I h 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
CGI-S h 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAMD h 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
IVR HAMD h 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
MADRS h 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
BIMF h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
EPDS h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
GAD-7 h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
PHQ-9 h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 


Protocol 547-PPD-202 
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      12   
 
 
Screening 
Period 
Treatment Period 
Clinic Period (Day 1 to Day 3) 
Follow-up 
Period 
Visit Days  
Screening 
D-5 to -1 
D1 
H0* 
D1 
H2 
D1 
H4 
D1 
H8 
D1 
H12 
D1 
H18 
D1 
H24 
D2 
H30 
D2 
H36 
D2 
H42 
D2 
H48 
D3 
H54 
D3 
H60 
D3 
H66 
D3 
H72 
D7 
(±1d) 
D30 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SSS i 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Plasma PK j 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
Breast Milk PK k 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Study Drug Infusion 
 
X 
 
 
 
 
Adverse Events 
X 
Concomitant Medications 
X 
O = optional 
* = All H0 procedures to be completed prior to dosing 
a  Safety laboratory tests will include hematology, serum chemistry, coagulation,  and select hormone parameters. The urine test will include a urinalysis. Lab 
assessments are to be completed within ± 30 minutes of the scheduled timepoint. 
b  Urine for selected drugs of abuse and alcohol (serum or breath) 
c  Serum at Screening and urine for all other timepoints 
d A blood sample for genetic testing, where consent is given 
e  Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Vital signs will be obtained within ± 30 minutes 
of the scheduled timepoint, unless the subject is asleep between the hours of 23.00h and 06.00h. 
f  Performed within ± 30 minutes of the scheduled time point on Day 2. 
g  The “Baseline” C-SSRS form will be completed on Day 1. The “Since Last Visit” C-SSRS form will be completed at all subsequent timepoints. 
h  To be completed within ± 30 minutes of the scheduled timepoint. 
i  To be completed within ± 15 minutes of the scheduled timepoint, unless the subject is asleep between the hours of 23.00h and 06.00h  
j  Blood samples for PK analysis will be collected at pre-infusion and at 4 (before change in infusion rate), 8, 12, 24 (before change in infusion rate), 30, 36, 48 
60 (before end of infusion) and 72 hours after the start of the infusion. PK blood draws after the start of infusion will have a window of ± 10 minutes. In the 
event of an  unplanned dose adjustment, an unscheduled PK sample should be collected just prior to the infusion rate change. 
k  Optional assessment per subject consent, breast milk will be collected and pooled over the following time periods of interest: 0, 1-12, 12-24, 24-36, 36-48, 48-
60 and 60-72 hours after the start of the infusion.  
 
BIMF = Barkin Index of Maternal Functioning; CGI-I = Clinical Global Impression of Improvement; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = 
electrocardiogram; EPDS = Edinburgh Postnatal Depression Scale; GAD-7 = Generalized Anxiety Disorder 7-Item Scale; HAMD = Hamilton Rating Scale for 
Depression, 17-item; MADRS = Montgomery-Asberg Depression Rating Scale; PHQ-9 = Patient Health Questionnaire; PK = pharmacokinetic; SSS = Stanford 
Sleepiness Scale. 


Protocol 547-PPD-202 
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      13   
3 TABLE OF CONTENTS, LIST OF TABLES, FIGURES AND 
APPENDICES 
Table of Contents 
1 
SIGNATURE PAGE ................................................................................ 2 
2 
SYNOPSIS ............................................................................................... 3 
3 
TABLE OF CONTENTS, LIST OF TABLES, FIGURES AND 
APPENDICES ........................................................................................ 13 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS......... 18 
5 
INTRODUCTION AND RATIONALE ................................................. 21 
5.1 
Role of Allopregnanolone in Affective Disturbances ............................ 22 
5.1.1 
Rationale for Allopregnanolone Treatment of PPD ............................... 22 
5.2 
SAGE-547 Injection (Allopregnanolone) ............................................... 23 
5.3 
Summary of Nonclinical and Clinical Experience With 
Allopregnanolone or SAGE-547 ............................................................ 24 
5.3.1 
Nonclinical Pharmacology ...................................................................... 24 
5.3.2 
Clinical Experience ................................................................................. 24 
5.4 
Potential Risks and Benefits ................................................................... 25 
5.5 
Study No. 547-PPD-202 ......................................................................... 25 
5.5.1 
Study Population ..................................................................................... 25 
5.5.2 
Route of Administration, Dosage, Dosage Regimen, and Treatment 
Period ...................................................................................................... 25 
5.5.3 
Dose Rationale ........................................................................................ 26 
6 
ETHICS .................................................................................................. 27 
6.1 
Institutional Review Board or Independent Ethics Committee .............. 27 
6.2 
Ethical Conduct of the Study .................................................................. 27 
6.3 
Subject Information and Informed Consent ........................................... 27 
7 
STUDY OBJECTIVES .......................................................................... 28 
7.1 
Primary Objective ................................................................................... 28 
7.2 
Secondary Objectives ............................................................................. 28 
7.3 
Exploratory Objectives ........................................................................... 28 
7.4 
Pharmacokinetic Objective ..................................................................... 28 
8 
INVESTIGATIONAL PLAN ................................................................. 29 


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8.1 
Overview of Study Design ...................................................................... 29 
8.2 
Blinding and Randomization .................................................................. 30 
9 
SELECTION AND WITHDRAWAL OF SUBJECTS .......................... 32 
9.1 
Inclusion Criteria .................................................................................... 32 
9.2 
Exclusion Criteria ................................................................................... 32 
9.3 
Subject Withdrawal/Study Termination ................................................. 33 
9.3.1 
Withdrawal/Discontinuation of Individual Subjects .............................. 33 
9.3.2 
Subject Withdrawal From the Study ....................................................... 33 
9.3.3 
Discontinuation of Study Drug by the Investigator ................................ 33 
9.3.4 
Study Termination .................................................................................. 34 
10 
INVESTIGATIONAL PRODUCT ........................................................ 35 
10.1 
Identity of Investigational Product ......................................................... 35 
10.2 
Clinical Supplies ..................................................................................... 35 
10.2.1 
SAGE-547 ............................................................................................... 35 
10.2.2 
Placebo .................................................................................................... 35 
10.3 
Preparation of SAGE-547 Injection or Placebo for Dosing ................... 35 
10.4 
Administration and Accountability ......................................................... 36 
11 
TREATMENT OF SUBJECTS .............................................................. 37 
11.1 
Dosing Schedule ..................................................................................... 37 
11.1.1 
Dose Regimen ......................................................................................... 37 
11.1.2 
Route of Administration ......................................................................... 38 
11.1.3 
Treatment Period .................................................................................... 38 
11.1.4 
Dosing of Intravenous SAGE-547 in the Case of AEs ........................... 38 
11.2 
Dosing Compliance ................................................................................ 38 
11.3 
Concomitant Medications and Restrictions ............................................ 39 
11.3.1 
Concomitant Medications ....................................................................... 39 
11.3.2 
Prohibited Medications ........................................................................... 39 
12 
STUDY ASSESSMENTS ...................................................................... 40 
12.1 
Safety Assessments ................................................................................. 40 
12.1.1 
Adverse Events ....................................................................................... 40 
12.1.2 
Clinical Laboratory Tests ....................................................................... 40 
12.1.2.1 
Hematology, Serum Chemistry, Coagulation ......................................... 40 
12.1.2.2 
Hepatitis and HIV ................................................................................... 41 


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      15   
12.1.2.3 
Hormones ................................................................................................ 41 
12.1.2.4 
Pregnancy Test ........................................................................................ 41 
12.1.2.5 
Genetic Testing ....................................................................................... 41 
12.1.2.6 
Urinalysis ................................................................................................ 41 
12.1.2.7 
Drugs of Abuse and Alcohol .................................................................. 41 
12.1.3 
Physical Examination ............................................................................. 42 
12.1.4 
Vital Signs .............................................................................................. 42 
12.1.5 
ECG ........................................................................................................ 42 
12.1.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................... 42 
12.1.7 
Stanford Sleepiness Scale (SSS) ............................................................. 42 
12.2 
Efficacy Assessments ............................................................................. 43 
12.2.1 
Primary Efficacy Outcome Measure ...................................................... 43 
12.2.1.1 
Hamilton Rating Scale for Depression (HAMD) ................................... 43 
12.2.2 
Secondary Efficacy Outcome Measures ................................................. 43 
12.2.2.1 
Montgomery Asberg Depression Rating Scale (MADRS) ..................... 43 
12.2.2.2 
Clinical Global Impression (CGI) Scale ................................................. 44 
12.2.2.3 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) ........................... 44 
12.2.3 
Exploratory Patient Reported Outcome Measures ................................. 45 
12.2.3.1 
Edinburgh Postnatal Depression Scale (EPDS) ...................................... 45 
12.2.3.2 
Patient Health Questionnaire (PHQ-9) ................................................... 45 
12.2.3.3 
Barkin Index of Maternal Functioning (BIMF) ...................................... 45 
12.2.3.4 
Interactive Voice Response (IVR) HAMD ............................................. 45 
12.3 
Pharmacokinetics .................................................................................... 46 
12.3.1 
Plasma PK Samples ................................................................................ 46 
12.3.2 
Breastmilk PK Samples .......................................................................... 46 
13 
STUDY PROCEDURES ........................................................................ 47 
13.1 
Screening Period ..................................................................................... 47 
13.2 
SAGE-547 Treatment Period (Day 1 to Day 3, Hours 0-60) ................. 48 
13.2.1 
Day 1 ....................................................................................................... 48 
13.2.2 
Day 2 ....................................................................................................... 49 
13.2.3 
Day 3 ....................................................................................................... 50 
13.3 
Follow-up Period (Day 7 through Day 60) ............................................. 50 
13.3.1 
Day 7 (± 1 day) ....................................................................................... 50 


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13.3.2 
Day 30 (± 3 days) ................................................................................... 50 
14 
STATISTICAL METHODS AND CONSIDERATIONS ..................... 52 
14.1 
Data Analysis Sets .................................................................................. 52 
14.2 
Handling of Missing Data ....................................................................... 53 
14.3 
Demographics and Baseline Characteristics ........................................... 53 
14.4 
Primary Endpoints .................................................................................. 53 
14.5 
Secondary Endpoints .............................................................................. 53 
14.6 
Determination of Sample Size ................................................................ 55 
14.7 
Interim Analysis ...................................................................................... 56 
14.8 
Changes From Protocol Specified Analyses ........................................... 56 
15 
ADVERSE EVENTS.............................................................................. 57 
15.1 
Adverse Event Definitions ...................................................................... 57 
15.1.1 
Adverse Event ......................................................................................... 57 
15.1.2 
Suspected Adverse Reaction ................................................................... 57 
15.1.3 
Life-Threatening ..................................................................................... 57 
15.1.4 
Serious .................................................................................................... 57 
15.1.5 
Unexpected ............................................................................................. 58 
15.2 
Investigator Responsibilities ................................................................... 58 
15.2.1 
Identification and Documentation of Adverse Events by Investigator ... 58 
15.2.2 
Adverse Event Classification .................................................................. 59 
15.2.2.1 
Relationship to Investigational Drug ...................................................... 59 
15.2.2.2 
Severity ................................................................................................... 59 
15.2.2.3 
Action Taken With Investigational Drug ............................................... 59 
15.2.2.4 
Assessment of Outcome ......................................................................... 60 
15.2.3 
Investigator Reporting to Sponsor and Sponsor Emergency Contact .... 60 
15.2.4 
Medical Monitor and Emergency Contact Information.......................... 61 
15.2.5 
SAE Reporting Contact Information ...................................................... 61 
15.2.6 
Reporting to Institutional Review Boards (IRBs) .................................. 61 
15.3 
Sponsor/Medical Monitor Responsibilities ............................................ 61 
15.3.1 
Monitoring of Adverse Event Data ......................................................... 61 
15.3.2 
Reporting to FDA ................................................................................... 61 
15.4 
Emergency Identification of Study Medication ...................................... 61 
16 
STUDY ADMINISTRATION ............................................................... 63 


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16.1 
Quality Control and Quality Assurance .................................................. 63 
16.2 
Data Handling and Recordkeeping ......................................................... 63 
16.2.1 
Data Handling ......................................................................................... 63 
16.2.2 
Case Report Form Completion ............................................................... 63 
16.2.3 
Retention of Study Records .................................................................... 64 
16.3 
Confidentiality ........................................................................................ 64 
16.4 
Publication Policy ................................................................................... 64 
16.5 
Protocol Amendments ............................................................................ 65 
17 
REFERENCES ....................................................................................... 66 
18 
APPENDICES ........................................................................................ 71 
APPENDIX 1. Columbia Suicide Severity Rating Scale (C-SSRS) ....................... 72 
APPENDIX 2. Hamilton Rating Scale for Depression, 17-Item (HAMD) ............ 79 
APPENDIX 3. Montgomery Asberg Depression Rating Scale (MADRS) ............ 81 
APPENDIX 4. Clinical Global Impression–Improvement Scale (CGI-I) and 
Severity Scale (CGI-S) ................................................................... 84 
APPENDIX 5. Stanford Sleepiness Scale (SSS) .................................................... 86 
APPENDIX 6. Edinburgh Postnatal Depression Scale (EPDS) ............................. 88 
APPENDIX 7. Generalized Anxiety Disorder 7-Item Scale (GAD-7) ................... 90 
APPENDIX 8. Patient Health Questionnaire (PHQ-9) ........................................... 92 
APPENDIX 9. Barkin Index of Maternal Functioning (BIMF).............................. 94 
APPENDIX 10. Selected Inducers, Inhibitors, and Substrates of CYP2C9 ........... 96 
 
List of Tables 
Table 1: 
Schedule of Events ................................................................................. 11 
Table 2:  
Infusion rates .......................................................................................... 38 
 
List of Figures 
Figure 1: 
Study Design ........................................................................................... 29 
Figure 2: 
Trial Design and Timeline for Dosing .................................................... 37 
 


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4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term 
Definition of Terms 
AE 
adverse event 
ALLO 
allopregnanolone 
ALT 
alanine aminotransferase 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUCinf 
area under the concentration-time curve from time 
zero to infinity 
AUC0-60 
area under the concentration-time curve from time 
zero to 60 hours 
BIMF 
Barkin Index of Maternal Functioning 
BMI 
body mass index 
BMP 
breast milk population 
BUN 
blood urea nitrogen 
Cavg 
average drug concentration in the plasma at steady-
state during a dosing interval 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression–Improvement 
CGI-S 
Clinical Global Impression–Severity 
cGMP 
Current Good Manufacturing Practice 
Cmax 
maximum (peak) plasma concentration of the drug 
CMO 
Chief Medical Officer 
CNS 
central nervous system 
CRF 
case report form 
CS 
clinically significant 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
Css 
Steady-state drug concentration in the plasma 
during constant-rate infusion 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
Cytochrome P450 enzyme involved in drug 
metabolism 
DSM-IV 
Diagnostic and Statistical Manual of Mental 
Disorders, Fourth Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture  
EEG 
electroencephalography 
EFF 
efficacy population 
Ph. Eur. 
European Pharmacopeia  
EPDS 
Edinburgh Postnatal Depression Scale 
ERα 
estrogen receptor alfa 
ERß 
estrogen receptor beta 


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Abbreviation or Specialist Term 
Definition of Terms 
FDA 
Food and Drug Administration 
GABA 
gamma-aminobutyric acid  
GABAA 
gamma-aminobutyric acid–gated chloride channel 
GAD-7 
Generalized Anxiety Disorder 7-Item Scale  
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
h 
hour 
HAMD 
Hamilton Rating Scale for Depression, 17-item 
HBsAg 
hepatitis B surface antigen  
Hct 
hematocrit 
HCV 
hepatitis C virus 
HEENT 
head, eyes, ears, nose, and throat 
Hgb 
hemoglobin 
HPLC MS/MS 
High-performance liquid chromatography tandem 
mass spectrometry 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
intention-to-treat population 
IV 
intravenous 
IVR 
interactive voice response 
LFT 
liver function test 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
NF 
National Formulary 
NIMH 
National Institute of Mental Health  
PHQ-9 
Patient Health Questionnaire  
PK 
pharmacokinetic 
PKP 
pharmacokinetic population 
PMID 
PubMed identification 
PP 
per-protocol population 
PPD 
postpartum depression 
PR 
progesterone receptor 
PT/INR 
prothrombin time/international normalized ratio 
RBC 
red blood cell 
RSE 
refractory status epilepticus 
SAE 
serious adverse event 


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Abbreviation or Specialist Term 
Definition of Terms 
SAF 
safety population 
SAP 
statistical analysis plan 
SBECD 
betadex sulfobutyl ether sodium 
SCID-I 
Structured Clinical Interview for DSM-IV Axis I 
Disorders 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
SRSE 
super refractory status epilepticus 
SSRI 
selective serotonin reuptake inhibitors 
SSS 
Stanford Sleepiness Scale 
SWFI 
sterile water for injection 
T1/2 
half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum (peak) plasma concentration 
TSH 
thyroid stimulating hormone 
US 
United States 
USP 
United States Pharmacopeia 
VAS 
Visual analogue scale 
Vd 
volume of distribution 
WBC 
white blood cell 


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5 INTRODUCTION AND RATIONALE 
This study is designed to evaluate the efficacy, safety, and pharmacokinetics (PK) of SAGE-
547 (allopregnanolone) as a treatment for women with severe postpartum depression (PPD), 
an area of high unmet medical need. 
PPD is considered to be moderate to severe depression in women who have recently given 
birth, otherwise defined as the occurrence of major depressive disorder (MDD) within 4 
weeks of delivery (DSM V 2013) or up to a year after giving birth (Okun 2013). There are 
two entry criteria for the diagnosis of depression (depressed mood and/or loss of interest) and 
seven 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 five symptoms of depression (DSM 
V 2013), although this diagnosis may be confounded by the relative frequency of symptoms 
such as sleep disturbance or appetite problems in pregnant and postpartum women. Most 
women experience onset of symptoms within the first three months following delivery, and 
PPD is most prevalent at 10 to 14 weeks following childbirth (Okun 2013). 
During pregnancy, estradiol and progesterone levels increase dramatically but then rapidly 
decline in the acute postpartum period (Gavin 2005). The onset of PPD symptoms coincides 
with the rapid decrease of the gonadal steroids postpartum. The duration of a PPD episode 
has been estimated as shorter than depressive episodes in the general population (approx. 5 
months), while other studies indicate time to remission is approximately the same (Chaudron 
2003). 
PPD is common and has devastating consequences for the woman and for her family (Fihrer 
2009; Verbeek 2012). Perinatal depression is reported to be the most underdiagnosed 
obstetric complication in America (Earls 2010). Furthermore, it is the most common 
psychiatric illness to occur in the puerperium (O’Hara 2014). A meta-analysis of 30 studies 
(Gaynes 2005) found that the point prevalence of major and minor depression ranged 
between 6.5% and 12.9% at different times during the first postpartum year. Overall 
incidence is estimated at around 15–20% with up to 10% being considered severe (Edge 
2007, O’Hara 2014). 
Current standard of care for severe PPD comprises cautious use of pharmacological therapies 
in nursing mothers combined with other interventions. Evidence for efficacy of tricyclic 
antidepressants and/or selective serotonin reuptake inhibitors (SSRIs) is based on use in the 
general population rather than any extensive studies in PPD (Austin 2013), and SSRIs tend to 
be preferred due to better data on safety while breastfeeding (Altshuler 2001). Based on the 
level of evidence for antidepressants in major depressive disorder (Kirsch 2008, Fournier 
2010), there is a considerable need for improved pharmacological therapy for PPD. 
Drugs may be combined with a number of counseling, behavioral, and other non-
pharmacological therapy approaches, which are generally used as the first-line therapy in less 
severe PPD (Altshuler 2001). Urgent referral and potentially admission are recommended for 
mothers at risk of self-harm, with their infants, if such facilities exist (Austin 2013). 
Therapeutic options in severe PPD are currently limited, and it is not clear whether the 
current standard of care impacts the natural history of the disease, although most women 
recover within a year. 


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5.1 Role of Allopregnanolone in Affective Disturbances 
The neurosteroid metabolite of progesterone, allopregnanolone, acutely regulates neuronal 
function (Gangisetty 2010) and appears to play a significant role in affective disturbances 
that occur with changes in reproductive endocrine function, such as during the postpartum 
period (Amin 2006, Nappi 2001, Epperson 2006). 
Neurosteroids are metabolites of cholesterol-derived steroid hormones that are synthesized in 
the brain and nervous system; they modulate the major inhibitory and excitatory central 
nervous system (CNS) neurotransmitter systems: γ-aminobutyric acid (GABA) and 
glutamate, respectively. Neurosteroids are among the most potent and effective modulators 
of GABAA receptors and augment GABAergic inhibition (Belelli 2005). The powerful 
anxiolysis that accompanies this potentiation of GABAA receptors has led to the speculation 
that neurosteroid dysregulation plays a central role in the etiology of affective disorders, 
including reproductive mood disorders, such as PPD (Amin 2006). 
There is increasing evidence supporting the role of neurosteroids in affective dysregulation. 
Allopregnanolone and pregnanolone have been shown to modulate the GABA receptor 
positively (Majewska 1986). Several groups have demonstrated decreased allopregnanolone 
levels in MDD, with an increase seen in both plasma and cerebrospinal fluid (CSF) following 
successful antidepressant treatment (Uzunova 1998; Romeo 1998; Ströhle 1999; Schüle 
2006; Eser 2006; Schüle 2007). In addition, allopregnanolone has demonstrated anxiolytic 
effects in several animal anxiety models (Bitran 1991; Wieland 1991; Bitran 1993).  
Allopregnanolone may also exert antidepressant effects by reducing the physiological impact 
of stress, promoting neuroprotection, and protecting against the pro-inflammatory immune 
activation and cytokine hypersecretion associated with MDD. In animals, allopregnanolone 
increases in response to stress, reduces pain sensitivity, and is thought to restore physiologic 
homeostasis following stress (Frye 1994; Morrow 1995). Allopregnanolone also exerts 
neuroprotective effects by reducing the expression of pro-apoptotic proteins and apoptotic 
DNA fragmentation (Djebaili 2005; Sayeed 2009), thereby reducing the cell death and gliosis 
associated with depression (Glantz 2010; Shelton 2011). Neuroprotection is mediated by 
immune regulation in depression (Licinio 1999), and allopregnanolone reduces the 
expression of the pro-inflammatory cytokine TNF-α (He 2004), which is elevated in 
depressed individuals (Dowlati 2010). Thus, allopregnanolone modulates biological 
processes dysregulated in major depressive disorder. 
5.1.1 Rationale for Allopregnanolone Treatment of PPD 
Genetic susceptibility to affective dysregulation may be unmasked during periods of 
reproductive hormone change such as during pregnancy and postpartum (Maguire 2008). 
Maguire and Mody demonstrated that a GABA receptor subunit mutation was behaviorally 
silent until the animal was exposed to pregnancy and the postpartum state, at which time the 
dams showed depressive-like behaviors and cannibalized their offspring (Maguire 2008). 
During pregnancy, the expression of the GABAA receptor δ-subunit is down-regulated as 
allopregnanolone levels increase, and at parturition, the expression of the GABAA receptor δ-
subunit is recovered in response to rapidly declining neurosteroid levels (Maguire 2009). In 
contrast, the GABAA receptor δ-subunit-deficient mice fail to adapt to the dramatic changes 
in allopregnanolone and experience depression-like and anxiety-like behavior and abnormal 


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maternal behaviors, which are reversed by administration of allopregnanolone (Maguire 
2008). This model provides compelling support for the hypothesis that changes in 
neurosteroid concentrations during pregnancy and postpartum are capable of provoking 
affective dysregulation, particularly in those with a genetically-determined susceptibility. 
The capacity of changes in neurosteroids, such as allopregnanolone, to function as behavioral 
switches suggests a potentially important treatment role of this hormone metabolite in 
reproductive endocrine-related mood disorders such as PPD. 
The onset of PPD symptoms coincides with the rapid decrease of the gonadal steroids 
postpartum and has been reproduced in a pivotal clinical study (Bloch 2000). The authors 
investigated the possible role of changes in gonadal steroid levels in PPD by simulating two 
hormonal conditions related to pregnancy and parturition in euthymic women, 8 with and 8 
without a history of PPD. They induced hypogonadism with leuprolide, adding back supra-
physiologic doses of estradiol and progesterone for 8 weeks to simulate pregnancy. They 
then withdrew both steroids under double-blind conditions to mimic the rapid decrease of sex 
steroids upon delivery. Five of the eight women with a history of postpartum depression 
(62.5%) and 0% of the comparison group developed significant mood symptoms typical of 
PPD during the withdrawal period. 
Although progesterone levels were measured in this study, allopregnanolone was not. 
However, since allopregnanolone is the major active metabolite of progesterone, it can be 
assumed that the decrease in progesterone would cause a similar precipitate drop in 
allopregnanolone levels, as observed in the postpartum period (Gilbert Evans 2005, Paoletti 
2006, Nappi 2001).These data provide direct evidence in support of the involvement of 
progesterone and its metabolites in the development of postpartum depression in a subgroup 
of women. Further, they suggest that women with a history of postpartum depression are 
differentially sensitive to mood-destabilizing effects of gonadal steroids (Bloch 2000). 
Additional details regarding the role of allopregnanolone in the etiology of affective 
disorders and its nonclinical pharmacology and pharmacokinetics are presented in the 
Investigational Brochure. 
5.2 SAGE-547 Injection (Allopregnanolone) 
Allopregnanolone is an endogenous, naturally occurring neuroactive steroid formed in the 
corpus luteum of the ovary, adrenal cortex, and CNS (Holzbauer 1985; Ottander 2005; Paul 
1992). It is a metabolite of progesterone created by the actions of 5-α reductase and 3-α 
hydroxy-steroid dehydrogenase. Allopregnanolone is a potent positive allosteric modulator of 
both synaptic and extra-synaptic GABAA receptors. 
SAGE-547 Injection is a solution of 5 mg/mL allopregnanolone in Sterile Water for Injection 
(SWFI), United States Pharmacopeia (USP), and 250 mg/mL betadex sulfobutyl ether 
sodium buffered with 10 mM citrate at a pH of 6.0, and will be administered intravenously. 
SAGE-547 Injection is also being developed for the treatment of adult patients with 
refractory status epilepticus (RSE), inclusive of super refractory status epilepticus (SRSE), 
who have not responded to standard treatment regimens, and investigated for the treatment of 
adults with essential tremor. 


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5.3 Summary of Nonclinical and Clinical Experience With 
Allopregnanolone or SAGE-547 
5.3.1 Nonclinical Pharmacology 
The primary pharmacological effects of allopregnanolone or SAGE-547 are described earlier 
in the rationale (Sections 5.1 and 5.1.1). Secondary pharmacologic effects comprise mainly 
the binding and consequent increased activity of steroid hormone receptors (androgen 
receptor [(AR], progesterone receptor [PR], and estrogen receptor beta [ERß]), with some 
evidence of inhibition at the highest doses (AR and estrogen receptor alfa [ERα]). These non-
target effects may yield some adverse events in the clinic. 
Nonclinical toxicology studies largely illustrate the sedative and anesthetic effects of 
allopregnanolone and/or SAGE-547 at higher equivalent doses than the proposed dose for the 
current study. PK data in animals indicate a short half-life and rapid clearance with a 
moderate volume of distribution and cerebral levels higher than plasma. See SAGE-547 
Investigational Brochure for more details. 
5.3.2 Clinical Experience 
The clinical PK data with intravenous (IV) administration of allopregnanolone in healthy 
women, men, and women on oral contraceptives confirmed the PK observations in animals 
of a short half-life (T1/2 20-40 mins), Cmax achievable at approximately 3rd trimester levels 
(150 nM), rapid clearance and moderate volume of distribution (Vd). See SAGE-547 
Investigational Brochure for more details. 
There are currently no double-blind, placebo-controlled clinical efficacy data for SAGE-547 
in PPD. An open-label, proof-of-concept study (547-PPD-201) evaluating the safety, 
tolerability, pharmacokinetics, and efficacy of SAGE-547 Injection in the treatment of adult 
female subjects with severe postpartum depression was started in 2014. This was the first-
ever study in this indication. Four women experienced significant improvement in depressive 
symptoms within 24 hours after administration of open-label intravenous SAGE-547. During 
the SAGE-547 treatment period, all four subjects rapidly achieved remission, as measured by 
the HAMD total score. All four subjects also demonstrated consistent improvement as 
measured by the CGI-I score. SAGE-547 was well-tolerated in all subjects treated with no 
serious adverse events observed during therapy or during the 30-day follow-up period. A 
total of 14 adverse events were reported in four subjects. The only adverse event reported in 
more than one subject was sedation, observed in two subjects. This trial was initially planned 
to enroll 10 women, however, due to the observed clinical activity, the 547-PPD-201 trial 
was stopped early with the plan to initiate a placebo-controlled clinical trial as rapidly as 
possible.  
There are six reported studies of allopregnanolone, mainly in healthy individuals and none in 
PPD (Timby 2006; Timby 2011a and 2011b; van Broekhoven 2007; Kask 2008; Kask 2009; 
Navarro 2003). Data indicate that normal physiological allopregnanolone levels in women 
vary during the menstrual cycle up to a maximum of 6-10 nM, with lower levels present 
post-menopause (Genazzani 1998). The highest physiological levels observed are in the third 
trimester of pregnancy, up to around 160 nM at time of delivery (Luisi 2000). Levels drop 
precipitously to baseline (<10 nM) with removal of the placenta (Klak 2003).  


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One study demonstrated subjective improvements in contentedness in women (van 
Broekhoven 2007). The clinical safety data are presented below in the Risks and Benefits 
section (Section 5.4). 
5.4 Potential Risks and Benefits 
In the recently completed open-label clinical trial of SAGE-547 in PPD (547-PPD-201), a 
total of 14 adverse events were reported in four subjects. The only adverse event reported in 
more than one subject was sedation, observed in two subjects.  
Consistent with these observations, published reports of human administration of exogenous 
allopregnanolone indicate that for exposures in men and women up to 150 nM, the most 
commonly reported adverse events (AEs) were sedation (recorded as sleepiness or tiredness), 
feelings of intoxication (like alcohol), flushing, vertigo, mild nausea, impaired episodic 
memory, and mild headache (Timby 2006 and 2011a and 2001b; van Broekhoven 2007). 
One subject experienced what was potentially a withdrawal effect, an anxiety attack (Timby 
2011b). No serious AEs (SAEs) were reported in the six clinical studies conducted to date 
(Timby 2006; Timby 2011a and 2011b; van Broekhoven 2007; Kask 2008; Kask 2009; 
Navarro 2003). There is also a potential risk of supra-additive sedative effects with other 
drugs interacting with the GABAA receptor, such as benzodiazepines and anti-epileptic 
medications (Norberg 1999); therefore, the Investigator is advised to avoid co-medication if 
possible and to exercise caution with these drug classes. As this is one of the first clinical 
trials of SAGE-547 in PPD, the potential benefits in this population are unknown, although 
the risks are likely to be similar to those mentioned above. Given the nonclinical rationale 
and the fact that endogenous allopregnanolone in humans appears to play a role in psychiatric 
disorders such as major depression, premenstrual dysphoric disorder, and anxiety disorders, it 
is possible that subjects may have a clinical benefit at the exposures selected for this trial. In 
view of the limited nature of the demonstrated risks of exogenous allopregnanolone infusion 
and the potential for benefit in severe PPD, there is a favorable benefit-risk evaluation for the 
conduct of the present study. 
5.5 Study No. 547-PPD-202 
5.5.1 Study Population 
This study will evaluate the efficacy, safety, and pharmacokinetics (PK) of SAGE-547 
Injection in the treatment of adult female subjects diagnosed with severe postpartum 
depression. 
5.5.2 Route of Administration, Dosage, Dosage Regimen, and Treatment Period 
SAGE-547 Injection or placebo will be administered over a 60 hour period by an IV infusion 
according to the dose regimen shown in Table 2. (see Section 11.1.1). 
The specific infusion dose of SAGE-547 Injection will be calculated based on weight for 
each subject. Infusion bags will be changed every 24 hours. Details about the preparation and 
administration of the study drug infusions will be included in the Pharmacy Manual. 


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6 ETHICS 
6.1 Institutional Review Board or Independent Ethics Committee 
This trial will be initiated only after the protocol has been reviewed and approved by the 
Institutional Review Board (IRB) where the study is to be conducted. The IRB must meet all 
US Food and Drug Administration (FDA) requirements governing IRBs (Code of Federal 
Regulations [CFR], Title 21, Part 56). The same applies for the implementation of changes 
introduced by an amendment. 
6.2 Ethical Conduct of the Study 
This study will be conducted according to the principles of the World Medical Association 
Declaration of Helsinki and the most recent amendment (2008).  
The Sponsor, the Medical Monitor, and the Investigator must comply with all instructions, 
regulations, and agreements in this protocol, and must also conduct the study in accordance 
with International Conference on Harmonisation (ICH) Guidelines on Good Clinical Practice 
(GCP) standards as well as local regulations.  
6.3 Subject Information and Informed Consent 
Prior to subject participation in the trial, written informed consent must be obtained from 
each subject according to ICH GCP and in accordance with local regulations. Written 
informed consent is required for each subject prior to any testing under this protocol not 
considered standard of care, including screening tests, SAGE-547 infusion, and study 
evaluations. Each subject’s signature must be dated by each signatory and the informed 
consent form (ICF) retained by the investigator as part of the trial records. As an additional 
assessment, the ICF will contain a provision for optional consent for the collection of breast 
milk for the duration of the 60-hour SAGE-547 infusion and up to Day 3 for biobanking and 
PK analysis purposes. The ICF, as specified by the clinical site’s IRB, must follow the 
Protection of Human Subjects regulations listed in the CFR, Title 21, Part 50. 
It is the responsibility of the Investigator to obtain consent and to provide the subject a copy 
of the signed and dated ICF. The ICF for subject participation must also be available as part 
of the subject’s file for review by the site’s dedicated study monitor. 
All ICFs used in this study must be approved by the appropriate IRB and by the Sponsor. The 
ICF must not be altered without the prior agreement of the relevant IRB and the Sponsor.  


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7 STUDY OBJECTIVES 
7.1 Primary Objective 
The primary objective of this study is to determine if SAGE-547 Injection infused 
intravenously for 60 hours reduces depressive symptoms in subjects with postpartum 
depression (PPD) compared to placebo injection as assessed by the change from baseline in 
Hamilton Rating Scale for Depression (HAMD) total score 
7.2 Secondary Objectives 
The secondary objectives of the study are: 
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
depressive symptoms compared to placebo injection as assessed by HAMD response, 
HAMD remission, change from baseline in Montgomery-Asberg Depression Rating 
Scale (MADRS) total score, change from baseline in Clinical Global Impression – 
Severity (CGI-S) score, Clinical Global Impression – Improvement (CGI-I) response, 
and changes from baseline in HAMD subscale and individual item scores.   
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces other 
mood symptoms compared to placebo injection as assessed by changes from baseline 
in the Generalized Anxiety Disorder 7-Item Scale (GAD-7) total score. 
• To determine if SAGE-547 Injection infused intravenously for 60 hours increases 
sedation levels compared to placebo injection as assessed by the changes from 
baseline in Stanford Sleepiness Scale (SSS) score. 
• To evaluate the safety and tolerability of SAGE-547 Injection compared with placebo 
as assessed by the incidence of adverse events, vital sign measurement, clinical 
laboratory evaluations, electrocardiogram (ECG) parameters, and the Columbia 
Suicide Severity Rating Scale (C-SSRS). 
7.3 Exploratory Objectives 
• To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
subject-reported depressive symptoms compared to placebo injection as assessed by 
the change from baseline in Edinburgh Postnatal Depression Scale (EPDS) total 
score, change from baseline in Patient Health Questionnaire (PHQ-9) total score, and 
change from baseline in Interactive Voice Response (IVR) HAMD total score. 
• To determine if SAGE-547 Injection infused intravenously for 60 hours improves 
maternal behaviors compared to placebo injection as assessed by the change from 
baseline in Barkin Index of Maternal Functioning (BIMF) total and sub-scale scores.  
7.4 Pharmacokinetic Objective 
• To assess the pharmacokinetic (PK) profile of SAGE-547, metabolites of SAGE-547, 
and betadex sulfobutyl ether sodium (SBECD) and the concentration of SAGE-547 in 
breast milk, when possible. 


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8 INVESTIGATIONAL PLAN 
8.1 Overview of Study Design 
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of 
the efficacy, safety, and pharmacokinetics of SAGE-547 Injection in adult female subjects 
diagnosed with severe PPD. The study design is presented in Figure 1. The study will consist 
of an up to 5-day Screening Period (Day -5 to -1), 3-day (60-hour) Treatment Period, and 30-
day Follow-up Period; see Figure 2. Subjects must remain as in-patient during the study 
Treatment Period, which is approximately 60 hours/2.5 days in duration. The Screening 
Period assessments may be conducted on an in-patient or an out-patient basis. The Follow-
Up Period assessments are conducted on an out-patient basis. 
 
FIGURE 1: STUDY DESIGN 
SAGE-547 Injection or placebo will be administered at the study center. Subjects will be 
monitored for safety during the Treatment and Follow-up Periods (through Study Day 30 ± 3 
days) including monitoring for AEs/SAEs, routine clinical laboratory assessments, physical 
examination, vital signs, and ECG. 
All study-related procedures will occur after written informed consent is obtained at the 
Screening Visit, which will occur on any one calendar day during the Screening Period 
window (Day -5 through Day -1). If applicable, standard of care data collected prior to 
obtaining informed consent may also be included as screening data, if appropriate, such as 
laboratory tests, ECG, physical examination, and vital signs conducted within the preceding 
48 hours, as long as the requirement for the screening assessment to be collected 
retrospectively is met in full. If applicable, to ensure protocol compliance, any standard of 


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care data eligible for inclusion as screening data must include the precise nature and timing 
of data collection. 
The end of the Screening Period coincides with the beginning of the Treatment Period. The 
Treatment Period is the period of Day 1 of SAGE-547 IV infusion through completion of the 
infusion on Day 2 and up to Day 3. Subjects will be confined to the study center from the 
Screening Visit until after the 60-hour assessments have been conducted on Day 3. On the 
morning of dosing (Day 1), subjects will begin a 4-hour dose titration period 30µg/kg/hour 
[0-4 hours], then 60 µg/kg/hour [4-24 hours], then 90 µg/kg/hour [24-60 hours]); see dose 
regimen presented in Section 11.1.1. Total SAGE-547 Injection or placebo dosing will occur 
over 60 hours. 
Trial-specific assessments for safety, PK, efficacy, and exploratory outcome measures will be 
completed at pre-specified times over a 72-hour period during the Treatment Period: 
• The safety and tolerability of SAGE-547 Injection will be assessed by AEs, clinical 
laboratory measures, physical examinations (including cognitive and mental health 
examinations), vital signs, ECG, use of concomitant medication, and the Columbia 
Suicide Severity Rating Scale (C-SSRS) during the Screening, Treatment, and 
Follow-up Periods (through Study Day 30 ± 3 days). 
• Plasma will be collected to formally assay for SAGE-547, metabolite, and SBECD 
levels prior to dosing through the treatment period and up to 12 hours post infusion 
on Day 3.  
• Primary efficacy assessment of the HAMD will be completed as scheduled during the 
Screening, Treatment, and Follow-up Periods (through Study Day 30). 
• Secondary efficacy assessments of MADRS, CGI-I, EPDS, Generalized Anxiety 
Disorder 7-Item Scale (GAD-7), PHQ-9 will be completed as scheduled during the 
Screening, Treatment, and Follow-up Periods (through Study Day 30).  
• Concentrations of SAGE-547 in breast milk will be measured for those subjects who 
consent to giving breast milk samples. 
The end of the Treatment Period coincides with the beginning of the Follow-up Period. 
Subjects will attend the clinic for safety follow-up assessment at one week (7±1d) and one 
month (30±3d) after the initiation of the study drug infusion. 
Scheduled assessments for all safety, PK, efficacy, and exploratory outcome measures 
planned for the trial are summarized in Table 1. All subjects who receive treatment with 
SAGE-547 are to complete all study assessments through Study Day 30 (±3d). 
The Medical Monitor will review AEs on an ongoing basis. 
8.2 Blinding and Randomization 
This is a double-blind study. Subjects will be randomized to SAGE-547 or placebo; subjects, 
clinicians, and study team will be blinded to treatment allocation. The pharmacist, who will 
prepare the infusion bags according to the randomization schedule, and an unblinded 
Monitor, who will preform drug accountability during the study, will be unblinded.  


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Subjects will be randomly assigned to receive SAGE-547 Injection followed by placebo 
according to a computer-generated randomization schedule.  
Only the clinic pharmacist, who is responsible for preparing the infusions, will be given a 
copy of the randomization schedule. In the event of a medical emergency, the pharmacist 
may reveal actual infusion contents to the primary investigator, who should also alert Sage of 
the emergency (see Section 15.4 for more details related to unblinding). In all cases where 
the study drug allocation for a subject is unblinded, pertinent information (including the 
reason for unblinding) must be documented in the subject’s records and on the electronic 
case report form (eCRF). If the subject or study center personnel have been unblinded, the 
subject will be terminated from the study. 


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9 SELECTION AND WITHDRAWAL OF SUBJECTS 
9.1 Inclusion Criteria 
The following inclusion criteria must be met for individuals to be eligible for the trial: 
1. Subject has signed an ICF prior to any study-specific procedures being performed 
2. Subject is an ambulatory female aged between 18 and 45 years of age 
3. Subject is in good physical health and has no clinically significant findings, as 
determined by the Investigator, on physical examination, 12-lead ECG, or clinical 
laboratory tests 
4. Subject agrees to adhere to the study requirements 
5. Subject either must have ceased lactating at Screening; or if still lactating at Screening, 
must have already fully and permanently weaned their infant(s) from breastmilk; or if 
still actively breastfeeding at Screening, must agree to cease giving breastmilk to their 
infant(s) prior to receiving study drug. For the avoidance of doubt, subjects who are 
breastfeeding and do not agree to permanently wean their infant(s) from breastmilk at 
Screening are not eligible for the study. 
6. Subject must have a negative pregnancy test at Screening and Day 1 prior to the start of 
study drug infusion 
7. Subject has had a Major Depressive Episode that began no earlier than the third trimester 
and no later than the first 4 weeks following delivery, as diagnosed by Structured Clinical 
Interview for DSM-IV Axis I Disorders (SCID-I) 
8. Subject has a HAMD total score of ≥26 at Screening and Day 1 (prior to randomization) 
9. Subject is ≤ six months postpartum 
10. Subject is willing to delay start of other antidepressant or anxiety medications and any 
new pharmacotherapy regimens, including prn benzodiazepine anxiolytics, until the study 
drug infusion and 72-hour assessments have been completed  
11. Subject has no detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus 
(HCV), and human immunodeficiency virus (HIV) antibody at Screening 
9.2 Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria: 
1. Recent history or active clinically significant manifestations of metabolic, hepatic, renal, 
hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eyes, ears, or nose and throat disorders, or 
any other acute or chronic condition that, in the Investigator’s opinion, would limit the 
subject’s ability to complete or participate in this clinical study 
2. Known allergy to progesterone or allopregnanolone 
3. Active psychosis per Investigator assessment 
4. Attempted suicide associated with index case of postpartum depression 


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5. Medical history of seizures 
6. Medical history of bipolar disorder 
7. History of active alcoholism or drug addiction (including benzodiazepines) in the 12 
months prior to Screening 
8. Exposure to another investigational medication or device within 30 days prior to 
Screening 
9. Administration of psychotropics that have been initiated within 14 days prior to 
Screening and are not being taken at a stable dose. 
9.3 Subject Withdrawal/Study Termination 
9.3.1 Withdrawal/Discontinuation of Individual Subjects  
The reasons for study drug discontinuation and/or subject withdrawal from the study must be 
recorded in the subject’s electronic case report form (eCRF). The Investigator must notify the 
Sponsor and/or the Medical Monitor immediately when a subject has been discontinued/ 
withdrawn for any reason, including withdrawal due to an AE. 
Subjects who do not have at least one efficacy observation after 12 hours of SAGE-547 
infusion are not considered evaluable for the efficacy assessment and may be replaced.  
9.3.2 Subject Withdrawal From the Study 
Subjects may withdraw from the study at any time for any reason without compromising the 
subject’s medical care. The Investigator will also withdraw subjects upon the request of Sage 
Therapeutics or upon termination of the study. 
9.3.3 Discontinuation of Study Drug by the Investigator 
If it is necessary for the Investigator to discontinue the study drug earlier than planned, 
subjects should continue to be followed per protocol to capture safety and efficacy 
assessments for the duration of the study period.  
The Investigator may withdraw the subject from the study drug for any of the following 
reasons:  
• The subject is unwilling or unable to adhere to the protocol 
• The subject experiences an intolerable AE 
• During the course of the study, the subject develops symptoms or conditions listed in 
the exclusion criteria 
• Other medical reason, at the discretion of the Investigator and/or the Medical Monitor 
Subjects who discontinue the study due to an AE, regardless of Investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the Investigator 
determines the event is no longer clinically significant.  


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9.3.4 Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
subjects, or for administrative reasons. In the event of study termination, Sage Therapeutics 
will provide written notification to the Investigator. Investigational sites must promptly 
notify their IRB and initiate withdrawal procedures for participating subjects.  


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10 INVESTIGATIONAL PRODUCT 
10.1 Identity of Investigational Product 
SAGE-547 Injection (allopregnanolone) 
10.2 Clinical Supplies 
10.2.1 SAGE-547 
SAGE-547 Injection and ancillary supply kits containing IV administration bags, solution 
sets, and IV bag labels will be provided to the sites. 
SAGE-547 Injection is a preservative-free, sterile, clear, colorless 5 mg/mL solution of 
SAGE-547 (allopregnanolone) and 250 mg/mL betadex sulfobutyl ether sodium buffered 
with 10 mM citrate at a pH of 6.0, intended for IV injection. All inactive excipients used in 
the formulation are compendial grade and conform to current United States Pharmacopeia 
(USP) and European Pharmacopeia (Ph. Eur.) standards. The product is aseptically 
processed, sterile filtered, and filled into 20 mL Type 1 parenteral glass vials with West 
FluroTec® coated stopper container closure systems, under current Good Manufacturing 
Practice (cGMP) conditions. SAGE-547 Injection is intended to be used as a single-use vial. 
An appropriate number of single-use vials to support the dosing duration of the study are 
packaged and delivered to the site. SAGE-547 Injection vials should be stored under 
refrigerated conditions (2–8 °C). Ancillary supply kits should be stored at controlled room 
temperature (20–25 °C). 
All study drug labels will contain information to meet the applicable regulatory requirements. 
10.2.2 Placebo 
Placebo will be identical to SAGE-547 and presented in identical vials. Placebo will be 
manufactured in a similar way to SAGE-547 and consisting of the same formulation without 
allopregnanolone.  Placebo vials should be stored under refrigerated conditions (2–8 °C).   
10.3 Preparation of SAGE-547 Injection or Placebo for Dosing 
The pharmacy will be responsible for preparing SAGE-547 Injection or placebo for subject 
dosing. The prepared admixture will be administered at room temperature. The prepared 
admixture will be assigned a room temperature (20–25 °C) storage shelf life of 24 hours from 
time of compounding.  
SAGE-547 Injection or placebo is not intended to be administered to subjects undiluted. Each 
single-use vial of SAGE-547 Injection, which is hypertonic, will require dilution with an 
appropriate volume of Sterile Water for Injection (SWFI) to render it isotonic. Refer to the 
Pharmacy Manual for specific instructions regarding infusion preparation and administration 
instructions. 


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10.4 Administration and Accountability 
The pharmacy will maintain accurate records of all investigational drug product supplies 
received, stored, dispensed, and discarded. Accurate records will be kept regarding the 
volume of SAGE-547 Injection or placebo used for each IV preparation, as well as the 
required infusion rate (or rates), and the date and time of preparation. Reasons for departure 
from the expected dosing regimen must be recorded. To satisfy regulatory requirements 
regarding drug accountability, all study medication needs to be reconciled in full.  
Refer to the Pharmacy Manual for complete details on preparation and administration. 


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11 TREATMENT OF SUBJECTS 
11.1 Dosing Schedule 
This is a double-blind study. Subjects will be randomized to receive 60 hours of intravenous 
treatment with either SAGE-547 Injection or placebo.  
The timing of infusion relative to the overall trial design is shown in Figure 2. 
 
FIGURE 2: TRIAL DESIGN AND TIMELINE FOR DOSING 
 
Clinical supply and preparation of SAGE-547 Injection for dosing is described Section 10.2 
and Section 10.3, respectively. 
11.1.1 Dose Regimen 
The specific infusion dose of SAGE-547 Injection will be calculated based on weight 
(obtained at screening) for each subject and administered according to dose regimen shown 
in Table 2). The infusion rates are the same for all subjects within a particular dosing period 
(0-4 hours, 4-24 hours, etc.) (Table 2).   
 
 


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TABLE 2: INFUSION RATES 
Timepoint 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2/3 
24-60 hours 
Infusion rates 
30 µg/kg/hour 
60 µg/kg/hour 
90 µg/kg/hour 
Dosing is to begin in the morning (on Day 1) to avoid awakening subjects during the night 
for completion of study assessments. 
If any subject has an SSS score of ≥5 for two or more consecutive assessments or an SSS 
score of ≥6 for a single occurrence during normal waking hours, the infusion rate will be 
decreased to the next lowest infusion dose (or turned off if this occurs on the 30 µg/kg/hour 
dose level) for the remainder of the study. Please refer to Section 11.1.4 for more details. 
11.1.2 Route of Administration 
SAGE-547 Injection is intended for IV administration only. The compatibility of SAGE-547 
with other drugs is unknown, and the product should be administered via a dedicated 
peripheral IV line with the supplied study-specific IV administration bags and lines. 
11.1.3 Treatment Period 
Total dosing with SAGE-547 or placebo will occur over 60 hours, including a 24-hour dose 
titration and a 36-hour maintenance infusion. 
11.1.4 Dosing of Intravenous SAGE-547 in the Case of AEs 
Since allopregnanolone levels in the proposed clinical trial are similar to physiological levels 
seen in the third trimester of pregnancy, and all the AEs reported with SAGE-547 or 
allopregnanolone to date were mild and non-serious, it is anticipated that the AEs associated 
with SAGE-547 will be mild and manageable without dose interruption or reduction. Based 
on the observed adverse events to date, the adverse events most likely to result in AE are 
sedation with or without hypotension.  
However, in the case of severe or life-threatening AEs occurring, the investigator is advised 
to interrupt infusion until regression of the AE to mild or resolution and only resume infusion 
if it is deemed in the best interest of the subject. Resumption of infusion at the next lowest 
dose (or turned off if this event occurs on the 30 µg/kg/hour dose level) for one hour, 
followed by re-escalation to the maintenance rate, may be considered to address potential 
recurrence of the AE. If the AE recurs infusion should be definitively discontinued. 
11.2 Dosing Compliance 
Investigational product will be prepared in the site pharmacy, administered as a continuous 
IV infusion by the study staff, and will be documented in the study record.  There should be 
no adjustments in dosing except those described in Section 11.1.4. 


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11.3 Concomitant Medications and Restrictions 
11.3.1 Concomitant Medications 
Subjects will receive standard of care for adult female patients diagnosed with PPD. Any 
concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 11.3.2. All concomitant medications should be documented throughout the study 
from Screening through Day 30 (± 3 days) and recorded on the eCRF. Prior medications (i.e., 
those taken prior to signing of informed consent) that required wash-out for study entry will 
also be documented. 
11.3.2 Prohibited Medications 
Restrictions on specific classes of medications include the following: 
• 
Initiation of new antidepressant therapy is prohibited upon admission to the study 
center for those eligible subjects who desire study participation. Those subjects 
already taking an antidepressant at the time of study entry (and meeting all study 
inclusion criteria) will be permitted to remain on the pre-existing antidepressant at 
their current dose if they were on this medication for at least 30 days prior to study 
enrollment. 
• 
Benzodiazepines are to be avoided as much as possible. Eligible subjects taking a 
benzodiazepine at the time of study entry will be permitted to continue to take their 
current dose of the benzodiazepine (to prevent acute withdrawal), but no new 
benzodiazepine use will be permitted during the course of the study. Particular 
attention should be paid to assessment of AEs and implementation of the dose 
interruption and reduction scheme in subjects on concomitant benzodiazepines since 
they have been shown to have a supra-additive effect with pregnenolone in an animal 
model of anesthesia (Norberg 1999). 
• 
The use of hypnotics for sleep/insomnia such as Ambien® and trazodone are to be 
avoided. 
• 
Anticonvulsants and atypical antipsychotics are to be avoided if possible and are not 
to be initiated at any time during active treatment period (60 hours).  However, if a 
subject is taking one of these medications for at least 30 days prior to study 
admission, they will be permitted to remain on this medication, at their current dose 
(no dose adjustments are allowed). 
• 
SAGE-547 has demonstrated inhibitory effects on cytochrome P-450 (CYP) 2C9 
(CYP2C9). The following medications are primarily metabolized by CYP2C9 and 
therefore are prohibited during SAGE-547 administration: fluconazole and 
miconazole (antifungal), amentoflavone (constituent of Ginkgo biloba and St. John’s 
Wort), sulfaphenazole (antibacterial), valproic acid (anticonvulsant, mood-
stabilizing), and apigenin. See Appendix 10 for a more complete list. 


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12 STUDY ASSESSMENTS 
12.1 Safety Assessments 
The safety and tolerability of SAGE-547 Injection will be evaluated by summarization of 
AEs by frequency, severity and seriousness, mean changes from baseline in clinical 
laboratory measures, physical examination, vital signs, ECGs, and concomitant medication 
usage. Suicidality will be monitored using the C-SSRS. All safety assessments should be 
performed per the study center’s standard of care and will be collected according to the 
Schedule of Events (Table 1). All safety assessments are to be completed within 
± 30 minutes of the scheduled time point. 
In addition to the schedule outlined in Table 1, completion of safety assessments including 
physical examination, vital signs, and clinical laboratory tests should occur in the event of an 
emergency or SAE, when possible.  
12.1.1 Adverse Events 
Adverse events will be collected after the ICF has been signed through the end of the study 
(see Section 15.2.1 for additional details). Medical conditions or adverse events that occur 
after the ICF has been signed and prior to completion of Screening will be captured on the 
Medical History eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA™) coding system (version 17.0 or higher), as described in Section 14.4.  
12.1.2 Clinical Laboratory Tests 
Blood samples will be collected for hematology, serum chemistry, coagulation, and specific 
hormone parameters, hepatitis, human immunodeficiency virus (HIV), pregnancy and genetic 
analysis. Urine samples for urinalysis and selected drugs of abuse will also be collected. 
These assessments will be performed in accordance with the Schedule of Events (Table 1) 
and as outlined individually below. 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as Abnormal; not clinically significant (NCS) or Abnormal; clinically significant 
(CS). Screening results considered Abnormal; CS will be recorded as medical history. 
Clinical laboratory results that are Abnormal; CS during the study and indicate a worsening 
from baseline will be considered AEs, assessed according to Section 15, and recorded in the 
eCRF.  
1. Hematology, Serum Chemistry, Coagulation 
Blood samples will be collected for analysis of the following:  
• Hematology: complete blood count (CBC) including white blood cell (WBC) count 
with differential (basophils, eosinophils, lymphocytes, monocytes, and neutrophils) 
platelet count, red blood cell (RBC) count, hemoglobin (Hgb) and hematocrit (Hct), 
mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) 


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• Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin (total), blood urea nitrogen (BUN), 
calcium, chloride, creatinine, gamma glutamyl transferase (GGT), glucose phosphate, 
potassium, sodium, total protein and triglycerides (Screening only) 
• Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT), 
international normalized ratio (INR) 
2. Hepatitis and HIV 
Blood samples will be collected for analysis of the following: 
• Hepatitis: hepatitis B virus surface antigen (HBsAg), antibody against hepatitis C 
virus (anti-HCV) 
• HIV: antibody against human immunodeficiency virus type 1/2 (anti-HIV 1/2) 
3. Hormones 
Blood samples will be collected for analysis of thyroid stimulating hormone (TSH), estrogen, 
progesterone, progesterone metabolites and oxytocin. 
4. Pregnancy Test 
All subjects will be tested for pregnancy by serum hCG at Screening and urine hGC on Day 
1 prior to administration of study drug.  Subjects with a positive pregnancy test at Screening 
or Day 1will be ineligible for study participation. 
5. Genetic Testing 
A blood sample for genetic testing will be collected at screening, where consent is given. 
This sample will be used to test for the GABAA receptor δ-subunit. Genetic susceptibility to 
affective dysregulation may be unmasked during periods of reproductive hormone change 
such as during pregnancy and postpartum (Maguire 2008). Maguire and Mody demonstrated 
that a GABA receptor subunit mutation was behaviorally silent until the animal was exposed 
to pregnancy and the postpartum state, at which time the dams showed depressive-like 
behaviors and cannibalized their offspring (Maguire 2008). 
6. Urinalysis 
Urinalysis will include assessment of bilirubin, glucose, ketones, leukocytes, nitrite, pH, 
protein and specific gravity.  
7. Drugs of Abuse and Alcohol 
Urine assessment for selected drugs of abuse (including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine and propoxyphene). Use of 
benzodiazepines at screening is not necessarily exclusionary, as subjects will be allowed to 
take psychotropics that have been initiated at least 14 days prior to admission to the study 
center at a stable dose (see Section 11.3). Alcohol will be assessed in plasma at Screening 
and in serum, via breathalyzer or urine dipstick on Day 1. 


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12.1.3 Physical Examination 
Body weight and height will be measured at Screening. Body mass index (BMI) will be 
programmatically calculated in the eCRF. 
Any condition present at the post-treatment physical examination that was not present at or 
worsened since the baseline examination is to be documented as an AE. Whenever possible, 
the same individual is to perform all physical examinations. Physical examinations will 
include assessment of body systems (e.g., HEENT, heart, lungs, abdomen, and extremities) 
as well as cognitive and neurological examination and mental status examination.  
12.1.4 Vital Signs 
Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure 
(supine and standing) and pulse oximetry A full set of vital signs will be obtained at all 
specified timepoints (± 30 minutes), unless the subject is asleep between the hours of 23.00h 
and 06.00h each day. Additional measures of pulse oximetry will be collected during 
sleeping hours. 
12.1.5 ECG 
A baseline 12-lead ECG will be performed during Screening to assess the presence of any 
current or historical cardiovascular conditions. The following ECG parameters will be 
recorded: heart rate, PR, QRS, QT, and QTc. Subjects with clinically significant 
abnormalities should not be entered into the study. 
12.1.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with 
suicidal ideation and behavior, and a post-baseline evaluation that focuses on suicidality 
since the last study visit. The C-SSRS includes “yes” or “no” responses for assessment of 
suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present 
(from 1 to 5, with 5 being the most severe). The “Baseline” C-SSRS form will be completed 
on Day 1 prior to dosing. The “Since Last Visit” C-SSRS form will be completed for all 
subsequent assessments.   
Copies of the C-SSRS are provided in APPENDIX 1. 
12.1.7 Stanford Sleepiness Scale (SSS) 
The Stanford Sleepiness Scale is patient-rated scale designed to quickly assess how sedated 
or sleepy a patient is feeling. Degrees of sleepiness and alertness are rated on a scale of 1 to 
7, where the lowest score of 1 indicates that the patient is “feeling active, vital, alert, or wide 
awake” and the highest score of 7 indicates that the patient is “no longer fighting sleep, sleep 
onset soon; having dream-like thoughts.” The SSS will be administered unless the subject is 
asleep between the hours of 23.00h and 06.00h each day. If the SSS is not scored due to a 
subject being asleep, a score of X will be reported in the CRF to indicate that the subject was 
asleep. All SSS assessments are to be completed within ± 15 minutes of the scheduled time 
point. 


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A copy of the SSS is provided in APPENDIX 5. 
12.2 Efficacy Assessments 
For all efficacy assessments, the baseline values will be calculated as the last recorded value 
prior to the start of infusion of randomized treatment.  Change from baseline values will be 
calculated as the assessment score minus the baseline value.  Change from baseline values 
will be calculated for each item and total score.   
12.2.1 Primary Efficacy Outcome Measure 
The primary outcome measure is the HAMD. The HAMD will be administered before, 
during, and after the infusion of blinded study drug.  
8. Hamilton Rating Scale for Depression (HAMD)  
The 17-item HAMD will be used to rate the severity of depression in subjects who are 
already diagnosed as depressed (Hamilton 1960). The 17-item HAMD is comprised of 
individual ratings related to the following symptoms: depressed mood (sadness, hopeless, 
helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and 
activities, retardation (slowness of thought and speech; impaired ability to concentrate; 
decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms 
(gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and 
insight. The HAMD assessments are to be completed within ± 30 minutes of the scheduled 
time point, but prior to starting dosing on D1 H0. 
The HAMD total score will be calculated as the sum of the 17 individual item scores.  Item 
16 can be rated according to history (item 16A) or actual weight change (item 16B).  The 
item 16 score is calculated as the item 16 response that is not equal to 3 (i.e., “Not assessed”).   
In addition to the primary efficacy endpoint of change from baseline in HAMD total score, 
several secondary efficacy endpoints will be derived for the HAMD.  HAMD subscale scores 
will be calculated as the sum of the items comprising each subscale.  HAMD response will 
be defined as having a 50% or greater reduction from baseline in HAMD total score. HAMD 
remission will be defined as having a HAMD total score of ≤7.   
A copy of the HAMD is provided in APPENDIX 2. 
12.2.2 Secondary Efficacy Outcome Measures 
Secondary efficacy assessments include evaluation of depressive symptom severity by the 
MADRS and CGI, as described in Section 12.2.2.1. Additional assessments of depressive 
symptom severity and reproductive mood disorders will be measured by the following 
clinician- and subject-rated outcome measures: EPDS, GAD-7 and PHQ-9, as described in 
Sections 12.2.3.1 through 12.2.3.2. 
9. Montgomery Asberg Depression Rating Scale (MADRS) 
The MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the 
severity of depressive episodes in patients with mood disorders. It was designed as an adjunct 


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to the HAMD which would be more sensitive to the changes brought on by antidepressants 
and other forms of treatment than the Hamilton Scale was. 
Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 
6. The overall score ranges from 0 to 60 (McDowell 2006, Müller-Thomsen 2005). 
The questionnaire includes questions on the following symptoms 1. Apparent sadness 2. 
Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration 
difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts. 
The MADRS total score will be calculated as the sum of the 10 individual item scores. 
A copy of the MADRS is provided in APPENDIX 3. 
10. Clinical Global Impression (CGI) Scale 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the patient’s condition. The CGI scale is 
comprised of 3 items. Only the first two items are being used in this study.   
The CGI-Severity (CGI-S) item uses a 7-point Likert scale to rate the severity of the patient’s 
illness at the time of assessment, relative to the clinician’s past experience with patients who 
have the same diagnosis. Considering total clinical experience, a patient is assessed on 
severity of mental illness at the time of rating 1 = normal, not at all ill, 2 = borderline 
mentally ill, 3 = mildly ill, 4 = moderately ill, 5 = markedly ill, 6 = severely ill, and 7 = 
extremely ill. The CGI-S will be rated by the clinician at screening and on Day 1 (prior to 
dosing). 
The CGI-Improvement (CGI-I) item employs a 7-point Likert scale to measure the overall 
improvement in the patient’s condition post-treatment. The investigator will rate the patient’s 
total improvement whether or not it is due entirely to drug treatment. Response choices 
include: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally 
improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. 
The CGI-I is only rated at post-treatment assessments.  By definition, all CGI-I assessments 
are evaluated against baseline conditions.  CGI-I response will be defined as having a CGI-I 
score of “very much improved” or “much improved”.   
A copy of the CGI is provided in APPENDIX 4. 
11. Generalized Anxiety Disorder 7-Item Scale (GAD-7) 
The GAD-7 is a patient-rated depressive symptom severity scale (Spitzer 2006). Scoring for 
GAD-7 generalized anxiety is calculated by assigning scores of 0, 1, 2, and 3 to the response 
categories, respectively, of “not at all sure,” “several days,” “over half the days,” and “nearly 
every day.” GAD-7 total score for the seven items ranges from 0 to 21, where a score of 0 to 
4 = minimal anxiety, 5 to 9 = mild anxiety, 10 to 14 = moderate anxiety, and 15 to 21 = 
severe anxiety. All assessments are to be completed within ± 30 minutes of the scheduled 
time point. 
The GAD-7 total score will be calculated as the sum of the 7 individual item scores. 
A copy of the GAD-7 is provided in APPENDIX 7. 


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12.2.3 Exploratory Patient Reported Outcome Measures 
Exploratory efficacy assessments include evaluation of depressive symptom severity and 
reproductive mood disorders. These will be measured by the following clinician- and subject-
rated outcome measures: EPDS, PHQ-9, BIMF and IVR HAMD. 
12. Edinburgh Postnatal Depression Scale (EPDS) 
The EPDS is a patient-rated depressive symptom severity scale specific to the perinatal 
period (Cox 1987). The EPDS total score will be calculated as the sum of the 10 individual 
item scores. 
A copy of the EPDS is provided in APPENDIX 6. 
13. Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is a patient-rated depressive symptom severity scale. To monitor severity over 
time for newly diagnosed patients or patients in current treatment for depression, patients 
may complete questionnaires at baseline and at regular intervals thereafter. Scoring is total 
based on responses to specific questions, as follows: “not at all” = 0; “several days” = 1; 
“more than half the days” = 2; and “nearly every day = 3.” All assessments are to be 
completed within ± 30 minutes of the scheduled time point. 
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores.  The 
PHQ-9 total score will be categorized as follows: 1-4 = minimal depression, 5-9 = mild 
depression, 10-14 = moderate depression, 15-19 = moderately severe depression; and 20-27 
= severe depression. 
A copy of the PHQ-9 is provided in APPENDIX 8. 
14. Barkin Index of Maternal Functioning (BIMF)  
The BIMF is a patient reported outcome scale BIMF covers a broad range of functional areas 
(self-care, infant care, mother-child interaction, psychological well-being of mother, social 
support, management, adjustment). This new application of maternal functional status is a 
robust construct where the physical and mental health of the mother is essential to optimal 
functioning. Each item is rated on a scale of 0 (strongly disagree) to 6 (strongly agree) , and 
subscales are drawn from these items.  
A copy of the BIMF is provided in APPENDIX 9. 
15. Interactive Voice Response (IVR) HAMD 
The IVR HAMD is a validated patient reported version of the clinician rated HAMD.  
Similar total and subscale scores as described in Section 12.2.1.1 will be calculated for the 
IVR HAMD. 


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12.3 Pharmacokinetics 
12.3.1 Plasma PK Samples 
Blood samples for PK analysis will be collected in accordance with the Schedule of Events 
(Table 1). Scheduled time points for PK blood draws after the start of infusion will have a 
window of ± 10 minutes. Samples will be processed according to the PK Manual, and 
analyzed for concentrations of SAGE-547, metabolites of SAGE-547, and SBECD. 
Additionally, PK samples may be obtained outside the planned collection times if issues 
administering study drug are encountered, such as incorrect infusion rate, interrupted 
infusion, or other administration deviations where PK level assessment may be important in 
understanding subject state. In the event of an unplanned dose adjustment, an unscheduled 
PK sample should be collected just prior to the infusion rate change. 
The following PK parameters will be derived from the plasma concentrations (where 
evaluable): area under the concentration-time curve (AUC) from time zero to 60 hours 
(AUC0-60), AUC from time zero to infinity (AUCinf), maximum (peak) plasma concentration 
(Cmax), time at maximum (peak) plasma concentration (Tmax), steady-state drug concentration 
in the plasma during constant-rate infusion (Css), and average drug concentration in the 
plasma at steady state during a dosing interval (Cavg). 
The plasma samples will be drawn from the arm contralateral to that used for drug 
administration. Subject-specific plasma PK kits for sampling including instructions on 
sample collection, processing methods, storage and shipping conditions, will be provided in 
the study PK Manual. 
12.3.2 Breastmilk PK Samples 
Women who are actively lactating at Screening, and who otherwise fulfill all of the inclusion 
and exclusion criteria for the study, will be asked if they will consent to pumping. Breastmilk 
will be collected and pooled at pre-defined intervals. The times of the first and last pumping 
of each collection period will be recorded. Breastmilk will be pooled within each collection 
period and the total volume will be measured. Detailed instructions for breastmilk PK 
sampling, processing methods, storage and shipping will be provided in the study PK 
Manual. After collection of the last breastmilk sample, women will reduce pumping to 
comfortably curtail breast milk production. 


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13 STUDY PROCEDURES 
The study procedures listed below by study day reflect the data collection times for this 
protocol.  
Scheduled assessments for all safety, efficacy, PK and exploratory outcome measures 
planned for the trial are summarized in Table 1 (Schedule of Events). All subjects who 
receive treatment with SAGE-547 should complete all study assessments through Study Day 
30 (± 3 days). 
Subjects who are evaluated at the Day 3 visit of the Treatment Period (i.e., all Hour 60 
assessments are completed, post-infusion) and complete the Day 30 (± 3 days) visit during 
the Follow-up Period will be defined as study completers.  
13.1 Screening Period 
The Screening Period consists of a window from Day -5 through Day -1 prior to starting 
SAGE-547 treatment. The Screening Period begins with the signature of the ICF. Eligibility 
is determined by applying the inclusion/exclusion criteria. The diagnosis of PPD must be by 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). A full medical and 
family history will be taken including recording of all depression, other Axis 1 and Axis 2 
disorders and post-partum depression episodes in primary probands (who may be subject to a 
SCID-I interview). 
The following assessments/procedures will be conducted at the Screening Visit, which will 
occur on any one calendar day of the Screening Period. Standard of care data collected prior 
to obtaining informed consent may also be included as screening data, if appropriate, such as 
laboratory tests, ECG, physical examinations, and vital signs conducted within the preceding 
48 hours, as long as the requirement for the screening assessment to be collected 
retrospectively is met in full, and all screening assessments are completed, reviewed and 
approved by the Investigator prior to administration of SAGE-547. 
Subjects will be confined to the study center from the Screening Visit until after the 60-hour 
assessments have been conducted on Day 3. 
• Written informed consent, with optional provision for breast milk collection (see 
Section 6.3 for more information). 
• Review of inclusion/exclusion criteria to determine subject eligibility. 
• Demographic information and medical/family history collected.  
• Blood will be collected for a pregnancy test. 
• Blood will be collected to screen for hepatitis and HIV. 
• Completion of physical examination, including body weight. Height should be 
recorded. BMI will be calculated. 
• Vital signs. 
• Blood and urine samples collected for clinical laboratory testing, including drug and 
alcohol screening. 


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• Blood sample will be taken for genetic analysis with subject consent. 
• An ECG reading taken. 
• Completion of the HAMD (including IVR HAMD), CGI-S and MADRS.  
• Recording of concomitant medications.  
13.2 SAGE-547 Treatment Period (Day 1 to Day 3, Hours 0-60) 
All safety, efficacy, pharmacokinetic and other outcome assessments described in this section 
are to be completed within ± 30 minutes of the scheduled time points, unless otherwise 
stated. Windows for PK collection time points are specified by respective time point for 
Study Days 1 to 3 in Section 13.2.1 to Section 13.2.3, respectively (see Section 12.3 for 
additional details). Subjects will be confined to the study center from the Screening Visit 
until after the 60-hour assessments have been conducted on Day 3. 
13.2.1 Day 1 
• Review of inclusion/exclusion criteria to determine subject eligibility. 
• Randomization (on a 1:1 basis: one group will receive SAGE-547 and one group will 
receive placebo). 
• Urine will be collected for a pregnancy test. 
• Begin study drug administration for dose titration in the morning followed by 
maintenance infusion. 
• Vital signs and pulse oximetry will be recorded prior to infusion and at 2, 4, 8, 12, 18, 
and 24 hours on Day 1 (± 30 minutes), unless the subject is asleep between the hours 
of 23.00h and 06.00h each day.  Additional measures of pulse oximetry will be 
collected during sleeping hours. 
• Blood and urine samples collected for drug and alcohol screening. 
• A blood sample for PK analysis will be collected prior to infusion (i.e., morning of 
Day 1 prior to dosing), and at Hours 4 (before change in infusion rate), 8, 12, and 24 
(before change in infusion rate) after the start of the infusion. PK blood draws after 
the start of infusion will have a window of ± 10 minutes. In the event of an unplanned 
dose adjustment, an unscheduled PK sample should be collected just prior to the 
infusion rate change. 
• Completion of the HAMD prior to dosing and at Hours 2, 4, 8, 12, and 24 on Day 1 
(± 30 minutes). 
• Completion of the IVR HAMD prior to dosing and at Hour 24 on Day 1 (± 30 
minutes). 
• Completion of the MADRS prior to dosing and at Hour 24 on Day 1 (± 30 minutes). 
• Completion of the CGI-S prior to dosing and the CGI-I at Hours 2, 4, 12, and 24 on 
Day 1 (± 30 minutes). 


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• Completion of the following questionnaires prior to dosing: BIMF, EPDS, GAD-7, 
and PHQ-9 (± 30 minutes). 
• Completion of the SSS prior to dosing and at Hours 2, 4, 8, 12, 18, and 24 on Day 1 
(± 15 minutes) unless the subject is asleep between the hours of 23.00h and 06.00h 
each day. 
• AEs will be monitored. 
• Concomitant medications will be recorded. 
• Completion of the “Baseline” C-SSRS form prior to dosing. Completion of the “Since 
Last Visit” C-SSRS form at Hour 24(± 30 minutes) . 
• Per subject consent (optional), collection of breast milk at pre-infusion and at the 
following time periods of interest: 0, 1-12, 12-24, 24-36, 36-48, 48-60, and 60-72 
hours after the start of the infusion. 
13.2.2 Day 2 
• Ongoing SAGE-547 maintenance infusion administration. 
• Vital signs and pulse oximetry will be recorded at Hours 30, 36, 42, and 48 
(± 30 minutes), unless the subject is asleep between the hours of 23.00h and 06.00h 
each day. 
• Additional measures of pulse oximetry will be collected during sleeping hours. 
• A blood sample for PK analysis will be collected at Hours 30, 36, and 48. PK blood 
draws will have a window of ± 10 minutes. In the event of an unplanned dose 
adjustment, an unscheduled PK sample should be collected just prior to the infusion 
rate change. 
• Completion of the HAMD at Hour 36 and Hour 48 (± 30 minutes). 
• Completion of the IVR HAMD at Hour 48 (± 30 minutes). 
• Completion of the CGI-I at Hour 36 and Hour 48 (± 30 minutes). 
• Completion of the MADRS at Hour 48 (± 30 minutes). 
• Completion of the SSS at Hours 30, 36, 42, and 48 on Day 2 (± 15 minutes) unless 
the subject is asleep between the hours of 23.00h and 06.00h each day. 
• An ECG reading taken at Hour 48. 
• AEs will be monitored. 
• Concomitant medications will be recorded. 
• Per subject consent (optional), ongoing collection of breast milk during the 
maintenance phase of infusion. 


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13.2.3 Day 3 
• Ongoing SAGE-547 maintenance infusion administration until Hour 60. 
• Completion of physical examination. 
• Vital signs will be recorded at Hours 54, 60, 66, and 72 (± 30 minutes) . 
• A blood sample for PK analysis will be collected at Hours 60 and 72 (± 10 minutes). 
In the event of an unplanned dose adjustment, an unscheduled PK sample should be 
collected just prior to the infusion rate change. 
• Blood sample collected for clinical laboratory testing at Hour 72. 
• Completion of the HAMD and MADRS at Hour 60 and 72 (± 30 minutes). 
• Completion of the IVR HAMD at Hours 60 and 72 (± 30 minutes). 
• Completion of the CGI-I at Hours 60 and 72 (± 30 minutes). 
• Completion of the following questionnaires at Hour 60: EPDS, GAD-7, and PHQ-9 
(± 30 minutes). 
• Completion of the SSS at Hours 54, 60, 66, and 72 on Day 3 (± 15 minutes) unless 
the subject is asleep between the hours of 23.00h and 06.00h each day. 
• AEs will be monitored.  
• Concomitant medications will be recorded. 
• Completion of the C-SSRS at Hours 60 and 72. 
• Per subject consent (optional), ongoing collection of breast milk. 
13.3 Follow-up Period (Day 7 through Day 60) 
13.3.1 Day 7 (± 1 day) 
The following assessments should be completed: 
• Completion of physical examination. 
• Vital signs. 
• Blood and urine samples collected for clinical laboratory testing. 
• An ECG reading taken. 
• Completion of the C-SSRS, HAMD, IVR HAMD, MADRS, CGI-I, EPDS, GAD-7, 
PHQ-9 and BIMF. 
• AEs will be monitored.  
• Concomitant medications will be recorded.  
13.3.2 Day 30 (± 3 days) 
The following assessments should be completed: 


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• Urine will be collected for a pregnancy test. 
• Vital signs. 
• Completion of the C-SSRS, HAMD, IVR HAMD, MADRS, CGI-I, EPDS, GAD-7, 
PHQ-9 and BIMF. 
• AEs will be monitored.  
• Concomitant medications will be recorded.  


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14 STATISTICAL METHODS AND CONSIDERATIONS 
In general, summary statistics for all study endpoints will be presented as mean, standard 
deviation (SD), median, and ranges for continuous endpoints, and as counts and percentages 
for categorical endpoints. For the purpose of all safety, efficacy, and exploratory analyses 
where applicable, baseline is defined as the last pre-dose measurement closest to the start of 
blinded study drug infusion. 
A statistical analysis plan (SAP) will be generated and approved by a representative of Sage 
Therapeutics prior to database lock. All statistical analyses will be conducted using SAS for 
Windows (version 9.1.3, or higher; Cary, NC), unless otherwise specified.  
Any deviations from the planned analyses will be described and justified in the final clinical 
study report (CSR). 
14.1 Data Analysis Sets 
The intent-to-treat (ITT) subject population in this study is adult female subjects who meet 
all eligibility criteria and who sign an informed consent to participate in this trial regardless 
whether or not study drug is administered. 
Safety Population (SAF): All ITT subjects who begin receiving a study drug infusion will 
be included in the safety population.  Subjects will be classified according to actual treatment 
received. This analysis population will be used for all safety analyses.   
Efficacy Population (EFF): All SAF subjects who complete at least 12 hours of infusion 
and have efficacy evaluations through the 12-hour timepoint on Day 1.  Subjects will be 
classified according to randomized treatment.  This analysis population will be used for all 
efficacy analyses. 
Per Protocol Population (PP): All EFF subjects who complete the full infusion with all 
efficacy assessments through hour 60, and without significant protocol violations or 
deviations.  Subjects will be classified according to randomized treatment.  This analysis 
population will be used for select sensitivity analyses of the primary and key secondary 
endpoints. 
PK Population (PKP): All SAF subjects treated with SAGE-547 for whom at least one 
evaluable PK sample is available. 
Breast Milk Population (BMP): All SAF subjects who begin receiving a study drug 
infusion and have at least one breast milk sample taken. 
The number and percentage of subjects who receive SAGE-547 Injection or placebo, 
prematurely discontinue, and complete the study will be summarized. The number and 
percentage of subjects will also be summarized for each reason for premature 
discontinuation. In addition, the number of subjects whose data should be used for the 
planned analyses will be identified for each respective analysis population (i.e., SAF, EFF, 
PKP, PP, and BMP). 


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14.2 Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, 
as per the analysis populations, using all non-missing data available. Any rules for the 
imputation of missing data will be described in the SAP. 
14.3 Demographics and Baseline Characteristics 
Demographics such as age, race, and ethnicity will be summarized. In addition, baseline 
characteristics such as height, weight, and BMI will be summarized. Categorical summaries, 
such as race and ethnicity, will be summarized by frequency and percentage. Continuous 
summaries, such as age, height, weight, BMI and baseline vital signs, will be summarized 
using descriptive statistics such as n, mean, SD, median, minimum, and maximum. 
Drug, alcohol, and pregnancy screening results will be collected and listed but not 
summarized, as they are considered part of the inclusion/exclusion criteria.  
Medical/family history will be collected and listed by subject. 
14.4 Primary Endpoints 
Change from baseline to each assessment in HAMD total score will be analyzed using a 
mixed effects repeated measures model (MMRM) including center, treatment, baseline 
HAMD total score, assessment timepoint, and timepoint-by-treatment.  Center will be treated 
as a random effect while all other explanatory variables will be treated as fixed effects. The 
primary comparison will be between SAGE-547 and placebo at the 60 hour assessment.  
Model based point estimates (i.e., LS means), 95% confidence intervals, and p-values will be 
reported for each assessment.   
Summaries of HAMD total scores and changes from baseline values will include n, mean, 
SD, median, minimum, and maximum.  
14.5 Secondary Endpoints 
Efficacy Analysis 
MMRM methods similar to those described in Section 14.4 will be used for the analysis of 
the following variables: MADRS total score, CGI-S score, EPDS total score, GAD-7 total 
score, PHQ-9 total score, and select individual item and subscale scores. For each model, the 
comparison of interest will be between SAGE-547 and placebo at the 48 hour assessment. 
Model based point estimates (i.e., LS means), 95% confidence intervals, and p-values will be 
reported.   
Logistic regression methods will be used for the analysis of the following response variables: 
HAMD response, HAMD remission, and CGI-I response.  Logistic regression models will 
include terms for center, treatment, and baseline score. The comparison of interest will be the 
difference between SAGE-547 and placebo at the 60-hour assessment. Model based point 
estimates (i.e., odds ratios), 95% confidence intervals, and p-values will be reported. For the 
CGI-I response analysis, baseline CGI-S score will be included in the model.   


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Descriptive statistics for all scores, change from baseline values, and response variables will 
be presented by treatment and assessment timepoint.  Summaries will include n, mean, SD, 
median, minimum, and maximum.  
Safety Analysis 
Safety and tolerability of SAGE-547 Injection will be evaluated by AEs, concomitant 
medications, changes from baseline in physical examination, vital signs, CBC, serum 
chemistry, urinalysis, and 12-lead ECG. Suicidality will be monitored by the C-SSRS. 
Sedation will be assessed using the SSS. Safety data will be listed by individual and 
summarized by treatment group. In addition, an analysis of SSS data will be performed 
comparing the treatment groups in the same way as for the primary endpoint. All safety 
summaries will be performed on the SAF population. 
Safety data will be examined for possible relationships between subject characteristics and 
plasma allopregnanolone concentrations, as appropriate. 
Scheduled visits for all safety assessments are described in Section 12.1 and summarized in 
Table 1. 
Adverse events: The analysis of AEs will be based on the concept of treatment-emergent AEs 
(TEAEs). A TEAE is defined as an AE with onset after the start of SAGE-547 infusion, or 
any worsening of a pre-existing medical condition/AE with onset after the start of SAGE-547 
infusion and until 7 days after the end of infusion (i.e., Day 10). A treatment-emergent 
serious AE (TESAE) is defined as an AE with onset after the start of SAGE-547 infusion, or 
any worsening of a pre-existing medical condition/AE with onset after the start of SAGE-547 
infusion and until 30 days after the end of infusion (i.e., Day 33). All TEAEs will be 
summarized and grouped by MedDRA® System Organ Class (SOC) and specific AE 
preferred term (PT). Results will be displayed in order of decreasing frequency by SOC and 
PT. For presentation, AE verbatim text will be coded into a MedDRA term and classified by 
SOC and PT using MedDRA® version 17.0 or higher. In addition, summaries will be 
provided by severity (mild, moderate, severe) and by causality (related, not related) to study 
drug (see Section 15.2.2). 
TEAEs and TESAEs leading to discontinuation will be summarized and listed. 
Adverse events with onset after the completion of screening but prior to the start of SAGE-
547 infusion (considered non-treatment emergent) will be listed by subject. 
Clinical laboratory evaluations: Results will be listed by Subject ID and timing of collection. 
Mean changes from baseline in clinical laboratory measures will be evaluated. 
Physical examinations: Physical examinations will be evaluated at Screening and Day 7. Any 
clinically significant change in physical examination compared to those observed at 
Screening should be noted as an AE.  
Vital signs: Vital signs, including oral temperature (°C), respiratory rate, heart rate, blood 
pressure (supine and standing), and pulse oximetry will be obtained at the scheduled time 
points described in Section 12.1.4. Mean changes from baseline (pre-infusion) in vital signs 
will be evaluated.  


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12-Lead ECG: The following ECG parameters will be listed for each subject: heart rate, PR, 
QRS, QT, and QTc. Any clinically significant abnormalities or changes in ECGs should be 
listed as an AE. ECG findings will be listed by subject and visit. 
Concomitant medications: A summary of all concomitant medications taken during the 
course of the study will be presented in tabular form by therapeutic drug class and generic 
drug name using the WHO Collaborating Centre for Drug Statistics Methodology Norwegian 
Institute of Public Health (http://www.whocc.no). 
C-SSRS: Suicidality data collected on the C-SSRS at baseline and by visit during the 
Treatment Period will be listed for all subjects. Listings will include behavior type and/or 
category for Suicidal Ideation and Suicidal Behavior of the C-SSRS. 
SSS: Changes in score over time will be represented graphically, and change from baseline 
will be measured. 
PK Analysis: Plasma will be collected to assay for concentrations of SAGE-547, metabolites 
of SAGE-547, and SBECD. The following PK parameters will be derived from the plasma 
concentrations (where evaluable): AUC0-60, AUCinf, Cmax, time at maximum (peak) plasma 
concentration (Tmax), steady-state drug concentration in the plasma during constant-rate 
infusion (Css), and average drug concentration in the plasma at steady state during a dosing 
interval (Cavg). 
Plasma concentrations will be listed by subject and summarized by nominal collection 
timepoint. PK parameters will be listed by subject and summarized by collection timepoint. 
Correlations between concentrations and AEs or tolerability measures may be performed as 
deemed necessary. 
In addition to typical descriptive statistics, summaries should include geometric mean, 
coefficient of variation, and geometric coefficient of variation. 
14.6 Determination of Sample Size 
Assuming a two-sided test at an alpha level of 0.10, a sample size of 10 evaluable subjects 
per group would provide 80% power to detect an effect size of 1.2 between the SAGE-547 
and placebo groups with regard to the primary outcome variable of change from baseline in 
HAMD total score. An effect size of 1.2 corresponds to a placebo adjusted difference of 12 
points in the change from baseline in HAMD total score at 60 hours with an assumed 
standard deviation of 10 points. By including two treatment groups and using a 1:1 
randomization ratio, a total of 20 evaluable subjects are required. Assuming a non-
evaluability rate of 10%, at least 22 subjects will be randomized. 
Based on the results of the interim analysis (see Section 14.7), the sample size could be increased to a 
maximum of 32 randomized subjects. This adjustment to the sample size would allow for an effect 
size of 1.0 to be detected.   
 


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14.7 Interim Analysis 
An interim analysis will be conducted by an independent DSMB for sample size re-
estimation purposes when at least 16 subjects have completed efficacy assessments through 
60 hours. Since the sponsor will be kept uninformed of the response rates at the time of the 
interim analysis, no statistical adjustment will be made to the level of significance for 
hypothesis testing at the end of the study. A detailed description of the interim analysis plan 
will be included in an interim analysis plan. 
14.8 Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the 
final SAP.  


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15 ADVERSE EVENTS 
Section 15.1 lists important AE definitions. 
Section 15.2 summarizes Investigator responsibilities regarding the identification and 
documentation of AEs, the classification of AEs for relationship to study drug and severity, 
and the reporting of AE information to the Sponsor and the IRB. 
Section 15.3 summarizes Sponsor/Medical Monitor Responsibilities regarding monitoring of 
AE data and reporting relevant safety information to FDA. 
15.1 Adverse Event Definitions 
15.1.1 Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  
15.1.2 Suspected Adverse Reaction  
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
15.1.3 Life-Threatening  
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either 
the Investigator or Sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death. 
15.1.4 Serious  
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
• Death 
• A life-threatening AE (see definition in Section 15.1.3) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability or incapacity  
• A congenital anomaly or birth defect 
• Other medically important condition (as described below)  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 


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allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
15.1.5 Unexpected  
An AE or suspected adverse reaction is considered “unexpected”:  
• If it is not listed in the Investigational Brochure or is not listed at the specificity or 
severity that has been observed, or  
• If an Investigational Brochure is not required or available, is not consistent with the 
risk information described in the general investigational plan or elsewhere in the 
current application, as amended.  
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the Investigational Brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the Investigational Brochure listed only cerebral vascular 
accidents.  
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the Investigational Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.  
15.2 Investigator Responsibilities 
15.2.1 Identification and Documentation of Adverse Events by Investigator 
Subjects will be evaluated and questioned generally (if possible) to identify AEs during the 
course of the study. AEs will be collected during subject preparation, study drug 
administration during Screening, after the initiation of study drug administration through to 
Day 3, and at the Follow-up Visits on Day 7 (± 1 day) and Day 30 (± 3 days). SAEs will 
continue to be collected until the Day 30 (± 3 days) follow-up visit. Medical conditions that 
occur prior to completion of the Screening Visit will be captured on the Medical History 
eCRF. Adverse events that occur after completion of the Screening Visit will be recorded on 
the AE page of the eCRF (AE eCRF).  
All AEs revealed by observation, physical examinations, other diagnostic procedures, or 
spontaneously reported by the subject and/or in response to an open question from study 
personnel will be recorded on the AE eCRF. Any clinically significant deterioration from 
baseline in laboratory assessments or other clinical findings is considered an AE and must be 
recorded on the AE eCRF, unless otherwise stated. AE information recorded on AE eCRF 
will be entered into the database on an ongoing basis. The database, including AE 
information, will be transferred to the Sponsor on a pre-defined schedule for review.  
All AEs, regardless of investigator-determined causality, should be followed until the event 
is resolved or the Investigator determines the event is stable or no longer clinically 
significant.  


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For all SAEs, an SAE report form must be completed with as much information as possible 
and submitted in the time frame described in Section 15.2.3. When new significant 
information is obtained as well as when the outcome of an event is known, the SAE report 
form should be updated on a follow-up report. If the subject was an outpatient at the time of 
the SAE and was re-hospitalized due to the SAE, a copy of relevant hospital records (e.g., 
admission report, laboratory test results, discharge summary, etc.) may be requested to be 
included as part of the subject’s medical file.  
All SAEs will be followed until the events are resolved or improved, a stable status has been 
achieved, or the subject is lost to follow-up.  
15.2.2 Adverse Event Classification 
Definitions for the categories of AE classification are included in this section.  
16. Relationship to Investigational Drug 
Not Related:  
The temporal relationship of the clinical event to study drug 
administration makes causal relationship unlikely AND other drugs, 
therapeutic interventions, or underlying conditions provide a plausible 
explanation for the observed event. 
Related:  
Reasonable temporal relationship of the clinical event to study drug 
administration AND cannot be reasonably explained by other factors 
(such as the subject’s clinical state, concomitant therapy, and/or other 
interventions).  
Possibly Related:  The temporal relationship of the clinical event to study drug 
administration makes causal relationship possible but not unlikely AND 
other drugs, therapeutic interventions, or underlying conditions do not 
provide a sufficient explanation for the observed event.  
17. Severity 
The severity of an adverse experience will be defined as follows and reported as indicated on 
the AE eCRF: 
Mild: 
 
Discomfort noticed, but no disruption to daily activity.  
Moderate: 
Discomfort sufficient to reduce or affect normal daily activity, but is 
not hazardous to health; prescription drug therapy may be employed to 
treat the AE. 
Severe: 
Inability to work or perform normal daily activity and represented a 
definite hazard to health; prescription drug therapy and/or 
hospitalization may be employed to treat the AE. 
18. Action Taken With Investigational Drug 
Action taken with regard to administration of SAGE-547 Injection for this trial will be 
recorded using the one of following categories (the category “dose increased” does not apply 
to this trial):  


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• Drug withdrawn: An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication.  
• Dose not changed: An indication that a medication schedule was maintained.  
• Drug interrupted: An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication.  
• Dose reduced: An indication that a medication schedule was modified to a reduced 
rate/dose.  
• Unknown: Unknown, not known, not observed, not recorded, or refused. 
• Not applicable: Determination of a value is not relevant in the current context.  
19. Assessment of Outcome 
Assessment of outcome of AEs will be categorized as one of the following:  
• Recovered/Resolved: The event has improved or recuperated.  
• Recovering/Resolving: The event is improving.  
• Not Recovered/Not Resolved: The event has not improved or recuperated.  
• Recovered/Resolved with Sequel: The subject recuperated but retained pathological 
conditions resulting from the prior disease or injury.  
• Fatal: The termination of life as a result of an adverse event.  
• Unknown: Not known, not observed, not recorded, or refused.  
15.2.3 Investigator Reporting to Sponsor and Sponsor Emergency Contact 
All SAEs that occur during the course of the study must be reported by the Investigator on 
the designated report form (study-specific SAE form or MedWatch 3500A form) and sent by 
facsimile to the medical monitor within 24 hours from the point in time when the Investigator 
becomes aware of the SAE. Investigators must report any SAE, whether or not considered 
drug related. The initial report must be as complete as possible, including assessment of the 
causal relationship (i.e., assessment of whether there is a reasonable possibility that the drug 
caused the event). The medical monitor will contact the investigator via telephone for follow-
up information regarding the SAE, as appropriate. 
Information not available at the time of the initial report must be documented on a follow-up 
report. As additional information becomes available, the designated report form must be 
updated and supporting information, including hospital records, laboratory and diagnostic 
testing results, etc. All supporting documentation must be de-identified. In addition, all SAEs 
that occur up to and including 30 days after administration of study drug must be reported 
within 1 working day from when the Investigator becomes aware of the SAE. A final report 
to document resolution of all SAEs is required. 
In a medical emergency (i.e., an event that requires immediate attention regarding the 
treatment of a subject, operation of the clinical study, and/or the use of investigational drug), 
study site staff will apply appropriate medical intervention according to current standards of 
care and contact the Medical Monitor. 


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15.2.4 Medical Monitor and Emergency Contact Information 
, MD  
Office (9-5 EST): 
  
24/7 Hotline:
  
 
15.2.5 SAE Reporting Contact Information 
Contact information and reporting instructions are provided in the Safety Management Plan. 
15.2.6 Reporting to Institutional Review Boards (IRBs) 
It is the responsibility of the Investigator to promptly notify the institution’s IRB of all 
serious and unexpected suspected adverse reactions (see Section 15.3.2). 
15.3 Sponsor/Medical Monitor Responsibilities 
15.3.1 Monitoring of Adverse Event Data 
The Medical Monitor or designee will review AEs on an ongoing basis. 
15.3.2 Reporting to FDA 
The Sponsor must report in an IND safety report any suspected adverse reaction to study 
treatment that is both serious and unexpected (21 CFR 312.32[c][1][i]). Before submitting an 
IND safety report, the Sponsor will ensure the event meets all three of the definitions: (1) 
suspected adverse reaction, (2) serious, (3) unexpected. If the AE does not meet all three of 
the definitions, it should not be submitted as an IND safety report. The Sponsor should 
evaluate the available information and decide whether there is a reasonable possibility that 
the drug caused the AE and, therefore, that the event meets the definition of a suspected 
adverse reaction. 
If there is a serious and unexpected suspected adverse reaction, the Sponsor will notify the 
appropriate regulatory agency(ies) and all appropriate parties on an expedited basis. In 
addition, Sponsors must submit expedited reports of an increased rate of occurrence of 
serious suspected adverse reactions over that listed in the protocol or Investigational 
Brochure. 
15.4 Emergency Identification of Study Medication 
In exceptional circumstances and for the safety of the study subject, the Investigator may 
request unblinding of an individual subject’s treatment from the pharmacist; this normally 
requires prior approval by the Medical Monitor. However, if the subject is at immediate risk 
and the Investigator believes that immediate knowledge of the study treatment will alter 
medical management, discussion with the Medical Monitor may take place after unblinding. 
The Investigator will not unblind the Medical Monitor during that discussion. The process of 


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unblinding will ensure that only the investigator is unblinded; the Medical Monitor, study 
management team, and data management team will not be made aware of the treatment 
allocation of an individual subject. All cases of emergency unblinding will be fully 
documented in a way that does not unblind the Medical Monitor, study management team, 
and data management team. 


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16 STUDY ADMINISTRATION 
16.1 Quality Control and Quality Assurance 
The Investigators and institutions will permit trial-related monitoring, audits, IRB review, 
and regulatory inspections as requested by FDA, the Sponsor, or the Sponsor’s designee, 
including direct access to source data/documents (i.e., original medical records, laboratory 
reports, hospital documents, progress reports, signed ICFs, etc.) in addition to CRFs. 
Quality assurance and quality control systems with written standard operating procedures 
(SOPs) will be followed to ensure that this trial will be conducted and data will be generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements.  
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals 
during the study. The monitoring visits must be conducted according to the applicable ICH 
and GCP guidelines to ensure protocol adherence, quality of data, drug accountability, 
compliance with regulatory requirements, and continued adequacy of the investigational site 
and its facilities. During these visits, CRFs and other data related to the study will be 
reviewed and any discrepancies or omissions will be identified and resolved. The study 
monitor will be given access to study-relevant source documents (including medical records) 
for purposes of source data verification. 
During and/or after completion of the study, quality assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The 
Investigator is expected to cooperate with any audit and provide assistance and 
documentation (including source data) as requested.  
Quality control will be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties 
involved with the clinical trial will be in writing in a separate agreement. 
16.2 Data Handling and Recordkeeping 
16.2.1 Data Handling 
Procedures for data handling (including electronic data) used in this protocol will be 
documented in a Data Management Plan.  
16.2.2 Case Report Form Completion 
Electronic CRFs (eCRFs) will be completed for each study subject. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
subject’s eCRF. Source documentation supporting the eCRF data should indicate the 
subject’s participation in the study and should document the dates and details of study 
procedures, AEs, and subject status. 
The Investigator will have access to the electronic data capture (EDC) system and will 
receive a copy of the subject eCRF data at the end of the study. For subjects who discontinue 


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or terminate from the study, the eCRFs will be completed as much as possible, and the reason 
for the discontinuation or termination clearly and concisely specified on the appropriate 
eCRF. 
16.2.3 Retention of Study Records 
The Investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirements. Records will be retained for at least two years after the last 
marketing application approval and until there are no pending or contemplated marketing 
applications or two years after formal discontinuation of the clinical development of the 
investigational product or according to applicable regulatory requirements. If the Investigator 
withdraws from the responsibility of keeping the study records, custody must be transferred 
to an appropriate person willing to accept the responsibility. The Sponsor must be notified in 
writing if a custodial change occurs.  
16.3 Confidentiality 
To maintain subject privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the subject by the assigned subject number. The Investigator 
will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authority(ies) access to the subject’s original medical records for verification of data gathered 
on the CRFs and to audit the data collection process. The subject’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable 
laws and regulations. 
Subjects will be notified that registration information, results, and other information about 
this study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used. 
All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information. The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent 
from the Sponsor. It is understood that there is an obligation to provide the Sponsor with 
complete data obtained during the study. The information obtained from the clinical study 
will be used towards the development of the investigational product and may be disclosed to 
regulatory authority(ies), other Investigators, corporate partners, or consultants as required. 
16.4 Publication Policy 
All information concerning SAGE-547 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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16.5 Protocol Amendments 
Changes to the conduct of the study should be prepared as a protocol amendment by the 
Sponsor. Protocol amendments should receive written IRB/IEC approval prior to 
implementation at the investigative site, except when necessary to eliminate immediate 
hazards to the subjects or when the changes involve only logistical or administrative aspects 
of the trial (e.g., change of monitor, telephone numbers). In this case, Sage Therapeutics will 
amend and implement the protocol change and subsequently notify the regulatory authorities 
and the Investigative sites who will notify the respective IRB, as appropriate. 


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D


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18 APPENDICES 
Copies of the rating scales and questionnaires included in APPENDIX 1 through APPENDIX 
9 are for reference only. 
 
 
APPENDIX 1. Columbia Suicide Severity Rating Scale (C-SSRS) ....................... 72 
APPENDIX 2. Hamilton Rating Scale for Depression, 17-Item (HAMD) ............ 79 
APPENDIX 3. Montgomery Asberg Depression Rating Scale (MADRS) ............ 81 
APPENDIX 4. Clinical Global Impression–Improvement Scale (CGI-I) and 
Severity Scale (CGI-S) ................................................................... 84 
APPENDIX 5. Standford Sleepiness Scale (SSS) .................................................. 86 
APPENDIX 6. Edinburgh Postnatal Depression Scale (EPDS) ............................. 88 
APPENDIX 7. Generalized Anxiety Disorder 7-Item Scale (GAD-7) ................... 90 
APPENDIX 8. Patient Health Questionnaire (PHQ-9) ........................................... 92 
APPENDIX 9. Barkin Index of Maternal Functioning (BIMF).............................. 94 
APPENDIX 10. Selected Inducers, Inhibitors, and Substrates of CYP2C9 ........... 96 
  
 


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APPENDIX 1. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The “Baseline” and “Since Last Visit” versions of the C-SSRS begin on the next full page 
(Posner et al. 2011). 
 


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APPENDIX 2. 
Hamilton Rating Scale for Depression, 17-Item (HAMD) 
The HAMD presents on the next full page (Hamilton 1960). 
The HAMD total score will be calculated as the sum of the 17 individual item scores. Item 16 
can be rated according to history (item 16A) or actual weight change (item 16B). The item 16 
score is calculated as the item 16 response that is not equal to 3 (i.e., “Not assessed). 
 


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APPENDIX 3. 
Montgomery Asberg Depression Rating Scale (MADRS) 
The MADRS presents on the next full page. (McDowell 2006, Müller-Thomsen 2005). 
 


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APPENDIX 4. 
Clinical Global Impression–Improvement Scale (CGI-I) 
and Severity Scale (CGI-S) 
The CGI-I and CGI-S presents on the next full page. For the purposes of Protocol 547-PPD-202, only 
Items 1 and 2, Severity of Illness and Global Improvement, will be assessed in subjects enrolled in the 
study. 
 


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APPENDIX 5. 
Stanford Sleepiness Scale (SSS) 
The SSS presents on the next full page. 
 


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Stanford Sleepiness Scale 
This is a quick way to assess how alert you are feeling. If it is during the day when you go about your 
business, ideally you would want a rating of a one. Take into account that most people have two peak 
times of alertness daily, at about 9 a.m. and 9 p.m. Alertness wanes to its lowest point at around 3 
p.m.; after that it begins to build again. Rate your alertness at different times during the day. If you go 
below a three when you should be feeling alert, this is an indication that you have a serious sleep debt 
and you need more sleep. 
An Introspective Measure of Sleepiness 
The Stanford Sleepiness Scale (SSS) 
Degree of Sleepiness 
Scale 
Rating 
Feeling active, vital, alert, or wide awake 
1 
Functioning at high levels, but not at peak; 
able to concentrate 
2 
Awake, but relaxed; responsive but not fully 
alert 
3 
Somewhat foggy, let down 
4 
Foggy; losing interest in remaining awake; 
slowed down 
5 
Sleepy, woozy, fighting sleep; prefer to lie 
down 
6 
No longer fighting sleep, sleep onset soon; 
having dream-like thoughts 
7 
Asleep 
X 
 


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APPENDIX 6. 
Edinburgh Postnatal Depression Scale (EPDS) 
The EPDS presents on the next full page (Cox et al. 1987). 
 


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APPENDIX 7. 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) 
The GAD-7 presents on the next full page (Spitzer 2006). 
 


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APPENDIX 8. 
Patient Health Questionnaire (PHQ-9) 
The PHQ-9 presents on the next full page. 
Developed by Drs. Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke, and colleagues 
with an educational grant from Pfizer Inc. No permission required to reproduce, translate, 
display or distribute. 
 
 


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APPENDIX 9. 
Barkin Index of Maternal Functioning (BIMF) 
The BIMF is presented on the next full page. 
 


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APPENDIX 10. Selected Inducers, Inhibitors, and Substrates of CYP2C9 
Inhibitors of CYP2C9 can be classified by their potency, such as: 
• 
Strong being one that causes at least a 5-fold increase in the plasma AUC values, or more 
than 80% decrease in clearance. 
• 
Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or 50-
80% decrease in clearance. 
• 
Weak being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma 
AUC values, or 20-50% decrease in clearance. 
Substrates 
Inhibitors 
Inducers 
• 
NSAIDs 
(analgesic, antipyretic, anti-
inflammatory) 
o 
celecoxib  
o 
lornoxicam  
o 
diclofenac  
o 
ibuprofen  
o 
naproxen  
o 
ketoprofen 
o 
piroxicam  
o 
meloxicam  
o 
suprofen 
• 
phenytoin (antiepileptic) 
• 
fluvastatin (statin) 
• 
sulfonylureas (antidiabetic) 
o 
glipizide  
o 
glibenclamide  
o 
glimepiride  
o 
tolbutamide  
o 
glyburide 
• 
angiotensin II receptor 
antagonists (in 
hypertension, diabetic 
nephropathy, CHF) 
o 
irbesartan  
o 
losartan  
• 
S-warfarin (anticoagulant) 
• 
sildenafil (in erectile dysfunction) 
• 
terbinafine (antifungal) 
• 
amitriptyline (tricyclic 
antidepressant) 
• 
fluoxetine (SSRI antidepressant) 
• 
nateglinide (antidiabetic) 
• 
rosiglitazone (antidiabetic) 
• 
tamoxifen (SERM) 
• 
torasemide (loop diuretic) 
• 
ketamine 
• 
THC 
• 
JWH-018 
• 
AM-2201 
Strong 
• 
fluconazole (antifungal) 
• 
miconazole (antifungal) 
• 
amentoflavone 
(constituent of Ginkgo 
biloba and St. John’s Wort) 
• 
sulfaphenazole (antibacterial) 
• 
valproic acid (anticonvulsant, 
mood-stabilizing) 
• 
apigenin 
 
Moderate 
• 
amiodarone (antiarrhythmic) 
 
Unspecified potency 
• 
antihistamines (H1 receptor 
antagonists) 
o 
cyclizine 
o 
promethazine 
• 
chloramphenicol 
• 
fenofibrate (fibrate) 
• 
flavones 
• 
flavonols 
• 
fluvastatin (statin) 
• 
fluvoxamine (SSRI) 
• 
isoniazid (in tuberculosis) 
• 
lovastatin (statin) 
• 
phenylbutazone (NSAID) 
• 
probenecid (uricosuric) 
• 
sertraline (SSRI) 
• 
sulfamethoxazole (antibiotic) 
• 
teniposide (chemotherapeutic) 
• 
voriconazole (antifungal) 
• 
zafirlukast (leukotriene 
antagonist) 
• 
quercetin (anti-inflammatory) 
Strong 
• 
rifampicin (bactericidal) 
• 
secobarbital 
(barbiturate) 
 
 
 







SAP_001.pdf: 
Clinical Study Report 
 
547-PPD-202C 
16.1 Study Information 
 
1 
 
 
  
 
9. 
DOCUMENTATION OF STATISTICAL METHODS 
Statistical Analysis Plan 


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-202C 
CONFIDENTIAL 
SAGE THERAPEUTICS INCORPORATED 
Statistical Analysis Plan 
Methods 
Protocol Number 547-PPD-202C/NCT02942017
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-
Controlled Study Evaluating the Efficacy, Safety, and Pharmacokinetics of 
SAGE-547 Injection in the Treatment of Adult Female Subjects with Severe 
Postpartum Depression and Adult Female Subjects with Moderate 
Postpartum Depression 
Author of SAP: 
 
Version: Version 1.0 
Date of SAP: 27 OCTOBER 2017 
Sponsor Representative: 
, PhD 
 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, Massachusetts 02142 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Sage Therapeutics Incorporated is strictly prohibited except to the extent required under applicable 
laws or regulations.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 
1 




Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-202C 
CONFIDENTIAL 
 
3 
 
1 
TABLE OF CONTENTS 
1 
Table of Contents ............................................................................................................. 3 
2 
List of Abbreviations ....................................................................................................... 6 
3 
Introduction...................................................................................................................... 8 
4 
Study Objectives .............................................................................................................. 8 
4.1 
Primary Objective ....................................................................................................... 8 
4.2 
Secondary Objectives ................................................................................................. 8 
4.3 
Other Objectives ......................................................................................................... 8 
4.4 
Pharmacokinetic Objectives ....................................................................................... 9 
5 
Study Endpoints ............................................................................................................... 9 
5.1 
Primary Endpoint ........................................................................................................ 9 
5.2 
Secondary Endpoints .................................................................................................. 9 
5.2.1 
Key Secondary Efficacy Endpoints .................................................................... 9 
5.2.2 
Other Secondary Efficacy Endpoints ................................................................. 9 
5.2.3 
Safety Endpoints ............................................................................................... 10 
5.3 
Other Endpoints ........................................................................................................ 10 
5.4 
Pharmacokinetic Endpoints ...................................................................................... 10 
6 
Study Design ................................................................................................................... 10 
6.1 
Overall Design .......................................................................................................... 10 
6.2 
Sample Size and Power ............................................................................................ 12 
6.3 
Randomization .......................................................................................................... 12 
6.4 
Blinding and Unblinding .......................................................................................... 12 
7 
Modifications .................................................................................................................. 13 
7.1 
Modifications from the Approved Clinical Study Protocol ..................................... 13 
7.2 
Modifications from the Approved Statistical Analysis Plan .................................... 13 
7.3 
Modifications from the Approved DMC Charter ..................................................... 13 
8 
Analysis Sets ................................................................................................................... 13 
8.1 
All Enrolled Set ........................................................................................................ 13 
8.2 
All Randomized Set .................................................................................................. 14 
8.3 
Safety Set .................................................................................................................. 14 
8.4 
Efficacy Set .............................................................................................................. 14 
8.5 
Per Protocol Set ........................................................................................................ 14 
8.6 
Pharmacokinetics Set ................................................................................................ 14 
9 
Statistical Analysis ......................................................................................................... 14 
9.1 
General Considerations ............................................................................................ 14 
9.1.1 
Study Day Definition ........................................................................................ 15 
9.1.2 
Baseline Definition ........................................................................................... 15 
9.1.3 
Missing Data ..................................................................................................... 15 
9.1.3.1 
Adverse Events Onset Date ........................................................................ 15 
9.1.3.2 
Prior and Concomitant Medications Date .................................................. 16 
9.2 
Background Characteristics ...................................................................................... 17 
9.2.1 
Subject Disposition ........................................................................................... 17 
9.2.2 
Demographics and Baseline Characteristics ..................................................... 17 


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-202C 
CONFIDENTIAL 
 
4 
 
9.2.3 
Medical/Family History .................................................................................... 18 
9.2.4 
Study Drug Exposure and Compliance ............................................................ 18 
9.3 
Efficacy Analysis ...................................................................................................... 19 
9.3.1 
Definition of Primary Efficacy Variable(s) ...................................................... 19 
9.3.2 
Definition of Secondary Efficacy Variable(s) .................................................. 19 
9.3.2.1 
HAM-D Response and HAM-D Remission ............................................... 19 
9.3.2.2 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................ 19 
9.3.2.3 
Clinical Global Impression – Improvement (CGI-I) and Clinical Global 
Impression – Severity (CGI-S) .................................................................. 20 
9.3.2.4 
HAM-D subscales and individual item scores ........................................... 20 
9.3.2.5 
Generalized Anxiety Disorder 7-item Scale (GAD-7) ............................... 21 
9.3.2.6 
Post-baseline Antidepressant Use .............................................................. 22 
9.3.3 
Other Efficacy Endpoints ................................................................................. 22 
9.3.3.1 
Edinburgh Postnatal Depression Scale (EPDS) ......................................... 22 
9.3.3.2 
Patient Health Questionnaire (PHQ-9)....................................................... 22 
9.3.3.3 
Barkin Index of Maternal Functioning (BIMF) ......................................... 23 
9.3.3.4 
Short Form-36 (SF-36) ............................................................................... 23 
9.3.3.5 
Healthcare Resource Utilization (HCRU) .................................................. 23 
9.3.4 
Multiplicity adjustment..................................................................................... 24 
9.3.5 
Visit Windows .................................................................................................. 24 
9.3.6 
Pooling of Centers ............................................................................................ 26 
9.3.7 
Analysis of Efficacy Variable(s) ...................................................................... 26 
9.3.7.1 
Analysis of Primary Efficacy Endpoints .................................................... 27 
9.3.7.2 
Analysis of Secondary Efficacy Endpoints ................................................ 30 
9.3.7.3 
Analysis of Other Efficacy Endpoints........................................................ 32 
9.4 
Safety Analysis ......................................................................................................... 34 
9.4.1 
Visit Windows .................................................................................................. 35 
9.4.2 
Adverse Events ................................................................................................. 36 
9.4.3 
Prior and Concomitant Medications ................................................................. 38 
9.4.4 
Clinical Laboratory ........................................................................................... 39 
9.4.4.1 
Hematology, Serum Chemistry, Coagulation ............................................ 40 
9.4.4.2 
Hormones and Exploratory Biochemistry .................................................. 41 
9.4.4.3 
Pregnancy Test ........................................................................................... 41 
9.4.4.4 
Urinalysis ................................................................................................... 41 
9.4.5 
Electrocardiogram ............................................................................................ 41 
9.4.6 
Vital Signs ........................................................................................................ 42 
9.4.7 
Physical Examination ....................................................................................... 42 
9.4.8 
Columbia Suicide Severity Rating Scale (C-SSRS) ......................................... 42 
9.5 
Pharmacokinetic Analysis ........................................................................................ 42 
9.5.1 
Collection schedule........................................................................................... 43 
9.5.2 
Derived PK parameters ..................................................................................... 43 
9.5.3 
Handling of dropouts or missing data............................................................... 43 
9.5.4 
Statistical analysis............................................................................................. 43 
9.5.5 
Data presentation .............................................................................................. 43 
10 Summary of Interim and DMC Analyses .................................................................... 44 


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-202C 
CONFIDENTIAL 
 
5 
 
11 Index of Tables ............................................................................................................... 45 
12 Index of Figures ............................................................................................................. 50 
13 Index of Listings ............................................................................................................. 51 
14 References ....................................................................................................................... 53 
15 List of Appendices.......................................................................................................... 54 
15.1 Appendix A: Schedule of Assessments .................................................................... 54 
15.2 Appendix B: Details of Statistical Methodology ...................................................... 57 
 


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-202C 
CONFIDENTIAL 
 
6 
 
2 
LIST OF ABBREVIATIONS 
Abbreviation or 
Specialist Term 
Explanation 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
AUC  
area under the concentration-time curve  
AUC∞  
area under the concentration-time curve from time zero to infinity  
BIMF 
Barkin Index of Maternal Functioning 
BMI  
body mass index  
bpm 
beats per minute 
CGI-I  
Clinical Global Impression - Improvement  
CGI-S  
Clinical Global Impression - Severity  
Cmax  
maximum (peak) plasma concentration  
CS 
clinically significant  
Css  
steady-state drug concentration in the plasma during oral intake  
Cavg 
steady-state drug concentration in the plasma 
C-SSRS  
Columbia-Suicide Severity Rating Scale  
ECG  
electrocardiogram  
eCRF  
electronic case report form  
EPDS 
Edinburgh Postnatal Depression Scale 
ET 
early termination 
FCS 
fully conditional specification 
GAD-7 
Generalized Anxiety Disorder 7-Item Scale 
GEE 
Generalized Estimating Equation 
HAM-D  
Hamilton Rating Scale for Depression, 17-item  
HCRU 
healthcare resource utilization 
HIV  
human immunodeficiency virus  
IV 
intravenous 
Kg 
kilogram 
m 
meter 
MADRS  
Montgomery-Åsberg Depression Rating Scale  
Max 
maximum 
MedDRA  
Medical Dictionary for Regulatory Activities  
Min 
minimum 
mmHg 
millimeter of mercury 
MMRM  
mixed effects model for reported measures  
msec 
millisecond 
n  
number  
NCS 
not clinically significant 
PHQ-9 
Patient Health Questionnaire 
PK  
pharmacokinetic(s)  
PPD 
postpartum depression 
PRO 
patient reported outcome 


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-202C 
CONFIDENTIAL 
 
7 
 
PT 
preferred term 
QTcB 
QT corrected with Bazett's formula 
QTcF 
QT corrected with Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBECD 
betadex sulfobutyl ether sodium 
SD  
standard deviation  
SF-36  
Short Form-36  
SI 
International System of Units 
SOC  
system organ class  
ss 
steady state 
TEAE  
treatment-emergent adverse event  
Tmax  
time at maximum (peak) plasma concentration  
WHO  
World Health Organization  
WHO-DDE  
World Health Organization-Drug Dictionary Enhanced 
 


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-202C 
CONFIDENTIAL 
 
Sage Therapeuticsa Inc 
Confidential Information 
 
3 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the approved clinical study protocol 
amendment 4, version 5.0 dated 16th March 2017, case report form (CRF) dated 30th June 
2017.  
Protocol 547-PPD-202 is an umbrella protocol that describes methods for three parts, 
referred to as Parts A, B, and C (hereafter referred to as Study 547-PPD-202A, Study 547-
PPD-202B, and Study 547-PPD-202C, respectively).  These three parts were conducted as 
three separate studies and will be analyzed and reported as such: Study 547-PPD-202A, 
Study 547-PPD-202B, and Study 547-PPD-202C.   
The purpose of the SAP is to describe in detail the statistical methodology and the statistical 
analyses to be conducted for data presentation for Study 547-PPD-202C, a randomized, 
multicenter, parallel-group, placebo-controlled study evaluating doses up to 90 µg/kg/h of 
SAGE-547 Injection in patients with severe postpartum depression.   
All analyses and summary outputs will be generated using SAS® version 9.3 (or higher).  
4 
STUDY OBJECTIVES  
4.1 Primary Objective 
 To determine if SAGE-547 Injection infused intravenously at up to 90 μg/kg/h for 60 
hours reduces depressive symptoms in subjects with moderate PPD compared to 
placebo injection as assessed by the change from baseline in HAM-D total score. 
4.2 Secondary Objectives 
The secondary objectives of Study 547-PPD-202C are: 
 
 To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
depressive symptoms compared to placebo injection as assessed by HAM-D 
response, HAM-D remission, change from baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) total score, Clinical Global Impression - 
Improvement (CGI-I) response, and changes from baseline in HAM-D subscale and 
individual item scores. 
 
 To determine if SAGE-547 Injection infused intravenously for 60 hours reduces other 
mood symptoms compared to placebo injection as assessed by changes from baseline 
in the Generalized Anxiety Disorder 7-Item Scale (GAD-7) total score. 
 
 To evaluate the safety and tolerability of SAGE-547 Injection compared with placebo 
as assessed by the incidence of adverse events (AEs), vital sign measurement, clinical 
laboratory evaluations, electrocardiogram (ECG) parameters, and the Columbia 
Suicide Severity Rating Scale (C-SSRS). 
4.3 Other Objectives 
The other objectives of Study 547-PPD-202C are: 


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-202C 
CONFIDENTIAL 
 
9 
 
  To determine if SAGE-547 Injection infused intravenously for 60 hours reduces 
subject-reported depressive symptoms compared to placebo injection as assessed by 
the change from baseline in Edinburgh Postnatal Depression Scale (EPDS) total score 
and the change from baseline in Patient Health Questionnaire (PHQ-9) total score. 
  To determine if SAGE-547 Injection infused intravenously for 60 hours improves 
maternal behaviors compared to placebo injection as assessed by the change from 
baseline in Barkin Index of Maternal Functioning (BIMF) total and sub-scale scores. 
  To determine if SAGE-547 Injection infused intravenously for 60 hours improves the 
general health status compared to placebo as assessed by the change from baseline in 
the Short Form-36 (SF-36) total score at Day 7 and Day 30. 
4.4 Pharmacokinetic Objectives 
The Pharmacokinetic (PK) objective of Study 547-PPD-202C is to assess the 
pharmacokinetic (PK) profile of SAGE-547, metabolites of SAGE-547, and betadex 
sulfobutyl ether sodium (SBECD). 
5 
STUDY ENDPOINTS 
5.1 Primary Endpoint 
  Change from baseline in HAM-D total score at the end of infusion (Day 3, 60 hours) 
5.2 Secondary Endpoints 
5.2.1 Key Secondary Efficacy Endpoints 
  Change from baseline in HAM-D total score at the end of follow up (Day 30) 
5.2.2  Other Secondary Efficacy Endpoints 
 Change from baseline in HAM-D total score at each time point 
  HAM-D response (defined as having a 50% or greater reduction from baseline in 
HAM-D total score) at each time point 
  HAM-D remission (defined as having a HAM-D total score of ≤7) at each time point 
  Change from baseline in MADRS total score at each time point  
  CGI-I response (defined as a CGI-I score of “very much improved” or “much 
improved”) at each time point 
  Change from baseline in HAM-D subscale and individual item scores at each time 
point 
  Change from baseline in GAD-7 total score at each time point 
  Time to first start or increase in the dose of any anti-depressant medication 
  Time to first decrease in the dose of any anti-depressant medication 


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-202C 
CONFIDENTIAL 
 
10 
 
5.2.3 Safety Endpoints 
  Frequency of AEs, severity and seriousness of AEs 
  Change from baseline in clinical laboratory measures: hematology, serum chemistry, 
coagulation and urinalysis parameters (including observed values and change from 
baseline) 
  Vital signs parameters (including observed values and change from baseline) 
  ECG parameters (including observed values and change from baseline) 
  Concomitant medication usage 
  Suicidal ideation using the C-SSRS 
5.3 Other Endpoints 
  Change from baseline in EPDS total score at each time point 
  Change from baseline in PHQ-9 total score at each time point 
  Change from baseline in BIMF total and subscale scores at each time point 
  Change from baseline in SF-36 subscale scores at each time point 
   Healthcare resource utilization (HCRU) 
5.4 Pharmacokinetic Endpoints 
  Plasma concentrations of SAGE-547 and calculated PK parameters 
  Plasma concentrations of metabolites of SAGE-547 
  Plasma concentrations of SBECD 
6 
STUDY DESIGN  
6.1 Overall Design  
Study 547-PPD-202C will consist of a Screening Period (up to 7-days [Day -7 to -1]), a 3-
day (60 hours of treatment and an additional 12 hours for completion of 72-hour 
assessments) Treatment Period, and a 30-day Follow-up Period.  Subjects must remain as 
inpatients during the study Treatment Period, which is approximately 72 hours/3 days in 
duration.  The Screening Period assessments may be conducted on an inpatient or an 
outpatient basis.  The Follow-up Period assessments are conducted on an outpatient basis.  
The study design for 547-PPD-202C is presented in Figure 1.  


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Figure 1: 
Study Design - 547-PPD-202C  
 
SAGE-547 Injection or placebo will be administered at the study center.  Subjects will be 
monitored for safety during the Treatment and Follow-up Periods (through Study Day 30 [±3 
days]) including monitoring for AEs/SAEs, routine clinical laboratory assessments, physical 
examination, vital signs, and ECG. 
The end of the Screening Period coincides with the beginning of the Treatment Period.  The 
Treatment Period is the period of Day 1 of study drug intravenous (IV) infusion through 
completion of the infusion on Day 2 and up to Day 3.  Subjects will be confined to the study 
center from Day 1 until after the 72-hour assessments have been conducted on Day 3. 
In Study 547-PPD-202C, once subjects are confirmed as eligible for the study, they will be 
randomized to one of two treatment groups (SAGE-547 90 μg/kg/hour or placebo) on a 1:1 
basis.  On the morning of dosing (Day 1), subjects will begin a 4-hour dose titration period of 
30 μg/kg/hour (0-4 hours), then 60 μg/kg/hour (4-24 hours), then 90 μg/kg/hour (24-52 
hours); followed by a decrease to 60 μg/kg/hour (52-56 hours), and 30 μg/kg/hour (56-60 
hours) as shown in Table 1 and Figure 2.  Subjects in the placebo group will receive infusion 
rates equivalent to the 90 μg/kg/hour group. 
Table 1: 
Infusion Rates for 547-PPD-202C 
 
Infusion Rate (µg/kg/hour) 
SAGE-547 
Dose 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2-3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
90 µg 
30  
60  
90  
60  
30 
 
Total SAGE-547 Injection or placebo dosing will occur over 60 hours. 
The end of the Treatment Period coincides with the beginning of the Follow-up Period.  
Subjects will attend the clinic for safety follow-up assessment at 1 week (7±1d), 2 weeks 


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(14±2d), 3 weeks (21±1d), and 1 month (30±3d) after the initiation of the study drug 
infusion. 
The study design and timing of infusion is shown in Figure 2. 
Figure 2: 
Study Design and Timeline for Dosing – Study 547-PPD-202C 
 
6.2 Sample Size and Power 
Using a two-sided test at an alpha level of 0.05, a sample size of 50 evaluable subjects per 
group (100 total) for 547-PPD-202C would provide 90% power to detect an effect size of 
0.667 between the SAGE-547 and placebo groups with regard to the primary outcome 
variable of change from baseline in HAM-D total score.  An effect size of 0.667 corresponds 
to a treatment difference of 8.0 points in the change from baseline in HAM-D total score at 
60 hours with an assumed common standard deviation of 12 points.  
6.3 Randomization 
Up to 100 subjects will be randomized.  Subjects will be randomized to one of two treatment 
groups (SAGE-547 90 μg/kg/hour or placebo) on a 1:1 basis.  
For subjects screened to Version 3.0 or lower of the protocol, randomization will not be 
stratified.  For subjects screened to Version 4.0 or greater of the protocol, randomization will 
be stratified by antidepressant use at baseline (yes/no).  Subjects will be randomized within 
stratum to receive SAGE-547 or placebo according to a computer-generated randomization 
schedules. 
6.4 
Blinding and Unblinding 
This is a double-blind study.  Subjects will be randomized to receive SAGE-547 or matching 
placebo; subjects, clinicians, and the clinical site study team will be blinded to treatment 
allocation until the study is unblinded at final database lock.  The pharmacist, who will 
prepare the infusion bags according to the randomization schedule, and an unblinded 
Monitor, who will perform drug accountability during the study, will be unblinded. 
In the event of a medical emergency, the Principal Investigator will discuss with the Medical 
Monitor if unblinding is warranted.  If there is agreement to unblind treatment assignment, 
the unblinding procedure described in the Safety Management Plan for the study will be 
followed.  In all cases where the study drug allocation for a subject is unblinded, pertinent 


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information (including the reason for unblinding) must be documented in the subject’s 
records and on the electronic case report form (eCRF). 
7 
MODIFICATIONS  
7.1 Modifications from the Approved Clinical Study Protocol 
Protocol Text 
SAP Text 
1. No protocol text. 
 
1. Section 9.3.6:  
For efficacy analysis purposes, centers with fewer than 10 subjects 
per center for Part C will be pooled within geographic regions 
(North America).  Within a region, first centers with fewer than 10 
subjects will be ranked by size.  Starting with the largest site, 
centers will be pooled until 10 or more subjects are reached to 
create a unique regional center.  Continue this process of creating 
unique regional centers until there are less than 10 subjects 
remaining.  The remaining centers will then be added to the last 
unique regional center created. 
Unless the combined number of subjects from all centers with 
fewer than 10 subjects in a region is fewer than 10 subjects, all 
pooled centers should have at least 10 subjects. 
2. Section 13.2/page 62: 
A sensitivity analysis may be 
carried out to investigate the 
impact of missing data if more 
than 5% of subjects are missing 
primary endpoint assessments. 
2. Section 9.1.3: 
Sensitivity analyses may be carried out to investigate the impact 
of missing data if more than 10% of subjects are missing HAM-D 
or MADRS total scores. The sensitivity analyses will only be 
performed on the endpoint(s) with sufficient missing data.  
Multiple imputation and Last Observation Carried Forward 
techniques will be considered.  
3. Section 2/page 4 and Section 
6.1/page 33: 
This objective applies to both 
Part A and B.  
3. Section 4.1: 
Primary objective:  
 
To determine if SAGE-547 Injection infused 
intravenously at up to 90 μg/kg/h for 60 hours reduces 
depressive symptoms in subjects with moderate PPD 
compared to placebo injection as assessed by the change 
from baseline in HAM-D total score. 
7.2 Modifications from the Approved Statistical Analysis Plan 
Not applicable. 
7.3 Modifications from the Approved DMC Charter 
Not applicable, as there is no DMC for this study. 
8 
ANALYSIS SETS 
8.1 All Enrolled Set 
The All Enrolled Set will include all subjects who have given written informed consent.  This 
analysis set will be used for subject disposition. 


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8.2 All Randomized Set 
The All Randomized Set will include the subset of subjects from the All Enrolled Set who 
have been randomized.  Subjects will be classified according to randomized treatment.  This 
analysis set will be used for subject disposition, demographic characteristics, and baseline 
characteristic summaries. 
8.3 Safety Set 
The Safety Set will include all randomized subjects who start the infusion of study drug.  
Subjects will be classified according to actual treatment received.  This analysis set will be 
used for all safety analyses. 
8.4 Efficacy Set 
The Efficacy Set will include the subset of the Safety Set who have a valid baseline HAM-D 
assessment and at least one post-baseline HAM-D assessment.  Subjects will be classified 
according to randomized treatment.  This analysis set will be used for all efficacy analyses, 
as well as for demographic and baseline characteristics summaries. 
8.5 Per Protocol Set 
The Per Protocol Set will include the subset of the Efficacy Set who complete the 60-hour 
infusion without significant protocol violations or deviations.  Completing the 60-hour 
infusion is defined as having total infusion time from all segments between 54 hours and 66 
hours.  Subjects will be classified according to randomized treatment.  This analysis set will 
be used for supportive analyses of the primary and selected secondary endpoints. 
8.6 Pharmacokinetics Set 
The PK Set will include the subset of the Safety Set who has at least one evaluable PK 
sample.  Subjects will be classified according to actual treatment received.  This analysis set 
will be used for all PK analyses. 
9 
STATISTICAL ANALYSIS 
9.1 General Considerations 
Unless otherwise specified, continuous endpoints will be summarized with n, mean, standard 
deviation (SD), median, minimum (min) and maximum (max).  The minimum and maximum 
will be reported with the same degree of precision (ie, the same number of decimal places) as 
the raw data.  Measures of location (mean and median) will be reported to one degree of 
precision more than the raw data and measures of spread (standard deviation) will be 
reported to two degrees of precision more than the raw data.  In addition, change from 
baseline values will be calculated at each time point and summarized descriptively.  For 
categorical endpoints, descriptive summaries will include counts and percentages.  
Percentages will be presented to one decimal place except for 0% which will be presented as 
“0” and 100% which will be presented as “100”.  
All analyses and summary outputs will be generated using SAS® version 9.3 (or higher). 


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All subject data, including those derived, will be presented in the subject data listings; 
listings will display all subjects who were enrolled.  In general, the subject data listings will 
be sorted by randomized treatment group, subject number and assessment visit and date (and 
time, if applicable).  The summary tables will be presented descriptively by treatment group. 
9.1.1 Study Day Definition 
Study day is defined as follows:  
  The day when the study drug infusion is started is designated as Day 1. 
  For visit days after Day 1, study day = visit date – Day 1 date + 1. 
  For visit days prior to Day 1, study day = visit date – Day 1 date. Thus, study days for 
screening visit are negative numbers.  There is no “Day 0”. 
9.1.2 Baseline Definition 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as 
the last non-missing measurement prior to the start of study drug administration. 
9.1.3 Missing Data 
Every attempt will be made to avoid missing data.  All subjects will be used in the analyses, 
as per the analysis sets using all non-missing data available.  SF-36 subscales will be 
calculated and missing responses will be handled using the built-in scoring tool.  For all the 
other efficacy endpoints, the pro-rating approach will be considered when calculating the 
total scores.  If no more than 20% of item responses are missing for a given subject on the 
same scale, we replace the missing responses with the mean score on all other non-missing 
responses; otherwise, if more than 20% of item responses are missing for a given subject on 
the same scale, the total score will not be calculated and will be left as missing.  See Section 
9.3.1, 9.3.2 and 9.3.3 for the details of this approach on each endpoint.  
A sensitivity analysis may be carried out to investigate the impact of missing data if more 
than 10% of subjects are missing primary endpoint assessment (ie, HAM-D total score).  
Two techniques will be considered for the sensitivity analysis: 1) Dropout reason based 
multiple imputation; 2) Stratified Wilcoxon rank-sum test.  See Section 9.3.7.1.4 for details. 
Safety data will not be subject to any imputation and will be summarized on an observed case 
basis. 
The following conventions will be used for missing adverse event dates and prior and 
concomitant medication dates. 
9.1.3.1 Adverse Events Onset Date 
If the AE onset date is completely missing in which the day, month, and year are all 
unknown, the AE onset date is set to the date of initiation of the blinded treatment.  
 
For the partial AE onset date and time, 
 If the year is present and the month and day are missing: 


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o If year of AE onset = year of initiation of the blinded treatment, then 
set month and day to month and day of initiation of the blinded 
treatment 
o If year of AE onset < year of initiation of the blinded treatment, then 
set month and day to December 31st. 
o If year of AE onset > year of initiation of the blinded treatment, then 
set month and day to January 1st. 
 If the year and day are present and the month is missing: 
o If year of AE onset = year of initiation of the blinded treatment, then 
set month to month of initiation of the blinded treatment 
o If year of AE onset < year of initiation of the blinded treatment, then 
set month to December. 
o If year > year of initiation of the blinded treatment, then set month to 
January. 
 If the month and year are present and the day is missing: 
o If year of AE onset = year of initiation of the blinded treatment and: 
o if month = month of initiation of the blinded treatment then set day 
to day of initiation of the blinded treatment 
o if month < month of initiation of the blinded treatment then set day 
to last day of month 
o if month > month of initiation of the blinded treatment then set day 
to 1st day of month 
o If year of AE onset < year of initiation of the blinded treatment then set 
day to last day of month 
o If year of AE onset > year of initiation of the blinded treatment then set 
day to 1st day of month 
If the imputed AE onset date is after AE stop date, then set the onset date to the AE stop date. 
9.1.3.2 Prior and Concomitant Medications Date 
If the start date (or end date) of a medication is completely missing in which the day, month, 
and year are all unknown or only the day is known, then the start date (or end date) will not 
be imputed.  
 
For the partial start date of medication,  
o If the year is present and the month and day are missing, set month and day to 
January 1. 
o If the year and day are present and the month is missing, set month to January. 
o If the year and month are present and the day is missing, set day to 1st day of 
month. 
o If the imputed start date of medication is after the non-imputed end date of 
medication, then the start date will be set to the end date of medication. 
For the partial end date of medication, 


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o If the year is present and the month and day are missing, set month and day to 
December 31. 
o If the year and day are present and the month is missing, set month to 
December. 
o If the year and month are present and the day is missing, set day to last day of 
the month. 
o If the imputed end date of medication is before the non-imputed start date of 
medication, then the end date will be set to the start date of medication. 
9.2 
Background Characteristics  
9.2.1 Subject Disposition 
The summaries of subject disposition will include the number and percentage of subjects 
who were enrolled, failed screening, randomized, received SAGE-547 Injection or placebo, 
prematurely discontinued, and completed the study.  The number and percentage of subjects 
will also be summarized for each reason for premature discontinuation.  In addition, the 
number of subjects whose data should be used for the planned analyses will be identified for 
each respective analysis set (ie, Safety, Efficacy, Per Protocol, and PK Set). 
For screen failure subjects, reasons for screen failure will be listed.  A screened subject is 
defined as any subject who signed the study specific informed consent.  A screen failure 
subject is defined as any subject who is screened but failed to meet study requirements 
(inclusion/exclusion criterion) during screening. Subjects were screened for both Part B and 
Part C. Therefore a common, pooled set of screen failed subjects is displayed in disposition 
tables for both study parts. 
Study completion and discontinuation details, eligibility, treatment allocation, population 
assignment, and protocol deviations will be presented in listings. 
Subject disposition analysis will be performed for both All Enrolled Set and All Randomized 
Set.  
9.2.2 Demographics and Baseline Characteristics 
Demographic data, such as age, gender, race and ethnicity, and baseline characteristics, such 
as height, weight, body mass index (BMI, calculated as weight (kg)/ [height (m)2]), and 
baseline antidepressants use, will be listed and summarized using the All Randomized Set 
and Efficacy Set.  For this summary as well as for the subsequence analyses, baseline 
antidepressant use will be defined as taking any medications belonging to the anatomical 
therapeutic checmical (ATC) 3 term N06A or N05A, or with indications containing terms 
depression, postpartum depression, major depression, PPD, MDD, or mood on Day 1.   
Age is calculated using the following SAS formula: 
age = INT(INTCK('MONTH', date of birth, date of informed consent)/12);  
IF MONTH(date of birth) = MONTH(date of informed consent)  
THEN age = age -(DAY(date of birth)>DAY(date of informed consent));  


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Hepatitis, human immunodeficiency virus (HIV), drug and alcohol, and pregnancy screening 
results will be collected and listed but not summarized, as they are considered part of the 
inclusion/exclusion criteria. 
9.2.3 Medical/Family History 
Medical history collected at screening will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 19.1.  Medical history data will be summarized by 
system organ class (SOC) and preferred term (PT) and listed by subject using the Safety Set. 
Type of psychiatric disorders, family history of psychiatric and perinatal conditions will be 
summarized using the Safety Set.  The subject history of psychiatric disorders including all 
episodes of PPD will be listed.  Family history of psychiatric and perinatal conditions will be 
listed. 
9.2.4 Study Drug Exposure and Compliance 
Drug administration information collected on the eCRF will be listed by subject using the 
Safety Set.  Details will include type of infusion (loading/maintenance/taper), dose, infusion 
rate and unit, start date/time of dose, and end date/time of dose, infusion stopped after this 
dose.  The dose categories and infusion rate for given dose are listed in Table 2. 
Table 2: 
Dose Categories and Infusion Rate for Given Dose for 547-PPD-202B  
Dose 
Category 
Infusion Rate for Given Dose (µg/kg/hour) 
90 μg 
Titration 
30 
(Day 1 0-4 hours) 
60 
(Day 1 4-24 hours) 
Maintenance 
90 
(Day 2 24 hours - Day 3 52 hours) 
Taper 
60 
(Day 3 52-56 hours) 
30 
(Day 3 56-60 hours) 
 
Overall exposure to study drug is defined as total number of hours treated with study drug 
during the study, which is calculated as (end time of infusion – start time of infusion [in 
seconds])/3600.  
Exposure to study drug in each planned infusion rate segment (loading dose, maintenance 
dose, and tapering dose) is defined as total number of hours treated with study drug during 
the corresponding segment, which is calculated as (end time of infusion in the corresponding 
segment-start time of infusion in the corresponding segment [in seconds])/3600. 
Study drug compliance (%) is calculated as [Actual total dose (in μg/kg)/Planned total dose 
(in μg/kg)] x 100. 
Overall exposure to study drug, exposure to study drug in each infusion rate segment and 
study drug compliance will be summarized using the Safety Set.  


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9.3 Efficacy Analysis  
All efficacy analyses will be performed for the Efficacy Set unless otherwise specified. 
9.3.1 Definition of Primary Efficacy Variable(s) 
The primary efficacy variable is the Hamilton Rating Scale for Depression (HAM-D). 
HAM-D consists of 17 items that will be used to rate the severity of depression in subjects 
who are already diagnosed as having a Major Depressive Episode, no earlier than the third 
trimester and no later than the first 4 weeks following deliveryusing the Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I Disorders (SCID-I). 
The 17-item HAM-D comprises individual ratings related to the following symptoms: 
depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia 
(early, middle, late), work and activities, retardation (slowness of thought and speech; 
impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and 
somatic), somatic symptoms (gastrointestinal and general), genital symptoms, 
hypochondriasis, loss of weight, and insight.  Each item is scored in a range of 0 to 2 or 0 to 
4, with higher scores indicating a greater degree of depression.  The score for each item will 
be summed to compute a total score, which ranges from 0 to 52.  If more than three 
individual items are missing, the HAM-D total score will not be calculated and will be left as 
missing.  If less than or equal to three individual item scores are missing, the missing item 
scores will be imputed by the maximum possible value of the item or the mean of all other 
available item scores, whichever is smaller to calculate the HAM-D total score.  Imputed 
individual scores will be rounded to the nearest integer. 
9.3.2 Definition of Secondary Efficacy Variable(s) 
The secondary efficacy variables are HAM-D Response, HAM-D Remission, Montgomery-
Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Improvement (CGI-
I), Clinical Global Impression-Severity (CGI-S), HAM-D Subscales and Individual Items, 
the Generalized Anxiety Disorder 7-Item scale (GAD-7) and post-baseline antidepressant 
use.  These secondary efficacy variables are described in the following sections.  
9.3.2.1 HAM-D Response and HAM-D Remission 
HAM-D response will be defined as having a 50% or greater reduction from baseline in 
HAM-D total score.  Any subject who meets this criterion will be defined as a HAM-D 
Responder.  
HAM-D remission will be defined as having a HAM-D total score of ≤7.  Any subject who 
meets this criterion will be defined as a subject in HAM-D remitter. 
9.3.2.2 Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire that psychiatrists use to measure the 
severity of depressive episodes in subjects with mood disorders.  It was designed as an 
adjunct to the HAM-D that would be more sensitive to the changes brought on by 
antidepressants and other forms of treatment than the Hamilton Scale. 


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Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 
6.  The MADRS total score will be calculated as the sum of the 10 individual item scores, 
which ranges from 0 to 60.  If more than two individual items are missing, the MADRS total 
score will not be calculated and will be left as missing.  If less than or equal to two individual 
item scores are missing, the missing item scores will be imputed by the mean of all other 
available item scores to calculate the MADRS total score.  Imputed individual scores will be 
rounded to the nearest integer. 
9.3.2.3 Clinical Global Impression – Improvement (CGI-I) and Clinical Global 
Impression – Severity (CGI-S)  
The CGI-I employs a 7-point Likert scale to measure the overall improvement in the 
subject’s condition posttreatment.  The Investigator will rate the subject’s total improvement 
whether or not it is due entirely to drug treatment.  Response choices include: 0=not assessed, 
1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 
5=minimally worse, 6=much worse, and 7=very much worse.  
CGI-I Response will be defined as having a CGI-I score of “very much improved” or “much 
improved”.  
The Clinical Global Impression - Severity (CGI-S) uses a 7-point Likert scale to rate the 
severity of the subject’s illness at the time of assessment, relative to the clinician’s past 
experience with subjects who have the same diagnosis.  Considering total clinical experience, 
a subject is assessed on severity of mental illness at the time of rating as 1=normal, not at all 
ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 
and 7=extremely ill. 
9.3.2.4 HAM-D subscales and individual item scores 
The HAM-D can be summarized using four subscales: Core, Anxiety, Bech-6 and Meier. 
Table 3 lists the items used to calculate each subscale. 
 
 


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Table 3: 
HAM-D Subscales and Items for Calculating Each Subscale  
HAM-D Subscales 
Items 
Calculation 
Core 
Depressed mood 
Feeling of guilt 
Suicide 
Work and activities 
Retardation 
Sum of the 5-item responses/20 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Anxiety 
Anxiety psychic 
Anxiety somatic 
Somatic symptoms gastrointestinal 
Somatic symptoms general 
Hypochondriasis 
Loss weight 
Sum of the 6-item responses/18 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Bech-6 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Anxiety psychic 
Somatic symptoms general 
Sum of the 6-item responses/22 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Meier 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Agitation 
Anxiety psychic 
Sum of the 6-item responses/24 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
 
9.3.2.5 Generalized Anxiety Disorder 7-item Scale (GAD-7) 
The GAD-7 is a patient-rated generalized anxiety symptom severity scale.  Scoring for GAD-
7 is calculated by assigning scores of 0, 1, 2, and 3 to the response categories, respectively, of 
“not at all sure,” “several days,” “over half the days,” and “nearly every day.”  
GAD-7 total score will be calculated as the sum of the 7 individual item scores, which ranges 
from 0 to 21.  If more than one individual items are missing, the GAD-7 total score will not 
be calculated and will be left as missing.  If only one individual item score is missing, the 
missing item score will be imputed by the mean of all other available item scores to calculate 
the GAD-7 total score.  As a measure of severity of anxiety, GAD-7 total score can be 
categorized as: 0 to 4 = minimal anxiety, 5 to 9 = mild anxiety, 10 to 14 = moderate anxiety, 
and 15 to 21 = severe anxiety. As a measure of severity of anxiety, GAD-7 total score can be 
categorized as: 0 to 4 = minimal anxiety, 5 to 9 = mild anxiety, 10 to 14 = moderate anxiety, 
and 15 to 21 = severe anxiety.  


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The GAD-7 response is defined as having a GAD-7 total score of 0 to 4. 
9.3.2.6 Post-baseline Antidepressant Use 
The doses of all antidepressant medications will be recorded throughout the study.  No 
changes and/or additions to antidepressant or anxiolytic medicine will be allowed from 14 
days prior to the initiation of the blinded study drug infusion to completion of the H72 
assessments.  Rescue antidepressant medications will be identified as all medications 
belonging to ATC 3 term N06A or N05A, or with indication containing terms depression, 
postpartum depression, major depression, PPD, MDD, or mood, starting or with increase in 
dose after 72 hours from the initiation of infusion.  But if the dosing frequency is “as 
needed”, the medication will not be classified as rescue antidepressant medications. 
For each rescue antidepressant medication, the time to start of this medication is calculated as 
the date of start minus the start date of the study drug infusion. For each antidepressant 
medication, the time to increase in dose of this medication is calculated as the date of 
increase minus the start date of the study drug infusion. For subjects who do not have any 
start/increase in any antidepressant dose, the date of start/increase is censored using the study 
completion date if available, otherwise the last date on study. For each subject, the time to 
first start in rescue antidepressant medications or first increase in dose of any antidepressant 
medication is the minimum time across all antidepressant medications. 
For each antidepressant medication, the time to stop or decrease in dose of this medication 
will be calculated as the date of stop/decrease in dose minus the start date of the infusion.  
For subjects who do not have any stop/decrease in antidepressant dose, the date of 
stop/decrease will be censored using the study completion date if available, otherwise the last 
date on study.  For each subject, the time to first stop/decrease in dose of any antidepressant 
medication will be calculated as the minimum time across all antidepressant medications.   
9.3.3 Other Efficacy Endpoints 
9.3.3.1 Edinburgh Postnatal Depression Scale (EPDS) 
The EPDS is a patient-rated depressive symptom severity scale specific to the perinatal 
period.  The scale consists of 10 questions.  Items 1, 2 and 4 are scored from 0 to 3. Items 3, 
5, 6, 7, 8, 9 and 10 are reverse scored from 3 to 0.  For all items, higher scores indicate more 
severe symptoms.  The EPDS total score will be calculated as the sum of the 10 individual 
item scores.  If more than two individual items are missing, the EPDS total score will not be 
calculated and will be left as missing.  If one or two individual item scores are missing, the 
missing item scores will be imputed by the mean of all other available item scores to 
calculate the EPDS total score. 
9.3.3.2 Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is a patient-rated depressive symptom severity scale.  This scale consists of 9 
items with scoring based on item responses as follows: “not at all” = 0; “several days” = 1; 
“more than half the days” = 2; and “nearly every day” = 3.  
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores.  If more 
than one individual items are missing, the PHQ-9 total score will not be calculated and will 


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be left as missing.  If only one individual item score is missing, the missing item scores will 
be imputed by the mean of all other available item scores to calculate the PHQ-9 total score.  
In addition, the PHQ-9 total score will be categorized as follows: 1-4 = minimal depression, 
5-9 = mild depression, 10-14 = moderate depression, 15-19 = moderately severe depression; 
and 20-27 = severe depression. 
The PHQ-9 response is defined as having a PHQ-9 total score of 0 to 4. 
9.3.3.3 Barkin Index of Maternal Functioning (BIMF) 
The BIMF is a patient-reported outcome scale. BIMF covers a broad range of functional 
areas (self-care, infant care, mother-child interaction, psychological well-being of mother, 
social support, management, adjustment).  Each item is rated on a scale of 0 (strongly 
disagree) to 6 (strongly agree).  Except for items 16 and 18, higher items scores indicate 
higher functioning.   
The BIMF total score will be calculated as the sum of the 20 item scores (after the reverse 
coding of items 16 and 18).  If more than four individual item scores are missing, the BIMF 
total score will not be calculated and will be left as missing.  If less than or equal to four 
individual item scores are missing, the missing item scores will be imputed by the mean of 
all other available item scores to calculate the BIMF total score.  The Mom’s Competency 
subscale score is calculated as the sum of items 1, 3, 4, 5, 10, 12, 14, 15, 17, 19, and 20; if 
there are more than two missing values, the Mom’s Competency subscale will be left as 
missing, otherwise the missing values will be imputed with the mean of non-missing values 
to calculate the sum.  The Mom’s Needs subscale score is calculated as the sum of items 2, 6, 
7, 8, 9, 11, and 13; if there is more than one missing value, the Mom’s Needs subscale will be 
set as missing, otherwise the missing values will be imputed with the mean of non-missing 
values to calculate the sum.  
9.3.3.4 Short Form-36 (SF-36) 
The SF-36 covers eight health dimensions including four physical health status domains 
(physical functioning, role participation with physical health problems [role-physical], bodily 
pain, and general health) and four mental health status domains (vitality, social functioning, 
role participation with emotional health problems [role-emotional], and mental health).  In 
addition, two summary scores, physical component summary (PCS) and mental component 
summary (MCS), are produced by taking a weighted linear combination of the eight 
individual domains.  All of the eight health dimension scale scores and two summary scores 
will be provided by the scoring tool and score calculations will not be provided in this SAP.  
9.3.3.5 Healthcare Resource Utilization (HCRU) 
Subject-reported healthcare resource utilization data, including baseline diagnosis history, 
baseline antidepressant treatment history, and healthcare visits, inpatient visits, and 
medication use, will be collected at screening and on Day 30 of follow-up (or at early 
termination).  


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9.3.4 Multiplicity adjustment 
To control the type 1 error rate for conducting multiple comparisons, a fixed sequence 
approach will be considered to adjust for multiplicity.  For the analyses of primary and 
secondary endpoints, the primary comparison will be on change from baseline in HAM-D 
total score between 90 μg SAGE-547 and placebo at the 60-hour assessment timepoint; 
followed by change from baseline in HAM-D total score at the Day 30 assessment timepoint 
between 90 μg SAGE-547 and placebo, in order.  
If the comparison of the HAM-D total score between SAGE-547 and placebo at the 
60-hour assessment is significant at the 0.05 alpha level, then the comparison of the 
HAM-D total score between SAGE-547 and placebo at the Day 30 assessment will be 
conducted at the 0.05 alpha level; else we will not be able to claim statistical 
significance in the comparison of HAM-D total score at Day 30. 
9.3.5 Visit Windows 
The unscheduled or early termination (ET) visit will be mapped to a scheduled visit for 
analysis using the date/time of collection/assessment as a basis to determine study day/hour 
and then study day/hour will be mapped to the intended visit.  Once analysis visit windows 
get assigned, all visits, including scheduled visits, unscheduled visits, and ET visits will be 
eligible for being flagged as the “analyzed record” within the analysis window.  A subject’s 
individual analysis visit window could potentially contain more than 1 visit.  In the event of 
multiple visits falling within an analysis window or in case of a tie, the following rules will 
be used in sequence to determine the “analyzed record” for the analysis visit window: 
 If there is a scheduled visit/day for the analysis visit window, then the scheduled 
visit/day data will be used. 
 If there is no scheduled visit/day for the analysis visit window, the data closest to the 
scheduled study day/hour will be used. 
 If there is no scheduled visit/day for the analysis visit window and there are visits 
equally close to the day/hour of scheduled visit, the latest data will be used. 
The data not flagged as the “analyzed record” will also be listed in subject listings. 
Table 4 displays the visit windows for analysis of HAM-D and CGI-I; Table 5 displays the 
visit windows for analysis of MADRS; Table 6 displays the visit windows for analysis of 
EPDS, GAD-7 andPHQ-9; Table 7 displays the visit windows for analysis of BIMF and SF-
36. 
 
 


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Table 4: 
Visit Windows for Analysis of HAM-D and CGI-I 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Screening a 
D -1 
D -7 to D -1 
Baseline a 
D1H0 
D1H0 
D1H2  
D1H2 
>D1H0, <=D1H3 
D1H4 
D1H4 
>D1H3, <=D1H6 
D1H8 
D1H8 
>D1H6, <=D1H10 
D1H12 
D1H12 
>D1H10, <=D1H18 
D1H24 
D1H24 
>D1H18, <=D2H30 
D2H36  
D2H36 
>D2H30, <=D2H42 
D2H48  
D2H48 
>D2H42, <=D3H54 
D3H60  
D3H60 
>D3H54, <=D3H66 
D3H72  
D3H72 
>D3H66, <=D3H72 
D7/ET 
D7 
>D4H0, <=D10 
D14 
D14 
>D10, <=D17 
D21 
D21 
>D17, <=D25 
D30 
D30 
>D25, <=D33 
Note: D=Day, H=Hour, ET=Early Termination. 
a This scheduled visit only applies to HAM-D. 
Table 5: 
Visit Windows for Analysis of MADRS 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Screening 
D -1 
D -7 to D -1 
Baseline 
D1H0 
D1H0 
D1H24 
D1H24 
>D1H0, <=D2H36 
D2H48 
D2H48 
>D2H36, <=D3H54 
D3H60 
D3H60 
>D3H54, <=D3H66 
D3H72 
D3H72 
>D3H66, <=D3H72 
D7/ET 
D7 
>D4H0, <=D10 
D14 
D14 
>D10, <=D17 
D21 
D21 
>D17, <=D25 
D30 
D30 
>D25, <=D33 
Note: D=Day, H=Hour, ET=Early Termination. 
 
 


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Table 6: 
Visit Windows for Analysis of EPDS, GAD-7 and PHQ-9 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Baseline 
D1H0 
D1H0 
D3H60 
D3H60 
>D1H0, <=D3H72 
D7/ET 
D7 
>D4H0, <=D10 
D14 
D14 
>D10, <=D17 
D21 
D21 
>D17, <=D25 
D30 
D30 
>D25, <=D33 
Note: D=Day, H=Hour, ET=Early Termination. 
Table 7: 
Visit Windows for Analysis of BIMF and SF-36 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Baseline 
D1H0 
D1H0 
D7/ET 
D7 
>D1H0, <=D10 
D14 
D14 
>D10, <=D17 
D21 
D21 
>D17, <=D25 
D30 
D30 
>D25, <=D33 
Note: D=Day, H=Hour, ET=Early Termination. 
9.3.6 Pooling of Centers 
For efficacy analysis purposes, centers with fewer than 10 subjects per center will be pooled 
within geographic regions (North America).  Within a region, first centers with fewer than 10 
subjects will be ranked by size.  Starting with the largest site, centers will be pooled until 10 
or more subjects are reached to create a uniqe regional center.  Continuing this process of 
creating unique regional centers until there are less than 10 subjects remaining.  The 
remaining centers will then be added to the last unique regional center created. 
Unless the combined number of subjects from all centers with fewer than 10 subjects in a 
region is fewer than 10 subjects, all pooled centers should have at least 10 subjects.  
9.3.7 Analysis of Efficacy Variable(s) 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; subject listings will be provided for all efficacy data.  
Subjects will be analyzed according to randomized treatment. 
Descriptive statistics including n, mean, SD, median, minimum, and maximum of actual 
values and change from baseline, and percentage change from baseline values will be 
presented by treatment group and assessment time point for the following continuous 
efficacy variables: 
  HAM-D total score; 
  MADRS total score; 
  HAM-D subscale and individual item scores (Note: percentage change from baseline 
values will not be presented for HAM-D individual item scores); 


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  CGI-I and CGI-S scale scores (Note: change and percentage change from baseline are 
not applicable); 
 GAD-7 total score; 
  PHQ-9 total score; 
  EPDS total score; 
  BIMF and SF-36 scale scores 
Raw values in HAM-D, MADRS, GAD-7, EPDS total score and CGI-I scale scores over 
time will be presented graphically by treatment group. 
Descriptive statistics including counts and percentages will be summarized by treatment 
group and assessment time point for the following categorical efficacy variables: 
  HAM-D response; 
  HAM-D remission; 
 CGI-I scale scores; 
  CGI-I response 
Bar plot will be presented for the percentage of HAM-D responders and HAM-D remitters.  
9.3.7.1 Analysis of Primary Efficacy Endpoints 
9.3.7.1.1  Hamilton Rating Scale for Depression (HAM-D) 
Mixed Effects Model for Repeated Measures (MMRM): 
Change from baseline to each assessment timepoint in HAM-D total score will be analyzed 
using a mixed effects model for repeated measures (MMRM).  
The model will include the change from baseline at each visit time point as the dependent 
variable, center (pooled), treatment, baseline antidepressant use, baseline HAM-D total score, 
visit time point, and visit time point-by-treatment interaction terms as explanatory variables.  
All explanatory variables including pooled center will be treated as a fixed effect in the 
primary analysis. 
The primary comparison will be between 90 μg SAGE-547 and placebo at the 60-hour 
assessment.  Comparisons at other time points, including the one for a key secondary 
endpoint at the Day 30 time point, will be conducted to support the findings for the primary 
comparison.  Model-based point estimates (ie, LS means), 95% confidence intervals, and p-
values will be reported for each assessment.  An unstructured covariance structure will be 
used to model the within-subject 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.  See sample SAS 
code for MMRM in section 15.2.  


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In addition, the LS means (+/- SE) estimates of change from baseline in HAM-D total score 
over time will be presented graphically by treatment group. 
9.3.7.1.2 Supportive Analysis of the Primary Endpoint 
The following supportive analyses will be performed for the primary endpoints:  
 A MMRM method similar to those described in section 9.3.7.1.1 will be used for the 
analysis of the HAM-D total score.  Center (pooled) will be treated as random effect.  
See sample SAS code for MMRM in section 15.2. 
 The Per Protocol Set will also be used for supportive analysis. 
9.3.7.1.3 Subgroup Analysis of the Primary Endpoint 
Summaries using descriptive analyses and MMRM model (if there are at least 5 subjects in 
each treatment arm for a subgroup) as described in section 9.3.7.1.1 will be performed base 
on the following subgroups. Due to smaller sample sizes, center (pooled) and baseline 
antidepressant use will be removed as covariates in the MMRM model. 
o Race category: White, Black or African American, and Other 
o Age category: 18-24, 25-45 
o Baseline antidepressant use: Yes, No 
o BMI category: <=18.4, 18.5-24.9, 25-29.9, >=30 kg/m2 
o  Onset of PPD: 3rd trimester and within 4 weeks of delivery 
o Family history of PPD: Yes, No 
9.3.7.1.4 Sensitivity Analysis of the Primary Endpoint  
1) Sensitivity analyses will be carried out to investigate the impact of missing data if more 
than 10% of subjects are missing primary endpoint assessment (ie, HAM-D total score).  
A dropout reason based imputation will be used.  An analysis of covariance (ANCOVA) 
model, including center (pooled), treatment, baseline antidepressant use, and baseline HAM-
D total score, will be used to assess the treatment difference in change from baseline in 
HAM-D total score at Hour 60 (MI imputed data).  The missing change from baseline in 
HAM-D total score at Hour 60 will be imputed using multiple imputation. 
Imputation distribution: 
The imputation distribution for the missing change from baseline in HAM-D total score at 
Hour 60 will be a normal distribution.  All randomized subjects will be classified as non-
missing category, missing category 1, or missing category 2, based on the following rules: 
 Non-missing category: Subject with non-missing change from baseline in HAM-D 
total score at Hour 60. 
 Missing category 1: Subject discontinued due to adverse events, physician decision, 
protocol violation or other, and is missing change from baseline in HAM-D total 
score at Hour 60. 


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 Missing category 2: Subject discontinued due to pregnancy, study terminated by 
sponsor, or withdrawal by subject, and is missing change from baseline in HAM-D 
total score at Hour 60, or subject completed study but is missing change from 
baseline in HAM-D total score at Hour 60. 
Imputation algorithm: 
Missing values of change from baseline in HAM-D total score at Hour 60 will be imputed 
separately within each treatment group using the following missing reason based algorithm: 
 Missing category 1: randomly draw a sample from the normal distribution 
N(µ25, σ2), where µ25 is the 75th percentile of the non-missing change from baseline 
in HAM-D total score and σ2 is the sample variance estimated using the non-missing 
change at Hour 60.  This respresents a conservative approach since higher values of 
change from baseline represents worse outcome. 
 Missing category 2: randomly draw a sample from the normal distribution N(µ, σ2), 
where µ is the mean of the non-missing change from baseline in HAM-D total score 
at Hour 60 and σ2 is the sample variance estimated using the non-missing change at 
Hour 60. 
Analysis model: 
The complete MI method is described below: 
 Impute missing values using the normal distribution specified in the above algorithm 
to form a complete dataset (imputed dataset).  After imputation, all Efficacy Set 
subjects will have non-missing change from baseline in HAM-D total score at Hour 
60. 
 Repeat the process K (K=5) times, using the procedure described above to form K 
imputed complete datasets. 
 Fit the ANCOVA model including center (pooled), treatment, baseline antidepressant 
use, and baseline HAM-D total score, to each imputed dataset, to estimate the 
treatment effect and its variance at Hour 60. 
 Combine the results from the K imputed datasets using the SAS procedure 
MIANALYZE, to derive the MI estimator. 
We fit the analysis model (ANCOVA model specified before) to the kth completed dataset, 
denoting the estimate of the treatment difference θ by θk from the kth completed dataset, and 
denoting the corresponding estimate of the variance Vk. The MI estimator of θ, 𝜃̃𝑀𝐼, is the 
average of the K individual estimators: 
𝜃̃𝑀𝐼= 1
𝐾∑𝜃𝑘
𝐾
𝑘=1
 
The estimated variance of 𝜃̃𝑀𝐼 is a combination of the between- and within-imputation 
variability as follows: 
𝑉𝑀𝐼= 𝑊+ (1 + 1
𝐾) 𝐵 
where W =
1
𝐾∑
𝑉𝐾 
𝐾
𝑘=1
is the within-imputation variability and B =
1
𝐾−1 ∑
(𝜃𝑘−𝜃̃𝑀𝐼)
2 
𝐾
𝑘=1
is 
the between-imputation variance. 


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It has been shown that the statistic 
T = 𝜃̃𝑀𝐼−𝜃
√𝑉𝑀𝐼
 
has an approximate tV distribution where V = (K −1) (1 +
𝑊
𝐵)
2
. 
2) The following sensitivity analysis will be performed to account for the possible scenario 
that the data is not normally distributed. 
Stratified Wilcoxon rank-sum test on change from baseline in the HAM-D total score at the 
60 hour timepoint, stratified by antidepressant use, will be used as a sensitivity analysis.  If 
necessary (e.g., serious violation of the primary analysis model assumptions on normality, as 
assessed by using QQ plot on the residual values from the primary analysis for HAM-D), this 
will be considered the primary analysis. 
See sample SAS code for PROC NPAR1WAY in section 15.2. 
9.3.7.2 Analysis of Secondary Efficacy Endpoints 
9.3.7.2.1 Montgomery-Åsberg Depression Rating Scale (MADRS) 
A MMRM method similar to those described in section 9.3.7.1.1will be used for the analysis 
of the change from baseline in MADRS total score.  The comparison of interest will be 
between 90 μg SAGE-547 and placebo at the 60-hour assessment.  Model based point 
estimates (ie, LS means), 95% confidence intervals, and p-values will be reported. 
In addition, the LS means (+/- SE) estimates of change from baseline in MADRS total score 
over time will be presented graphically by treatment group. 
9.3.7.2.2 Generalized Anxiety Disorder 7-item Scale (GAD-7) 
A MMRM method similar to those described in section 9.3.7.1.1will be used for the analysis 
of the change from baseline in GAD-7 total score.  The comparison of interest will be 
between 90 μg SAGE-547 and placebo at the 60-hour assessment.  Model based point 
estimates (ie, LS means), 95% confidence intervals, and p-values will be reported. 
In addition, the LS means (+/- SE) estimates of change from baseline in GAD-7 total score 
over time will be presented graphically by treatment group. 
Number and percent of subjects GAD-7 response will be tabulated by treatment and 
timepoint.  Odds ratios and the 95% confidence intervals and the p-values for each SAGE-
547 treatment group vs. placebo will be estimated using Fisher’s exact test. 
9.3.7.2.3 HAM-D subscales and individual item scores 
A MMRM method similar to those described in section 9.3.7.1.1 will be used for the analysis 
of the change from baseline in HAM-D subscales and individual item scores.  The 
comparison of interest will be between 90 μg SAGE-547 and placebo at the 60-hour 
assessment.  Model based point estimates (ie, LS means), 95% confidence intervals, and p-
values will be reported. 


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9.3.7.2.4 HAM-D Response and HAM-D Remission 
A Generalized Estimating Equation (GEE) method will be used for the analysis of HAM-D 
response and HAM-D remission.  GEE models will include the response variables above at 
each visit time point as the dependent variable, center (pooled), treatment, baseline 
antidepressant use, baseline HAM-D total score, visit time point, and visit time point-by-
treatment interaction terms as explanatory variables.  An unstructured working correlation 
structure for the binary outcome variables will be assumed for the model parameters 
estimation.  Exchangable, independence or compound symmetry working correlation 
structure will be used if there is a convergence issue with the unstructured working 
correlation model.  Only data from the Hour 24 visit and later will be included in the model 
to avoid non-convergence arising from sparse data. 
The comparison of interest will be the difference between 90 μg SAGE-547 and placebo at 
the 60-hour assessment.  Model based point estimates (ie, odds ratios), 95% confidence 
intervals, and p-values will be reported. See sample SAS code for GEE in section 15.2. 
9.3.7.2.5 Clinical Global Impression – Improvement (CGI-I) 
A GEE method similar to those described in section 9.3.7.2.4 will be used for the analysis 
CGI-I response.  For the CGI-I response analysis, baseline CGI-S score will be included as 
the baseline value in the model. 
The comparison of interest will be the difference between 90 μg SAGE-547 and placebo at 
the 60-hour assessment.  Model based point estimates (ie, odds ratios), 95% confidence 
intervals, and p-values will be reported. 
In addition, the CGI-I score will be analyzed using a MMRM method similar to those 
described in section 9.3.7.1.1.  The LS means (+/- SE) estimates of CGI-I score over time 
will be presented graphically by treatment group. 
9.3.7.2.6 Post-baseline Antidepressant Use 
The time to first start/increase and the time to first stop/decrease in dose of any rescue 
antidepressant medication will be summarized descriptively using Kaplan-Meier methods.  
Descriptive statistics including n, median, 1st quartile, 3rd quartile, minimum, maximum and 
censored values will be presented.  
Kaplan-Meier plots for the analysis of antidepressant use will also be presented. 
9.3.7.2.7 Supportive Analysis of the Secondary Endpoints 
The Per Protocol Set will also be used for supportive analysis for change from baseline in 
MADRS total score. 
9.3.7.2.8 Subgroup Analysis of the Secondary Endpoints 
Summaries using descriptive analyses and MMRM model will be performed for MADRS, in 
a similar way as described in Section 9.3.7.1.3.  Only subgroup by baseline antidepressant 
use will be considered. 


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Summary analysis using descriptive statistics and GEE method as described in 9.3.7.2.4 will 
be performed for HAM-D response and HAM-D remission based on subgroup by  baseline 
antidepressant use as described in 9.3.7.1.3. 
Summary analysis using descriptive statistics and GEE method as described in 9.3.7.2.5 will 
be performed for CGI-I response based on subgroup by baseline antidepressant use as 
described in 9.3.7.1.3. 
9.3.7.2.9 Sensitivity Analyses of the Secondary Endpoints 
 Sensitivity analyses similar to those described in 9.3.7.1.4 will be performed on the 
change from baseline in HAM-D total score at each timepoint and change from 
baseline in MADRS total score at the 60 hour assessment.  
 Logistic regression methods will be used for the analysis of the following binary 
variables as a sensitivity analyses for the sencondary endpoints: HAM-D response, 
HAM-D remission and CGI-I response.  Logistic regression models will include the 
response variables above at each visit time point as the dependent variable, center 
(pooled), treatment, baseline antidepressant use, and baseline score as explanatory 
variables.  The Firth penalized likelihood method will be used to reduce bias in the 
parameter estimates and to avoid non-convergence due to quasi separation.  For the 
CGI-I response analysis, baseline CGI-S score will be included in the model as the 
baseline score.  The comparison of interest will be the difference between 90 μg 
SAGE-547 and placebo.  Model-based point estimates (i.e., odds ratios), 95% 
confidence intervals, and p-values will be reported. See sample SAS code for logistic 
regression in section 15.2. 
 As a sensitivity analysis to assess the impact of rescue antidepressant use, subject will 
be set as HAM-D non-responders and not achieving HAM-D remission following the 
use of rescue antidepressant. Logistic regression methods as described above will be 
used to compare the treatment difference in HAM-D response and HAM-D remission 
at these follow-up visits: Day 7, Day 14, Day 21, and Day 30. 
9.3.7.3 Analysis of Other Efficacy Endpoints 
9.3.7.3.1 Edinburgh Postnatal Depression Scale (EPDS) 
 A MMRM method similar to those described in section 9.3.7.1.1 will be used for the analysis 
of the change from baseline in EPDS total score.  The comparison of interest will be between 
90 μg SAGE-547 and placebo at the 60 hours and the follow-up visits.  Model based point 
estimates (ie, LS means), 95% confidence intervals, and p-values will be reported. 
9.3.7.3.2 Patient Health Questionnaire (PHQ-9) 
A MMRM method similar to those described in section 9.3.7.1.1 will be used for the analysis 
of the change from baseline in PHQ-9 total score.  The comparison of interest will be 
between 90 μg SAGE-547 and placebo at Day 3, 60 hours and the follow-up visits.  Model 
based point estimates (ie, LS means), 95% confidence intervals, and p-values will be 
reported. 


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Number and percent of subjects with PHQ-9 response will be tabulated by treatment and 
timepoint.  Odds ratios and the 95% confidence intervals and the p-values for each SAGE-
547 treatment group vs. placebo will be estimated using Fisher’s exact test. 
9.3.7.3.3 Barkin Index of Maternal Functioning (BIMF) 
A MMRM method similar to those described in section 9.3.7.1.1 will be used for the analysis 
of the change from baseline in BIMF total score.  The comparison of interest will be between 
90 μg SAGE-547 and placebo at the follow-up visits.  Model based point estimates (ie, LS 
means), 95% confidence intervals, and p-values will be reported. 
The same analysis will be done for the Mom’s competency subscale score and Mom’s needs 
subscale score. 
9.3.7.3.4 Short Form-36 (SF-36) 
A MMRM method similar to those described in section 9.3.7.1.1 will be used for the analysis 
of the change from baseline in each of the 8 health dimension scale scores and 2 summary 
scores.  The comparison of interest will be between 90 μg SAGE-547 and placebo at the Day 
3, 60 hours and the follow-up visits.  Model based point estimates (ie, LS means), 95% 
confidence intervals, and p-values will be reported. 
9.3.7.3.5 Healthcare Resource Utilization (HCRU) 
Data on each type of HCRU will be reported by reasons for utilization (depression related, 
pregnancy/labor/delivery related, other) with appropriate descriptive statistics at screening 
and on the Day 30 (end of study) in patients comprising the Efficacy Set.  Table 8 
summarized the type of HCRU, reasons for utilization and descriptive statistics to be used to 
analyze these data.  
 
 


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Table 8: 
 Descriptive Statistics to be Used to Analyze HCRU Data 
Utilization Type 
Reason for Utilization 
Descriptive Statistics 
Emergency room visit, 
use of an ambulance, 
outpatient primary care 
physician visit, 
outpatient specialist visit 
(e.g. OB/GYN, surgeon), 
outpatient counselling 
visit 
Depression related 
Number of patients reporting use;  
Percentage of patients reporting use out of 
the total number of patients; 
Number of visits, mean, median, minimum 
and maximum of those reporting use of 
that utilization type and for that reason; 
Number of visits mean and median for the 
total number of patients 
Pregnancy/labor/delivery 
related 
Other 
Hospital admission 
Depression related 
Number of patients reporting use;  
Percentage of patients reporting use out of 
the total number of patients; 
Number of visits, mean, median, 
minimum/maximum of those reporting 
hospital admission; 
Length of stay mean, median, minimum 
and maximum of those reporting hospital 
admission; 
Number of visits mean and median for the 
total number of patients; 
Length of stay mean and median for the 
total number of patients 
Pregnancy/labor/delivery 
related 
Other 
 
9.4 Safety Analysis 
The secondary objectives include the safety and tolerability of SAGE-547 Injection, as 
evaluated by AEs, clinical laboratory tests, vital signs, ECGs and concomitant medication 
usage.  Suicidality will be monitored by the C-SSRS. 
Safety data will be listed by subject and summarized descriptively by treatment group.  All 
safety analyses will be performed on the Safety Set.  
The safety endpoints and variables considered in the summary tables for this study are 
summarized in Table 9. 
 
 


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Table 9: 
Safety Endpoints and Variables in the Summary Tables and Listings 
Safety Evaluation 
Incidence  
Actual 
Value 
Change from 
Baseline 
Abnormality/Clinical 
Significance (CS) 
AEs 
X 
* 
 
 
Con Meds 
X 
* 
 
 
Labs 
 
X 
X 
* 
ECG 
 
X 
X 
* 
Vital Signs 
 
X 
X 
* 
Physical Examination 
 
* 
 
* 
C-SSRS 
X 
* 
 
 
X = Safety Assessment will be summarized in tables 
* = Safety Assessment will be presented in individual subject data listings only  
9.4.1 Visit Windows 
The mapping rule of unscheduled or early termination (ET) visit and the rule of flagging 
“analyzed record” are the same as described in section 9.3.5.  
Table 10 displays the visit windows for analysis of clinical laboratory parameters (including 
hematology, serum chemistry, coagulation) parameters; Table 11 displays the visit windows 
for analysis of urinalysis parameters; Table 12 displays the visit windows for analysis of 12-
lead ECG; Table 13 displays the visit windows for analysis of vital signs parameters; Table 
14 displays the visit windows for analysis of C-SSRS parameters.  
Table 10: 
Visit Windows for Analysis of Clinical Laboratory Parameters 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Baseline 
D -1 
D -7 to D1H0 
D3H72 
D3H72 
>D1H0, <=D3H72 
D7/ET 
D7 
>D4H0, <=D33 
Note: D=Day, H=Hour, ET=Early Termination. 
Table 11: 
Visit Windows for Analysis of Urinalysis Parameters 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Baseline 
D -1 
D -7 to D1H0 
D7/ET 
D7 
>D1H0, <=D33 
Note: D=Day, H=Hour, ET=Early Termination. 
 
 


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Table 12: 
Visit Windows for Analysis of 12-lead ECG Parameters 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Baseline 
D -1 
D -7 to D1H0 
D2H48 
D2H48 
>D1H0, <=D3H72 
D7/ET 
D7 
>D4H0, <=D33 
Note: D=Day, H=Hour, ET=Early Termination. 
Table 13: 
Visit Windows for Analysis of Vital Signs Parameters 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Screening 
D -1 
D -7 to D -1 
Baseline 
D1H0 
D1H0 
D1H2  
D1H2 
>D1H0, <=D1H3 
D1H4 
D1H4 
>D1H3, <=D1H6 
D1H8 
D1H8 
>D1H6, <=D1H10 
D1H12 
D1H12 
>D1H10, <=D1H15 
D1H18 
D1H18 
>D1H15, <=D1H21 
D1H24 
D1H24 
>D1H21, <=D2H27 
D2H30 
D2H30 
>D2H27, <=D2H33 
D2H36 
D2H36 
>D2H33, <=D2H39 
D2H42 
D2H42 
>D2H39, <=D2H45 
D2H48 
D2H48 
>D2H45, <=D3H51 
D3H54 
D2H54 
>D3H51, <=D3H57 
D3H60 
D3H60 
>D3H57, <=D3H63 
D3H66 
D3H66 
>D3H63, <=D3H69 
D3H72 
D3H72 
>D3H69, <=D3H72 
D7/ET 
D7 
>D4H0, <=D33 
Note: D=Day, H=Hour, ET=Early Termination. 
Table 14: 
Visit Windows for Analysis of C-SSRS Parameters 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Baseline 
D1H0 
D -7 to D1H0 
D1H24 
D1H24 
>D1H0, <=D2H42 
D3H60 
D3H60 
>D2H42, <=D3H66 
D3H72 
D3H72 
>D3H66, <=D3H72 
D7/ET 
D7 
>D4H0, <=D10 
D14 
D14 
>D10, <=D17 
D21 
D21 
>D17, <=D25 
D30 
D30 
>D25, <=D33 
Note: D=Day, H=Hour, ET=Early Termination. 
9.4.2 Adverse Events  
The analysis of AEs will be based on the concept of treatment-emergent AEs (TEAEs).  A 
TEAE is defined as an AE with onset on or after the start of study drug infusion, or any 


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worsening of a pre-existing medical condition/AE with onset on or after the start of study 
drug infusion.  
All adverse events will be coded using MedDRA version 19.1 and summarized by SOC and 
PT.  Multiple occurrences of an AE are counted only once per subject per SOC and PT for 
summary tables.  Incidences will be presented in order of decreasing frequency of the SAGE-
547 90 μg/kg/hour group by SOC and PT.  Incidences will also be presented in order of 
decreasing frequency of the SAGE-547 90 μg/kg/hour group by PT only.  In addition, 
summaries will be provided by severity (mild, moderate, severe) and by causality (related, 
not related) to study drug (see protocol section 14.2.2.1 for definitions).  TEAEs leading to 
discontinuation and Serious AEs (SAEs) (see protocol section 14.1.4 for definition) with 
onset after the start of randomized infusion will also be summarized. 
Summary tables of TEAEs will be presented by treatment and will summarize the number 
and percentage of subjects for the following: 
  Any TEAE 
  TEAEs by relatedness to study drug (not related, related) 
  TEAEs by severity to study drug (mild, moderate, severe) 
  Treatment-emergent serious AEs (SAEs) 
  TEAEs leading to discontinuation of study drug 
  Overall summary of the number and percentage of subjects reporting TEAEs, drug-
related TEAEs, severe TEAEs, SAEs and TEAEs leading to study drug 
discontinuation. 
Subjects will be counted only once within each SOC and PT at the maximum severity in the 
following order: severe, moderate, and mild.  An AE with missing severity will be 
considered as a severe AE.  Subjects will be counted only once within each SOC and PT at 
the strongest relationship to study drug in the following order: related, not related to study 
drug.  If the relationship between the adverse event and the study drug is determined to be 
“possible” or “probable”, the event will be considered as related to the study drug.  An AE 
with missing relationship to study drug will be considered as related to study drug. 
All AEs, SAEs (including those with onset or worsening before the start of randomized 
infusion), AEs Leading to study drug discontinuation and AEs leading to death through the 
Day 30 Follow-up Visit (±3 days) will be listed.  
During the study, the categories of outcome of AEs were changed slightly.  Originally, the 
follow categories were used: 
 Recovered/resolved 
 Recovered/resolved with sequelae 
 Recovering/resolving 
 Not recovered/not resolved 


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 Fatal 
 Unknown 
However, starting from Version 4.0 of the protocol, the following categories were used: 
 Ongoing 
 Resolved 
 Resolved with sequelae 
 Unknown 
 Death 
In the data listings, the following mapping will be applied: 
From 
To 
Resolved 
Recovered/resolved 
Resolved with sequelae 
Recovered/resolved with sequelae 
 
Recovering/resolving 
Ongoing 
Not recovered/not resolved 
Death 
Fatal 
Unknown 
Unknown 
 
9.4.3 Prior and Concomitant Medications   
Concomitant medications will be coded using World Health Organization-Drug Dictionary 
Enhanced (WHO-DDE) September 1, 2016. 
Medications will be presented according to whether they are being taken prior to and/or 
during the study (concomitant): 
  Prior medications are defined as all medications taken prior to the infusion of study 
treatment.  
  Concomitant medications are defined as all medications taken on or after the infusion 
of study treatment starts through the Day 30 (±3 days) visit.  If medication dates are 
incomplete and it is not clear whether the medication was concomitant, it will be 
assumed to be concomitant. 
Note that medication that started prior to the infusion of study drug and continued after the 
start of infusion will be summarized as prior medication and separately as concomitant 
medication.  Details of prior and concomitant medications will be listed by subject, start date, 
and verbatim term. 
Medication summaries will be performed by ATC level 2 term and PT based on the Safety 
Set. 


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Antidepressant medications will be summarized by ATC level 2 term and PT based on the 
Safety Set. 
9.4.4 Clinical Laboratory 
Blood samples will be collected for hematology, serum chemistry, coagulation, specific 
hormone parameters, and exploratory biochemistry; pregnancy testing; and genetic analysis.  
Urine samples for urinalysis and selected drugs of abuse will also be collected. 
Summary tables will include descriptive statistics for the actual values and changes from 
baseline by scheduled time point in hematology, serum chemistry, coagulation and 
quantitative urinalysis test results by treatment group.  For qualitative urinalysis parameters, 
test results will be categorized as normal and abnormal.  Frequency counts and percentages 
will be presented over time for these categorical data by treatment.  Genetic sample results 
will be listed.  
Shift analysis pre- and post-treatment will be presented for the following laboratory 
categories (low, normal and high).  
Number of percent of subjects with liver injury as defined by Hy’s law will be presented. 
Hy’s law is defined as ALT or AST > 3 times of upper limit of normal; and total bilirubin > 2 
times of upper limit of normal, and alkaline phosphatase < 2 time of upper limit of normal. 
All parameters will be converted to consistent units according to the International System of 
Units (SI) before summarization. 
All clinical laboratory results will be listed by subject and timing of collection.  Out-of-range 
values will be flagged as low, high, or abnormal, where applicable. 
The number and percentage of subjects with potentially clinically significant (PCS) values at 
any time after study drug infusion will be summarized by treatment group for the hematology 
and chemistry parameters defined in Table 15 and Table 16.  PCS laboratory values will also 
be listed by subject. 
 
 


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Table 15: 
Hematology PCS Values 
Hematology parameter 
Potentially clinically significant values 
Hemoglobin 
<110 g/L or >165 g/L  
Hematocrit (HCT) 
<0.359 or >0.446 
Platelet count 
<125 GI/L or >600 GI/L 
Leukocytes 
<2.5 GI/L or >15 GI/L 
Basophils 
>0.5 GI/L 
Eosinophils 
>1.5 GI/L 
Lympocytes 
<0.5 GI/L or >6.0 GI/L 
Monocytes 
>1.4 GI/L 
Neutrophils 
<1.5 GI/L 
GI/L = giga/L = 10^9/L 
Table 16: 
Chemistry PCS Values 
Chemistry parameter 
Potentially clinically significant values 
Alanine aminotransferase (ALT) 
>3 x ULN 
Albumin 
<28 g/L or >70 g/L 
Aspartate aminotransferase (AST) 
>3 x ULN 
Bicarbonate 
<18 mmol/L or >30 mmol/L 
Bilirubin 
>2 x ULN 
Blood urea nitrogen (BUN) 
>10.71 mmol/L 
Calcium  
<2.0 mmol/L or >2.75 mmol/L 
Chloride 
<90 mmol/L or >120 mmol/L 
Creatine kinase 
>3 x ULN 
Creatinine 
>140 μmol/L 
Potassium 
<3.5 mmol/L or >5.2 mmol/L 
Sodium 
<132 mmol/L or >145 mmol/L 
Protein 
<45 g/L 
Glucose 
<2.8 mmol/L or >13.9 mmol/L 
Gamma Glutamyl Transferase (GGT) 
>3 x ULN 
ULN = upper limit of normal. 
 
A summary of subjects with abnormal liver enzymes and liver function tests post-baseline 
will be presented, including abnormalities that worsened for subjects with baseline abnormal 
levels and ALT and AST shifts from baseline. 
9.4.4.1  Hematology, Serum Chemistry, Coagulation 
Blood samples will be collected for analysis of the following:  
  Hematology: complete blood count including white blood cell count with differential 
(basophils, eosinophils, lymphocytes, monocytes, and neutrophils) platelet count, red 
blood cell count, hemoglobin and hematocrit, mean corpuscular volume, and mean 
corpuscular hemoglobin 
  Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, bilirubin (total), blood urea nitrogen, calcium, chloride, creatinine, 


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gamma glutamyl transferase, glucose, phosphate, potassium, sodium, total protein, 
and triglycerides (Screening only) 
  Coagulation: activated partial thromboplastin time, prothrombin time, international 
normalized ratio 
9.4.4.2 
 Hormones and Exploratory Biochemistry 
Blood samples will be collected and may be analyzed for thyroid stimulating hormone, 
estrogen, progesterone, progesterone metabolites, oxytocin, tryptophan, kynurenine, and 
markers of inflammation. 
9.4.4.3 
 Pregnancy Test 
All subjects will be tested for pregnancy by serum at screening and urine human chorionic 
gonadotropin on Day 1 prior to administration of study drug and Day 30.  Subjects with a 
positive pregnancy test at screening or Day 1 will be ineligible for study participation. 
Preganancy test results will be listed by subject.  
9.4.4.4 
 Urinalysis 
Urinalysis will include assessment of bilirubin, glucose, ketones, leukocytes, nitrite, pH, 
protein, and specific gravity. 
9.4.5 Electrocardiogram 
A baseline 12-lead ECG will be performed during screening.  The following ECG parameters 
will be recorded: heart rate (bpm), PR (msec), QRS (msec), QT (msec), and QT corrected 
with Fridericia’s formula (QTcF) (msec).  
QTcF (msec) is calculated as: QT (msec) / RR1/3, where RR = 60 / heart rate (bpm). 
All ECG results will be interpreted by the Investigator as Normal, Abnormal; not clinically 
significant (NCS), or Abnormal; clinically significant (CS).  If Abnormal, details will be 
provided. 
The actual value at each time point and change from baseline at each post-baseline time point 
will be summarized by treatment group.  The number and percentage of subjects with 
‘normal’, ‘abnormal, not clinically significant’ and ‘abnormal, clinically significant’ ECG 
results will be summarized at baseline and each post-baseline time point. 
All ECG data will be listed by subject and time of measurement.  Mean values of ECG 
parameters over time will be presented graphically by treatment group.  
Additionally, the number and percentage of subjects in each treatment group who meet any 
of the following criteria for QT or QTcF will be tabulated. 
 Maximum value >450 to 480 msec  
 Maximum value >480 to 500 msec  
 Maximum value >500 msec 
 Maximum increase from baseline >30 to 60 msec 
 Maximum increase from baseline >60 msec 


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9.4.6 Vital Signs 
Descriptive summaries of actual values and changes from baseline will be calculated for vital 
signs, which include oral temperature (°C), respiratory rate (breaths/min), heart rate (bpm), 
and blood pressure (mmHg, supine and standing).  A full set of vital signs will be obtained at 
all specified time points (±30 minutes), unless the subject is asleep between the hours of 
23.00h and 06.00h each day. 
To evaluate potential orthostatic hypotension, difference between supine and standing 
systolic blood pressure, and difference between supine and standing diastolic blood pressure 
(supine – standing), will be calculated. Orthostatic hypotension is defined as decrease in 
systolic blood pressure of at least 20 mmHg or decrease in diastolic blood pressure of at least 
10 mmHg. 
All vital sign data will be listed by subject and time of measurement.  Mean values of vital 
signs parameters, including the difference between supping and standing blood pressure 
values over time will be presented graphically by treatment group.  Number and percent of 
subjects who developed orthostatic hypotension will be presented in a table by visit and 
treatment group.  
9.4.7 Physical Examination 
Body weight and height will be measured at screening.  Body mass index (BMI) will be 
programmatically calculated in the eCRF.  The date of assessment and study day of physical 
examinations will be listed.  
Note: Any condition present at the post-treatment physical examination that was not present 
at or worsened since the baseline examination is to be documented as an AE and will be 
presented in AE listings and tables. 
9.4.8 Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS.  This scale consists of a 
pre-dose evaluation that assesses the lifetime/ past 3 months of the subject with suicidal 
ideation and the lifetime/ past 1 year of the subject with suicidal behavior, and a post-
baseline evaluation that focuses on suicidality since the last study visit.  The C-SSRS 
includes “yes” or “no” responses for assessment of suicidal ideation and behavior as well as 
numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe).  
The “Baseline/Screening” C-SSRS form will be completed on Day 1 prior to dosing.  The 
“Since Last Visit” C-SSRS form will be completed for all subsequent assessments. 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be listed for all subjects.  Listings will include behavior type and/or category for Suicidal 
Ideation and Suicidal Behavior of the C-SSRS.  In addition, the number and percentage of 
subjects with a response of ‘Yes’ to any C-SSRS Suicidal Ideation or Suicidal Behavior item 
will be presented. 
9.5 Pharmacokinetic Analysis 
Plasma will be collected to assay for concentrations of SAGE-547, SAGE-547 metabolites, 
and SBECD. PK analyses will be performed using the PK Population.  


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9.5.1 Collection schedule 
Blood samples for PK analysis Blood samples for PK analysis will be collected at pre-
infusion and at 4 (before change in infusion rate, if applicable), 8, 12, 24 (before change in 
infusion rate, if applicable), 30, 36, 48, 60 (before end of infusion), and 72 hours after the 
start of the infusion.  PK blood draws after the start of infusion will have a window of ±10 
minutes.  In the event of an unplanned dose adjustment, an unscheduled PK sample should be 
collected just prior to the infusion rate change (see section 15.1). 
9.5.2 Derived PK parameters 
The following PK parameters will be derived from the plasma concentrations of SAGE-547 
(where evaluable): 
Table 17: 
PK parameters and definitions 
AUC0-60 (or AUC) 
Area under the plasma concentration time curve from time 0 to 60 hours 
AUC∞ 
AUC from time 0 to infinity 
Cmax 
Maximum (peak) plasma concentration 
Tmax 
Time at maximum (peak) plasma concentration 
Css  
Steady-state drug concentration in the plasma during constant-rate infusion 
Cavg 
Average drug concentration in the plasma at steady state during a dosing 
interval 
9.5.3 Handling of dropouts or missing data 
PK parameters will be provided by a third party.  Missing data will not be addressed.  
9.5.4 Statistical analysis 
The plasma concentrations along with time point deviation from scheduled time will be listed 
by subject. 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics.  All 
PK parameters will be summarized using n, geometric mean, geometric coefficient of 
variation, coefficient of variation, median, minimum, and maximum and listed by subject. 
 
9.5.5 Data presentation 
The descriptive statistics will be generated as discussed above in Section 9.5.4. 
The following figures will be produced: 
  Mean ± SD plasma concentration-time profiles through Day 3, 60 hours will be 
plotted on linear and semi-log scales  
  Individual subject concentration-time profiles on linear and semi-logarithmic 
concentration scales 


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  Spaghetti plots for each treatment through Day 3, 60 hours (linear and semi-
logarithmic scale) 
10 SUMMARY OF INTERIM AND DMC ANALYSES 
Not applicable


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11 INDEX OF TABLES 
Number 
Title 
Analysis Set 
Table 14.1.1 
Subject Disposition  
All Enrolled Set 
Table 14.1.2 
Summary of Analysis Sets 
All Enrolled Set 
Table 14.1.4.1 
Demographic Characteristics 
All Randomized Set 
Table 14.1.4.2 
Demographic Characteristics 
Efficacy Set 
Table 14.1.5 
Medical History 
Safety Set 
Table 14.1.6 
Psychiatric and Perinatal Conditions History 
Safety Set 
Table 14.1.7 
Study Drug Exposure and Compliance 
Safety Set 
Table 14.1.8.1 
Prior Antidepressant Medications 
Safety Set 
Table 14.1.8.2 
Concomitant Antidepressant Medications 
Safety Set 
Table 14.1.9.1 
Non-Antidepressant Prior Medications 
Safety Set 
Table 14.1.9.2 
Non-Antidepressant Concomitant Medications 
Safety Set 
Table 14.2.1.1 
Hamilton Rating Scale for Depression (HAM-D) Total Score - Descriptive Statistics 
Efficacy Set 
Table 14.2.1.2 
Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect) 
Efficacy Set 
Table 14.2.1.3.1 
Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) Total Score - 
MMRM Analysis (Pooled Center as Random Effect) 
Efficacy Set 
Table 14.2.1.3.2 
Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect) - Per Protocol Set 
Per Protocol Set 
Table 14.2.1.4.1 
Hamilton Rating Scale for Depression (HAM-D) Total Score - Descriptive Statistics 
Subgroup Analysis: Race Category (White, Black or African American, and Other) 
Efficacy Set 
Table 14.2.1.4.2 
Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect)  
Subgroup Analysis: Race Category (White, Black or African American, and Other) 
Efficacy Set 
Table 14.2.1.5.1 
Hamilton Rating Scale for Depression (HAM-D) Total Score - Descriptive Statistics 
Subgroup Analysis: Age Category (18-24, 25-45) 
Efficacy Set 
Table 14.2.1.5.2 
Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect)  
Subgroup Analysis: Age Category (18-24, 25-45) 
Efficacy Set 


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Table 14.2.1.6.1 
Hamilton Rating Scale for Depression (HAM-D) Total Score - Descriptive Statistics 
Subgroup Analysis: Baseline Antidepressant Use (Yes vs No) 
Efficacy Set 
Table 14.2.1.6.2 
Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect)  
Subgroup Analysis: Baseline Antidepressant Use (Yes vs No) 
Efficacy Set 
Table 14.2.1.7.1 
Hamilton Rating Scale for Depression (HAM-D) Total Score - Descriptive Statistics 
Subgroup Analysis: BMI Category (<=18.4, 18.5-24.9, 25-29.9, >=30 kg/m2) 
Efficacy Set 
Table 14.2.1.7.2 
Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect) 
Subgroup Analysis: BMI Category (<=18.4, 18.5-24.9, 25-29.9, >=30 kg/m2) 
Efficacy Set 
Table 14.2.1.8.1 
Hamilton Rating Scale for Depression (HAM-D) Total Score - Descriptive Statistics 
Subgroup Analysis: Onset of PPD (3rd Trimester and Within 4 Weeks of Delivery) 
Efficacy Set 
Table 14.2.1.8.2 
Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect)  
Subgroup Analysis: Onset of PPD (3rd Trimester and Within 4 Weeks of Delivery) 
Efficacy Set 
Table 14.2.1.9.1 
Hamilton Rating Scale for Depression (HAM-D) Total Score - Descriptive Statistics 
Subgroup Analysis: Family history of PPD (Yes vs No) 
Efficacy Set 
Table 14.2.1.9.2 
Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect) 
Subgroup Analysis: Family history of PPD (Yes vs No) 
Efficacy Set 
Table 14.2.1.10.1 
Sensitivitiy Analysis - Change from Baseline in Hamilton Rating Scale for Depression (HAM-
D) Total Score - Dropout Reason Based Imputation and ANCOVA Model 
Efficacy Set 
Table 14.2.1.10.2 
Sensitivity Analysis - Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) 
Total Score - Stratified Wilcoxon Rank-Sum Test 
Efficacy Set 
Table 14.2.1.11.1 
Hamilton Rating Scale for Depression (HAM-D) Subscale and Individual Item Scores - 
Descriptive Statistics 
Efficacy Set 
Table 14.2.1.11.2 
Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) Subscale and 
Individual Item Scores - MMRM Analysis (Pooled Center as Fixed Effect) 
Efficacy Set 
Table 14.2.1.12 
Hamilton Rating Scale for Depression (HAM-D) Response - Descriptive Statistics and GEE 
Analysis 
Efficacy Set 
Table 14.2.1.13.1 
Hamilton Rating Scale for Depression (HAM-D) Response - Descriptive Statistics and Logistic 
Regression Analysis 
Efficacy Set 
Table 14.2.1.13.2 
Hamilton Rating Scale for Depression (HAM-D) Response - Descriptive Statistics and GEE 
Analysis 
Subgroup Analysis: Baseline Antidepressant Use (Yes vs No) 
Efficacy Set 


Statistical Analysis Plan (Methods) 
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Study 547-PPD-202C 
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Table 14.2.1.14 
Hamilton Rating Scale for Depression (HAM-D) Remission - Descriptive Statistics and GEE 
Analysis 
Efficacy Set 
Table 14.2.1.15.1 
Hamilton Rating Scale for Depression (HAM-D) Remission - Descriptive Statistics and Logistic 
Regression Analysis 
Efficacy Set 
Table 14.2.1.15.2 
Hamilton Rating Scale for Depression (HAM-D) Remission - Descriptive Statistics and GEE 
Analysis 
Subgroup Analysis: Baseline Antidepressant Use (Yes vs No) 
Efficacy Set 
Table 14.2.1.16.1 
Hamilton Rating Scale for Depression (HAM-D) Non-Response - Descriptive Statistics and 
Logistic Regression Analysis 
Efficacy Set 
Table 14.2.1.16.2 
Hamilton Rating Scale for Depression (HAM-D) Non-Remission - Descriptive Statistics and 
Logistic Regression Analysis 
Efficacy Set 
Table 14.2.2.1 
Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score - Descriptive Statistics 
Efficacy Set 
Table 14.2.2.2 
Change from Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect) 
Efficacy Set 
Table 14.2.2.3 
Change from Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect) - Per Protocol Set 
Per Protocol Set 
Table 14.2.2.4.1 
Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score - Descriptive Statistics  
Subgroup Analysis: Baseline Antidepressant Use (Yes vs No) 
Efficacy Set 
Table 14.2.2.4.2 
Change from Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect)  
Subgroup Analysis: Baseline Antidepressant Use (Yes vs No) 
Efficacy Set 
Table 14.2.2.5.1 
Sensitivity Analysis - Change from Baseline in Montgomery-Åsberg Depression Rating Scale 
(MADRS) Total Score - Dropout Reason Based Imputation and ANCOVA Model 
Efficacy Set 
Table 14.2.2.5.2 
Sensitivity Analysis - Change from Baseline in Montgomery-Åsberg Depression Rating Scale 
(MADRS) Total Score - Stratified Wilcoxon Rank-Sum Test 
Efficacy Set 
Table 14.2.3.1 
Generalized Anxiety Disorder 7-item Scale (GAD-7) Total Score - Descriptive Statistics 
Efficacy Set 
Table 14.2.3.2 
Change from Baseline in Generalized Anxiety Disorder 7-item Scale (GAD-7) Total Score - 
MMRM Analysis (Pooled Center as Fixed Effect) 
Efficacy Set 
Table 14.2.3.3 
Generalized Anxiety Disorder 7-item Scale (GAD-7) Response - Descriptive Analysis and 
Fisher’s Exact Test 
Efficacy Set 
Table 14.2.4.1 
Clinical Global Impression-Severity (CGI-S) Score (Continuous) - Descriptive Statistics 
Efficacy Set 
Table 14.2.4.2.1 
Clinical Global Impression-Improvement (CGI-I) Score (Continuous) - Descriptive Statistics 
Efficacy Set 
Table 14.2.4.2.2 
Clinical Global Impression-Improvement (CGI-I) Score - MMRM Analysis (Pooled Center as 
Fixed Effect) 
Efficacy Set 


Statistical Analysis Plan (Methods) 
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48 
 
Table 14.2.4.3 
Clinical Global Impression-Improvement (CGI-I) Score (Categorical) - Descriptive Statistics 
Efficacy Set 
Table 14.2.4.4 
Clinical Global Impression-Improvement (CGI-I) Response - Descriptive Analysis and GEE 
Analysis 
Efficacy Set 
Table 14.2.4.5.1 
Clinical Global Impression-Improvement (CGI-I) Response - Descriptive Statistics and Logistic 
Regression Analysis 
Efficacy Set 
Table 14.2.4.5.2 
Clinical Global Impression-Improvement (CGI-I) Response - Descriptive Analysis and GEE 
Analysis  
Subgroup Analysis: Baseline Antidepressant Use (Yes vs No) 
Efficacy Set 
Table 14.2.5 
Changes in Post-baseline Antidepressant Medications - Kaplan Meier Analysis 
Efficacy Set 
Table 14.2.6.1 
Edinburgh Postnatal Depression Scale (EPDS) Total Score - Descriptive Statistics 
Efficacy Set 
Table 14.2.6.2 
Change from Baseline in Edinburgh Postnatal Depression Scale (EPDS) Total Score - MMRM 
Analysis (Pooled Center as Fixed Effect) 
Efficacy Set 
Table 14.2.7.1 
Patient Health Questionnaire (PHQ-9) Total Score - Descriptive Statistics 
Efficacy Set 
Table 14.2.7.2 
Change from Baseline in Patient Health Questionnaire (PHQ-9) Total Score - MMRM Analysis 
(Pooled Center as Fixed Effect) 
Efficacy Set 
Table 14.2.7.3 
Patient Health Questionnaire (PHQ-9) Response - Descriptive Analysis and Fisher’s Exact Test 
Efficacy Set 
Table 14.2.8.1 
Barkin Index of Maternal Functioning (BIMF) Total Score and Subscales - Descriptive 
Statistics 
Efficacy Set 
Table 14.2.8.2 
Change from Baseline in Barkin Index of Maternal Functioning (BIMF) Total Score and 
Subscales - MMRM Analysis (Pooled Center as Fixed Effect) 
Efficacy Set 
Table 14.2.9.1 
Short Form-36 (SF-36) - Descriptive Statistics 
Efficacy Set 
Table 14.2.9.2 
Change from Baseline in Short Form-36 (SF-36) Scales - MMRM Analysis (Pooled Center as 
Fixed Effect) 
Efficacy Set 
Table 14.2.10 
Health Care Resource Utilization (HCRU) - Descriptive Statistics 
Efficacy Set 
Table 14.3.1.1 
Summary of Overall Treatment-Emergent Adverse Events (TEAEs) 
Safety Set 
Table 14.3.1.2 
Treatment  Emergent Adverse Events (TEAEs) by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.3 
Treatment Emergent Adverse Events (TEAEs) by Preferred Term   
Safety Set 
Table 14.3.1.4 
Treatment Emergent Serious Adverse Events (SAEs) by System Organ Class and Preferred 
Term 
Safety Set 
Table 14.3.1.5 
Treatment Emergent Adverse Events (TEAEs) by System Organ Class, Preferred Term and 
Maximum Severity 
Safety Set 
Table 14.3.1.6 
Treatment Emergent Adverse Events (TEAEs) by System Organ Class, Preferred Term and 
Strongest Relatedness to SAGE-547 
Safety Set 


Statistical Analysis Plan (Methods) 
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49 
 
Table 14.3.1.7 
Treatment Emergent Adverse Events (TEAEs) Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term 
Safety Set 
Table 14.3.4.1.1 
Hematology - Descriptive Statistics 
Safety Set 
Table 14.3.4.1.2 
Shift from Baseline in Hematology Parameters 
Safety Set 
Table 14.3.4.1.3 
Number and Percentage of Subjects with Potentially Clinically Significant (PCS) values in 
Hematology Parameters 
Safety Set 
Table 14.3.4.2.1 
Serum Chemistry - Descriptive Statistics 
Safety Set 
Table 14.3.4.2.2 
Shift from Baseline in Serum Chemistry Parameters 
Safety Set 
Table 14.3.4.2.3 
Number and Percentage of Subjects with Potentially Clinically Significant (PCS) values in 
Serum Chemistry Parameters 
Safety Set 
Table 14.3.4.2.4 
Number and Percentage of Subjects with Liver Function Abnormalities Meeting Hy’s Law 
Safety Set 
Table 14.3.4.2.5 
Number and Percentage of Subjects with Worsened Abnormal Liver Enzymes and Liver 
Function Tests Results 
Safety Set 
Table 14.3.4.3.1 
Coagulation - Descriptive Statistics 
Safety Set 
Table 14.3.4.3.2 
Shift from Baseline in Coagulation Parameters 
Safety Set 
Table 14.3.4.4.1 
12-lead ECG - Descriptive Statistics 
Safety Set 
Table 14.3.4.4.2 
Investigator Interpretation of 12-lead ECG Result - Descriptive Statistics 
Safety Set 
Table 14.3.4.4.3 
Number and Percentage of Subjects Meeting ECG Threshold Criterion 
Safety Set 
Table 14.3.4.5.1 
Vital Signs - Descriptive Statistics 
Safety Set 
Table 14.3.4.5.2 
Number and Percentage of Subjects with Orthostatic Hypotension 
Safety Set 
Table 14.3.4.6.1 
Number and Percentage of Subjects with a Response of Yes to Any Columbia Suicide Severity 
Rating Scale (C-SSRS) Suicidal Ideation Item 
Safety Set 
Table 14.3.4.6.2 
Number and Percentage of Subjects with a Response of Yes to Any Columbia Suicide Severity 
Rating Scale (C-SSRS) Suicidal Behavior Item 
Safety Set 
Table 14.4.1.1 
Plasma Pharmacokinetic Parameters of SAGE-547  - Descriptive Statistics 
PK Set 
 
 
 


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12 INDEX OF FIGURES 
Number 
Title 
Analysis Set 
Figure 14.2.1.1 
Mean (± SD) Across Days in Hamilton Rating Scale for Depression (HAM-D) Total Score 
Efficacy Set 
Figure 14.2.1.2 
LS Mean (± SE) Change from Baseline Across Days in Hamilton Rating Scale for Depression 
(HAM-D) Total Score 
Efficacy Set 
Figure 14.2.1.3 
Percentage of Subjects Achieving Response in Hamilton Rating Scale for Depression (HAM-D) 
Efficacy Set 
Figure 14.2.1.4 
Percentage of Subjects Achieving Remission in Hamilton Rating Scale for Depression (HAM-D) 
Efficacy Set 
Figure 14.2.2.1 
Mean (± SD) Across Days in Montgomery-Åsberg Depression Rating Scale (MADRS) Total 
Score 
Efficacy Set 
Figure 14.2.2.2 
LS Mean (± SE) Change from Baseline Across Days in Montgomery-Åsberg Depression Rating 
Scale (MADRS) Total Score 
Efficacy Set 
Figure 14.2.3.1 
Mean (± SD) Across Days in Generalized Anxiety Disorder 7-item Scale (GAD-7) Total Score 
Efficacy Set 
Figure 14.2.3.2 
LS Mean (± SE) Change from Baseline Across Days in Generalized Anxiety Disorder 7-item 
Scale (GAD-7) Total Score 
Efficacy Set 
Figure 14.2.4 
LS Mean (± SE) Clinical Global Impression - Improvement (CGI-I) Scale 
Efficacy Set 
Figure 14.2.5.1 
Mean (± SD) Across Days in Edinburgh Postnatal Depression Scale (EPDS) Total Score 
Efficacy Set 
Figure 14.2.5.2 
LS Mean (± SE) Change from Baseline Across Days in Edinburgh Postnatal Depression Scale 
(EPDS) Total Score 
Efficacy Set 
Figure 14.2.6.1 
Kaplan-Meier Plot for Time to First Start in Rescue Antidepressant Medications or First Increase 
in Dose of Any Antidepressant Medications 
Efficacy Set 
Figure 14.2.6.2 
Kaplan-Meier Plot for Time to First Stop/Decrease in Dose of Any Antidepressant Medications 
Efficacy Set 
Figure 14.3.1 
Mean (± SD) Values of 12-Lead ECG Parameters Over Time 
Safety Set 
Figure 14.3.2 
Mean (± SD) Values of Vital Signs Parameters Over Time 
Safety Set 
Figure 14.4.1.1 
Mean (± SD) Plasma Concentration-Time Profiles through Day 3, 60 hours (Linear Scale) 
PK Set 
Figure 14.4.1.2 
Mean (± SD) Plasma Concentration-Time Profiles through Day 3, 60 hours (Semi-Logarithmic 
Scale) 
PK Set 
Figure 14.4.2.1 
Individual Plasma Concentration-Time Profiles through Day 3, 60 hours (Linear Scale) 
PK Set 
Figure 14.4.2.2 
Individual Plasma Concentration-Time Profiles through Day 3, 60 hours (Semi-Logarithmic 
Scale) 
PK Set 
 
 
 


Statistical Analysis Plan (Methods) 
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13 INDEX OF LISTINGS 
Number 
Title 
Analysis Set 
Listing 16.2.1.1 
Subject Disposition 
All Subjects 
Listing 16.2.1.2 
Subjects not Meeting Study Eligibility Criteria 
All Subjects 
Listing 16.2.2 
Protocol Deviations 
Protocol Deviations 
Listing 16.2.3 
Analysis Sets 
All Enrolled Set 
Listing 16.2.4.1 
Demographics and Baseline Characteristics 
All Enrolled Set 
Listing 16.2.4.2 
Drug and Alcohol Screening Results 
All Enrolled Set 
Listing 16.2.4.3 
Hepatitis and HIV Screening Results 
All Enrolled Set 
Listing 16.2.4.4 
Genetic Testing 
All Enrolled Set 
Listing 16.2.4.5 
Medical History 
All Enrolled Set 
Listing 16.2.4.6 
Subject History of Psychiatric Disorders 
All Enrolled Set 
Listing 16.2.4.7 
Post-Partum Depression Episode Current and Previous 
All Enrolled Set 
Listing 16.2.4.8 
Psychiatric Family History 
All Enrolled Set 
Listing 16.2.4.9 
Perinatal Family History 
All Enrolled Set 
Listing 16.2.4.10.1 
Prior and Concomitant Medications 
All Enrolled Set 
Listing 16.2.4.10.2 
Antidepressant Use 
All Enrolled Set 
Listing 16.2.5.1 
Study Drug Administration 
All Enrolled Set 
Listing 16.2.5.2 
Plasma Pharmacokinetic Sampling and SAGE-547 Concentrations Over Time 
All Enrolled Set 
Listing 16.2.5.3 
Individual Pharmacokinetic Parameters of SAGE-547 
All Enrolled Set 
Listing 16.2.5.4 
Plasma Pharmacokinetic Sampling and SAGE-547 Metabolites Concentrations 
Over Time 
All Enrolled Set 
Listing 16.2.5.5 
Plasma Pharmacokinetic Sampling and SBECD Concentrations Over Time 
All Enrolled Set 
Listing 16.2.6.1.0 
Hamilton Rating Scale for Depression (HAM-D) - Preface 
 
Listing 16.2.6.1.1 
Hamilton Rating Scale for Depression (HAM-D) - Individual Item Scores 
All Enrolled Set 
Listing 16.2.6.1.2 
Hamilton Rating Scale for Depression (HAM-D) - Subscale and Total Scores 
All Enrolled Set 
Listing 16.2.6.2.0 
Montgomery-Åsberg Depression Rating Scale (MADRS) - Preface 
 
Listing 16.2.6.2.1 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
All Enrolled Set 
Listing 16.2.6.3.0 
Generalized Anxiety Disorder 7-item Scale (GAD-7) - Preface 
 
Listing 16.2.6.3.1 
Generalized Anxiety Disorder 7-item Scale (GAD-7) 
All Enrolled Set 


Statistical Analysis Plan (Methods) 
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Listing 16.2.6.4 
Clinical Global Impression(CGI) 
All Enrolled Set 
Listing 16.2.6.5.0 
Edinburgh Postnatal Depression Scale (EPDS) - Preface 
 
Listing 16.2.6.5.1 
Edinburgh Postnatal Depression Scale (EPDS) 
All Enrolled Set 
Listing 16.2.6.6.0 
Patient Health Questionnaire (PHQ-9) - Preface 
 
Listing 16.2.6.6.1 
Patient Health Questionnaire (PHQ-9) 
All Enrolled Set 
Listing 16.2.6.7.0 
Barkin Index of Maternal Functioning (BIMF) - Preface 
 
Listing 16.2.6.7.1 
Barkin Index of Maternal Functioning (BIMF) 
All Enrolled Set 
Listing 16.2.6.8.0 
Short Form-36 (SF-36) - Preface 
 
Listing 16.2.6.8.1 
Short Form-36 (SF-36) - Individual Item Scores 
All Enrolled Set 
Listing 16.2.6.8.2 
Short Form-36 (SF-36) - Subscale and Summary Scores 
All Enrolled Set 
Listing 16.2.6.9 
Healthcare Resource Utilization (HCRU) Questionnaire 
All Enrolled Set 
Listing 16.2.7.1 
Adverse Events 
All Enrolled Set 
Listing 16.2.7.2 
Serious Adverse Events 
All Enrolled Set 
Listing 16.2.7.3 
Adverse Events Leading to Study Drug Discontinuation 
All Enrolled Set 
Listing 16.2.7.4 
Adverse Events Leading to Death 
All Enrolled Set 
Listing 16.2.8.1 
Serum Chemistry 
All Enrolled Set 
Listing 16.2.8.2 
Hematology 
All Enrolled Set 
Listing 16.2.8.3 
Coagulation 
All Enrolled Set 
Listing 16.2.8.4 
Urinalysis 
All Enrolled Set 
Listing 16.2.8.5 
Hormones 
All Enrolled Set 
Listing 16.2.8.6 
Exploratory Biochemistry 
All Enrolled Set 
Listing 16.2.8.7 
Serum and Urine Pregnancy Test 
All Enrolled Set 
Listing 16.2.8.8 
Vital Signs 
All Enrolled Set 
Listing 16.2.8.9 
12-lead ECG 
All Enrolled Set 
Listing 16.2.8.10 
Physical Examination  
All Enrolled Set 
Listing 16.2.8.11 
Columbia Suicide Severity Rating Scale (C-SSRS) 
All Enrolled Set 


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Confidential Information 
 
 
14 REFERENCES 
Clinical Study Protocol: amendment 4, version 5.0 (16th March, 2017), Company: Sage Therapeutics 
Inc.  
 
Implementation of Pattern-Mixture Models Using Standard SAS/STAT Procedures. Bohdana Ratitch, 
Quintiles, Montreal, Quebec, Canada and Michael O’Kelly, Quintiles, Dublin, Ireland.  
 


Statistical Analysis Plan (Methods) 
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15 LIST OF APPENDICES 
15.1 Appendix A: Schedule of Assessments 
Table 15: Schedule of Events - Part C 
 
Screening 
Period 
Treatment Period 
Clinic Period (Day 1 to Day 3) 
Follow-up Period 
Visit Days  
Screening 
D-7 to -1 
D1 
H0* 
D1 
H2 
D1 
H4 
D1 
H8 
D1 
H12 
D1 
H18 
D1 
H24 
D2 
H30 
D2 
H36 
D2 
H42 
D2 
H48 
D3 
H54 
D3 
H60 
D3 
H66 
D3 
H72 
D7/ET 
(±1d) 
D14 
(+2d) 
D21 
(+3d) 
D30 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Lab 
Assessments a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Urinalysis a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Drug & Alcohol 
Screenb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Genetic Sample d 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
12-Lead ECG f 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
C-SSRS g 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
Confinement 
 
X 
 
 
 
 
CGI-I h 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-I 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAM-D h 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 


Statistical Analysis Plan (Methods) 
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Visit Days  
Screening 
D-7 to -1 
D1 
H0* 
D1 
H2 
D1 
H4 
D1 
H8 
D1 
H12 
D1 
H18 
D1 
H24 
D2 
H30 
D2 
H36 
D2 
H42 
D2 
H48 
D3 
H54 
D3 
H60 
D3 
H66 
D3 
H72 
D7/ET 
(±1d) 
D14 
(+2d) 
D21 
(+3d) 
D30 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MADRS h 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
BIMF h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
EPDS h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
GAD-7 h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
PHQ-9 h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
SF-36 (acute version) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
HCRU 
X 
X 
Plasma PKi 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
Instructions for 
Lactating Subjectsj 
 
X 
X 
X 
 
 
 
 
Study Drug Infusion 
 
X 
 
 
 
 
 
 
Adverse Events 
X 
Prior/Concomitant 
Medicationsk 
X 
O = optional; * = All H0 procedures to be completed prior to dosing 
a  Safety laboratory tests will include hematology, serum chemistry, coagulation, and select hormone parameters.  The urine test will include a urinalysis.  
Lab assessments are to be completed within ±30 minutes of the scheduled time point. 
b  Urine for selected drugs of abuse and alcohol (serum or breath) 
c  Serum at screening and urine for all other time points; lactation status (ie, subject is breastfeeding, subject is lactating but not breastfeeding, or subject is 
not lactating) will be recorded at screening 
d  A blood sample for genetic testing, where consent is given 
e  Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing).  Vital signs will be obtained within ±30 
minutes of the scheduled time point, unless the subject is asleep between the hours of 23.00h and 06.00h. 
f  Performed within ±30 minutes of the scheduled time point on Day 2. 
g  The “Baseline/Screening” C-SSRS form will be completed on Day 1.  The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points. 
h  To be completed within ±30 minutes of the scheduled time point during the Treatment Period. 
i  Blood samples for PK analysis will be collected at pre-infusion and at 4 (before change in infusion rate, if applicable), 8, 12, 24 (before change in infusion 
rate, if applicable), 30, 36, 48, 60 (before end of infusion), and 72 hours after the start of the infusion.  PK blood draws after the start of infusion will have 
a window of ±10 minutes.  In the event of an unplanned dose adjustment, an unscheduled PK sample should be collected just prior to the infusion rate 
change. 
j  Breast milk will be pumped and discarded by subjects who are lactating.  On Day 3, subjects who are lactating will be reminded that they must continue to 
pump and discard breast milk through Day 12 of the study.   


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k  To include those taken within 60 days prior to signing the informed consent through the Day 30 visit. 
BIMF = Barkin Index of Maternal Functioning; CGI-I = Clinical Global Impression of Improvement; C-SSRS = Columbia Suicide Severity Rating Scale; 
ECG = electrocardiogram; EPDS = Edinburgh Postnatal Depression Scale; GAD-7 = Generalized Anxiety Disorder 7-Item Scale; HAM-D = Hamilton 
Rating Scale for Depression, 17-item; HCRU = Health Care Resource Utilization; MADRS = Montgomery-Asberg Depression Rating Scale; PHQ-9 = 
Patient Health Questionnaire; PK = pharmacokinetic; SF-36 = Short Form-36; SCID-I = Structured Clinical Interview for DSM-IV Axis I Disorders.


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15.2 Appendix B: Details of Statistical Methodology 
Sample SAS code for MMRM (center as fixed effect): 
PROC MIXED DATA = xxx; 
   CLASS center trt avisit usubjid strata; 
   MODEL change = base center trt avisit avisit*trt strata / ddfm=kr; 
   REPEATED avisit/subject = usubjid type= un;  
* if type= un does not converge, use type= toep; 
* if type=toep still does not converge, use type= ar(1); 
   LSMEANS avisit*trt / diff=all cl alpha=0.05; 
RUN; 
Sample SAS code for MMRM (center as random effect): 
PROC MIXED DATA = xxx; 
   CLASS center trt avisit usubjid strata; 
   MODEL change = base center trt avisit avisit*trt strata / DDFM=KR; 
   REPEATED subject = usubjid /type= un; 
   RANDOM center /type= un; 
   RANDOM intercept / subject=usubjid type = un; 
* if type= un does not converge, use type= toep; 
* if type=toep still does not converge, use type= ar(1); 
   LSMEANS avisit*trt / diff=all cl alpha=0.05; 
RUN; 
Sample SAS code for GEE: 
PROC GENMOD DATA = xxx; 
   CLASS center trt avisit usubjid strata; 
   MODEL resp = base center trt avisit avisit*trt strata/ DIST= bin link=logit; 
   REPEATED subject=usubjid / type = un; 
   LSMEANS avisit*trt / diff exp cl; 
RUN; 
 
 


Statistical Analysis Plan (Methods) 
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Sample SAS code for Stratified Wilcoxon Rank Sum Test: 
PROC FREQ DATA = xxx; 
   WHERE trtan in (1, 2); 
   TABLES strata*trtan*chg/cmh2 scores=modridit noprint; 
RUN; 
Sample SAS code for Fisher’s Exact Test: 
PROC FREQ DATA = xxx ORDER=DATA; 
   WHERE trta in ('PLACEBO','SAGE-547 90ug'); 
   BY avisitn; 
   TABLE trta*crit2fl / NOCOL NOPERCENT; 
   EXACT OR Fisher; 
   ODS OUTPUT CrossTabFreqs=freq FishersExact=fisher OddsRatioCL=cl; 
RUN; 
Sample SAS code for Logistic Regression: 
PROC LOGISTIC DATA = xxx; 
   CLASS center trt avisit usubjid strata; 
   MODEL resp (event=’1’) = base center trt avisit avisit*trt strata; Note: for CGI-S, add cgisbase 
independent variable as well  
   LSMEANS trtan*avisitn / diff oddsratio cl exp; 
RUN; 
Sample SAS code for MI with FCS statement: 
PROC MI DATA = xxx SEED = 1213 NIMPUTE = 4 ROUND = 1 OUT = fcs_reg; 
   CLASS usubjid trt strata avisit center; 
   FCS DISCRIM (usubjid trt avisit center/ details classeffects=include); 
   FCS NBITER = 20 LOGISTIC (strata = usubjid/details);  
   FCS NBITER = 20 REG(change = usubjid base center trt avisit avisit*trt strata/details); 
   VAR change strata usubjid trt avisit center base; 
RUN; 
Sample SAS code for ANOVA: 
PROC ANOVA DATA = xxx; 
   CLASS center trt strata; 
   MODEL aval = center trt strata; 
RUN; 
 
 


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-202C 
CONFIDENTIAL 
 
59 
 
Sample SAS code for ANCOVA:  
PROC MIXED DATA = xxx; 
   CLASS center trt strata; 
   MODEL change = base center trt strata; 
RUN; 
Sample SAS code for ANOVA: 
PROC ANOVA DATA = xxx; 
CLASS center trt strata; 
MODEL aval = center trt strata; 
RUN; 
Sample SAS code for ANCOVA:  
PROC MIXED DATA = xxx; 
   CLASS center trt strata; 
   MODEL change = base center trt strata; 
RUN;