Conditions: Major Depressive Disorder Insomnia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 87
Healthy volunteers: no

Brief summary:
This study is a randomized, double-blind, placebo-controlled study of the safety, tolerability, and efficacy of SAGE-217 compared to placebo in adult participants with comorbid major depressive disorder (MDD) and insomnia.

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

Arms:
arm 1: Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out \[polysomnography (PSG)\] on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21. arm 2: Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 milligrams (mg) capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.

Interventions: intervention 1: SAGE-217 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered as capsules. intervention 2: Administered as capsules.

Protocol document:
Prot_000.pdf: 
Official Title: 
A Randomized, Double-blind, Placebo-controlled Study of the Safety, Tolerability, 
and Efficacy of SAGE-217 Compared to Placebo in Adult Subjects With Comorbid 
Major Depressive Disorder and Insomnia
NCT Number: 
NCT03771664
Document Date: 
Protocol Version 4.0: 18 July 2019


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-304, v4.0 
 
CONFIDENTIAL 
1 
 
 
 
 
A Randomized, Double-blind, Placebo-controlled Study of the 
Safety, Tolerability, and Efficacy of SAGE-217 Compared to 
Placebo in Adult Subjects with Comorbid Major Depressive 
Disorder and Insomnia 
 
 
PROTOCOL NUMBER: 217-MDD-304 
 
Study Drug 
SAGE-217 
Clinical Phase 
Phase 3  
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
 
Tel: 
 
email: 
 
Sponsor Medical Monitor 
MD, PhD 
Tel: 
 
E-mail: 
 
Date of Original Protocol 
Version 1.0, 11 October 2018 
Date of Amendment 1 
Version 2.0, 22 February 2019 
Date of Amendment 2 
Version 3.0, 25 April 2019 
Date of Amendment 3 
Version 4.0, 17 July 2019 
 
 
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 Sage Therapeutics, Inc. 




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


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PROCEDURES IN CASE OF EMERGENCY 
 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sage Study Physician 
 MD, PhD  
 
Email
 
Tel: 
  
Syneos Health Medical 
Monitor 
 MD 
 
Email: 
 
Office: 
 
Mobile
 
24-Hour Serious Adverse 
Event reporting 
IQVIA Lifecycle Safety 
Email: 
 
SAE Hotline Tel: 
 
Fax: 
  
Product Complaints 
Sage Therapeutics, Inc. 
Email: productcomplaints@sagerx.com 
Tel: 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or Sage) 
Name of Study Drug: 
SAGE-217 Capsules 
Name of Active Ingredient: 
SAGE-217  
Title of Study:  
A Randomized, Double-blind, Placebo-controlled Study of the Safety, Tolerability, and Efficacy of 
SAGE-217 Compared to Placebo in Adult Subjects with Comorbid Major Depressive Disorder and 
Insomnia 
Number of Sites and Study Location: This study will take place at approximately 25 sites in the 
United States. 
Phase of Development: 3 
Planned Duration of Subject Participation: 
The planned duration of subject participation is approximately 72 days. During this time, there will be 
11 study visits, which will include 4 overnight stays. 
Objectives: 
Primary: 
• 
To determine the effect of SAGE-217 on overall insomnia symptoms in subjects with 
comorbid Major Depressive Disorder (MDD) and insomnia. 
Secondary: 
• 
To measure the effects of SAGE-217 on individual objective and subjective symptoms of 
insomnia including difficulties with sleep maintenance and sleep onset. 
• 
To measure the effects of SAGE-217 on sleep architecture. 
• 
To evaluate the effect of SAGE-217 on depressive symptoms.  
• 
To assess patient-reported outcome (PRO) measures as they relate to depressive symptoms. 
• 
To evaluate the safety and tolerability of SAGE-217.  
 
 
 
 
  
 
 
 
 
 
 
Endpoints: 
Primary: 
• 
Change from baseline in sleep efficiency (SE), defined as the percentage of time in bed spent 
asleep, at end of double-blind treatment (EODBT) as assessed by polysomnography (PSG) 


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Secondary: 
• 
Change from baseline of the following PSG-derived endpoints at EODBT: 
• 
Wake after sleep onset (WASO, defined as the total wake time in minutes) from 
persistent sleep onset to lights-on (final wake time) 
• 
WASO by quarter (2-hour period) of the PSG recording (8-hour period) 
• 
Total sleep time (TST) and TST by quarter of the PSG recording 
• 
Latency to persistent sleep (LPS) 
• 
Number of awakenings (NAW) and mean duration of awakenings, in total and by 
quarter of the PSG recording 
• 
Minutes and percent of stage N1, N2, N3, and Rapid Eye Movement (REM) sleep  
• 
Latency to the first period of REM Sleep and latency to each subsequent period of 
REM Sleep 
• 
REM Density 
• 
REM Activity 
• 
Change from baseline in subjective sleep endpoints at EODBT: 
• 
Insomnia Severity Index (ISI) 
• 
Consensus Sleep Diary – Core (CSD-C) endpoints 
▪ 
Subjective total sleep time (sTST) 
▪ 
Subjective wake after sleep onset (sWASO) 
▪ 
Subjective sleep latency (sSL) 
▪ 
Subjective sleep quality (sSQ) 
• 
Change from baseline in Clinical Global Impression - Severity (CGI-S) at EODBT (based on 
the insomnia disorder) 
• 
Clinical Global Impression - Improvement (CGI-I) at EODBT (based on the insomnia 
disorder)  
• 
Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total 
score at EODBT 
• 
Change from baseline in the 9-item subject-rated Patient Health Questionnaire (PHQ) at the 
EODBT 
• 
Safety: Incidence and severity of adverse events/serious adverse events; changes from baseline 
in vital sign assessments, clinical laboratory data, electrocardiogram (ECG) parameters, and 
suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale (C-SSRS). 
Evaluation of withdrawal symptoms as measured by the Physician Withdrawal Checklist 
(PWC-20) 


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Study Description:  
Insomnia symptoms have been reported in a majority of people with MDD. The relationship between 
MDD and insomnia disorder is bidirectional where the presence of one increases the risk of developing 
the other and people with severe depression are likely to also have severe insomnia. In previous 
studies, SAGE-217 significantly improved depression in subjects with MDD and improved sleep in a 
phase-advance model of transient insomnia in healthy adults. The purpose of this study is to examine 
the effects of SAGE-217 on symptoms of sleep disruption in subjects with comorbid insomnia and 
MDD. 
This is a randomized, double-blind, parallel group, placebo-controlled study of the safety, tolerability, 
efficacy, 
 of SAGE-217 compared to placebo in adult subjects with 
insomnia (ISI ≥15) and comorbid MDD (MADRS total score ≥28, HAM-D score ≥20). The study 
schematic is shown in Figure 1. 
After the subject has provided written informed consent, eligibility will be determined by applying the 
inclusion/exclusion criteria. The diagnosis of insomnia and MDD must be confirmed according to 
Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5) (SCID-5-CT) performed by a qualified healthcare professional. 
Subjects who pass initial screening will be asked to complete an electronic sleep diary for a minimum 
of 4 of 7 nights from evening of Day -9 to the morning of Day -2. Continued eligibility for the study 
will be based on subjects having a sleep diary with the following: a minimum of 4 nights completed 
and a TST of <390 minutes (<6.5 hours) on at least 3 nights between Day -9 and Day -2. Subjects who 
do not meet the sleep diary eligibility criteria will not qualify for continued participation in the study. 
Subjects who meet the sleep diary continuation criteria will return for a PSG qualification visit. The 
PSG qualification visit (Visit 2) will begin on Day -2 and will continue to Day 1. The clinical research 
coordinator (CRC) will determine the habitual bedtime from their sleep diary. Subjects should arrive at 
the clinic approximately 2 hours prior to their habitual bedtime for the 2-night PSG qualification visit. 
For each night, subjects will receive a standard meal and be prepared for overnight PSG recording. 
Lights out and PSG recording will begin within approximately 1 hour of their habitual bedtime. 
Subjects will receive a single-blind placebo, with food, 30 (±15) minutes prior to lights out prior to the 
PSG qualification (Visit 2). Subjects will be required to remain in bed for 8 hours, after which time the 
PSG recording will end, lights will turn on, and subjects will be awakened if asleep. 
 
 
 The electronic CSD-C will be completed at the clinic on all days following the 
PSG recordings.   
Eligible subjects who meet the PSG qualification criteria will be randomized to 1 of 2 treatment groups 
(SAGE-217 30 mg or placebo) on a 1:1 basis. Starting on Day 1, subjects will self-administer a single 
dose of study drug once daily in the evening with food, on an outpatient basis, for 12 days. Practically, 
subjects may consider taking the study medication within 1 hour following a dinner including solid 
food, or taking study medication later in the evening with solid food. Given the substantially improved 
absorption of SAGE-217 with food, administering the study medication in the presence of food is 
important. Subjects will return to the study center during the treatment and follow-up periods as 
outlined in Table 1. Efficacy and safety assessments will be performed at pre-specified times during 
the study, and blood samples will be collected for analysis of SAGE-217, as outlined in the Schedule 
of Assessments (Table 1). Subjects will return to the clinic for Visit 5 (Day 13) for a 2-night overnight 
stay; subjects will be administered study drug on Days 13 and 14 in the clinic. Subjects will have 


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2 consecutive PSGs as described above which will begin on Day 13 and will continue to Day 15. 
Subjects will be allowed to remain in the clinic between the consecutive PSG visits. At the discretion 
of the Investigator, subjects may be allowed to leave the clinic between consecutive PSG visits 
following all post-treatment evaluations and return to the clinic 2 hours prior to their habitual bedtime 
as determined by the CRC. 
On Days 15 through 21, inclusive, all subjects will self-administer a single dose of single-blind study 
drug (placebo) daily in the evening with food, on an outpatient basis.  
Follow-up Visits will be conducted on Days 18, 22, 28, 35, and 42. The blind will be maintained 
through the Follow-up period. Subjects who cannot tolerate study drug will be discontinued from study 
drug and will receive treatment as clinically indicated. Subjects who discontinue treatment during the 
double-blind treatment period should return to the site for an end of double-blind treatment visit (Visit 
6) as soon as possible, preferably the day after treatment is discontinued. If at any time after Visit 6, a 
subject decides to terminate the study (ie, not be available for the last follow-up visit 4 weeks after the 
last double-blind study treatment), the subject should return for an early termination (ET) visit. The 
end of double-blind treatment and ET visits can be on the same day if a subject discontinues study drug 
and terminates the study on the same day during a clinic visit; in this case, events scheduled for these 
visits will be conducted. 
Number of Subjects (Planned): Approximately 102 subjects will be randomized and dosed to obtain 
82 evaluable subjects, with a total of 41 subjects per treatment arm. 
Eligibility Criteria:  
Inclusion Criteria: 
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject agrees to adhere to the study requirements. 
3. Subject is a male or female between 18 and 64 years of age, inclusive, at the time of consent. 
4. Subject has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that have been 
present for at least a 4-week period.  
5. Subject has insomnia that has been present for ≥4 weeks and is confirmed at Screening based 
on the DSM-5 diagnostic criteria (using the SCID-5-CT) for insomnia disorder, excluding 
DSM-5 criterion D (requiring 3 months duration) and allowing the presence of coexistent 
MDD as it applies to DSM-5 criterion H. 
6. Subject has an Insomnia Severity Index (ISI) score ≥15 (moderate to severe insomnia) at 
Visits 1 and 3. 
7. Subject has completed the Consensus Sleep Diary-Core (CSD-C) for a minimum of 4 days 
between the evening of Day -9 and after awakening on the morning of Day -2, inclusive. 
8. Subject reports a total sleep time (TST) of <390 minutes (<6.5 hours) based on CSD-C 
Questions #2 through 6, on at least 3 nights between the evening of Day -9 and after 
awakening on the morning of Day -2, inclusive.  
9. Subject has a habitual bedtime between 9:00 PM and 12:00 AM (midnight). 
10. Subject has a mean wakefulness after persistent sleep onset (WASO) ≥30 minutes on 
combined baseline PSG nights (Days -2 and -1), with neither night ≤20 minutes.  


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11. Subject has a MADRS score of ≥28 and a HAM-D total score ≥20 at Visit 1 and Visit 3 (prior 
to dosing). 
12. Subject taking antidepressants must have been taking these medications at the same dose for at 
least 60 days prior to Day 1. 
13. Subject is willing to delay start of other antidepressant or antianxiety medications and any new 
pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics and sleep aids, 
and Cognitive Behavioral Therapy for Insomnia (CBTI) until after study completion. 
14. 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. Subject 
has a body mass index (BMI) within the range of 18.0 to 40.0 kg/m2, inclusive. 
15. Female subject agrees to use one of the following methods of highly effective contraception 
during participation in the study and for 30 days following the last dose of study drug, unless 
she is postmenopausal (defined as no menses for 12 months without an alternative medical 
cause and confirmed by follicle stimulating hormone [FSH] level >40 mIU/mL) and/or 
surgically sterile (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or does 
not engage in sexual relations which carry a risk of pregnancy (does not include abstinence): 
• 
Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation. 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation.  
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal occlusion/ligation. 
• 
Vasectomized partner. 
16. Male subject agrees to use an acceptable method of effective contraception for the duration of 
study and for 5 days after receiving the last dose of the study drug, unless the subject does not 
engage in sexual relations which carry a risk of pregnancy (does not include abstinence). 
Acceptable methods of effective contraception for males includes vasectomy, or a condom 
with spermicide used together with highly effective female contraception methods if the 
female partner(s) is of child-bearing potential (see Inclusion Criteria #15 for acceptable 
contraception methods).  
17. Male subject is willing to abstain from sperm donation for the duration of the study and for 
5 days after receiving the last dose of the study drug. 
18. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
Exclusion Criteria: 
1. Subject has attempted suicide associated within the current episode of MDD. 
2. Subject had onset of the current depressive episode during pregnancy or 4 weeks postpartum, 
or the subject has presented for screening during the 6-month postpartum period. 


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3. Subject has a recent history or active clinically significant manifestations of metabolic, hepatic, 
renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eyes, ears, nose, and throat disorders, or any other 
acute or chronic condition that, in the Investigator's opinion, would limit the subject's ability to 
complete or participate in this clinical study. 
4. Subject has treatment-resistant depression, defined as persistent depressive symptoms despite 
treatment with adequate doses of antidepressants within the current major depressive episode 
(excluding antipsychotics) from 2 different classes for at least 4 weeks of treatment. 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire will be 
used for this purpose. 
5. Subject has undergone vagus nerve stimulation, electroconvulsive therapy, or has taken 
ketamine (including esketamine) within the current major depressive episode. 
6. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
7. Subject has a positive pregnancy test at Visit 1, 2, or 3 prior to the start of study drug 
administration or is breastfeeding at Visit 1, 2, or 3 prior to the start of study drug 
administration and plans to continue to breastfeed through the treatment period or within 
7 days from the last dose of study drug.  
8. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) and 
positive HCV viral load, or human immunodeficiency virus (HIV) antibody at Visit 1. 
9. Subject has a clinically significant abnormal 12-lead ECG at Visit 1 or 3 prior to study drug 
administration. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the study. 
10. Subject has active psychosis per Investigator assessment. 
11. Subject has a medical history of seizures. 
12. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder. 
13. Subject has a history of mild, moderate, or severe substance use disorder (including 
benzodiazepines) diagnosed using DSM-5 criteria in the 12 months prior to Visit 1. 
14. Subject has a PSG-confirmed or clinically suspected diagnosis of obstructive sleep apnea 
(OSA, AHI ≥15), or a reported history of moderate to severe sleep apnea, or a clinically 
suspected or PSG-confirmed diagnosis of restless leg syndrome (RLS), periodic limb 
movements in sleep (PLMS or PLMD), or narcolepsy.   
15. Subject has a Restless Leg Syndrome – Diagnostic Index (RLS-DI) score of ≥11 at Visit 1.  
16. Subject has an Apnea-Hypopnea Index (AHI) ≥15 and/or a Periodic Limb Movement Arousal 
Index (PLMAI) ≥10 as determined at the Day -2 PSG. 
17. Subject has a recent history of circadian rhythm disorder or has done shift work or rotating 
shifts within 30 days prior to Visit 1.  
18. Subject is taking or participating in any of the following:  
a. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem, brexanolone) within 28 days prior to Visit 2,  
b. benzodiazepines, barbiturates, or GABAA modulators daily or near-daily (≥4 days per 
week) for 1 year in the last year prior to Visit 2,  
c. CBTI and/or psychotherapy for insomnia within 28 days prior to Visit 2,  


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d. benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) from 
60 days prior to Day 1. 
19. Subject is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids), or first generation or second 
generation (typical/atypical) antipsychotics at Day -14. Note that non-sedating anti-histamines 
are permitted. 
20. Subject has had exposure to another investigational medication or device within 30 days prior 
to Visit 1. 
21. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical trial. 
22. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days 
or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to Visit 2. 
23. Subject has used any of the following strong CYP3A inducers within 28 days prior to Visit 2: 
rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, or St John’s Wort. 
24. Subject has a positive drug and/or alcohol screen at Visit 1 or Visit 2 prior to dosing. 
25. Subject plans to undergo elective surgery during participation in the study. 
26. Subject has traveled >1 time zone within 7 days prior to Visit 1 or is planning to travel >1 time 
zone through study completion.  
27. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal cell 
carcinoma and melanoma in situ) within the past year prior to Screening. 
28. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any related 
procedures that interfere with gastrointestinal transit. 
29. Subject has been taking psychostimulants (eg, methylphenidate, amphetamine) or opioids 
regularly or as needed within 28 days prior to Visit 2. 
30. Subject uses a continuous positive airway pressure (CPAP) machine. 
Study Drug, Dosage, and Mode of administration:  
SAGE-217 capsules (30 mg) for oral administration. 
Reference Therapy, Dosage and Mode of Administration:  
Matched placebo capsules for oral administration. 
Duration of Treatment:  
On Days -2 and -1, subjects will be given a single-blind placebo dose orally, once daily with food, 
30 minutes (±15 minutes) prior to lights out (PSG). Starting on Day 1, Subjects will self-administer 
SAGE-217 (30 mg) or matching placebo orally once daily in the evening with food for 12 days. On 
Days 13 and 14, subjects will be given a double-blind dose of SAGE-217 or matching placebo orally, 
once daily with food, 30 minutes (±15 minutes) prior to lights out (PSG). On Days 15 through 21, 
subjects will self-administer a single-blind placebo dose, orally, once daily with food, in the evening. 
Statistical Methods: 
A separate statistical analysis plan (SAP) will provide a detailed description of the analyses to be 
performed in the study. The SAP will be finalized and approved prior to database lock. Any deviations 
from or changes to the SAP following database lock will be described in detail in the clinical study 
report. 
Randomization: 


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On Day 1, eligible subjects will be randomized to receive SAGE-217 Capsules or matching placebo 
capsules in a 1:1 ratio. Randomization will be stratified by based on use of antidepressant treatment 
(current/stable or not treated/withdrawn ≥60 days). Subjects, clinicians, and the study team will be 
blinded to treatment assignment. Randomization will be performed centrally via an interactive 
response technology (IRT) system. 
General Considerations 
Since insomnia is known to be intermittent in nature and prone to adaptation effects, to reduce 
variability and to reduce selection bias, PSG is performed for 2 consecutive nights before 
randomization as well as at end of double-blind treatment. In analysis, the average of values over 2 
nights measurement will be used as the parameter value. Subjective measures of sleep will also be 
similarly analyzed. Following the double-blind treatment period, possible rebound insomnia and 
withdrawal effects will be evaluated during a single-blind placebo run-out period. 
For the purpose of all safety, efficacy, and other analyses where applicable, baseline is defined as the 
last measurement prior to the start of double-blinded study drug administration. For sleep parameters 
from PSG and subjective sleep measures this is the average of 2 nights values from Day -1 and Day-2 
when both values are available. 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each time 
point and summarized descriptively. For categorical endpoints, descriptive summaries will include 
counts and percentages.  
Analysis Sets 
The All Randomized Set, defined as all subjects who have been randomized, will be used for subject 
disposition. Subjects will be classified according to randomized treatment. 
The Safety Set is defined as all subjects receiving at least 1 dose of study drug and will be used to 
provide descriptive summaries of safety data, demographics, and baseline characteristics. Data will be 
summarized according to treatment received. 
The Full Analysis Set, defined as all randomized subjects in the Safety Set who have at least one post-
baseline efficacy evaluation, will be used for analysis of efficacy data. Data will be summarized 
according to randomized treatment. 
 
Determination of Sample Size 
Assuming a 2-sided test at an alpha level of 0.05, a sample size of 41 subjects per group would provide 
90% power to detect a treatment difference of 11 points between the SAGE-217 and matching placebo 
groups with regard to the primary outcome variable of change from baseline in SE score, assuming a 
standard deviation of 15 points. By including 2 treatment groups and using a 1:1 randomization, a total 
of 82 evaluable subjects are required. Assuming a non-evaluability rate of 20%, up to 102 subjects will 
be randomized. 
Additional subjects may be enrolled if the drop-out rate is higher than 20%. Randomization will be 
performed centrally via an IRT system. 
Analysis of Primary Endpoint 
The change from baseline to post-baseline SE at end of double-blind treatment will be analyzed using 
Analysis of Covariance (ANCOVA); the model will include treatment, antidepressant treatment use 
(current/stable or not treated/withdrawn ≥60 days), baseline SE score, as explanatory variables, change 
from baseline in SE at end of double-blind treatment as the response variable. The Kenward and Roger 
correction to the degrees of freedom will be used. The main comparison will be between SAGE-217 
and placebo at end of double-blind treatment. Model-based point estimates (ie, least squares [LS] 
means, 95% confidence intervals, and p-values) will be reported where applicable. The baseline value 


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of SE was defined as the average of over 2 nights PSG measurements at Day -2 and Day -1. The post-
baseline PSG SE value at end of double-blind treatment was defined as the average of over 2 nights 
PSG measurements at Day 13 and 14.   
Analysis of Secondary Endpoints 
The secondary endpoints of the change from baseline to post-baseline will be analyzed using a mixed 
effects model for repeated measures; the model will include treatment, baseline score, antidepressant 
treatment use (current/stable or not treated/withdrawn ≥60 days), assessment time point, and time 
point-by-treatment as explanatory variables. All explanatory variables will be treated as fixed effects. 
All post-baseline time points will be included in the model.  
 
 
Safety Analysis 
Safety and tolerability of study drug will be evaluated by adverse events/serious adverse events, vital 
signs, clinical laboratory evaluations, and 12-lead ECGs. Suicidal ideation and behavior will be 
monitored by the C-SSRS. Safety data will be listed by subject and summarized by treatment group. 
All safety summaries will be performed on the Safety Set. 
 
 
 
 
 












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3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF
FIGURES
1.
TITLE PAGE ................................................................................................................1 
2.
SYNOPSIS ...................................................................................................................5 
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............19 
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................23 
5.
INTRODUCTION ......................................................................................................26
5.1. 
SAGE-217 ...................................................................................................................27 
5.2. 
Potential Risks and Benefits .......................................................................................28 
5.3. 
Dose Justification ........................................................................................................28 
6.
STUDY OBJECTIVES AND PURPOSE ..................................................................30 
6.1. 
Study Objective ..........................................................................................................30 
6.1.1. 
Primary Objective .......................................................................................................30 
6.1.2. 
Secondary Objective(s) ...............................................................................................30 
 
30 
 
30 
6.2. 
Endpoints ....................................................................................................................30 
6.2.1. 
Primary Endpoint ........................................................................................................30 
6.2.2. 
Secondary Endpoints ..................................................................................................30 
 
31 
 
32 
7.
INVESTIGATIONAL PLAN .....................................................................................33 
7.1. 
Overall Study Design ..................................................................................................33 
7.2. 
Number of Subjects ....................................................................................................34 
7.3. 
Treatment Assignment ................................................................................................34 
7.4. 
Dose Adjustment Criteria ...........................................................................................34 
7.5. 
Criteria for Study Termination ...................................................................................34 
8.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................35 
8.1. 
Subject Inclusion Criteria ...........................................................................................35 
8.2. 
Subject Exclusion Criteria ..........................................................................................36 
8.3. 
Subject Withdrawal Criteria .......................................................................................38 
8.3.1. 
Replacement of Subjects .............................................................................................39 


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9.
TREATMENT OF SUBJECTS ..................................................................................40 
9.1. 
Description of Study Drug ..........................................................................................40 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................40 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................40 
9.2.2. 
Prohibited Medications ...............................................................................................40 
9.2.3. 
Other Restrictions .......................................................................................................41 
9.3. 
Treatment Adherence ..................................................................................................41 
9.4. 
Randomization and Blinding ......................................................................................41 
9.4.1. 
Single-blind Placebo Treatment .................................................................................42 
10.
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................43 
10.1. 
Study Drug ..................................................................................................................43 
10.2. 
Study Drug Packaging and Labeling ..........................................................................43 
10.3. 
Study Drug Storage .....................................................................................................43 
10.4. 
Study Drug Administration.........................................................................................43 
10.5. 
Study Drug Accountability .........................................................................................43 
10.6. 
Study Drug Handling and Disposal ............................................................................44 
10.7. 
Study Drug ..................................................................................................................44 
10.8. 
Product Complaints ....................................................................................................45 
11.
ASSESSMENT OF EFFICACY 
 .............................46 
11.1. 
Screening Assessments ...............................................................................................46 
11.1.1. 
Montgomery-Åsberg Depression Rating Scale ..........................................................46 
11.2. 
Efficacy assessments ..................................................................................................46 
11.2.1. 
Polysomnogram (PSG) ...............................................................................................46 
11.2.2. 
Hamilton Rating Scale for Depression .......................................................................47 
11.2.3. 
Clinical Global Impression .........................................................................................47 
11.2.4. 
Insomnia Severity Index .............................................................................................48 
11.2.5. 
Consensus Sleep Diary-Core ......................................................................................48 
 
48 
 
48 
 
49 
11.2.9. 
Patient Health Questionnaire (PHQ-9) .......................................................................49 
 
49 
 
49 


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50 
12.
ASSESSMENT OF SAFETY .....................................................................................51 
12.1. 
Safety Parameters .......................................................................................................51 
12.1.1. 
Demographic/Medical History ...................................................................................51 
12.1.2. 
Weight and Height ......................................................................................................51 
12.1.3. 
Physical Examination .................................................................................................51 
12.1.4. 
Vital Signs ..................................................................................................................51 
12.1.5. 
Electrocardiogram .......................................................................................................52 
12.1.6. 
Laboratory Assessments .............................................................................................52 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................54 
12.1.6.2. 
Pregnancy Screen ........................................................................................................54 
12.1.7. 
Columbia-Suicide Severity Rating Scale ....................................................................54 
12.1.8. 
Physician Withdrawal Checklist .................................................................................54 
12.2. 
Adverse and Serious Adverse Events .........................................................................55 
12.2.1. 
Definition of Adverse Events .....................................................................................55 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................55 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................55 
12.3. 
Relationship to Study Drug ........................................................................................56 
12.4. 
Recording Adverse Events .........................................................................................57 
12.5. 
Reporting Adverse Events ..........................................................................................57 
12.6. 
Emergency Identification of Study Drug ....................................................................58 
13.
STATISTICS ..............................................................................................................59 
13.1. 
Data Analysis Sets ......................................................................................................59 
13.2. 
Handling of Missing Data ...........................................................................................59 
13.3. 
General Considerations ...............................................................................................59 
13.4. 
Demographics and Baseline Characteristics ...............................................................60 
13.5. 
Efficacy Analyses .......................................................................................................60 
13.6. 
Safety Analyses ..........................................................................................................60 
13.6.1. 
Adverse Events ...........................................................................................................60 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................61 
13.6.3. 
Physical Examinations ................................................................................................61 
13.6.4. 
Vital Signs ..................................................................................................................61 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................61 


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13.6.6. 
Prior and Concomitant Medications ...........................................................................61 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................62 
13.6.8. 
Physician Withdrawal Checklist .................................................................................62 
 
62 
13.8. 
Determination of Sample Size ....................................................................................62 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................63 
14.1. 
Study Monitoring ........................................................................................................63 
14.2. 
Audits and Inspections ................................................................................................63 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................64 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................65 
16. 
ETHICS ......................................................................................................................66 
16.1. 
Ethics Review .............................................................................................................66 
16.2. 
Ethical Conduct of the Study ......................................................................................66 
16.3. 
Written Informed Consent ..........................................................................................66 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................67 
17.1. 
Inspection of Records .................................................................................................67 
17.2. 
Retention of Records ..................................................................................................67 
18. 
PUBLICATION POLICY ..........................................................................................68 
19. 
LIST OF REFERENCES ............................................................................................69 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................14 
Table 2: 
Abbreviations and specialist terms .............................................................................23 
Table 3: 
Clinical Laboratory Tests ...........................................................................................52 
Table 4: 
Relationship to Study Drug ........................................................................................56 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................18 
 
  


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and specialist terms  
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
AHI 
Apnea-Hypopnea Index 
ANCOVA 
Analysis of Covariance 
BMI 
body mass index 
CBTI 
Cognitive Behavioral Therapy for Insomnia 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression - Severity 
CL/F 
apparent total body clearance following extravascular 
administration 
CPAP 
continuous positive airway pressure 
CRC 
clinical research coordinator 
 
 
CS 
clinically significant 
CSD-C 
Consensus Sleep Diary – Core 
CSSR-S 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition 
 
 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EODBT 
End-of-Double-blind-Treatment 
EOG 
electrooculographic 
ET 
early termination 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GABA 
γ-aminobutyric acid 
HAM-A 
Hamilton Anxiety Rating Scale 
HAM-D 
Hamilton Rating Scale for Depression 


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Abbreviation or specialist term 
Explanation 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
ICF 
informed consent form 
ICD-10 
International Statistical Classification of Diseases and 
Related Health Problems 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICSD-3 
International Classification of Sleep Disorders Third 
Edition 
IMP 
investigational medicinal product 
IND 
investigational new drug  
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
 
 
LPD 
latency to persistent sleep 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
mDURAW 
mean duration of awakenings 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed effects model for repeated measures 
NAW 
number of awakenings 
NCS 
not clinically significant 
OSA 
obstructive sleep apnea 
PHQ-9 
9-item Patient Health Questionnaire 
PI 
Principal Investigator; the investigator who leads the study 
conduct at an individual study center. Every study center 
has a principal investigator. 
PK 
pharmacokinetic 
PLMS 
periodic limb movements in sleep 
PLMAI 
Periodic Limb Movement Arousal Index 
PWC-20 
Physician Withdrawal Checklist 
QTcF 
QT corrected according to Fridericia’s formula 
REM 
Rapid Eye Movement 
REMA 
REM Activity 


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Abbreviation or specialist term 
Explanation 
RLS 
restless leg syndrome 
RLS-DI 
Restless Leg Syndrome – Diagnostic Index 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
sleep efficiency 
SMCC 
silicified microcrystalline cellulose 
SOC 
system organ class 
 
 
SS 
Safety Set 
sSL 
subjective sleep latency 
sSQ 
subjective sleep quality 
SSRIs 
selective serotonin reuptake inhibitors 
SUSARs 
serious, adverse reactions 
sTST 
subjective total sleep time 
sWASO 
subjective wake after sleep onset 
TEAE 
treatment-emergent adverse event 
TIB 
time in bed 
TST 
total sleep time 
WASO 
wakefulness after sleep onset 
WHO 
World Health Organization 
 


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5. 
INTRODUCTION 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5; American 
Psychiatric Association 2013), depression refers to an overarching set of diagnoses, including 
major depressive disorder (MDD). Diagnostic criteria for MDD includes a set of at least 5 
depressive symptoms out of 9, including depressed mood and/or loss of interest or pleasure, and 
other changes affecting appetite or weight, sleep, psychomotor activity, energy level, feelings of 
guilt, concentration ability and suicidality during the same 2-week period, that represents a 
change from previous functioning. 
Antidepressants are a mainstay of pharmacological treatment for depressive disorders. Selective 
serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors, tricyclic 
antidepressants, monoamine oxidase inhibitors, and other compounds that affect monoaminergic 
neurotransmission, such as mirtrazapine and bupropion, represent the major classes of 
antidepressants. While antidepressants are widely used, large scale studies have demonstrated 
their limited efficacy, including low remission rates and untreated symptoms (Trivedi 2006; 
Conradi 2011; Romera 2013).  
Converging preclinical and clinical evidence (Gerner 1981; Honig 1988; Drugan 1989; 
Luscher 2011; Mann 2014) implicates deficits in γ-aminobutyric acid (GABA)-ergic 
neurotransmission in the pathophysiology of depressive disorders including MDD. Furthermore, 
experimental data implicate deficiencies in the normal regulation of endogenous neuroactive 
steroids in depressive disorders (Maguire 2008; Maguire 2009). Depressed patients show low 
levels of GABA in the brain and of neurosteroids in the cerebrospinal fluid and plasma, and 
antidepressant therapy restores GABA levels in relevant animal models and neurosteroid 
concentrations in depressed patients (Luscher 2011; Schüle 2014). 
With the publication of the DSM-5 in 2013, a single, overarching diagnosis of insomnia disorder 
replaced the previous diagnoses of primary and secondary insomnia defined in the DSM-IV and 
is closely aligned with the International Classification of Sleep Disorders Third Edition (ICSD-3) 
(Sateia 2014). Key DSM-5 diagnostic criteria for insomnia disorder include a predominant 
complaint of poor sleep quality or quantity and can include one or more of the following: 
difficulty falling asleep, difficulty staying asleep and/or early morning awakening. For an 
insomnia diagnosis, the sleep difficulty occurs at least 3 nights per week, is present for at least 3 
months, and occurs despite adequate opportunity for sleep (DSM-5).   


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Cognitive behavioral therapy and other psychological therapies are recommended as first-line for 
the treatment of insomnia by both the American Academy of Sleep Medicine and the European 
Sleep Research Society (Schutte-Rodin 2008; Riemann 2017). Benzodiazepines and 
benzodiazepine receptor agonists, which enhance GABAergic function, are the predominant 
pharmacologic options available for the treatment of insomnia. Additionally, H1 histamine, 
melatonin, and orexin receptor antagonists have been approved for the treatment of insomnia.   
Insomnia disorder commonly occurs with comorbid medical and mental health disorders. 
Insomnia symptoms have been reported in up to 80% of subjects in a major depressive episode 
and up to 90% of subjects with concomitant anxiety and MDD (Ohayon 2002). The relationship 
between MDD and insomnia disorder is bidirectional where the presence of one increases the 
risk of developing the other and people with severe depression are likely to also have severe 
insomnia. In addition, symptoms of insomnia and changes in sleep architecture, observed in 
patients with MDD, may worsen following treatment with antidepressants (eg, SSRIs and TCAs) 
that are commonly prescribed for MDD (Lam 2006). Residual insomnia symptoms are common 
and have been reported to occur in up to 60% of patients who are in remission following 
treatment for MDD (Carney 2007, Iovieno 2011). 
Development of a pharmacotherapy that effectively treats both symptoms of comorbid major 
depressive and insomnia disorders remains an unmet medical need. 
5.1. 
SAGE-217 
SAGE-217 is a synthetic positive allosteric modulator of GABAA receptors, the major class of 
inhibitory neurotransmitter receptors in the brain. In pharmacokinetic (PK) studies in mice and 
rats, SAGE-217 demonstrated rapid penetration and equilibrium across the blood brain barrier 
and is generally expected to have good extravascular exposure. In exploratory in vitro receptor 
and ion channel assays and in vivo safety pharmacology studies, SAGE-217 was highly selective 
for GABAA receptors, and, consistent with the actions of other GABAA receptor potentiators 
(Rudolph 2011), exhibits potent anticonvulsant, anxiolytic, and sedative activity when 
administered in vivo. 
Data from an open-label Phase 2a study of SAGE-217 administered to subjects with moderate to 
severe MDD showed clinically significant improvements from baseline in depression and 
anxiety scale scores (Hamilton Rating Scale for Depression [HAM-D], Montgomery-Åsberg 
Depression Rating Scale [MADRS], Hamilton Anxiety Rating Scale [HAM-A], and Clinical 
Global Impression – Improvement [CGI-I]) as early as Day 2 of the 14-day treatment period, 
with durable responses following the end of treatment. This result was further supported by the 
randomized, double-blind portion of this study including 89 subjects, in which a rapid and 
substantial decrease in HAM-D scores was observed at Day 15 (primary endpoint, following 
14 days of double-blind treatment), starting at Day 2. This response pattern was also observed 
with other efficacy scales, including MADRS, CGI-I, and HAM-A. 
The effect of SAGE-217, at 30 and 45 mg doses, on sleep was studied in a double-blind, 
placebo-controlled, 3-way crossover study in healthy adults using a 5-hour phase advance model 
of transient insomnia. The 5-hour phase-advance model of (transient) insomnia, has been shown 
to be most sensitive and appropriate for measuring changes in sleep maintenance and less 
sensitive to changes in sleep onset and REM minutes and latency to REM sleep (Horoszok, 
2014). SAGE-217 at both doses (30 and 45 mg) resulted in significant improvements in sleep 


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efficiency (SE), decreased wakefulness after sleep onset (WASO), increased total sleep time 
(TST), and decreased mean duration of awakenings (mDURAW) compared with placebo. There 
were no differences in the median number of awakenings (NAW) or latency to persistent sleep 
(LPS) following administration of SAGE-217 (at either dose level) compared with placebo.   
In addition, analysis of sleep architecture changes following treatment with SAGE-217 compared 
with placebo showed an increase in time spent in NREM Stages N2 and N3 sleep without 
a significant decrease in total time spent in N1 or rapid-eye movement (REM) sleep. The greatest 
numerical increases were observed for time spent in N2 sleep (approximately 60 to 70 minutes) 
followed by N3 sleep (approximately 10 to 20 minutes). Therefore, when measured as a percent 
of time spent asleep, the percent of time spent in N2 sleep was increased following SAGE-217 
treatment compared to placebo with decreases observed in overall percent of N1 and REM sleep 
and no significant effect on percent of N3 sleep. 
The primary objective of this study is to determine the effect of SAGE-217 on overall insomnia 
symptoms in subjects with comorbid MDD and insomnia disorder.  
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) were sedation, somnolence, and dizziness. Most 
adverse events (AEs) were reported as mild or moderate in intensity. Among the over 
260 subjects exposed to SAGE-217 in clinical trials, there have been no deaths and only one 
subject with essential tremor experienced a serious adverse event (SAE) of transient confusion 
leading to discontinuation of study drug. No other SAEs have been reported in any study of 
SAGE-217.  
Additional information on nonclinical and clinical data is provided in the Investigator’s 
Brochure. 
5.2. 
Potential Risks and Benefits 
Non-serious events of sedation, somnolence, and dizziness were the most commonly reported 
AEs with SAGE-217. Given the outcome of the Phase 2a study of SAGE-217 in subjects with 
MDD, improvement in sleep outcomes following treatment with SAGE-217 in a model of 
transient insomnia in healthy adults, the current significant unmet need in the treatment of 
comorbid insomnia disorder and MDD, and a favorable benefit-risk profile, further investigation 
of SAGE 217 in patients with comorbid insomnia and MDD is justified. 
5.3. 
Dose Justification 
The dose level of 30 mg per day was considered effective and generally well tolerated in a 
Phase 2 study in subjects with MDD (217-MDD-201). In the Phase 1 study of SAGE-217 in a 
model of transient insomnia, single doses of 30 mg and 45 mg SAGE-217, compared to placebo, 
showed similar benefits on measures of sleep maintenance (SE) and duration of sleep (SE and 
TST) and was generally well tolerated. Phase advance models in healthy adults show disruption 
in sleep parameters that are very similar to that observed in insomnia disorder and improvement 
in sleep parameters with pharmacotherapy in this model may predict treatment responses in 
chronic insomnia (Bonnet and Arand 2003). Therefore, 2-week nightly treatment with SAGE-
217 (30 mg) will be used to test for the durability of the improved sleep response in subjects who 
have comorbid insomnia and MDD disorders. Due to sedation/somnolence observed in previous 


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clinical trials when administered in the morning, and improved tolerability when given in the 
evening, SAGE-217 will be administered as a 30 mg single dose in the evening with food, in this 
study. There is no dose reduction allowed during the treatment period. 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Study Objective 
6.1.1. 
Primary Objective 
The primary objective of this study is to determine the effect of SAGE-217 on overall insomnia 
symptoms in subjects with comorbid MDD and insomnia. 
6.1.2. 
Secondary Objective(s) 
Secondary objectives of this study are: 
• To measure the effects of SAGE-217 on individual objective and subjective 
symptoms of insomnia including difficulties with sleep maintenance and sleep onset. 
• To measure the effects of SAGE-217 on sleep architecture. 
• To evaluate the effect of SAGE-217 on depressive symptoms. 
• To assess patient-reported outcome (PRO) measures as they relate to depressive 
symptoms. 
• To evaluate the safety and tolerability of SAGE-217.  
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
The primary endpoint of this study is change from baseline in SE, defined as the percentage of 
time in bed spent asleep, at end of double-blind treatment (EODBT) as assessed by PSG. 
6.2.2. 
Secondary Endpoints 
Secondary endpoints of this study are: 
• Change from baseline of the following PSG-derived endpoints at EODBT: 
− Wake after sleep onset (WASO, defined as the total wake time in minutes) from 
persistent sleep onset to lights-on (final wake time)  
− WASO by quarter (2-hour period) of the PSG recording (8-hour period) 


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− Total sleep time and TST by quarter of the PSG recording 
− Latency to persistent sleep  
− Number of awakenings and mean duration of awakenings, in total and by quarter 
of the PSG recording 
− Minutes and percent of stage N1, N2, N3, and REM sleep  
− Latency to the first period of REM Sleep and latency to each subsequent period of 
REM Sleep 
− REM density 
− REM activity 
• Change from baseline in subjective sleep endpoints at EODBT: 
− Insomnia Severity Index (ISI) 
− Consensus Sleep Diary – Core (CSD-C) endpoints 
− Subjective total sleep time (sTST) 
− Subjective wake after sleep onset (sWASO) 
− Subjective sleep latency (sSL) 
− Subjective sleep quality (sSQ) 
• Change from baseline in Clinical Global Impression - Severity (CGI-S) at EODBT 
(based on the insomnia disorder) 
• Clinical Global Impression - Improvement at EODBT (based on the insomnia 
disorder)  
• Change from baseline in the 17-item HAM-D total score at EODBT 
• Change from baseline in the 9-item Patient Health Questionnaire (PHQ-9) at the 
EODBT 
• Safety: Incidence and severity of adverse events/serious adverse events; changes from 
baseline in vital sign assessments, clinical laboratory data, electrocardiogram (ECG) 
parameters, and suicidal ideation and behavior using the Columbia Suicide Severity 
Rating Scale (C-SSRS). Evaluation of withdrawal symptoms as measured by the 
Physician Withdrawal Checklist (PWC-20) 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, parallel group, placebo-controlled study of the safety, 
tolerability, efficacy, 
 of SAGE-217 compared to placebo in adult 
subjects with insomnia (ISI ≥15) and comorbid MDD (MADRS total score ≥28, HAM-D total 
score ≥20). The study schematic is shown in Figure 1. 
The Screening Period begins with the signing of the informed consent form (ICF) at the 
Screening Visit; the ICF must be signed prior to beginning any screening activities. At the time 
of providing informed consent for the study, subjects will also be required to authorize that their 
unique subject identifiers be entered into a registry (www.subjectregistry.com) with the intent of 
identifying subjects who may meet exclusion criteria due to participation in another clinical 
study (Section 8.2). 
After the subject has provided written informed consent, eligibility will be determined by 
applying the inclusion/exclusion criteria. The diagnosis of insomnia and MDD must be 
confirmed according to Structured Clinical Interview for DSM-5 (SCID-5-CT) performed by a 
qualified healthcare professional. 
Subjects will complete an electronic sleep diary during the screening period. Between Day -9 
and awakening on Day -2, subjects are required to complete the sleep diary for a minimum of 
4 of the 7 nights. Continued eligibility for the study will be based on subjects having a sleep 
diary with the following: a minimum of 4 nights completed and a TST of <390 minutes 
(<6.5 hours) on at least 3 nights between Day -9 and Day-2.  
The PSG qualification visit (Visit 2) will begin on Day -2 and will continue to Day 1. The 
clinical research coordinator (CRC) will determine each subject’s habitual bedtime from their 
sleep diary. Subjects should arrive at the clinic approximately 2 hours prior to their habitual 
bedtime for the 2-night PSG qualification visit. For each night, subjects will receive a standard 
meal and be prepared for overnight PSG recording. Lights out and PSG recording will begin 
within approximately 1 hour of their habitual bedtime. Subjects will receive a single-blind 
placebo, with food, 30 (±15) minutes prior to PSG lights out. Subjects will be required to remain 
in bed for 8 hours, after which time the PSG recording will end, lights will turn on, and subjects 
will be awakened if asleep. 
 
 The electronic CSD-C 
will be completed at the clinic on all days following the PSG recordings.   
Eligible subjects who meet the PSG qualification criteria will be randomized to 1 of 2 treatment 
groups (SAGE-217 30 mg or placebo) on a 1:1 basis. Starting on Day 1, subjects will self-
administer a single dose of study drug once daily in the evening with food, on an outpatient 
basis, for 12 days.  
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 1. 
Subjects will be allowed to remain in the clinic between the consecutive PSG visits. At the 
discretion of the Investigator, subjects may be allowed to leave the clinic between consecutive 


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PSG visits following all post-treatment evaluations and return to the clinic approximately 2 hours 
prior to their habitual bedtime, as determined by the CRC, for the subsequent PSG visit. 
7.2. 
Number of Subjects 
Approximately 102 subjects will be randomized and dosed to obtain 82 evaluable subjects, with 
a total of 41 subjects per treatment arm. 
7.3. 
Treatment Assignment 
Subjects will be randomly assigned to a treatment group on Day 1. Randomization will be 
performed in a 1:1 ratio to receive SAGE-217 30 mg or matching placebo. Randomization will 
be stratified based on use of antidepressant treatment (current/stable or not treated/withdrawn 
≥60 days) at baseline. 
7.4. 
Dose Adjustment Criteria 
Dose adjustments are not permitted in this study. Subjects who cannot tolerate study drug will be 
discontinued from study drug and will receive treatment as clinically indicated (Section 8.3). 
7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of adverse events (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 ethics committee and initiate withdrawal procedures for participating 
subjects.  
 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Qualified subjects will meet all of the following criteria: 
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject agrees to adhere to the study requirements. 
3. Subject is a male or female between 18 and 64 years of age, inclusive, at the time of 
consent. 
4. Subject has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that have 
been present for at least a 4-week period.  
5. Subject has insomnia that has been present for ≥4 weeks and is confirmed at Screening 
based on the DSM-5 diagnostic criteria (using the SCID-5-CT) for insomnia disorder, 
excluding DSM-5 criterion D (requiring 3 months duration) and allowing the presence of 
coexistent MDD as it applies to DSM-5 criterion H. 
6. Subject has an ISI score ≥15 (moderate to severe insomnia) at Visits 1 and 3. 
7. Subject has completed the CSD-C for a minimum of 4 days between the evening of 
Day -9 and after awakening on the morning of Day -2, inclusive. 
8. Subject reports a TST of <390 minutes (<6.5 hours) based on CSD-C Questions #2 
through 6, on at least 3 nights between the evening of Day -9 and after awakening on the 
morning of Day -2, inclusive.  
9. Subject has a habitual bedtime between 9:00 PM and 12:00 AM (midnight). 
10. Subject has a mean wakefulness after persistent sleep onset (WASO) ≥30 minutes on 
combined baseline PSG nights (Days -2 and -1), with neither night ≤20 minutes.  
11. Subject has a MADRS score of ≥ 28 and a HAM-D total score of ≥20 at Visit 1 and 
Visit 3 (prior to dosing). 
12. Subject taking antidepressants must have been taking these medications at the same dose 
for at least 60 days prior to Day 1. 
13. Subject is willing to delay start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics and 
sleep aids, and Cognitive Behavioral Therapy for Insomnia (CBTI) until after study 
completion. 
14. 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. Subject has a body mass index (BMI) within the range of 18.0 to 
40.0 kg/m2, inclusive. 
15. Female subject agrees to use one of the following methods of highly effective 
contraception during participation in the study and for 30 days following the last dose of 
study drug, unless she is postmenopausal (defined as no menses for 12 months without an 
alternative medical cause and confirmed by follicle stimulating hormone [FSH] level 
>40 mIU/mL) and/or surgically sterile (hysterectomy, bilateral oophorectomy, or bilateral 


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salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy 
(does not include abstinence): 
− Combined (estrogen and progestogen containing) oral, intravaginal, or 
transdermal hormonal contraception associated with inhibition of ovulation. 
− Oral, injectable, or implantable progestogen-only hormonal contraception 
associated with inhibition of ovulation.  
− Intrauterine device. 
− Intrauterine hormone-releasing system. 
− Bilateral tubal occlusion/ligation. 
− Vasectomized partner. 
16. Male subject agrees to use an acceptable method of effective contraception for the 
duration of study and for 5 days after receiving the last dose of the study drug, unless the 
subject does not engage in sexual relations which carry a risk of pregnancy (does not 
include abstinence). Acceptable methods of effective contraception for males includes 
vasectomy, or a condom with spermicide used together with highly effective female 
contraception methods if the female partner is of child-bearing potential (see Inclusion 
Criteria #15 for acceptable contraception methods).  
17. Male subject is willing to abstain from sperm donation for the duration of the study and 
for 5 days after receiving the last dose of the study drug. 
18. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study.  
8.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria are disqualified from participation in this study: 
1. Subject has attempted suicide associated within the current episode of MDD. 
2. Subject had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the subject has presented for screening during the 6-month postpartum 
period. 
3. Subject has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
musculoskeletal, dermatological, urogenital, neurological, or eyes, ears, nose, and throat 
disorders, or any other acute or chronic condition that, in the Investigator's opinion, 
would limit the subject's ability to complete or participate in this clinical study. 
4. Subject has treatment-resistant depression, defined as persistent depressive symptoms 
despite treatment with adequate doses of antidepressants within the current major 
depressive episode (excluding antipsychotics) from 2 different classes for at least 4 weeks 
of treatment. Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire will be used for this purpose. 
5. Subject has undergone vagus nerve stimulation, electroconvulsive therapy, or has taken 
ketamine (including esketamine) within the current major depressive episode. 


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6. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
7. Subject has a positive pregnancy test at Visit 1, 2, or 3 prior to the start of study drug 
administration or is breastfeeding at Visit 1, 2, or 3 prior to the start of study drug 
administration and plans to continue to breastfeed through the treatment period or within 
7 days from the last dose of study drug. 
8. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) 
and positive HCV viral load, or human immunodeficiency virus (HIV) antibody at 
Visit 1. 
9. Subject has a clinically significant abnormal 12-lead ECG at Visit 1 or 3 prior to study 
drug administration. NOTE: mean QT interval calculated using the Fridericia method 
(QTcF) of >450 msec in males or >470 msec in females will be the basis for exclusion 
from the study. 
10. Subject has active psychosis per Investigator assessment. 
11. Subject has a medical history of seizures. 
12. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder. 
13. Subject has a history of mild, moderate, or severe substance use disorder (including 
benzodiazepines) diagnosed using DSM-5 criteria in the 12 months prior to Visit 1. 
14. Subject has a PSG-confirmed or clinically suspected diagnosis of obstructive sleep apnea 
(OSA, AHI ≥15), or a reported history of moderate to severe sleep apnea, or a clinically 
suspected or PSG-confirmed diagnosis of restless leg syndrome (RLS), periodic limb 
movements in sleep (PLMS or PLMD), or narcolepsy.   
15. Subject has a Restless Leg Syndrome – Diagnostic Index (RLS-DI) score of ≥11 at 
Visit 1.  
16. Subject has an Apnea-Hypopnea Index (AHI) ≥15 and/or a Periodic Limb Movement 
Arousal Index (PLMAI) ≥10 as determined at the Day -2 PSG. 
17. Subject has a recent history of circadian rhythm disorder or has done shift work or 
rotating shifts within 30 days prior to Visit 1.  
18. Subject is taking or participating in any of the following: 
a. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem, brexanolone) within 28 days prior to Visit 2, 
b. benzodiazepines, barbiturates, or GABAA modulators daily or near-daily (≥4 days per 
week) for 1 year in the last year prior to Visit 2, 
c. CBTI and/or psychotherapy for insomnia within 28 days prior to Visit 2, 
d. benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) 
from 60 days prior to Day 1. 
19. Subject is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over-the-counter sleep aids) or first or second generation 
(typical/atypical) antipsychotics at Day -14. Note that non-sedating antihistamines are 
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20. Subject has had exposure to another investigational medication or device within 30 days 
prior to Visit 1. 
21. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical 
trial. 
22. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 
28 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or 
Seville oranges, or products containing these within 14 days prior to Visit 2. 
23. Subject has used any of the following strong CYP3A inducers within 28 days prior to 
Visit 2: rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, or St John’s Wort. 
24. Subject has a positive drug and/or alcohol screen at Visit 1 or Visit 2 prior to dosing. 
25. Subject plans to undergo elective surgery during participation in the study. 
26. Subject has traveled >1 time zone within 7 days prior to Visit 1 or is planning to travel 
>1 time zone through study completion.  
27. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal 
cell carcinoma and melanoma in situ) within the past year prior to Screening. 
28. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
29. Subject has been taking psychostimulants (eg, methylphenidate, amphetamine) or opioids 
regularly or as needed within 28 days prior to Visit 2. 
30. Subjects uses a continuous positive airway pressure (CPAP) machine. 
8.3. 
Subject Withdrawal Criteria 
Subjects may withdraw from the study drug or terminate from the study at any time for any 
reason. The Investigator may withdraw the subject from the study drug or terminate the subject 
from the study for any of the following reasons: 
• The subject is unwilling or unable to adhere to the protocol 
• The subject experiences an intolerable AE 
• Other medical or safety reason, at the discretion of the Investigator and/or the 
Medical Monitor 
The Investigator must notify the Sponsor and/or the Medical Monitor immediately when a 
subject withdraws from study drug or terminates the study for any reason. The reason must be 
recorded in the subject’s electronic case report form (eCRF).  
If a subject is persistently noncompliant, the Investigator should discuss with the Sponsor the 
potential discontinuation of the subject. Any reasons for unwillingness or inability to adhere to 
the protocol must be recorded in the subject’s eCRF, including: 
• missed visits 
• interruptions in the schedule of study drug administration 


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• non-permitted medications (Section 9.2.2). 
Subjects who discontinue the study drug due to an AE, regardless of Investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the Investigator 
determines the event is no longer clinically significant.  
Subjects who discontinue study drug early during the double-blind treatment period should return 
to the site for the end of double-blind treatment visit as soon as possible, preferably the day after 
treatment is discontinued. Follow-up visits should take place according to the Schedule of 
Assessments. If at any time after the end of double-blind treatment visit, a subject decides to 
terminate the study, the subject should return for an early termination (ET) visit. The end of 
double-blind treatment and ET visits can be on the same day if a subject discontinues study drug 
and terminates the study on the same day during a clinic visit; in this case, all events scheduled 
for the ET visit will be conducted.  
A subject will be deemed lost to follow-up after attempts at contacting the subject have been 
unsuccessful. 
If a subject failed to attend scheduled assessments during the course of the study, the 
Investigators must determine the reasons and the circumstances as completely and accurately as 
possible, and document this in the subject's source documents. 
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. 
8.3.1. 
Replacement of Subjects 
Subjects will not be replaced. Additional subjects may be randomized if the drop-out rate is 
higher than anticipated (Section 13.8). 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
Subjects will be treated with SAGE-217 or matching placebo capsules according to the study and 
randomization schedules. 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route, dose/units, frequency, and indication for all medications and/or 
supplements taken within 30 days prior to Screening and throughout the duration of the study 
will be recorded. In addition, psychotropic medications taken 6 months prior to Screening and 
GABAergic medications taken 12 months prior to Screening will be recorded. 
Any medication and/or supplement determined necessary for the welfare of the subject may be 
given at the discretion of the Investigator at any time during the study.  
Antidepressants that have been taken at the same dose for at least 60 days prior to Day 1 are 
permitted if the subject intends to continue the stable dose through the follow-up period 
(Day 42).  
9.2.2. 
Prohibited Medications 
The following specific classes of medications are prohibited: 
• Initiation of new psychotropic medications at any time during the study 
• Initiation of new antidepressant therapy from 60 days prior to Visit 2 through the 
duration of the study 
• Use of any benzodiazepines, barbiturates, GABAA modulators/GABA-containing 
agents from 28 days prior to Visit 2 through the duration of the study 
• Use of any non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over-the-counter sleep aids) from 14 days prior to 
Visit 2 through the duration of the study. Note that non-sedating anti-histamines are 
permitted. 
• First or second generation (typical/atypical) antipsychotics from 14 days prior to Visit 
2 through the duration of the study 
• Use of psychostimulants (eg, methylphenidate, amphetamine) or opioids regularly or 
as needed from 28 days prior to Visit 2 through the duration of the study. 
• Exposure to another investigational medication or device from 30 days prior to 
Screening through the duration of the study 
• Use of any known strong CYP3A4 inhibitors from 28 days prior to Visit 2 or 5 half-
lives prior to Visit 2 (whichever is longer) through the duration of the study 


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• Use of strong CYP inducers, such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, and St John’s Wort from 28 days prior to Visit 2 through the 
duration of the study 
9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited throughout the treatment period. 
Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study.  
Female subjects who are lactating or actively breastfeeding must stop giving breast milk to the 
baby(ies) starting on Day -2 until 7 days after the last dose of study drug following the treatment 
period. 
Elective surgeries or procedures are prohibited during participation in the study. 
Subjects are prohibited from participating in CBTI and/or psychotherapy for insomnia within 
28 days prior to Visit 2 and through the duration of the study. 
Use of CPAP machines is prohibited. 
Subjects are restricted from traveling >1 time zone within 7 days prior to Visit 1 and any time 
through study completion. 
9.3. 
Treatment Adherence 
SAGE-217 or placebo will be self-administered by subjects once daily in the evening with food.  
Practically, subjects may consider taking the study medication within 1 hour following a dinner 
including solid food or taking study medication later in the evening with solid food. Given the 
substantially improved absorption of SAGE-217 with food, administering the study medication 
in the presence of food is important. 
Sites will dispense study drug to the subjects with instructions for use (see Section 10.3 and 
Table 1).  
In addition, the subject will be instructed to bring their dosing kit to the site as outlined in 
Table 1, at which time the Investigator or designee will be responsible for ensuring the kit 
contains sufficient doses for the duration of the treatment period.  
All subjects should be reinstructed about the dosing requirement during study contacts. The 
authorized study personnel conducting the re-education must document the process in the subject 
source records. 
The Investigator(s) will record any reasons for non-compliance in the source documents. 
9.4. 
Randomization and Blinding 
This is a randomized double-blind, placebo-controlled study. Subjects who meet the entrance 
criteria will be randomized in a stratified manner based on use of antidepressant treatment 
(current/stable or not treated/withdrawn ≥60 days) at baseline; randomization will be done within 
each stratum in a 1:1 ratio to receive SAGE-217 30 mg or matched placebo. Subjects, clinicians, 


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and the study team will be blinded to treatment allocation. Randomization will be performed 
centrally via an interactive response technology (IRT) system.  
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group (SAGE-217 30 mg or placebo) will be based on the randomization schedule. 
The randomization schedules will be kept strictly confidential, accessible only to authorized 
personnel until the time of unblinding. 
In exceptional circumstances and for the safety of the study subject, the Investigator may request 
unblinding of an individual subject’s treatment in the study via the IRT (see Section 12.6 for 
more details related to unblinding).  
9.4.1. 
Single-blind Placebo Treatment 
Before a subject is randomized, there is a 2-day single-blind placebo treatment. In addition, 
following the double-blind treatment period subjects will take single-blind placebo treatment 
once daily until Visit 8. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
SAGE-217 and matched placebo are to be stored at room temperature (59 to 86°F; 15 to 30°C), 
safely and separately from other drugs. 
10.2. 
Study Drug Packaging and Labeling 
Not applicable. 
10.3. 
Study Drug Storage 
SAGE-217 capsules and matched placebo capsules will be provided to the clinic pharmacist 
and/or designated site staff responsible for dispensing the study drug in appropriately labeled, 
subject-specific kits containing sealed unit doses. Additional information regarding the 
packaging and labeling is provided in the Pharmacy Manual.  
Study drug labels with all required information and conforming to all applicable FDA Code of 
Federal Regulations and Good Manufacturing Practices/Good Clinical Practices guidelines will 
be prepared by the Sponsor. 
10.4. 
Study Drug Administration 
On Days -2 and -1, subjects will be given a single-blind placebo dose orally, once daily with 
food, 30 minutes (±15 minutes) prior to lights out (PSG). 
Starting on Day 1, Subjects will self-administer SAGE-217 (30 mg) or matching placebo orally 
once daily in the evening with food for 12 days. Practically, subjects may consider taking the 
study medication within 1 hour following a dinner including solid food or taking study 
medication later in the evening with solid food. Given the substantially improved absorption of 
SAGE-217 with food, administering the study medication in the presence of food is important. 
On Days 13 and 14, subjects will be given a double-blind dose of SAGE-217 or matching 
placebo orally, once daily with food, 30 minutes (±15 minutes) prior to lights out (PSG). 
On Days 15 through 21, subjects will self-administer a single-blind placebo dose, orally, once 
daily with food, in the evening. 
10.5. 
Study Drug Accountability 
Upon receipt of study drug, the Investigator(s), or the responsible pharmacist or designee, will 
inspect the study drug and follow the instructions regarding receipt in the Pharmacy Manual. A 
copy of the shipping documentation will be kept in the study files. 
The designated site staff will dispense the supplied subject-specific kits to subjects at the planned 
dispensation visit intervals outlined in Table 1.  
Site staff will access the IRT at the Screening Visit to obtain a subject identification (ID) number 
for each subject. On Day 1, site staff will access the IRT and provide the necessary subject-
identifying information, including the subject ID number assigned at Screening, to randomize the 
eligible subject into the study and obtain the medication ID number for the study drug to be 


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dispensed to that subject. The medication ID number and the number of capsules dispensed must 
be recorded. 
At the subsequent study drug-dispensing visit, the investigator or designee will access the IRT, 
providing the same subject ID number assigned at Screening, to obtain the medication ID 
number for the study drug to be dispensed at that visit. The medication ID number, the number 
of capsules dispensed, and the number of capsules returned by the subject at this visit must be 
recorded.  
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
Sponsor must be notified immediately. 
The study drug provided is for use only as directed in this protocol. After the study is completed, 
all unused study drug must be returned as directed or destroyed on site per the Sponsor’s 
instructions. The Investigator or designee must keep a record of all study drug received, 
dispensed and discarded.  
Sage Therapeutics will be permitted access to the study supplies at any time and with appropriate 
notice during or after completion of the study to perform drug accountability and reconciliation. 
10.6. 
Study Drug Handling and Disposal 
At the end of the study, all used and unused study drug will be reconciled and returned to Sage 
for destruction or destroyed locally; disposition of study drug will be documented. 
A copy of the inventory record and a record of any clinical supplies that have been received, 
dispensed or destroyed must be documented by the site as directed. This documentation must 
include at least the information below:  
• the number of dispensed units 
• the number of unused units 
• the number of units destroyed at the end of the study 
• the date, method and location of destruction. 
10.7. 
Study Drug 
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose (SMCC), colloidal 
silicon dioxide, and sodium stearyl fumarate as excipients. Colloidal silicon dioxide may be 
either a component of the SMCC or a standalone excipient in the formulation. Capsules will be 
available in 30-mg dose strengths.  
Matching placebo capsules are hard gelatin capsules containing only the excipients listed for the 
active capsule. 


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10.8. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution.  
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in the 
Emergency Contact Information table . Where possible, personnel should segregate any product, 
materials, or packaging associated with the product complaint. 
 


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11. 
ASSESSMENT OF EFFICACY 
  
All assessments will be conducted according to the schedule of assessments (Table 1). Study 
assessments that involve subject interviews, including the HAM-D, may be audiotaped for 
independent quality control purposes. All assessments must be conducted by raters that have 
been trained and certified to conduct assessments in this study. 
11.1. 
Screening Assessments 
11.1.1. 
Montgomery-Åsberg Depression Rating Scale 
The MADRS is a 10-item questionnaire that 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 Hamilton Scale to the 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 (Williams 2008). The MADRS total score was calculated 
as the sum of the individual item scores.   
11.2. 
Efficacy assessments 
11.2.1. 
Polysomnogram (PSG) 
The primary endpoint, SE, defined as the percentage of time in bed spent asleep, will be 
determined during an 8-hour overnight PSG recording. Subjects will be allowed to remain in the 
clinic between the consecutive PSG visits. At the discretion of the Investigator, subjects may be 
allowed to leave the clinic between consecutive PSG visits following all post-treatment 
evaluations and return to the clinic approximately 2 hours prior to their habitual bedtime, as 
determined by the CRC, for the subsequent PSG visit.  
The PSG measures the physiological process of sleep by monitoring body functions including 
brain waves via EEG, eye movements via electrooculography, muscle activity or skeletal muscle 
activation via electromyography, heart rhythm via ECG, blood oxygen saturation via pulse 
oximetry, and breathing functions. Stages of sleep will be scored through evaluation of the EEG 
signal. Sleep stage scoring includes REM, non-rapid eye movement (NREM), NREM 
stage 1 (N1), NREM stage 2 (N2), and NREM stage 3 (N3) sleep. Other sleep efficacy variables 
listed as secondary endpoints to be quantified and/or examined, include: 
• Latency to persistent sleep: Duration in minutes from lights off to the first epoch of 
20 consecutive non-wake epochs  
• Wakefulness after sleep onset: Total wake time in minutes from persistent sleep onset 
to lights on and by quarter (2-hour periods) of the 8-hour PSG recording 
• Total sleep time: Duration of total sleep time (NREM + REM) from lights off to 
lights on during recording   
• Number of awakenings and mean duration of awakenings: Number of awakenings 
from the onset of persistent sleep until lights on. An awakening is defined as at least 
2 consecutive epochs of wake. Individual awakenings must be separated by at least 


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1 epoch of stage N2, N3, or REM. Mean duration of awakenings is an arithmetic 
mean calculated as the sum of awakenings in minutes divided by the number of 
awakenings 
• Minutes and percent of stage N1, N2, N3, and REM sleep (from lights off to lights 
on) 
• Latency to REM sleep (REML): The number of non-REM epochs (stages N1, N2, 
N3) from LPS to the first epoch of REM sleep. 
− REML for second and subsequent REM periods: The number of non-REM and 
REM epochs (stages N1, N2, N3, and REM) from LPS to the first epoch of the 
2nd REM period, or subsequent REM period. 
• REM density: Total number of rapid eye movements divided by the total duration of 
REM sleep in minutes during time in bed (TIB).  
• REM Activity (REMA): Total number of rapid eye movements during REM sleep, 
observed on the electrooculographic (EOG) channels of the PSG. The rapid eye 
movements must be at least 25 uV in amplitude. 
11.2.2. 
Hamilton Rating Scale for Depression  
The 17-item HAM-D will be used to rate the severity of depression in subjects who are already 
diagnosed as depressed (Williams 2013a; Williams 2013b). The 17-item HAM-D comprises 
individual ratings related to the following symptoms: depressed mood (sadness, hopeless, 
helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, 
retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor 
activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and 
general), genital symptoms, hypochondriasis, loss of weight, and insight.  
Every effort should be made for the same rater to perform all HAM-D assessments for an 
individual subject. An assessment timeframe of 7 days will be used at first HAM-D 
administration and “Since Last Visit” will be used for all other visits. 
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  
11.2.3. 
Clinical Global Impression 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The CGI-S uses a 7-point Likert scale to rate the severity of the subject’s illness at the time of 
assessment, relative to the clinician’s past experience with subjects who have the same diagnosis. 
Considering total clinical experience, a subject is assessed on severity of mental illness at the 
time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately 
ill; 5=markedly ill; 6=severely ill; and 7=extremely ill (Busner 2007a). In this study the CGI-S 
will be assessed based on the severity of their insomnia disorder. 
The CGI-I employs a 7-point Likert scale to measure the overall improvement in the subject’s 
condition posttreatment. The Investigator will rate the subject’s total improvement whether or 


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not it is due entirely to drug treatment. Response choices include: 0=not assessed, 1=very much 
improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 
6=much worse, and 7=very much worse (Busner 2007b). The CGI-I is only rated at 
posttreatment assessments. By definition, all CGI-I assessments are evaluated against baseline 
conditions. CGI-I response will be defined as having a CGI-I score of “very much improved” or 
“much improved.” In this study the CGI-I will be assessed based on the improvement of their 
insomnia disorder. 
11.2.4. 
Insomnia Severity Index 
The ISI is a validated questionnaire designed to assess the nature, severity, and impact of 
insomnia (Morin 2011). The ISI uses a 5-point Likert Scale to measure various aspects of 
insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = severe; 4 = very severe), satisfaction 
with current sleep pattern (ranging from 0 = very satisfied, 1 = satisfied, 2 = neutral, 
3 = dissatisfied, 4 = very dissatisfied), and various aspects of the impact of insomnia on daily 
functioning (0 = not at all, 1 = a little, 2 = somewhat, 3 = much, 4 = very much). A total score of 
0 to 7 = “no clinically significant insomnia,” 8 to 14 = “subthreshold insomnia,” 
15 to 21 = “clinical insomnia (moderate severity),” and 22 to 28 = “clinical insomnia (severe).”  
11.2.5. 
Consensus Sleep Diary-Core 
The Consensus Sleep Diary-Core (Carney 2012) collects subjective responses to a series of 
questions related to their daily sleep pattern (ie, time to bed, time to fall asleep, time to final 
awakening and a question related to quality of sleep). From the CSD-C responses sleep 
parameters including sleep latency, TST, WASO, and sleep quality will be derived. The 
take-home subject sleep diary assessment will be administered using an eDiary solution. The 
eDiary will be captured using either a provisioned smartphone device or bring-your-own-device 
solution, depending on the subject’s preference. 


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11.2.9. 
Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is a subject-rated depressive symptom severity scale. To monitor severity over time 
for newly diagnosed subjects or subjects in current treatment for depression, subjects may 
complete questionnaires at baseline and at regular intervals thereafter. Scoring is based on 
responses to specific questions, as follows: 0=not at all; 1=several days; 2=more than half the 
days; and 3=nearly every day.  
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores. The PHQ-9 
total score will be categorized as follows: 1 to 4=minimal depression, 5 to 9=mild depression, 
10 to 14=moderate depression, 15 to 19=moderately severe depression; and 20 to 27=severe 
depression. 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
All assessments will be conducted according to the schedule of assessments (Table 1). 
12.1.1. 
Demographic/Medical History 
Demographic characteristics (age, race, gender, ethnicity, employment status, highest education 
level, marital/civil status) and a full medical history, including psychotherapeutic treatment for 
insomnia, and family psychiatric and sleep disorder history, will be documented. The diagnoses 
of MDD and insomnia will be determined using the SCID-5-CT. If available, the disease code 
associated with the diagnoses of MDD and insomnia based on the 10th revision of the 
International Statistical Classification of Diseases and Related Health Problems (ICD-10) should 
be recorded. 
The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire will be 
used to determine whether the subject has treatment-resistant depression, defined as persistent 
depressive symptoms despite treatment during the current major depressive episode with 
adequate doses of antidepressants from 2 different classes for at least 4 weeks of treatment. 
The RLS-DI will be used as a tool to screen for subjects with RLS. The RLS-DI is made up of 
10 items that are based on the essential International RLS Study Group diagnostic criteria for 
RLS (5 items) combined with supportive criteria and additional features of RLS (5 items). The 
RLS-DI is administered as a structured diagnostic interview. Total possible RLS-DI scores range 
from -14 to 14, with a score of ≥11 considered diagnostic for RLS (Benes, 2009; Walters, 2014). 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 
12.1.3. 
Physical Examination 
A full physical examination will be conducted at Screening and abbreviated physical 
examinations will be conducted thereafter. A full physical examination includes assessment of 
body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities). An 
abbreviated physical exam includes a brief medical history followed by targeted physical exam. 
Whenever possible, the same individual is to perform all physical examinations for a given 
subject. Unscheduled brief, symptom-driven physical examinations may also be conducted per 
the Investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by the Investigator as abnormal, 
not clinically significant (NCS); or abnormal, clinically significant (CS) in source documents. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2. 
12.1.4. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
subject has been resting for 5 minutes and then after approximately 3 minutes in the standing 


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position. Respiratory rate and temperature are collected once, in either position. Vital signs will 
be documented. When vital signs are scheduled at the same time as blood draws, vital signs will 
be obtained first. 
Any abnormality in vital signs will be interpreted by the Investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
clinically significant will be recorded as AEs, assessed according to Section 12.2. 
12.1.5. 
Electrocardiogram  
Supine 12-lead ECGs will be performed in triplicate at all scheduled time points. The standard 
intervals (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities will be 
recorded. When ECG and 
 collection occur during the same visit, the ECGs will be 
conducted first.  
Any abnormality in ECGs will be interpreted by the Investigator as abnormal, NCS or abnormal, 
CS in source documents. New or worsening abnormalities that are judged to be clinically 
significant will be recorded as AEs, assessed according to Section 12.2. 
12.1.6. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual.   
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count 
with differential  
Platelet count 
Red Blood Cell Indices 
(MCV, MCH, 
MCHC) 
Reflex to red blood 
cell morphology if 
indices are abnormal 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone (TSH) 
Reflex to free T3/T4 if TSH is 
abnormal 
pH 
Specific gravity 
Color 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 


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Table 3: 
Clinical Laboratory Tests (Continued) 
Diagnostic  
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B surface antigen 
Hepatitis C antibody 
   Reflex HCV RNA if 
Hepatitis C antibodies are 
detected 
HIV-1 and -2 serology 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: serum hCG 
Female subjects, if 
menopause is suspected 
and not surgically sterile: 
FSH 
Drug screen including: 
amphetamines, 
barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, and phencyclidine 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: urine hCG  
Alcohol 
 
Abbreviations: FSH = follicle stimulating hormone; hCG = human chorionic gonadotropin; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus 
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
and coagulation. The results of laboratory tests will be returned to the Investigator, who is 
responsible for reviewing and filing these results. All laboratory safety data will be transferred 
electronically to Sage Therapeutics or designee in the format requested by Sage Therapeutics.  
Laboratory reports must be signed and dated by the Investigator or subinvestigator indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified prior to first dose will require clear and complete 
documentation in the source documents as to the Investigator’s assessment of not clinically 
significant before proceeding with randomization.  
All clinical laboratory test results outside the central laboratory’s reference range will be 
interpreted by the Investigator as abnormal, NCS; or abnormal, CS in source documents. New or 
worsening abnormalities that are judged to be CS will be recorded as AEs, assessed according to 
Section 12.2. A clinically significant laboratory abnormality following subject randomization 
will be followed until the abnormality returns to an acceptable level or a satisfactory explanation 
has been obtained. 
A serum follicle stimulating hormone test will be conducted at Screening to confirm whether a 
female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria 
for being post-menopausal (Section 8.1). 
 
 
 
 
 


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12.1.6.1. Drugs of Abuse and Alcohol 
Urine toxicology tests will be performed for selected drugs of abuse (Table 3). A breath test for 
alcohol will be performed. 
12.1.6.2. Pregnancy Screen 
For female subjects that are not surgically sterile and do not meet the protocol-defined criteria 
for being post-menopausal, a serum pregnancy test will be performed at Screening and a urine 
pregnancy test will be performed at all other scheduled timepoints thereafter, including the ET 
visit for subjects who prematurely discontinue treatment.  
12.1.7. 
Columbia-Suicide Severity Rating Scale  
Suicidality will be monitored during the study using the C-SSRS (Posner, 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).  
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 1. 
12.1.8. 
Physician Withdrawal Checklist 
The PWC is based on the 35-item Penn Physician Withdrawal Checklist that was developed in 
the 1960s to measure benzodiazepine and benzodiazepine-like discontinuation symptoms. The 
PWC-20 is a shorter version of the Penn Physician Withdrawal Checklist based on the 20 items 
that provided the best differentiation from placebo in previous trials. The PWC-20 is made up of 
a list of 20 symptoms (eg, loss of appetite, nausea-vomiting, diarrhea, anxiety-nervousness, 
irritability, etc) that are rated on a scale of 0 (not present) to 3 (severe) (Rickels, 2008). The 
PWC-20 will be used to monitor for the presence of potential withdrawal symptoms following 
discontinuation of SAGE-217. 


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12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A treatment-emergent adverse event is an AE that occurs after the first administration of double-
blind study drug. The term study drug includes any Sage investigational product, a comparator, 
or a placebo administered in a clinical trial. 
Laboratory abnormalities and changes from baseline in vital signs, ECGs, and physical 
examinations are considered AEs if they result in discontinuation or interruption of study 
treatment, require therapeutic medical intervention, meet protocol specific criteria (if applicable) 
and/or if the Investigator considers them to be clinically significant. Laboratory values and vital 
signs that meet the criteria for an SAE should be reported in an expedited manner. Laboratory 
abnormalities and changes from baseline in vital signs, ECGs, and physical examinations that are 
clearly attributable to another AE do not require discrete reporting (eg, electrolyte disturbances 
in the context of dehydration, chemistry and hematologic disturbances in the context of sepsis). 
All AEs that occur after any subject has signed the informed consent and throughout the duration 
of the study, whether or not they are related to the study, must be reported to Sage Therapeutics. 
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up by 
the Investigator for as long as medically indicated, but without further recording in the eCRF. 
The Sponsor or its representative retains the right to request additional information for any 
patient with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the subject or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 


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treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any subject has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics within 24 hours of first awareness (Section 12.5). Serious adverse 
events occurring after a subject’s final visit (including the last follow-up visit) should be reported 
to Sage, or designee, only if the Investigator considers the SAE to be related to study treatment.  
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or on a waiting list to be scheduled) prior to obtaining the subject’s consent to participate 
in the study 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of the 
Investigator, between the subject’s consent to participate in the study and at the time of 
the procedure or treatment. 
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 4: 
Relationship to Study Drug 
Relationship 
Definition 
Not Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject, but this is not known for sure. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered related to the 
investigational product for the purposes of expedited regulatory reporting. 


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12.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, serious outcome (if applicable), and 
whether or not it caused the subject to discontinue the study drug or withdraw early from the 
study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1.2 . An AE of severe intensity 
may not be considered serious. 
If a female subject becomes pregnant during this study, pregnancy information must be collected 
and recorded on the Sage Therapeutics pregnancy form and submitted to the sponsor within 24 
hours of learning of the pregnancy. The investigator will also attempt to collect pregnancy 
information on any male subject’s female partner who becomes pregnant while the male subject 
is participating in study. After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the investigator will follow the same pregnancy reporting 
procedures specified for pregnant female subjects. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. If the pregnancy ends for any reason before the anticipated date, the 
investigator should notify Sage.   
Pregnancy in itself is not regarded as an AE unless there is a suspicion that a study drug may 
have interfered with the effectiveness of a contraceptive medication. If the outcome of the 
pregnancy meets the criteria for immediate classification as an SAE (ie, postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly/birth 
defects), the investigator should follow the procedures for reporting an SAE.  
12.5. 
Reporting Adverse Events 
All SAEs must be reported to Sage Therapeutics, or designee, immediately. A written account of 
the SAE must be sent to Sage, or designee, within 24 hours of the first awareness of the event by 
the investigator and/or his or her staff. The Investigator must complete, sign, and date the SAE 
report form, verify the accuracy of the information recorded on the SAE report form with the 
corresponding source documents, and send a copy to Sage, or designee.  
Additional follow-up information, if required or available, should all be sent to Sage 
Therapeutics, or designee, within 24 hours of receipt on a follow-up SAE report form and placed 


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with the original SAE information and kept with the appropriate section of the CRF and/or study 
file. 
Any SAEs discovered by the Investigator after the designated follow up time for the study, 
should be promptly reported to Sage, or designee, according to the timelines noted above. 
The contact information for reporting SAEs and/or pregnancies is located in the study reference 
manual.  
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the Principal Investigator’s responsibility to notify the ethics committee of all SAEs 
that occur at his or her site. Investigators will also be notified of all suspected, unexpected, 
serious, adverse reactions (SUSARs) that occur during the clinical study. Ethics Committee 
(EC)/Institutional Review Boards (IRBs) will be notified of SAEs and/or SUSARs as required by 
local law. In addition, appropriate Sage Drug Safety and Pharmacovigilance personnel, or 
designee, will unblind SUSARs for the purpose of regulatory reporting. Sage, or designee, will 
submit SUSARs (in blinded or unblinded fashion) to regulatory agencies according to local law. 
Sage, or designee, will submit SUSARs to investigators in a blinded fashion.  
12.6. 
Emergency Identification of Study Drug  
During the study, the blind is to be broken by the Investigator only when the safety of a subject is 
at risk and the treatment plan is dependent on the study treatment received. Unless a subject is at 
immediate risk, the Investigator must make diligent attempts to contact Sage prior to unblinding 
the study treatment administered to a subject. Any request from the Investigator about the 
treatment administered to study subjects must be discussed with Sage. If the unblinding occurs 
without Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later 
than the next business morning. All circumstances surrounding a premature unblinding must be 
clearly documented in the source records. Unless a subject is at immediate risk, any request for 
the unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures.  
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 
eCRF. If the subject or study center personnel have been unblinded, the subject will be 
permanently discontinued from the study.  


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13. 
STATISTICS 
A separate statistical analysis plan (SAP) will provide a detailed description of the analyses to be 
performed in the study. The SAP will be finalized and approved prior to database lock. Any 
deviations from or changes to the SAP following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
The All Randomized Set, defined as all subjects who have been randomized, will be used for 
subject disposition. Subjects will be classified according to randomized treatment. 
The Safety Set (SS) is defined as all subjects receiving at least 1 dose of study drug and will be 
used to provide descriptive summaries of safety data, demographics, and baseline characteristics. 
Data will be summarized according to treatment received. 
The Full Analysis Set, defined as all randomized subjects in the SS who have at least 1 post-
baseline efficacy evaluation, will be used for analysis of efficacy data. Data will be summarized 
according to randomized treatment. 
 
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. No imputation process will be 
used to estimate missing data.  
13.3. 
General Considerations 
Since insomnia is known to be intermittent in nature and prone to adaptation effects, to reduce 
variability and to reduce selection bias, PSG will be performed for 2 consecutive nights before 
randomization as well as at end of double-blind treatment. In the primary endpoint analysis, the 
average of values over 2 nights measurement will be used as the parameter value. Subjective 
measures of sleep will also be similarly analyzed. Following the double-blind treatment period, 
possible rebound insomnia and withdrawal effects will be evaluated during a single-blind 
placebo run-out period. 
For the purpose of all safety, efficacy, and other analyses, where applicable, baseline is defined 
as the last measurement prior to the start of double-blinded study drug administration. For sleep 
parameters from PSG and subjective sleep measures, this is the average of 2 nights values from 
Day -1 and Day-2 when both values are available. 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each 
time point and summarized descriptively. For categorical endpoints, descriptive summaries will 
include counts and percentages.  


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13.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized using the SS.  
Pregnancy results will be listed but not summarized.  
Medical history will be listed by subject.  
13.5. 
Efficacy Analyses 
The primary efficacy endpoint, the change from baseline in SE at end of double-blind treatment, 
will be analyzed using Analysis of Covariance (ANCOVA); the model will include treatment, 
antidepressant treatment use (current/stable or not treated/withdrawn ≥60 days), baseline SE 
score, as explanatory variables, change from baseline in SE at end of double-blind treatment as 
the response variable. The Kenward and Roger correction to the degrees of freedom will be used. 
The main comparison will be between SAGE-217 and placebo at end of double-blind treatment. 
Model-based point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-
values) will be reported where applicable. The baseline value of SE was defined as the average 
of over 2 nights PSG measurements at Day -2 and Day -1. The post-baseline PSG SE value at 
end of double-blind treatment is defined as the average of over 2 nights PSG measurements at 
Day 13 and 14. 
The secondary endpoints of the change from baseline to post-baseline will be analyzed using a 
mixed effects model for repeated measures (MMRM); the model will include treatment, 
antidepressant treatment use (current/stable or not treated/withdrawn ≥60 days), baseline score, 
assessment time point, and time point-by-treatment as explanatory variables. All explanatory 
variables will be treated as fixed effects. All post-baseline time points will be included in the 
model.  
 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-217 will be evaluated by AEs/SAEs, concomitant medication 
usage, changes from baseline in vital signs, clinical laboratory evaluations, and 12-lead ECG. 
Suicidality will be monitored by the C-SSRS. Safety data will be listed by subject and 
summarized by treatment group. All safety summaries will be performed on the SS.  
13.6.1. 
Adverse Events 
The analysis of adverse events will be based on the concept of TEAEs. The incidence of TEAEs 
will be summarized overall and by Medical Dictionary for Regulatory Activities (MedDRA) 
Version 18.1 or higher, system organ class (SOC), and preferred term. Incidences will be 
presented in order of decreasing frequency. In addition, summaries will be provided by intensity 
(mild, moderate, severe) and by causality (related, not related) to study drug.  
Any TEAEs leading to discontinuation and SAEs with onset after the start of study drug will also 
be summarized.  


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All AEs and SAEs (including those with onset or worsening before the start of study drug) 
through the end of the study will be listed.  
13.6.2. 
Clinical Laboratory Evaluations 
Results of clinical laboratory parameters in each scheduled visit and mean changes from baseline 
will be summarized.in standard units. Normal range of each parameter is provided by the 
laboratory; shift from baseline to post-baseline values in abnormality of results will be provided. 
Potentially clinically significant values will be summarized by treatment. Any abnormal values 
deemed clinically significant by the investigator will be reported as an AE (see Section 12.2). 
Clinical laboratory results will be listed by subject and timing of collection.  
13.6.3. 
Physical Examinations 
The occurrence of a physical examination (Y/N) and the date performed will be listed by subject. 
Any clinically significant observation in physical examination will be reported as an AE (see 
Section 12.2).  
13.6.4. 
Vital Signs 
Results from each visit and mean changes from baseline in vital signs will be summarized by 
scheduled visit. Any abnormality deemed clinically significant by the investigator will be 
reported as an AE (see Section 12.2). Potentially clinically significant values will be summarized 
by treatment. Vital sign results will be listed by subject and timing of collection.  
13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each of the triplicate ECGs for each subject: 
heart rate, PR, QRS, QT, and QTcF; the derived mean of each parameter will also be listed. Any 
clinically significant abnormalities or changes in mean ECGs should be reported as an AE (see 
Section 12.2). Mean ECG data will be summarized by visit. Potentially clinically significant 
values of QTcF will be summarized by treatment. Electrocardiogram findings will be listed by 
subject and visit.  
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
All medications taken within 30 days prior to informed consent through the duration of the study 
will be recorded. In addition, all psychotropic medications taken in the previous 6 months prior 
to screening and GABAergic medications taken 12 months prior to screening will be recorded on 
the eCRF. Those medications taken prior to the initiation of the start of study drug will be 
denoted “Prior”. Those medications taken prior to the initiation of the study drug and continuing 
beyond the initiation of the study drug or those medications started at the same time or after the 
initiation of the study drug will be denoted “Concomitant” (ie, those with a start date on or after 
the first dose of study drug, or those with a start date before the first dose of study drug that are 
ongoing or with a stop date on or after the first dose of study drug).  


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Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by subject, start date, and verbatim 
term.  
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be listed for all subjects. Listings will include behavior type and/or category for Suicidal 
Ideation and Suicidal Behavior of the C-SSRS.  
13.6.8. 
Physician Withdrawal Checklist 
Potential withdrawal symptoms collected on the PWC-20 will be summarized by visit and 
treatment. Listings will include all data by subject. 
 
13.8. 
Determination of Sample Size 
Assuming a 2-sided test at an alpha level of 0.05, a sample size of 41 subjects per group would 
provide 90% power to detect a treatment difference of 11 points between the SAGE-217 and 
matching placebo groups with regard to the primary outcome variable of change from baseline in 
SE score, assuming a standard deviation of 15 points. By including 2 treatment groups and using 
a 1:1 randomization, a total of 82 evaluable subjects are required. Assuming a non-evaluability 
rate of 20%, up to 102 subjects will be randomized. 
Additional subjects may be enrolled if the drop-out rate is higher than 20%.  


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


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


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


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


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


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


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19. 
LIST OF REFERENCES 
Benes H, Kohnen R. Validation of an algorithm for the diagnosis of Restless Legs Syndrome: 
The Restless Legs Syndrome-Diagnostic Index (RLS-DI). 2009;10(5):515-523. 
Bonnet MH, Arand DL. Situational insomnia: consistency, predictors, and outcomes. Sleep. 
2003;26(8):1029-1036. 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:15971.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Carney CE, Segal ZV, Edinger JD, Krystal AD. A comparison of rates of residual insomnia 
symptoms following pharmacotherapy or cognitive-behavioral therapy for major depressive 
disorder. J Clin Psychiatry. 2007 Feb;68(2):254-60. 
Carney CE, Buysse DJ, Ancoli-Israel S, Edinger JD, Krystal AD, Lichstein KL, Morin CM. The 
consensus sleep diary: standardizing prospective sleep self-monitoring. Sleep. 2012 Feb 
1;35(2):287-302.  
Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive 
episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011 
Jun;41(6):1165-74. 
Drugan RC, Morrow AL, Weizman R, et al. Stress-induced behavioral depression in the rat is 
associated with a decrease in GABA receptor-mediated chloride ion flux and brain 
benzodiazepine receptor occupancy. Brain Res. 1989;487: 45–51. 


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DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Gerner RH, Hare TA. GABA in normal subjects and patients with depression, schizophrenia, 
mania, and anorexia nervosa. Am J Psychiatry. 1981;138:1098–101. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 
2015;76(2):155-62. 
Honig A, Bartlett JR, Bouras N, Bridges PK. Amino acid levels in depression: a preliminary 
investigation. J Psychiatr Res. 1988;22:159–64. 
Horoszok L, Baleeiro T, D'Aniello F, Gropper S, Santos B, Guglietta A, Roth T. A single‐dose, 
randomized, double‐blind, double dummy, placebo and positive‐controlled, five‐way cross‐over 
study to assess the pharmacodynamic effects of lorediplon in a phase advance model of insomnia 
in healthy Caucasian adult male subjects. Human Psychopharmacology: Clinical & Experimental 
2014;29(3):266-273. 
Iovieno N, van Nieuwenhuizen A, Clain A et al. Residual symptoms after remission of major 
depressive disorder with fluoxetine and risk of relapse. Depress Anxiety. 2011;28(2):137-44. 
Lam RW. Sleep disturbances and depression: a challenge for antidepressants. Int Clin 
Psychopharmacol. 2006;21(S1):S25-29. 
Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. 
Mol Psychiatry. 2011;16(4):383-406. 
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: Relevance to postpartum 
depression. Neuron. 2008;59(2);207-213.   
Maguire J, Ferando I, Simonsen C, Mody I. Excitability changes related to GABAA receptor 
plasticity during pregnancy. J Neurosci. 2009;29(30):9592-9601.   
Mann JJ, Oguendo MA, Watson KT, et al. Anxiety in major depression and cerebrospinal fluid 
free gamma-aminobutyric acid. Depress Anxiety. 2014;31(10):814-821. 
Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: Psychometric 
Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011;34(5):601-
608. 
Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep 
Med Rev. 2002;6(2):97-111. 
Olfson M, Blanco C, Wall M, et al. National Trends in Suicide Attempts Among Adults in the 
United States. JAMA Psychiatry. 2017;74(11):1095–1103. 


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Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, 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):1266-1277. 
Rickels K, Garcia-Espana F, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20). 
J Clin Psychopharmacol. 2008;28(4):447-451. 
Riemann D, Baglioni C, Bassetti C, et al. European guideline for the diagnosis and treatment of 
insomnia. J Sleep Res. 2017;26(6):675-700. 
Romera I, Pérez V, Ciudad A, et al. Residual symptoms and functioning in depression, does the 
type of residual symptom matter? A post-hoc analysis. BMC Psychiatry. 2013 Feb 11;13:51. 
Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of 
GABAA receptor subtypes. Nat Rev Drug Discov. 2011;10(9):685-97. 
Sateia MJ. International classification of sleep disorders-third edition: highlights and 
modifications. Chest. 2014;146(5):1387-1394. 
Schüle C, Nothdurfter C, Rupprecht R.  The role of allopregnanolone in depression and anxiety. 
Prog Neurobiol. 2014;113:79-87. 
Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management 
of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487-504. 
Trivedi MH, Rush AJ, Wisniewski SR, et al. (STAR*D Study Team). Evaluation of outcomes 
with citalopram for depression using measurement-based care in STAR*D: implications for 
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Williams JBW.  SIGH-D Past week:  Past Week Version. 2013b. 
 

SAP_001.pdf: 
Official Title: 
A Randomized, Double-blind, Placebo-controlled Study of the Safety, Tolerability, 
and Efficacy of SAGE-217 Compared to Placebo in Adult Subjects With Comorbid 
Major Depressive Disorder and Insomnia
NCT Number: 
NCT03771664
Document Date: 
SAP Version 1.0: 24 April 2020


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SAGE THERAPEUTICS INCORPORATED 
 
Statistical Analysis Plan 
Methods 
Protocol Number SAGE-217-MDD-304 
A Randomized, Double-blind, Placebo-controlled Study of the Safety, Tolerability, 
and Efficacy of SAGE-217 Compared to Placebo in Adult Subjects with Comorbid 
Major Depressive Disorder and Insomnia 
Author of SAP: 
 
Version: Version 1.0 
Version Date of SAP: 22 APR 2020 
Sponsor: Sage Therapeutics, Inc. 
215 First Street 
Cambridge, Massachusetts 02142 
 
 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written 
consent of Therapeutics Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them. 




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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ............................................................................................... 3 
2. 
LIST OF ABBREVIATIONS ....................................................................................... 7 
3. 
INTRODUCTION......................................................................................................... 9 
4. 
STUDY OBJECTIVES ............................................................................................... 10 
4.1. 
Primary Objective ....................................................................................................... 10 
4.2. 
Secondary Objectives .................................................................................................. 10 
 
 10 
 
 10 
5. 
STUDY ENDPOINTS ................................................................................................. 11 
5.1. 
Primary Endpoint ........................................................................................................ 11 
5.2. 
Secondary Endpoints ................................................................................................... 11 
 
 12 
 
 12 
6. 
STUDY DESIGN ........................................................................................................ 13 
6.1. 
Overall Design ............................................................................................................ 13 
6.2. 
Sample Size and Power ............................................................................................... 14 
6.3. 
Randomization ............................................................................................................ 14 
6.4. 
Blinding and Unblinding ............................................................................................. 14 
7. 
MODIFICATIONS ..................................................................................................... 16 
7.1. 
Modifications to the Approved Clinical Study Protocol .............................................. 16 
7.2. 
Modifications to the Approved Statistical Analysis Plan ............................................ 16 
7.3. 
Modifications to the Approved DMC Charter ............................................................ 16 
8. 
ANALYSIS SETS ....................................................................................................... 17 
8.1. 
All Randomized Set .................................................................................................... 17 
8.2. 
Run-in Safety Set ........................................................................................................ 17 
8.3. 
Safety Set .................................................................................................................... 17 
8.4. 
Full Analysis Set ......................................................................................................... 17 
8.5. 
Per Protocol Set ........................................................................................................... 17 
 
 17 


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9. 
STATISTICAL ANALYSIS ........................................................................................ 18 
9.1. 
General Considerations ............................................................................................... 18 
9.1.1. 
Study Day Definition .................................................................................................. 18 
9.1.2. 
Missing Data ................................................................................................................ 19 
9.2. 
Background Characteristics ......................................................................................... 19 
9.2.1. 
Subject Disposition ..................................................................................................... 19 
9.2.2. 
Protocol Deviations ..................................................................................................... 19 
9.2.3. 
Demographics and Baseline Characteristics ............................................................... 20 
9.2.4. 
Medical/Surgical History ............................................................................................ 21 
9.2.5. 
Prior and Concomitant Medications ............................................................................ 21 
9.2.6. 
Study Drug Exposure .................................................................................................. 22 
9.2.7. 
Study Drug Adherence ................................................................................................ 23 
9.3. 
Efficacy Analysis ........................................................................................................ 23 
9.3.1. 
Visit Windows for Efficacy Analysis .......................................................................... 23 
9.3.2. 
Analysis of Primary Efficacy Endpoint ....................................................................... 25 
9.3.2.1. 
Definition of Primary Efficacy Variable ..................................................................... 25 
9.3.2.2. 
Visit Windows ............................................................................................................. 25 
9.3.2.3. 
Analysis of Primary Endpoint ..................................................................................... 25 
9.3.2.4. 
Subgroup Analyses for Primary Endpoint ................................................................... 26 
9.3.2.5. 
Multiplicity Adjustment .............................................................................................. 26 
9.3.3. 
Analysis of Secondary Efficacy Endpoints ................................................................. 26 
9.3.3.1. 
Definition of Secondary Efficacy Variables ................................................................ 26 
9.3.4. 
Analysis of Secondary Efficacy Endpoints ................................................................. 32 
9.3.4.1. 
Descriptive Summary of Secondary Efficacy Endpoints ............................................. 32 
9.3.4.2. 
ANCOVA - PSG-derived Sleep Secondary Endpoints ............................................... 33 
9.3.4.3. 
Mixed effects model for repeated measures (MMRM) – Non PSG- 
derived Sleep Secondary Endpoints ............................................................................. 33 
9.3.4.4. 
Generalized Estimating Equations (GEE) ................................................................... 34 
 
 34 
 
 34 
 
 35 
 
 35 




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Table 3: 
Visit Windows for Efficacy Analysis Other than Endpoints Assessed by 
PSG at Unscheduled Visit .......................................................................................... 25 
Table 4: 
HAM-D Subscale Score Calculations ........................................................................ 28 
Table 5: 
Safety endpoints and variables in the summary tables ............................................... 37 
Table 6: 
Clinical Laboratory Tests ........................................................................................... 39 
Table 7: 
Laboratory Parameters - Criteria for PCS Values ...................................................... 40 
Table 8: 
Vital Signs - Criteria for PCS and PCSC Values ....................................................... 42 
Table 9: 
ECG Parameters - Criteria for PCS and PCSC Values .............................................. 43 




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Abbreviation or specialist term 
Explanation 
REM 
Rapid Eye Movement 
REMA 
REM Activity 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SEFF 
sleep efficiency 
SI 
International System of Units 
sNAW 
subjective number of awakenings 
SOC 
system organ class 
SS 
Safety Set 
sSL 
subjective sleep latency 
sSQ 
subjective sleep quality 
sTST 
subjective total sleep time 
sWASO 
subjective wake after sleep onset 
TEAE 
treatment-emergent adverse event 
TIB 
time in bed 
TST 
total sleep time 
WASO 
wake after sleep onset 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 


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3. 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis of 217-MDD-304 study, and is based on 
the approved clinical study protocol, dated 17 JULY 2019, version 4.0. 
The purpose of the SAP is to describe in detail the statistical methodology and the statistical analyses 
to be conducted for the above-mentioned protocol. The SAP will be approved and finalized before 
database lock. 




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5. 
STUDY ENDPOINTS 
5.1. 
Primary Endpoint 
The primary endpoint of this study is change from baseline in sleep efficiency (SEFF), defined as the 
percentage of time in bed spent asleep, at end of double-blind treatment (EODBT) as assessed by 
Polysomnography (PSG). 
 
5.2. 
Secondary Endpoints 
Secondary endpoints of this study are: 
• 
Change from baseline of the following PSG-derived endpoints at EODBT: 
‒ 
Wake after sleep onset (WASO, defined as the total wake time in minutes) from 
persistent sleep onset to lights-on (final wake time) 
‒ 
WASO by quarter (2-hour period) of the PSG recording (8-hour period) 
‒ 
Total sleep time (TST) and TST by quarter of the PSG recording 
‒ 
Latency to persistent sleep (LPS) 
‒ 
Number of awakenings (NAW) and mean duration of awakenings (mDURAW), in total 
and by quarter of the PSG recording 
‒ 
Minutes and percent of stage N1, N2, N3, and rapid eye movement (REM) sleep 
‒ 
Latency to the first period of REM Sleep and latency to each subsequent period of REM 
Sleep 
‒ 
REM Density 
‒ 
REM Activity 
• 
Change from baseline in subjective sleep endpoints to EODBT: 
‒ 
Insomnia Severity Index (ISI) 
‒ 
Consensus Sleep Diary – Core (CSD-C) endpoints 
‒ 
Subjective total sleep time (sTST) 
‒ 
Subjective wake after sleep onset (sWASO) 
‒ 
Subjective sleep latency (sSL) 
‒ 
Subjective sleep quality (sSQ) 
• 
Change from baseline in Clinical Global Impression - Severity (CGI-S) at EODBT and all 
other timepoints (based on the insomnia disorder). 
• 
Clinical Global Impression - Improvement (CGI-I) at EODBT (based on the insomnia 
disorder). 
• 
Change from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) total score 
at EODBT.Change from baseline Patient-reported outcome measures of depressive 
symptoms, as assessed by the 9-item Patient Health Questionnaire (PHQ-9) at the EODBT. 






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Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Appendix A. 
Figure 1: 
Study Design (217-MDD-304) 
 
 
 
6.2. 
Sample Size and Power 
Assuming a 2-sided test at an alpha level of 0.05, a sample size of 41 subjects per group would 
provide 90% power to a treatment difference of 11 points between the SAGE-217 and matching 
placebo groups with regard to the primary outcome variable of change from baseline in SE score, 
assuming a standard deviation of 15 points. 
By including 2 treatment groups and using a 1:1 randomization, a total of 82 evaluable subjects are 
required. Evaluable subjects are defined as those randomized subjects who received double-blinded 
study drug and have a valid baseline and at least 1 post-baseline SEFF assessment. Assuming a non- 
evaluability rate of 20%, up to 102 subjects will be randomized. 
Additional subjects may be enrolled if the drop-out rate is higher than 20%. 
 
6.3. 
Randomization 
This is a randomized double-blind, placebo-controlled study. Subjects who meet the entrance criteria 
will be randomized in a stratified manner based on use of antidepressant treatment (current/stable or 
not treated/withdrawn ≥60 days) at baseline; randomization will be done within each stratum in a 1:1 
ratio to receive SAGE-217 30 mg or matched placebo. Subjects, clinicians, and the study team will be 
blinded to treatment allocation. Randomization will be performed centrally via an interactive response 
technology (IRT) system. 
 
6.4. 
Blinding and Unblinding 
Subjects in run-in period and run-out placebo period are single-blinded. 
Subjects, clinicians, and the study team will be blinded to treatment allocation. 


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Randomization schedules will be generated by an independent statistician. The allocation to treatment 
group (SAGE-217 30 mg or placebo) will be based on the randomization schedule. The 
randomization schedules will be kept strictly confidential, accessible only to authorized personnel 
until the time of unblinding. 
In case of medical emergency, the Investigator may request unblinding of an individual subject’s 
treatment in the study via the IRT. 




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8. 
ANALYSIS SETS 
8.1. 
All Randomized Set 
The All Randomized Set is defined as all subjects who have been randomized. 
 
8.2. 
Run-in Safety Set 
The Run-in Safety Set is defined as all subjects who took at least 1 dose of run-in placebo but did not 
receive any double-blind study drug. 
 
8.3. 
Safety Set 
The Safety Set (SS) is defined as all subjects receiving at least 1 dose of double-blind study drug. 
 
8.4. 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all randomized subjects in the SS with valid baseline and at 
least 1 post-baseline efficacy evaluation. 
 
8.5. 
Per Protocol Set 
The Per Protocol Set is defined as all subjects in the Full Analysis Set and without major protocol 
deviations, which could potentially affect efficacy. The review of major protocol deviations will be 
completed, and the decision on whether the deviation affects efficacy will be documented before 
database unblinding. 
 


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9. 
STATISTICAL ANALYSIS 
9.1. 
General Considerations 
Since insomnia is known to be intermittent in nature and prone to adaption effects, to reduce 
variability and to reduce selection bias, PSG will be performed with single-blind placebo 
administration for 2 consecutive nights before randomization. Following the double-blind treatment 
period, possible rebound insomnia and withdrawal effects will be evaluated during a 1-week single- 
blind placebo run-out period. 
For the purpose of all safety, efficacy, and other analyses, where applicable, baseline is defined as the 
last non-missing measurement prior to the start of double-blind study drug administration. For sleep 
parameters from PSG and subjective sleep measures, this is the average of 2 nights values from Day - 
1 and Day -2 when both values are available; otherwise, the single available assessment at either Day 
-2 or Day -1 will be used as the baseline. For PWC-20, the baseline is defined as the measurement on 
Day 15 for subjects who complete double-blind treatment or the last measurement on double-blind 
treatment for subjects who discontinue early from double-blind treatment. 
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 observed 
data. Measures of location (mean and median) will be reported to 1 degree of precision more than the 
observed data and measures of spread (standard deviation) will be reported to 2 degrees of precision 
more than the observed data. In addition, change from baseline values (visit value – baseline value) 
will be calculated at each time point and summarized descriptively. For categorical endpoints, 
descriptive summaries will include counts and percentages. Percentages will be presented to 1 
decimal place unless otherwise specified; the denominator of percentages will be the number of 
subjects in the analysis set used unless specified otherwise. 
All analyses and summary outputs will be generated using SAS® 9.4 or higher. 
All summaries and figures will be provided by treatment group. Efficacy data are analyzed using the 
Full Analysis Set by the randomized treatment. Safety data are analyzed using the Safety Set by the 
actual treatment received. If the subject takes any dose of SAGE-217 during the study, the subject 
will be considered under SAGE-217 for treatment received. 
All subject data, including those derived, to support tables and figures will be presented in the subject 
data listings. In general, the subject data listings will be sorted by treatment group, subject number 
and assessment visit and date (and time, if applicable). 
 
9.1.1. 
Study Day Definition 
Study day is defined as number of days since the first dose of double-blind study drug: 
• 
The day of subject receiving the first dose of double-blind study drug is designated as Day 1. 
• 
For visit days after Day 1, study day = visit date – Day 1 date + 1. 
• 
For visit days prior to Day 1, study day = visit date – Day 1 date. Thus, study days for 
screening visit and run-in period are negative numbers. There is no “Day 0”. 


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9.1.2. 
Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as per the 
analysis populations, using all non-missing data available. Imputation of missing data in scoring of 
questionnaires is discussed in respective sections below. Handling of missing or incomplete dates has 
been discussed in Appendix C. 
 
9.2. 
Background Characteristics 
9.2.1. 
Subject Disposition 
The analyses of subject disposition will use all subjects who provided written informed consent to the 
study. 
These data will be presented by single-blind run-in, double-blind, single-blind run-out periods of the 
study; and by treatment the subject is randomized to within double-blind period. The summaries of 
subject disposition will include the number of subjects who screened, screened failed, received any 
study drug (placebo or SAGE-217), the number of subjects randomized, number of subjects who 
completed each period, who prematurely discontinued from each period, and primary reasons for 
discontinuation of the study, and/or treatment. If a subject has been rescreened because the subject 
had been a screen failure the first time, the status of the subject will be determined from the second 
screening. In the count of screened subjects, this subject will be counted only once. A completer for 
the study is defined as one who completed the final follow up visit (Day 42), and is derived from the 
study conclusion CRF page with completion question answered Yes. A subject who is marked as 
discontinuing treatment prematurely in the treatment discontinuation CRF page is considered 
prematurely discontinuing treatment; the main reason is provided in the same CRF page. 
Separate data listings will be provided for subject randomization and screen failures/run-in failures. 
The number and percentage of subjects in each analysis set will be provided. 
A separate data listing will be provided for all subjects who prematurely withdrew from the study or 
prematurely discontinued study drug with reasons. 
 
9.2.2. 
Protocol Deviations 
Protocol deviations identified during site monitoring will be captured on an electronic case report 
form (eCRF) and categorized by the study team as major and minor deviations, without any 
unblinding information. These deviations will be summarized by type and by randomized treatment 
group using the All Randomized Set. The subjects who were not randomized, but who had protocol 
deviations identified will be presented in a data listing. 
Major protocol deviations are identified as affecting efficacy analysis. This list will be finalized 
before database lock by a study team review in a blinded review of data and will be documented as 
such. Subjects with any of these deviations will be excluded from the FAS to define the Per Protocol 
Set. The major protocol deviations that are potentially affecting efficacy analysis include, but are 
not limited to: 
• Did not meet key inclusion/meet key exclusion criteria 
• Received any disallowed concomitant medication during the treatment period 
• Had overall treatment compliance rate < 75% Other 
A summary of the reasons for exclusion from analysis sets will be presented by treatment group. 


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9.2.3. 
Demographics and Baseline Characteristics 
The following analyses will use the Safety Set (using actual treatment received) and the FAS (using 
randomized treatment). 
Demographic data (age, race, gender, ethnicity, employment status, highest education level category, 
marital/civil status) and baseline characteristics, such as height, weight, body mass index (BMI), 
baseline Montgomery-Asberg Depression Rating Scale (MADRS) score, HAM-D total score, ISI total 
score, Apnea-Hypopnea Index (AHI) score, Periodic Limb Movement Arousal Index (PLMAI) scores 
and WASO score, will be summarized by treatment groups, where AHI score, PLMAI score, and 
WASO score were from central lab read . Highest education level will be categorized in the summary 
tables as follows: 
Less than or equal to 12th grade, no diploma 
12th grade diploma or GED 
Some college but no degree 
Associate degree 
Bachelor’s degree 
Master’s degree 
Professional degree 
Doctoral degree 
Baseline subgroups will also be summarized for the following categories: 
• 
Race (Black or African American, White, Other) 
• 
Gender (Male, Female) 
• 
Age (18-24, 25-50, 51-64 years) 
• 
Baseline antidepressant use (Yes, No) 
• 
BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
• 
ISI score (15-21 moderate, 22-28 severe) 
Diagnostic labs are part of screening; a data listing using Safety Set will be provided. The following 
diagnostic screening test results will be included in this listing. 


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Table 1: 
Diagnostic Screening Test Results 
 
Diagnostic Screening 
Serum 
Urine 
Breathalyzer 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
HIV-1 and -2 
Female subjects that are not surgically 
sterile and do not meet the protocol- 
defined criteria for being post- 
menopausal: serum hCG 
Female subjects, if menopause is 
suspected and not surgically sterile: 
FSH 
Drug screen including: 
amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, 
opiates, and phencyclidine 
Female subjects that are not surgically 
sterile and do not meet the protocol- 
defined criteria for being post- 
menopausal: urine hCG 
Alcohol 
 
 
9.2.4. 
Medical/Surgical History 
The following analyses will use the FAS (using randomized treatment). 
Medical/surgical history collected at screening will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 21.0 or higher. 
Medical/surgical history data will be summarized by system organ class (SOC) and preferred term 
(PT). A summary of medical/surgical history that is ongoing at the time of screening will be provided 
separately. Subject history of psychiatric disorders, family psychiatric history, and sleep history will 
be summarized. These data will be provided by treatment groups. 
The history related to MDD (date of initial diagnosis of MDD, lifetime antidepressant medication 
usage, information of depressive episodes, etc.) will be collected. Years since initial diagnosis of 
MDD, lifetime anti-depressant medication usage, and information of depressive episodes will be 
summarized. Years since initial diagnosis of MDD, days since start of current episode and days since 
first episode will be calculated using: first dose date of double-blind study drug – date of interest). For 
imputation of incomplete dates in disease history, please see Section 12.3.3. 
The medical history related to sleep disorders will be collected and summarized. In addition, Days 
since start of current episode of insomnia, history of recurrent insomnia will be summarized by 
treatment. 
 
9.2.5. 
Prior and Concomitant Medications 
The following analyses will use the FAS (using randomized treatment). 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug Dictionary Enhanced (WHO-DDE) March 2018, or later. 
All medications taken within 30 days prior to informed consent through the duration of the study will 
be recorded. In addition, all psychotropic medications taken in the previous 6 months prior to 


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Screening and GABAergic medications taken 12 months prior to Screening will be recorded on the 
eCRF. 
Medications will be presented according to whether they are being taken prior to and/or after first 
administration of double-blind study drug. Prior medications are defined as those taken prior to the 
initiation of the start of double-blind study drug. Concomitant medications are defined as those taken 
prior to the initiation of the double-blind study drug and continuing beyond the initiation of the 
double-blind study drug or those medications started at the same time or after the initiation of the 
double-blind study drug (i.e., those with a start date on or after the first dose of double-blind study 
drug, or those with a start date before the first dose of double-blind study drug that are ongoing or 
with a stop date on or after the first dose of study drug). If medication dates are incomplete and it is 
not clear whether the medication was concomitant, it will be assumed to be concomitant. For 
imputation of missing concomitant medication dates, please refer to Appendix C, Section 12.3. 
Concomitant medications will be further divided by period (double-blind, run-out, or post-treatment) 
as follows (if time is missing, the date will be used for this algorithm): 
• 
Double-blind period concomitant medications are those that have been used any time from 
start of first double-blind dose to the last dose of double-blind study drug + 1 Day. 
• 
Run-out period concomitant medications are those that have been started after 1 day from the 
end of double-blind study drug, but on or before the last dose of run-out treatment period 
• Post-treatment period concomitant medications are those that have been started after the end 
of run-out treatment period. 
Prior and concomitant non-psychotropic medication use will be summarized by anatomical 
therapeutic chemical (ATC) level 2 and Standard Medication Name. Similar summary tables will be 
provided for psychotropic medications. Separate but similar summaries will be provided for 
concomitant medication use for on-treatment and post-treatment periods as defined above. 
Antidepressants that have been taken at the same dose for at least 60 days prior to Day 1 are permitted 
if the subject intends to continue the stable dose through the follow-up period (Day 42). Anti- 
depressant medications are identified by (ATC3 code of N06A. A summary of anti-depressant use at 
first dose of double-blind treatment and any change in these medications post-baseline (including the 
follow up period) will be summarized. 
Anti-insomnia treatments are identified by ATC3 code N05C and will be summarized and listed 
separately. 
Details of prior and concomitant medications will be listed by subject, start date, and verbatim term. 
Concomitant procedures will be presented in a listing by subject and will not be summarized. 
9.2.6. 
Study Drug Exposure 
The following analyses will use the Safety Set (using actual treatment) and will only be performed for 
the double-blind period. 
Total drug exposure (in mg) is defined as the total study drug in mg for SAGE-217 that was taken 
during the double-blind period of the study. Total drug exposure for subjects randomized to placebo 
is zero unless the subject has taken SAGE-217 by mistake, in which case the total exposure comes 
from SAGE-217 exposure. If the patient skips the dose on any of the days, the dose taken is 0 mg. 


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Total exposure duration to study drug (in days) is defined as total number of days treated with study 
drug during the double-blind period of the study: date of last dose – date of first dose + 1. Note that 
this includes days when the dose has been missed. 
Percent of planned exposure received is defined as the total drug exposure (in mg) divided by total 
amount of planned doses exposure (in mg), times 100, which mathematically is equivalent to [the 
total drug exposure (in mg) / (30*14], times 100 for subjects who complete the treatment. For 
subjects who discontinued the treatment early, the planned exposure is (Last dose date – First dose 
date + 1), times 30 mg for subjects randomized to SAGE-217. For subjects randomized to placebo, 
this measure is not applicable. 
Total drug exposure, total exposure duration and percent of the planned exposure received will be 
summarized descriptively. 
 
9.2.7. 
Study Drug Adherence 
The following analyses will use the Full Analysis Set (using randomized treatment). Study drug 
adherence (%) is defined as the total number of capsules taken divided by total number of planned 
capsules, times 100. 
The schedule of study drug is one capsule per day, so the number of days planned for study drug 
intake is same as the number of capsules planned to be taken. Number of planned days for study drug 
intake is defined as follows: 
1. If the subject discontinues treatment within Day 2 and Day 14 (both inclusive), the planned 
number of days is the last dose day of study drug. 
2. If the subject does not discontinue treatment, the planned number of days is 14. 
Study drug adherence will be summarized descriptively. 
9.3. 
Efficacy Analysis 
All efficacy analyses will be performed for the FAS unless otherwise specified. 
 
9.3.1. 
Visit Windows for Efficacy Analysis 
The scheduled visits will not be windowed and will be used at nominal visit value for analysis 
purposes. The unscheduled, end-of-treatment (EOT) and early termination (ET) visit will be mapped 
to a scheduled visit for analysis. Unscheduled visits that happens on or before EOT visit (date 
(including EOT visit) will be mapped using the date of collection/assessment and Day 1 date of first 
double-blind dose) will be used as a basis to determine study day, which will be mapped to the 
intended visit according to the visit windows specified in the table below. Unscheduled visits after 
EOT visit date, including ET visit, will be windowed using relative days since last dose date; the 
mapping will follow the table below. In order to accommodate as much data as possible into analysis, 
these windows have been widened compared to protocol-specified operational window, to have no 
gap between them; these windows are used for analysis purposes only. Note that Day 18 data will not 
be windowed; it will be presented in summaries as nominal visit values, and will not be included in 
the modeling or in figures. 
 
Once analysis visit windows are assigned, all visits, including scheduled visits, unscheduled visits, 
and EOT/ET visits will be eligible for being flagged as the “analyzed record” within the analysis 
window; a subject’s individual analysis visit window could potentially contain more than 1 visit. In 


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the event of multiple visits falling within an analysis window or in case of a tie, the following rules 
will be used in sequence to determine the “analyzed record” for the analysis visit window: 
• 
If the data from the scheduled visit is available, then the scheduled visit data will be used. 
• 
If there is no data from the scheduled visit available, the data closest to the scheduled study 
day for that window will be used 
• 
If there is a tie between the data in the number of days before and after the scheduled day, the 
later data will be used. 
The summary by visit will use the “analyzed records” only – at most one per subject. The data not 
flagged as the “analyzed record” will be included in listings. An unscheduled visit that does not fall 
under any analysis window will remain in the database, and will be included in the listings. 
Table 2 and Table 3 display windows for efficacy analysis. 
Table 2: 
Visit Windows for Analysis of Efficacy Endpoint Assess by Unscheduled 
PSG 
 
Scheduled Day (Visit) 
Target Study Day 
Study Day Window for Visit 
Day (-2) (Visit 2) 
Day -2 
Two consecutive Days 
between Day -3 to Day -1. 
Map the first measurement to 
Day -2 and the last one to Day 
-1, if only one measurement, 
Day -3 or Day -2, it will be 
mapped to Day -2. 
Day (-1) (Visit 2) 
Day -1 
Two consecutive Days 
between Day -3 to Day -1. 
Map the first measurement to 
Day -2 and the last one to Day 
-1, if only one measurement, 
Day -1 will be mapped to Day 
-1. 
Day 13 (Visit 5) 
Day 13 
Two consecutive Days 
between Day 12 to 15. Map the 
first measurement to Day 13 
and the last one to Day 14. If 
only one measurement, Day 12 
or Day 13 will be mapped to 
Day 13 
Day 14 (Visit 5) 
Day 14 
Two consecutive Days 
between Day 12 to 15. Map the 
first measurement to Day 13 
and the last one to Day 14. If 
only one measurement, Day 14 
or Day 15, it will be mapped to 
Day 14. 


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Table 3: 
Visit Windows for Efficacy Analysis Other than Endpoints Assessed by 
PSG at Unscheduled Visit 
Scheduled Day (Visit) 
Target 
Study 
Study Day Window for Visit 
Day 1 (Visit 3) 
Day 1 Pre- 
dose 
Day 1 Pre-dose 
Day 7 (Visit 4) 
Day 7 
Day 1 Post-dose -Day 11 
Day 15(Visit 6) 
Day 15 
Day 12 - Day 17 
Day 18 (±1 day) (Visit 7) 
Day 18 
NA 
Day 22 (±1 day) (Visit 8) 
Day 22 (last 
dose date +8 
Days) 
Day 18 - Day 24 (last dose date +4 days, +10 days) 
Day 28 (±3 day) (Visit 9) 
Day 28 (last 
dose date +14 
Days) 
Day 25 - Day 31 (last dose date +11 days, +17 days) 
Day 35 (±3 day) (Visit 10) 
Day 35 (last 
dose date +21 
Days) 
Day 32 - Day 38 (last dose date +18 days, +24 days 
Day 42 (±3 day) (Visit 11) 
Day 42 (last 
dose date +28 
Days) 
Day 39- Day 45 (last dose date +25 days, +31 Days) 
Note: Parenthesized study day and study day window are for unscheduled visits, EOT and ET for 
subjects who have discontinued treatment prematurely and such visit date is >=4 days from the last 
dose of study drug intake (i.e. visit date – last dose date + 1 >=4). 
 
9.3.2. 
Analysis of Primary Efficacy Endpoint 
 
9.3.2.1. 
Definition of Primary Efficacy Variable 
The primary endpoint, change from baseline in sleep efficiency (SEFF), is defined as the percentage 
of time in bed spent asleep) at end of double-blind treatment (EODBT) as assessed by 8-hour 
overnight PSG recordings. The PSG recordings used to derive the primary endpoint are performed 
over 2 nights at visit 2 (Day -2 and Day -1) prior to randomization (baseline) and Visit 5 (Day 13 and 
Day 14) (EODBT). 
 
9.3.2.2. 
Visit Windows 
For efficacy analyses, visit windows do not apply for scheduled PSGs. Unscheduled/EOT/ET PSG 
measurements will only be included if a scheduled measurement is not available and the 
unscheduled/EOT/ET measurement falls in the window of the same Visit, as defined in Section 9.3.1. 
 
9.3.2.3. 
Analysis of Primary Endpoint 
The FAS will be used for all efficacy summary tables. Subjects will be analyzed according to the 
randomized treatment. 
Observed values and change/percent change from baseline to EODBT in SEFF total score will be 
summarized descriptively by scheduled visit and treatment. 
The estimand for the primary efficacy analysis is the difference between SAGE-217 and placebo 
treatments in mean change from baseline in sleep efficiency at EODBT. 


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The primary efficacy endpoint, the change from baseline in SEFF at EODBT, will be analyzed using 
ANCOVA. The model will include treatment, antidepressant treatment use (current/stable or not 
treated/withdrawn ≥ 60 days), baseline SEFF score, as exploratory variables, change from baseline in 
SEFF at end of double-blind treatment as the response variable. The main comparison will be 
between SAGE-217 and placebo at EODBT. Model based point estimates (i.e., least square [LS] 
means, 95% confidence intervals, and p-values) will be reported, where applicable. The baseline 
value of SEFF is defined as the average of over 2 nights PSG measurements at Day -2 and Day -1 or 
the PSG measurement at Day -2 or Day -1 if only one night measurement is available. The post- 
baseline PSG SEFF value at EODBT is defined as the average of over 2 nights PSG measurements at 
Day 13 and 14 or the PSG measurement at Day 13 or Day 14 if only one night measurement is 
available. 
Line plot of model-based LS Mean (± standard error) will be prepared for change from baseline in 
SEFF at end of double-blinded period. 
A 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 SEFF at Day 15, 
stratified by antidepressant use. If necessary (e.g., serious violation of the primary analysis model 
assumptions on normality, as assessed by quantile-quantile plot of the residual values from the 
primary analysis for SEFF), this will be considered the primary analysis. 
 
9.3.2.4. 
Subgroup Analyses for Primary Endpoint 
Subgroups defined in Section 9.2.3 will be used for subgroup analyses of the primary efficacy 
endpoint of change from baseline in SEFF. 
An ANCOVA model for subgroup analysis will be used. Antidepressant use may be excluded from 
the model due to the potential small number of subjects in antidepressant use group in each subgroup. 
Observed values and change/percent change from baseline to the EODBT (Day 15 – Baseline) in 
SEFF total score will be summarized by treatment group and subgroup. 
A forest plot will be generated to show the model-based estimates of LS mean difference along with 
95% CI and p-values within each subgroup. 
 
9.3.2.5. 
Multiplicity Adjustment 
No adjustments for multiplicity will be performed for this Phase 3 trial. Only the primary endpoint 
analysis will be treated as a formal hypothesis test, and the secondary endpoints will be considered as 
supportive of the primary endpoint. 
 
9.3.3. 
Analysis of Secondary Efficacy Endpoints 
All secondary analyses will be conducted using the FAS. Subjects will be analyzed according to the 
randomized treatment. 
 
9.3.3.1. 
Definition of Secondary Efficacy Variables 
 
9.3.3.1.1. PSG-derived Sleep Variables 
The PSG measures the physiological process of sleep by monitoring body functions including brain 
waves via electroencephalogram (EEG), eye movements via electrooculography, muscle activity or 
skeletal muscle activation via electromyography, heart rhythm via ECG, blood oxygen saturation via 
pulse oximetry, and breathing functions. Stages of sleep are scored through evaluation of the EEG 
signal. Sleep stage scoring includes REM, non-rapid eye movement (NREM), NREM stage 1 (N1), 


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NREM stage 2 (N2), and NREM stage 3 (N3) sleep. Other sleep efficacy variables listed as secondary 
endpoints to be quantified and/or examined, include: 
• 
LPS: Duration in minutes from lights off to the first epoch of 20 consecutive non-wake 
epochs 
• 
WASO: Total wake time in minutes from persistent sleep onset to lights on 
• 
TST: Duration of total sleep time (NREM + REM) from lights off to lights on during 
recording 
• 
NAW and mDURAW: Number of awakenings from the onset of persistent sleep until lights 
on. An awakening is defined as at least 2 consecutive epochs of wake. Individual awakenings 
must be separated by at least 1 epoch of stage N2, N3, or REM. mDURAW is an arithmetic 
mean calculated as the sum of awakenings in minutes divided by the number of awakenings 
• 
Minutes and percent of stage N1, N2, N3, and REM sleep (from lights off to lights on) 
• 
Latency to REM sleep (REML): The number of non-REM epochs (stages N1, N2, N3) from 
LPS to the first epoch of REM sleep. 
‒REML for second and subsequent REM periods: The number of non-REM and REM epochs 
(stages N1, N2, N3, and REM) from LPS to the first epoch of the 2nd REM period, or 
subsequent REM period. 
• 
REM density: Total number of rapid eye movements divided by the total duration of REM 
sleep in minutes during time in bed (TIB). 
• 
REM Activity (REMA): Total number of rapid eye movements during REM sleep, observed 
on the ECG channels of the PSG. The rapid eye movements must be at least 25 uV in 
amplitude. 
 
9.3.3.1.2. 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. HAM-D is collected during the clinic visit on Days 1, 7, 15, 18, 22, 28, 35, 
and 42. 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 3 individual items are missing, the HAM-D total score will not be calculated and 
will be left as missing. If less than or equal to 3 individual item scores are missing, the missing item 
scores will be imputed by the mean of all other available item scores, or the maximum possible values 
for the missing responses, whichever is smaller, to calculate the HAM-D total score. 
 
Four HAM-D subscale scores will be calculated will be calculated as the sum of the individual rating 
scores related to each subscale, divided by the total possible score within the subscale, multiplied by 
100, and rounded to a whole number. If more than one item is missing or HAM-D total score is 
missing, the subscale score is left as missing; if one item on a particular subscale is missing, but has 
been imputed for the calculation of total score, the imputed value from total score calculation will be 


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used in subscale score calculation for that item. Following table describes the subscale score 
calculation: 
 
Table 4: 
HAM-D Subscale Score Calculations 
 
HAM-D Subscales 
Items 
Calculation 
Core 
Depressed mood 
Feeling of guilt 
Suicide 
Work and activities 
Retardation 
Sum of the 5-item responses/20 x 100. 
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale. 
Anxiety 
Anxiety psychic 
Anxiety somatic 
Somatic symptoms gastrointestinal 
Somatic symptoms general 
Hypochondriasis 
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. 
Maier 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Agitation 
Anxiety psychic 
Sum of the 6-item responses/24 x 100. 
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale. 
 
HAM-D Response will be defined as having a 50% or greater reduction from baseline in HAM-D 
total score; only subjects who have non-missing total score of HAM-D at baseline as well as the visit 
will be considered in HAM-D response evaluation. HAM-D Remission will be defined as having a 
HAM-D total score of ≤7; if HAM-D total score is missing, remission will not be defined. For a 
sensitivity analysis, missing response and remission will be considered as No response/remission. 
Subjects with missing values, even after treatment discontinuation, will be considered as a Non- 
responder/non-remitter. 
 
9.3.3.1.3. Clinical Global Impression – Improvement (CGI-I) 
The CGI-I employs a 7-point Likert scale to measure the overall improvement in the subject’s 
condition post-treatment. 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 


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7=very much worse. The CGI-I is only rated at post-treatment assessments on Days 7, 15, 18, 22, 28, 
35, 42. 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.” In 
this study the CGI-I will be assessed based on the improvement of their insomnia disorder. Missing 
CGI-I at the visit will not be evaluated for response. 
 
9.3.3.1.4. Clinical Global Impression – Severity (CGI-S) 
The CGI-S uses a 7-point Likert scale to rate the severity of the subject’s illness at the time of 
assessment, relative to the clinician’s past experience with subjects who have the same diagnosis. 
Considering total clinical experience, a subject is assessed on severity of mental illness at the time of 
rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 
5=markedly ill; 6=severely ill; and 7=extremely ill. The CGI-S is rated on Days 1, 7, 15, 18, 22, 28, 
35, and 42. In this study the CGI-S will be assessed based on the severity of their insomnia disorder. 
 
9.3.3.1.5. Insomnia Severity Index (ISI) 
The ISI is a validated, 7-item questionnaire designed to assess the nature, severity, and impact of 
insomnia. It is collected at Screening, and during the clinic visit on Days 1, 7, 15, 18, 22, 28, 35, and 
42. The ISI uses a 5-point Likert Scale to measure various aspects of insomnia severity (0 = none, 1 
= mild, 2 = moderate; 3 = severe; 4 = very severe), satisfaction with current sleep pattern (ranging 
from 0 = very satisfied, 1 = satisfied, 2 = neutral, 3 = dissatisfied, 4 = very dissatisfied), and various 
aspects of the impact of insomnia on daily functioning (0 = not at all, 1 = a little, 2 = somewhat, 3 = 
much, 4 = very much). The total score is derived as the sum of item scores. If more than 1 individual 
item is missing, the ISI total score will not be calculated and will be left as missing. If 1 individual 
item score is missing, the missing item score will be imputed by the mean of all other available item 
scores to calculate the ISI total score. A total score of 0 to 7 = “no clinically significant insomnia,” 8 
to 14 = “subthreshold insomnia,” 15 to 21 = “clinical insomnia (moderate severity),” and 22 to 28 = 
“clinical insomnia (severe).” Missing ISI total score will not be categorized. 
 
9.3.3.1.6. Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is a subject-rated depressive symptom severity scale. It is collected during the clinic visit 
on Days 1, 13, 15, 18, 22, 28, 35, and 42. To monitor severity over time for newly diagnosed subjects 
or subjects in current treatment for depression, subjects may complete questionnaires at baseline and 
at regular intervals thereafter. Scoring is based on responses to specific questions, as follows: 0=not 
at all; 1=several days; 2=more than half the days; and 3=nearly every day. 
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores. If more than 1 
individual item is missing, the PHQ-9 total score will not be calculated and will be left as missing. If 
1 individual item score is missing, the missing item score will be imputed by the mean of all other 
available item scores to calculate the PHQ-9 total score. The PHQ-9 total score will be categorized as 
follows: 0 to 4=minimal depression, 5 to 9=mild depression, 10 to 14=moderate depression, 15 to 
19=moderately severe depression; and 20 to 27=severe depression. Missing PHQ-9 total score will 
not be categorized. 
 
9.3.3.1.7. Consensus Sleep Diary-Core (CSD-C) 
The Consensus Sleep Diary-Core collects subjective responses to a series of questions related to their 
daily sleep pattern (ie, time to bed, time to fall asleep, time to final awakening and a question related 
to quality of sleep). From the CSD-C responses sleep parameters including sleep latency, TST, 
WASO, and sleep quality will be derived. The take-home subject sleep diary assessment will be 
administered using an eDiary solution. The eDiary will be captured using either a provisioned 
smartphone device or bring-your-own-device solution, depending on the subject’s preference. 


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Subjects will complete an electronic sleep diary during the screening period. Between Day -9 and 
awakening on Day -2, subjects are required to complete the sleep diary for a minimum of 5 of the 7 
nights. Eligibility for the study will be based on subjects having a sleep diary with the following: a 
minimum of 5 nights completed and a TST of <390 minutes (<6.5 hours) on at least 3 nights 
between Day -9 and Day-2. 
 
Eligible subjects will complete the sleep diary each day through Day 42, preferably in the morning 
after awakening from sleep, regarding the last night’s sleep. Subjective sleep parameters will be 
derived for clinic visit Days 1, 7, 15, 18, 22, 28, 35 and 42 using the mean of non-missing 
assessments between the previous visit day (exclusive) and the current visit day (inclusive): 
 
Scheduled Visit 
No. of Days b/w Visits 
Date stamp from the sleep diary used for averaging 
Day 1(Baseline) 
7d 
Day 1 date -7 days, and <= Day 1 VS date 
Day 7 
6d/number of days b/w V4 and V3 
>Day 1 VS date, and <= Day 7 VS date 
Day 15 
8d/ number of days b/w V6 and V5 
>Day 7 VS date, and <= Day 15 VS date 
Day 18* 
3d/ number of days b/w V7 and V6 
> Day 15 VS date, and <= Day 18 VS date 
Day 22 
7d/ number of days b/w V8 and V7 
> Day 18 VS date, and <= Day 22 VS date 
Day 28 
6d/ number of days b/w V9 and V8 
> Day 22 VS date, and <= Day 28 VS date 
Day 35 
7d/ number of days b/w V10 and V9 
> Day 28 VS date, and <= Day 35 VS date 
Day 42 
7d/ number of days b/w V11 and 
V10 
> Day 35 VS date, and <= Day 42 VS date 
*only for descriptive summary, not in the MMRM model. 
 
The baseline subjective sleep parameters will be calculated as the mean of 7 days immediately 
preceding Day 1. 
 
Parameters to be analyzed are as follows: 
• sTST (in minutes) (Total sleep time) = (Time of final awakening - Time when tried to sleep) - 
time taken to fall asleep-sWASO 
• sSL (in minutes) (Sleep Latency) 
• sWASO (in minutes) (Wake after Sleep Onset) 
• sNAW (Number of awakenings) 
• sSQ (Sleep Quality) 
 
The date/time stamp on the day’s entry is compared to clinic visit date to identify records that go into 
the calculation of a visit assessment. In case of duplicate assessment on the same day, the first 
assessment will be counted toward the mean, but all assessments will be listed. The times entered in 
the diary by the subject, e.g. time when went to bed, time when tried to fall asleep, etc. need to be 
associated with a date in order to make meaningful comparisons or to be used in calculations. The 
following algorithm will be followed for this purpose: If Time to Bed is AM, then all time questions 
are associated with stamped date. If Time to Bed is PM or Time out of Bed is PM, then all time 
questions are associated with date one day before the stamped date. Otherwise, when Time to Bed is 
PM, all times in diary marked as PM are associated with day before the stamped date, and all times in 
diary marked as AM are associated with stamped date. 


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Since the data is subject-entered and not monitored, a record may be invalid when it fails to make 
logical sense. A record is considered invalid if any of the following holds true (use date/time 
combination to do these comparisons): 
1. Any of the eight response or date stamp is missing. 
2. sTST > sTTB (Total time in bed, in minutes, calculated as Time out of bed – Time to bed) 
3. sTST < 0 
4. sTTB <= 0 
5. Time to bed > Time when tried to sleep 
6. Time to bed > Time of final awakening 
7. Time when tried to sleep > Time of final awakening 
8. Time tried to sleep > Time out of bed 
9. Time of final awakening > Time out of bed 
An invalid record will be dropped from analysis of sTST, but not from the analysis of other sleep 
diary endpoints. The sleep diary data will not be windowed. 
 
Sleep quality (sSQ) response will be defined as having a sSQ score of “very good” or “good.” 
Missing sSQ at the visit will not be evaluated for response. 


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9.3.4. 
Analysis of Secondary Efficacy Endpoints 
The FAS will be used for all secondary efficacy summary tables. Subjects will be analyzed according 
to the randomized treatment. 
 
9.3.4.1. 
Descriptive Summary of Secondary Efficacy Endpoints 
The following continuous efficacy endpoints will be summarized descriptively by scheduled 
assessment time point using observed values, change from baseline (for post-baseline visits only) and 
percentage change from baseline (for post-baseline visits only): 
• 
WASO (in minutes) in total and by quarter 
• 
TST (in minutes) in total and by quarter 
• 
LPS (in minutes) 
• 
NAW in total and by quarter 
• 
mDURAW in total and by quarter 
• 
Minutes and percent of stage N1, N2, N3 
• 
Minutes and percent of REM 
• 
Latency to REM sleep (REML): The number of non-REM epochs (stages N1, N2, N3) from 
LPS to the first epoch of REM sleep 
• 
REML for second and subsequent REM periods: The number of non-REM and REM epochs 
(stages N1, N2, N3, and REM) from LPS to the first epoch of the 2nd REM period, or 
subsequent REM period 
• 
REM density: Total number of rapid eye movements divided by the total duration of REM 
sleep in minutes during TIB. 
• 
REM activity: Total number of rapid eye movements during REM sleep. 
• 
HAM-D total score 
• 
HAM-D subscale 
• 
HAM-D individual item score 
• 
CGI-I score (observed value only) 
• 
CGI-S score 
• 
ISI total score 
• 
PHQ-9 total scoreCSD-C derived endpoints including sTST (in minutes), sWASO (in 
minutes), sSL (in minutes), and sNAW 
The following categorical efficacy endpoints will be summarized descriptively by scheduled 
assessment time point using counts and percentages: 
• 
HAM-D response – missing response not accounted 
• 
HAM-D response – missing response counted as No response 
• 
HAM-D remission – missing remission not accounted 


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• 
HAM-D remission – missing remission counted as No remission 
• 
CGI-I response 
• 
Sleep Quality response 
• 
ISI total score categories (0 to 7 = “no clinically significant insomnia,” 8 to 14 = 
“subthreshold insomnia,” 15 to 21 = “clinical insomnia (moderate severity),” and 22 to 28 = 
“clinical insomnia (severe)) 
Bar chart will be prepared for HAM-D response, HAM-D remission, ISI total score categories and 
CGI-I response by treatment group. 
 
9.3.4.2. 
ANCOVA - PSG-derived Sleep Secondary Endpoints 
Similar to those methods described above for the primary endpoint, an ANCOVA model will be used 
for the analysis of the change from baseline in other PSG-derived sleep variables (WASO, TST and 
TST by quarter of the PSG recording,LPS, NAW and mDURAW, in total and by quarter of the PSG 
recording,minutes and percent of stage N1, N2, N3, and REM sleep, latency to the first period of 
REM Sleep and latency to each subsequent period of REM Sleep, REM density) at EODBT, which 
are described in Section 9.3.3.1.1. 
For each model, the comparison of interest will be between SAGE-217 and matching placebo at the 
end of double-blind treatment. Model based point estimates (i.e., least square [LS] means, 95% 
confidence intervals, and p-values) will be reported where applicable. 
Line plot of model-based LS Mean (± standard error) over time will be prepared for HAM-D score, 
%SEFF, WASO, TST, LPS and ISI total score by treatment group. 
 
9.3.4.3. 
Mixed effects model for repeated measures (MMRM) – Non PSG-derived 
Sleep Secondary Endpoints 
The secondary efficacy endpoint, the change from baseline in ISI total score at end of double-blind 
treatment, will be analyzed using a MMRM. The model will include treatment, antidepressant 
treatment use (current/stable or not treated/withdrawn ≥60 days), baseline ISI total score, assessment 
time point, and time point-by-treatment as explanatory variables. All explanatory variables will be 
treated as fixed effects. All post-baseline time points will be included in the model. The main 
comparison will be between SAGE-217 and placebo at end of double-blind treatment. Model based 
point estimates (i.e., LS means, 95% confidence intervals, and p-values) will be reported for all time 
points. An unstructured (UN) covariance structure will be used to model the within-subject errors. If 
there is a convergence issue with the unstructured covariance model, Toeplitz 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. The p-value will 
be interpreted at 5% level of significance. 
Similar to those methods described above for ISI total score, a MMRM will be used for the analysis 
of the change from baseline in CSD-C derived variables (sTST (in minutes), sWASO (in minutes), 
sSL (in minutes) and sNAW, HAM-D total score, HAM-D subscales and individual item scores, and 
PHQ-9 total score. 
For each model, the comparison of interest will be between SAGE-217 and matching placebo at end 
of double-blind period. Model-based point estimates (i.e., LS means), 95% confidence intervals, and 
p-values will be reported for all time points. 


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Line plot of model-based LS Mean (± standard error) will be prepared for change from baseline in ISI 
total score and HAM-D total score over time. 
 
9.3.4.4. 
Generalized Estimating Equations (GEE) 
The GEE method will be used for the analysis of HAM-D response and HAM-D remission. GEE 
models will include treatment, baseline HAM-D total score, antidepressant treatment use 
(current/stable or not treated/withdrawn ≥60 days), assessment time point, and time point-by- 
treatment interaction as explanatory variables. The comparison of interest will be the difference 
between SAGE-217 and matching placebo at end of double-blind period. Model-based point 
estimates (i.e., odds ratios), 95% confidence intervals, and p-values will be reported for all time 
points. 
A GEE method will also be used for the analysis of CGI-I response including terms of treatment, 
baseline CGI-S score, antidepressant treatment use (current/stable or not treated/withdrawn ≥60 
days), assessment time point, and time point-by-treatment as explanatory variables. 
A GEE method will also be used for the analysis of sleep quality (sSQ) response including terms of 
treatment, baseline sSQ, antidepressant treatment use (current/stable or not treated/withdrawn ≥60 
days), assessment time point, and time point-by-treatment as explanatory variables. 
 
 
 
 


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9.4. 
Safety Analysis 
Safety and tolerability of SAGE-217 will be evaluated by AEs/SAEs, changes from baseline in vital 
signs, clinical laboratory evaluations, and 12-lead ECG. Suicidality will be monitored by the C- 
SSRS. Withdrawal symptoms will be measured by PWC-20. Safety data will be listed by subject 
and summarized by treatment group. All safety summaries will be performed on the Safety Set. The 
data will be presented by the treatment received rather than the treatment to which the subject has 
been randomized; for definition of actual treatment assignment, please see Section 9.1. 
The safety endpoints evaluated at scheduled visits are taken as done in nominal visit, without any 
windowing. If a value is available for a nominal scheduled visit, that value will be used in summary 
by visit. The summary will also include “Last Value on Treatment (counts the last available 
measurement that is after baseline and on or before Day 15, this will include EODBT visit values) 
and Last Value on Study (count the last available measurement after baseline, this will include ET 
visit and Day 42). The safety endpoints and variables considered in the summary tables for this study 
are summarized in Table 5. 


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Table 5: 
Safety endpoints and variables in the summary tables 
 
Safety 
Evaluation 
Incidence 
Observed 
Value 
Change 
from 
Baseline 
Shift 
from 
Baseline 
Abnormality/ 
Clinical 
Significance (CS) 
Potentially 
Clinical 
Significance 
(PCS) 
AEs 
X 
Labs 
X 
X 
X 
X 
X 
ECG 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
C-SSRS 
X 
X 
X 
Note: PCS criteria are outlined in sections 9.4.2-9.4.4. 
X = to be summarized in tables 
9.4.1. 
Adverse Events 
AEs are collected starting at the time of informed consent and throughout the duration of the subject’s 
participation in the study. 
A treatment-emergent adverse event (TEAE) is defined as an AE with onset on or after the start of 
double-blind study drug. The term study drug includes any Sage investigational product, a 
comparator, or a placebo administered in a clinical trial. The TEAEs will be further categorized by 
the phase of occurrence as follows: 
A double-blind treatment period TEAE is defined as an adverse event with onset on or after the start 
of double-blind study drug, but on or before the last dose of double-blind study drug + 1 Day. 
A run-out treatment period TEAE is defined as an adverse event with onset after 1 day from the end 
of double-blind study drug, but on or before the last dose of run-out treatment period. 
A follow-up TEAE is defined as an adverse event with onset after the end of run-out treatment period 
to the end of the study. If the date of an adverse event is incomplete and an unambiguous 
determination could not be made with respect to its onset time versus the first dose of double-blind 
study drug and/or last dose of double-blind study drug, the adverse event will be assumed to be a 
TEAE. For imputation of missing AE dates, please refer to Appendix C, Section 12.3.1. All adverse 
events will be coded using MedDRA version 21.0 or higher. An overview summary table of AEs will 
present the number and percentage of subjects as well as the number of events for the following: 
• 
TEAE 
o Double-Blind Treatment Period TEAEs 
o Run-out Treatment Period TEAEs 
o Follow-up Period TEAEs 
• 
TEAEs by maximum severity (severe>moderate>mild) 
o Double-Blind Treatment Period TEAEs 
o Run-out Treatment Period TEAEs 


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o Follow-up Period TEAEs 
• 
Double-Blind Treatment Period TEAE leading to discontinuation of study drug 
• 
TEAE leading to withdrawal from the study 
o Double-Blind Treatment Period TEAEs 
o Run-out Treatment Period TEAEs 
o Follow-up Treatment Period TEAEs 
• 
Death 
o Double-Blind Treatment Period TEAEs 
o Run-out Treatment Period TEAEs 
o Follow-up Period TEAEs 
• 
SAE 
o Double-Blind Treatment Period TEAEs 
o Run-out Treatment Period TEAEs 
o Follow-up Period TEAEs 
Incidence of TEAEs in following categories will be provided by SOC and PT. A subject is counted 
only once under each SOC and PT in case of multiple occurrences of the same AE. 
• 
TEAE 
• 
Double-Blind Treatment Period TEAE 
• 
Run-out Treatment Period TEAE 
• 
Follow-up Period TEAE 
• 
TEAEs by maximum severity 
• 
TEAEs by relationship to study drug 
• 
TEAEs leading to discontinuation of study drug 
• 
TEAEs leading to withdrawal from the study 
• 
Serious TEAEs 
• 
Run-out Treatment Period Serious TEAEs 
• 
Follow-up Period Serious TEAEs 
• 
Double-Blind Treatment Period TEAEs leading to dose interruption of study drug 
Most common TEAEs are defined as those, which occurred in more than 5% of subjects in either 
treatment group. A summary of most common TEAE just by preferred term where the incidence is 
more than 5% will be provided, sorted by decreasing frequency by SAGE-217. 
For maximum severity, subjects will be counted only once within each SOC and PT at the maximum 
severity in the following order: severe> moderate> mild; an AE with missing severity will be omitted 
from severity presentation. For relationship to study drug, subjects will be counted only once within 
each SOC and PT at the strongest relationship to study drug in the following order: probably related > 


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possibly related > not related. ‘Related’ is defined as relationship being “possible” or “probable” or 
missing., The incidences will be presented by descending frequency of SOC in SAGE-217 group and 
then, within a SOC, by descending frequency of PT based on the subject count, and in alphabetical 
order of PT if the incidence within a PT is a tie. 
Adverse events with onset before the first dose of double-blind study drug will be provided in a 
separate listing. Separate data listings for deaths and non-fatal SAEs will be provided. 
In addition, TEAE summary by SOC/PT will also be presented by the following subgroups: 
1. Anti-depressant use at baseline 
2. Age group: 18-24, 25-50, 51-65 years 
3. Gender: Male, Female 
4. Race: White, Black or African American, Other 
In addition, AEs that occurred during placebo run-in period will be summarized for Safety Set 
separately according to treated received during double-blind treatment period. AEs that occurred for 
run-in failure subjects will be summarized and listed. 
 
9.4.2. 
Clinical Laboratory 
The clinical laboratory tests to be performed for monitoring of safety are listed in Table 6. They are 
collected at Screening and during clinic visits on Days 1, 7, 15, 22, 28, 42. 
Table 6: 
Clinical Laboratory Tests 
 
Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin 
Hematocrit 
White blood cell count with 
differential 
Platelet count 
Red blood cell indices 
(MCV, MCH, MCHC) 
Reflex to red blood cell 
morphology if indices are 
abnormal 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone 
(TSH) 
Reflex to free T3/T4 if 
TSH is abnormal 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 


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All parameters will be converted to consistent units according to the International System of Units 
(SI) before presentation. 
For the laboratory results that are “< or = x”, where x is a number as collected in the data, the numeric 
part of the result will be used in calculation in the summary tables. Same is true if the result is 
presented as below the limit of quantitation (BLQ) and a lower limit of quantification (LLOQ) value 
is provided – LLOQ value will be used for calculation in the summary tables. The actual results as 
collected will be displayed in the listings. 
Summary tables on lab parameters will include descriptive statistics for the observed values and 
changes from baseline by scheduled assessment timepoint in hematology, serum chemistry, 
coagulation and quantitative urinalysis test results. It will also include the summary of last values on 
treatment and on study. If a normal range is provided for the parameter, out-of-range values will be 
flagged as low or high, where applicable, in the subject data listings. A shift table for these 
parameters from baseline to each scheduled assessment time point will be provided. This table will 
also include the shift from normal at baseline to high or low at any time during treatment on or after 
first dose, on or before last dose + 7 days), any time post-baseline during the study (on or after first 
dose) and at the end of study (i.e. the last available value in the database). Qualitative urinalysis 
parameters will be summarized descriptively. 
The number and percentage of subjects with PCS values will be provided in separate displays in 
hematology, serum chemistry and liver function tests provided for such occurrence any time post- 
baseline (irrespective of whether it happens in scheduled or unscheduled assessments). Potentially 
clinically significant values will be identified for specific laboratory parameters as outlined in the 
following table. 
Table 7: 
Laboratory Parameters - Criteria for PCS Values 
 
Laboratory 
Parameter 
Gender 
Units 
Criteria for PCS Values (Observed values) 
High 
Low 
Hematology 
Hemoglobin 
Male 
g/L 
>185 
<115 
Female 
g/L 
>170 
<100 
Hematocrit 
Male 
Fraction of 1 
>0.55 
<0.385 
Female 
Fraction of 1 
>0.49 
<0.345 
Platelet count 
10^9/L 
>600 
<125 
White blood cell 
10^9/L 
>15 
<2.5 
Basophils 
10^9/L 
>0.5 
NA 
Eosinophils 
10^9/L 
>1.5 
NA 
Neutrophils 
10^9/L 
NA 
<1.5 
Lymphocytes 
10^9/L 
>6.0 
<0.5 
Monocytes 
10^9/L 
>1.4 
NA 
Serum Chemistry 
Albumin 
g/L 
>70 
<28 
Blood urea nitrogen 
mmol/L 
>10.71 
NA 
Calcium 
mmol/L 
>2.75 
<2.0 
Chloride 
mmol/L 
>120 
<90 
Creatinine 
mmol/L 
>3xULN or >3x Baseline 
Gamma Glutamyl Transferase 
>3xULN 
Glucose 
mmol/L 
>13.9 
<2.8 
Sodium 
mmol/L 
>150 
<132 


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Potassium 
mmol/L 
>5.4 
<3.3 
Protein 
g/L 
<45 
Bicarbonate 
mmol/L 
>34 
<18 
Phosphorus 
mmol/L 
>1.94 
<0.61 
Liver Function Tests (LFT) 
Bilirubin 
μmol/L 
>2xULN 
NA 
Aspartate Aminotransferase 
U/L 
>3xULN 
NA 
Alanine Aminotransferase 
U/L 
>3xULN 
NA 
Alkaline Phosphatase 
U/L 
>1.5xULN 
NA 
Liver function tests will be monitored closely for potentially clinically significant values, and will be 
summarized for occurrence any time post-baseline for the following parameters for these PCS 
threshold (for condition involving more than one parameters, the results need to be from the same 
timepoint): 
Alanine Aminotransferase: >3xULN, >5xULN, >10xULN 
Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alanine Aminotransferase or Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alkaline Phosphatase: >1.5xULN, >2xULN 
Total Bilirubin: >1.5xULN, >2xULN 
Total Bilirubin > 2xULN AND (Alanine Aminotransferase or Aspartate Aminotransferase >3xULN) 
Total Bilirubin >2xULN AND Alkaline Phosphatase >2xULN AND (Alanine Aminotransferase or 
Aspartate Aminotransferase >3xULN) 
 
Any lab results considered clinically significant by the investigator will be captured as adverse events, 
hence will show up in AE displays. 
Pregnancy test results will be listed but not summarized. 
 
9.4.3. 
Vital Signs 
Vitals for the following parameters - Supine Systolic Blood Pressure (mmHg), Standing Systolic 
Blood Pressure (mmHg), Supine Diastolic Blood Pressure (mmHg), Standing Diastolic Blood 
Pressure (mmHg), Supine Heart Rate (beats/minute), Standing Heart Rate (beats/minute), Respiratory 
Rate (breaths/minute), Pulse Oximetry (SpO2, %), Temperature (degrees C) – are collected at 
Screening, and during clinic visits on Days -2, 1, 7, 13, 14, 15, 18, 22, 28, 35, 42. Descriptive 
summaries of observed values and changes from baseline will be provided for vital sign parameters - 
by scheduled assessment time point. It will also include the summary of last values on treatment and 
on study. 
Additionally, the number and percentage of subjects with PCS and potentially clinically significant 
change (PCSC) values will be summarized for such occurrence any time post-baseline. PCS and 
PCSC values will be identified for vital sign parameters as outlined in the following table. 


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Table 8: 
Vital Signs - Criteria for PCS and PCSC Values 
 
Vital Sign 
Units 
Criteria for PCS Values 
(Observed values) 
Criteria for PCSC values (Change 
from Baseline values) 
High 
Low 
Increase 
Decrease 
Heart rate (supine and 
standing) 
Beats/min 
>120 
<40 
NA 
NA 
Systolic Blood Pressure 
(supine and standing) 
mmHg 
>180 
<90 
≥30 
≥30 
Diastolic Blood pressure 
(supine and standing) 
mmHg 
>110 
<50 
≥20 
≥20 
Supine - Standing Systolic 
Blood Pressure* 
mmHg 
≥20 
Supine - Standing 
Diastolic Blood Pressure* 
mmHg 
≥10 
Orthostatic hypotension: 
supine – standing SBP 
and DBP 
mmHg 
SBP >= 20 and 
DBP >= 10 
mmHg 
SBP >= 20 or 
DBP >= 10 
*Orthostatic systolic/diastolic blood pressure is defined as supine -standing systolic/diastolic blood 
pressure. 
The change from supine to standing (Supine – Standing) vital signs – heart rate, systolic and diastolic 
blood pressure – will be summarized by scheduled assessment timepoint. 
Any vital signs results considered clinically significant by the investigator will be captured as adverse 
events, hence will show up in AE displays. 
 
9.4.4. 
Electrocardiogram 
Supine 12-lead ECGs will be performed in triplicate, and are collected during the clinic visits at 
Screening, Days 1, 15, 28. The following ECG parameters will be listed for each subject: heart rate 
(beats per minute), PR (msec), QRS (msec), QT (msec), QTc (msec) and QTcF (msec). 
The average of the triplicate values will be used in the summary, including baseline ECG values. The 
observed value at each time point and change from baseline at each post-baseline scheduled time 
point will be summarized. This summary will also include the last values on treatment and on study. 
Each ECG is evaluated as ‘normal’, ‘abnormal, not clinically significant’ and ‘abnormal, clinically 
significant’; the number and percentage of subjects with at least one of the triplicate values in the 
categories of ‘abnormal, clinically significant’ and ‘abnormal, not clinically significant’ will be 
provided at baseline and each post-baseline scheduled assessment time point. 
Additionally, the number and percentage of subjects with PCS and PCSC values will be summarized 
for such occurrence any time post-baseline. PCS and PCSC values will be identified for ECG 
parameters as outlined in the following table. This analysis includes triplicate values individually and 
is not based on average value. In addition, any PCS value at any time post-baseline will be 
summarized. 


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Table 9: 
ECG Parameters - Criteria for PCS and PCSC Values 
 
ECG 
Units 
Criteria for PCS Values (Observed values) 
Criteria for PCSC values 
(Change from Baseline) 
High 
Low 
Increase 
Decrease 
QTcF 
Interval 
msec 
females: >450 to 480, male: >450 to 470 
females: >480 to 500, male: >470 to 500 
>500 
NA 
>=30 to 60 
>60 
NA 
 
9.4.5. 
Physical Examination 
Physical examination is scheduled at Screening, Days 1, 22, 28, and 42. Only clinically significant 
abnormalities are captured in the database – for post-baseline observations, these will be reported as 
adverse events, hence these will be included in AE displays; for pre-baseline observations, these will 
be reported as medical history, hence these will be included in Medical History displays. The dates of 
physical examination will be listed to confirm that the examination was done. 
 
9.4.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
C-SSRS scale consists of a screening evaluation that assesses the lifetime experience as well as past 
24 months experience of the subject for suicidal ideation and behavior, and baseline and post-baseline 
evaluations 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 score on suicidal ideation is 
derived as the highest question number (out of five questions) that is answered ‘yes’; if all five 
responses are ‘no’, the score is 0. 
The “Baseline/Screening” C-SSRS form will be completed at Screening (lifetime history and past 24 
months). The “Since Last Visit” C-SSRS form will be completed on Days -2, 1, 7, 13, 14, 15, 18, 22, 
28, 35, 42. Baseline suicidal ideation/behavior is defined as the worst of suicidal ideation/behavior 
before the first dose of double-blind study drug, excluding the lifetime experience assessment. 
Summary of shift from baseline in C-SSRS suicidal ideation and suicidal behavior will be presented 
for the following categories - no suicidal ideation/behavior, suicidal ideation, suicidal behavior - by 
scheduled assessment time point. The number and percentage of subjects with at least one response of 
‘Yes’ to any C-SSRS suicidal ideation or suicidal behavior item will be summarized for baseline, any 
time post-baseline, and by each scheduled assessment time point separately. In addition, summary of 
shift from baseline in C-SSRS maximum severity score in suicidal ideation for any time post-baseline 
will be presented. The distribution of subjects with suicide-related events will be plotted. 
 
9.4.7. 
Physician Withdrawal Checklist (PWC-20) 
The PWC is based on the 35-item Penn Physician Withdrawal Checklist that was developed in the 
1960s to measure benzodiazepine and benzodiazepine-like discontinuation symptoms. The PWC-20 
is a shorter version of the Penn Physician Withdrawal Checklist based on the 20 items that provided 
the best differentiation from placebo in previous trials. It is collected during the clinic visit on Days 
1, 15, 18, 22, 28, 35, 42. The PWC-20 is made up of a list of 20 symptoms (eg, loss of appetite, 
nausea-vomiting, diarrhea, anxiety-nervousness, irritability, etc) that are rated on a scale of 0 (not 
present) to 3 (severe). The total score is derived as the sum of individual item scores, which ranges 
from 0 to 60. Missing item score will not be imputed to calculate the total score. The PWC-20 will 
be used to monitor for the presence of potential withdrawal symptoms following discontinuation of 
SAGE-217. 




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10. 
SUMMARY OF INTERIM AND DMC ANALYSES 
Not applicable. 


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11. 
REFERENCES 
Clinical Study Protocol: Version 4.0 (17 July 2019), Company: Sage Therapeutics Inc 


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12. 
LIST OF APPENDICES 
 
 
12.1. 
Appendix A: Schedule of Assessments 


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Screening 
Single-blind 
Placebo Run-in 
Double-blind Period 
Follow-up Visits 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day 
-30 to -3 
-2 
-1 
1 
7 (±1 d) 
13 
14 
15/EODBTa 
18 
(±1 d) 
22 
(±1 d) 
28 
(±3 d) 
35 
(±3 d) 
42/ETa 
(±3 d) 
Study Procedure 
Informed consent 
X 
Duplicate subject 
checkb 
X 
Inclusion/ exclusion 
criteria 
X 
Xc 
Xc 
Demographics 
X 
Medical/family history 
X 
Serum FSH testd 
X 
Pregnancy testg 
X 
Xc 
Xc 
X 
X 
MGH ATRQ 
X 
SCID-CT 
X 
Physical examinatione 
X 
X 
X 
X 
X 
X 
RLS-DI 
X 
Body weight 
X 
X 
X 
Height 
X 
Clinical laboratory 
assessmentsf 
X 
Xc 
Xc 
X 
X 
X 
X 
Drug and alcohol testh 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
X 
X 
X 
X 
X 
Hepatitis and HIV 
Screen 
X 


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Screening 
Single-blind 
Placebo Run-in 
Double-blind Period 
Follow-up Visits 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day 
-30 to -3 
-2 
-1 
1 
7 (±1 d) 
13 
14 
15/EODBTa 
18 
(±1 d) 
22 
(±1 d) 
28 
(±3 d) 
35 
(±3 d) 
42/ETa 
(±3 d) 
Vital signsj 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
X 
X 
X 
X 
X 
12-lead ECGk 
X 
Xc 
Xc 
X 
C-SSRSl 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
X 
X 
X 
X 
X 
MADRS 
X 
Xc 
CGI-I 
Xc 
Xc 
X 
X 
X 
X 
X 
CGI-S 
Xc 
Xc 
Xc 
X 
X 
X 
X 
X 
HAM-Dm 
X 
Xc 
Xc 
Xc 
X 
X 
X 
X 
X 
PWC-20 
Xc 
Xc 
X 
X 
X 
X 
X 
ISI 
X 
Xc 
Xc 
Xc 
X 
X 
X 
X 
X 
PHQ-9 
X 
X 
X 
X 
X 
X 
X 
X 
PSG 
X 
X 
X 
X 
Sleep Diaryt 
X 
X 
Subject training 
Xr 
Xr 
Study Drug 
Dispensation 
X 
X 
X 
X 
X 
X 
X 


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Screening 
Single-blind 
Placebo Run-in 
Double-blind Period 
Follow-up Visits 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day 
-30 to -3 
-2 
-1 
1 
7 (±1 d) 
13 
14 
15/EODBTa 
18 
(±1 d) 
22 
(±1 d) 
28 
(±3 d) 
35 
(±3 d) 
42/ETa 
(±3 d) 
Study Drug 
Administration 
Single-blind 
Placebo 
Double-blind (SAGE-217 or placebo) 
Single-blind Placebo 
(Day 15 to Day 21)u 
Study Drug Adherence 
Review 
X 
X 
X 
X 
(ET 
only) 
AEs /SAEs 
X 
Prior/ concomitant 
medicationss 
X 
AE = adverse event; CGI-I = Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression Severity; C-SSRS = Columbia Suicide Severity Rating Scale; 
ECG = electrocardiogram; EODBT = End of double-blind treatment; ET = early termination; FSH = follicle stimulating hormone; HAM-D = Hamilton Rating Scale for 
Depression, 17 item; ISI = Insomnia Severity Index; 
; MADRS=Montgomery-Åsberg Depression Rating Scale; MGHATRQ = 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; O = optional; PHQ-9 = 9-item Patient Health Questionnaire; 
 
PSG = Polysomnography; PWC = Physician Withdrawal Checklist; RLS-DI = The Restless Legs Syndrome-Diagnostic Index; SAE = serious adverse event; SCID-CT = 
Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Clinical Trials version. 
a Subjects who discontinue study drug early during the double-blind treatment period should return to the site for the end of double-blind treatment (EODBT) visit as soon as 
possible, preferably the day after treatment is discontinued. 
 Follow-up visits should take 
place as scheduled. If at any time after the EODBT visit, a subject decides to terminate the study, the subject should return for an early termination (ET) visit. The EODBT 
and ET visits can be on the same day if a subject discontinues study drug and terminates the study on the same day during a clinic visit; in this case, all events scheduled for 
the ET visit will be conducted. 
b Subjects will be required to authorize that their unique subject identifiers be entered into a registry (www.subjectregistry.com) with the intent of identifying subjects who 
may meet exclusion criteria for participation in another clinical study. 
c To be completed predose 
d A serum FSH test will be conducted for female subjects who are not surgically sterile to confirm whether a female subject with ≥12 months of spontaneous amenorrhea 
meets the protocol-defined criteria for being post-menopausal. 
e A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. A full physical examination includes 
assessment of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities). An abbreviated physical exam includes a brief medical history 
followed by targeted physical exam. 
f Clinical laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
g Serum pregnancy test at screening and urine pregnancy test thereafter for female subjects that are not surgically sterile and do not meet the protocol-defined criteria for 
being post-menopausal. 
h Urine toxicology for selected drugs of abuse and breath test for alcohol. 
i Optional blood sample, where consent is given. 


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j Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and blood pressure to be collected in supine 
position at all scheduled time points after the subject has been resting for 5 minutes and then after approximately 3 minutes in the standing position. Vital signs may be 
repeated at the discretion of the Investigator as clinically indicated. When vital signs are scheduled at the same time as blood draws, vital signs will be obtained first. 
k Triplicate ECGs will be collected. When ECGs and 
 collection occur on the same day, the 12-lead ECGs will be performed before 
 collection. 
l “Baseline/Screening” C-SSRS form will be completed at Visit 1. The “Since Last Visit” C-SSRS form will be completed at all subsequent time points. 
m HAM-D is to be completed as early during the visit as possible. The assessment timeframe for HAM-D will refer to the past 7 days (1 week) at the first HAM-D 
administration and “Since Last Visit” for all other visits. 
r Subjects will be trained on use of software applications and devices necessary for the conduct of the study by site personnel 
s Prior medications and cognitive behavioral therapy will be collected at Visit 1 and concomitant medications and/or procedures will be collected at each subsequent visit. 
t Sleep diary (eDiary) will be distributed during the Screening visit (Visit 1). Subjects who pass initial screening will be asked to complete an electronic sleep diary during the 
screening period and for a minimum of 4 of 7 nights from evening of Day -9 to the morning of Day -2 (inclusive.) 
u Following the double-blind treatment period, subjects will take single-blind placebo treatment once daily until Visit 8. 


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12.2. 
Appendix B: Details of Statistical Methodology 
 
Sample SAS code for Analysis of Covariance (ANCOVA): 
proc mixed data=&data; 
class trtan antidep; 
model chg=base trtan antidep; 
lsmeans trtan /diff cl; 
run; 
 
 
Sample SAS code for Mixed Effects Model for Repeated Measures (MMRM): 
proc mixed data=&data; 
by param; 
class trtan antidep avisitn usubjid; 
model chg=base trtan antidep avisitn trtan*avisitn / ddfm=kr; 
repeated avisitn / subject=usubjid type=un; 
* if type= un does not converge, use type= toep; 
* if type= toep still not converge, use type=ar(1); 
lsmeans trtan*avisitn /cl diff adjdfe=row; 
ods output ConvergenceStatus=conv LSMeans=lsmean Diffs=diff; 
run; 
 
 
Sample SAS code for Generalized Estimating Equation (GEE): 
proc genmod data=&data; 
by param; 
class usubjid trtan antidep avisitn; 


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model resp=base trtan antidep avisitn trtan*avisitn/dist=bin link=logit; 
repeated subject=usubjid / type=un; 
* if convergence not met, use type=exch; 
* if type= exch still not converge or has error, use type=ind; 
* if type= ind still not converge or has error, use type=cs; 
lsmeans trtan*avisitn / diff exp cl adjdfe=row; 
ods output ConvergenceStatus=conv LSMeans=lsmean Diffs=diff; 
run; 
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; 


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12.3. 
Appendix C: Handling of Missing Dates 
Dates missing the day or both the day and month of the year will adhere to the following conventions in order to classify TEAEs and to 
classify prior and concomitant medications. 
In general, listings will present the actual partial or missing values rather than the imputed values that may be used in derivation. In instances 
where imputed values will be presented, imputed values will be flagged. 
 
12.3.1. 
Adverse Events 
If the AE start date is completely missing, do not impute a date but consider it as TEAE, unless the AE end date is before the first dose of 
treatment, in which case the AE will be considered prior. 
For partial AE start dates: 
• When the year is known, but the month and day is unknown, then: 
oIf the year matches the year of first dose date and the end date (if present) is after first dose date, or AE is ongoing, then impute 
the month as the month of the first dose date, and day as the day of the first dose date + 1 day. 
oIf the year of AE onset < year of initiation of the treatment, then the month and day will be set to December 31st . 
oIf the year of AE onset > the year of initiation of treatment, then the month and day will be set to January 1st. 
 
• If the year and month are known, but the day is unknown, then: 
oIf the year of AE onset = the year of initiation of the treatment and: 
 the month of AE onset = the month of initiation of the treatment, then the day will be set to the day of first dose day + 
1 day. 
 the month of AE onset < the month of initiation of the treatment, then the day will be set to the last day of month. 
 if the month of AE onset > the month of initiation of the treatment, then the day will be set to the 1st day of month. 
oIf the year of AE onset < the year of initiation of the treatment, then the day will be set to the last day of month. 
oIf the year of AE onset > the year of initiation of the treatment, then the day will be set to the 1st day of month. 
 If the imputed AE onset date is after the AE stop date, then the onset date will be set to the stop date. 
 
• When the year and day are present and the month is missing, treat it as if the day is missing, and only year is present. Follow the 
imputation rules for “year is known, but the month and day is unknown”. 


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• When the year is missing, but the month and/or day is known, treat this date as missing; do not impute. 
 
 
12.3.2. 
Prior and Concomitant Medications 
If the conmed start date is completely missing, do not impute a date but consider it as a concomitant medication, unless the conmed end date is 
before the initiation of treatment, in which case the conmed will be considered prior. 
 
For the partial start date of medication: 
oIf the year is present and the month and day are missing, then the month and day will be set to January 1. 
oIf the year and day are present and the month is missing, then treat it as if the day is also missing. Set the month and day to be 
January 1. 
oIf the year and month are present and the day is missing, then the day will be set to the 1st day of month. 
oIf 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: 
oIf the year is present and the month and day are missing, then the month and day will be set to December 31. 
oIf the year and month are present and the day is missing, then the day will be set to the last day of the month. 
oIf the year and day are present and the month is missing, then treat it as if the day is also missing. Set the month and day to be 
December 31. 
 
 
12.3.3. 
Dates in Disease History (Dates of diagnosis, current episode, first episode) 
o If the year is present and the month and day are missing, then the month and day will be set to January 1. 
o If the year and day are present and the month is missing, then the month will be set to January. 
oIf the year and month are present and the day is missing, then the day will be set to the 1st day of month 


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12.4. 
Appendix D: List of Displays 
12.4.1. 
Index of Tables 
Number 
Title 
Analysis Set 
Table 14.1.1.1 
Summary of Subject Disposition 
All Subjects 
Table 14.1.1.2 
Protocol Deviations 
All Randomized Set 
Table 14.1.1.3 
Reasons for Exclusion from Analysis Sets 
All Randomized Set 
Table 14.1.2.1.1 
Demographics and Baseline Characteristics 
Safety Set 
Table 14.1.2.1.2 
Demographics and Baseline Subgroups 
Safety Set 
Table 14.1.2.2.1 
Demographics and Baseline Characteristics 
Full Analysis Set 
Table 14.1.2.2.2 
Demographic and Baseline Subgroups 
Full Analysis Set 
Table 14.1.3.1.1 
Summary of Disease History 
Full Analysis Set 
Table 14.1.3.1.2 
Summary of Medical and Surgical History 
Full Analysis Set 
Table 14.1.3.1.3 
Summary of Medical and Surgical History Which are Ongoing at the Time of Screening 
Full Analysis Set 
Table 14.1.3.1.4 
Summary of History of Psychiatric Disorders 
Full Analysis Set 
Table 14.1.3.1.5 
Summary of Family History of Psychiatric Disorders 
Full Analysis Set 
Table 14.1.3.1.6 
Summary of Other Sleep History 
Full Analysis Set 
Table 14.1.3.1.7 
Summary of History of Insomnia Disorder 
Full Analysis Set 
Table 14.1.3.2.1 
Summary of Prior Non-Psychotropic Medications 
Full Analysis Set 
Table 14.1.3.2.2 
Summary of Concomitant Non-Psychotropic Medications 
Full Analysis Set 
Table 14.1.3.2.3 
Summary of Double-blind Period Concomitant Non-Psychotropic Medications 
Full Analysis Set 
Table 14.1.3.2.4 
Summary of Run-Out Period Concomitant Non-Psychotropic Medications 
Full Analysis Set 
Table 14.1.3.2.5 
Summary of Post-treatment Period Concomitant Non-Psychotropic Medications 
Full Analysis Set 
Table 14.1.3.3.1 
Summary of Prior Psychotropic Medications 
Full Analysis Set 
Table 14.1.3.3.2 
Summary of Concomitant Psychotropic Medications 
Full Analysis Set 
Table 14.1.3.3.3 
Summary of Double-blind Period Concomitant Psychotropic Medications 
Full Analysis Set 
Table 14.1.3.3.4 
Summary of Run-Out Period Concomitant Psychotropic Medications 
Full Analysis Set 
Table 14.1.3.3.5 
Summary of Post-treatment Period Concomitant Psychotropic Medications 
Full Analysis Set 
Table 14.1.3.4.1 
Summary of Use of Antidepressant Medication at First Dose of Double-blind Treatment 
Full Analysis Set 


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Table 14.1.4.1 
Summary of Study Drug Exposure (Double-blind Period) 
Safety Set 
Table 14.1.4.2 
Summary of Study Drug Adherence (Double-blind Period) 
Full Analysis Set 
Table 14.2.1.1.1 
Summary of % Sleep Efficiency by Study Visit and Treatment Group 
Full Analysis Set 
Table 14.2.1.1.2 
Model-based Summary of Change from Baseline in % Sleep Efficiency --ANCOVA 
Full Analysis Set 
Table 14.2.1.1.3.1 
Summary of % Sleep Efficiency by Study Visit, Treatment Group and Gender 
Full Analysis Set 
Table 14.2.1.1.3.2 
Summary of % Sleep Efficiency by Study Visit, Treatment Group and Race 
Full Analysis Set 
Table 14.2.1.1.3.3 
Summary of % Sleep Efficiency by Study Visit, Treatment Group and Age 
Full Analysis Set 
Table 14.2.1.1.3.4 
Summary of % Sleep Efficiency by Study Visit, Treatment Group and Baseline 
Antidepressant Use 
Full Analysis Set 
Table 14.2.1.1.3.5 
Summary of % Sleep Efficiency by Study Visit, Treatment Group and BMI 
Full Analysis Set 
Table 14.2.1.1.3.6 
Summary of % Sleep Efficiency by Study Visit, Treatment Group and Baseline ISI 
Full Analysis Set 
Table 14.2.1.1.4.1 
Model-based Summary of Change from Baseline in % Sleep Efficiency by Gender -- 
ANCOVA 
Full Analysis Set 
Table 14.2.1.1.4.2 
Model-based Summary of Change from Baseline in % Sleep Efficiency by Race --ANCOVA 
Full Analysis Set 
Table 14.2.1.1.4.3 
Model-based Summary of Change from Baseline in % Sleep Efficiency by Age--ANCOVA 
Full Analysis Set 
Table 14.2.1.1.4.4 
Model-based Summary of Change from Baseline in % Sleep Efficiency by Baseline 
Antidepressant Use --ANCOVA 
Full Analysis Set 
Table 14.2.1.1.4.5 
Model-based Summary of Change from Baseline in % Sleep Efficiency by BMI --ANCOVA 
Full Analysis Set 
Table 14.2.1.1.4.6 
Model-based Summary of Change from Baseline in % Sleep Efficiency by ISI --ANCOVA 
Full Analysis Set 
Table 14.2.1.2.1 
Summary of PSG-derived Sleep Variables, by Study Visit and Treatment Group 
Full Analysis Set 
Table 14.2.1.2.2 
Model-based Summary of Change from Baseline in PSG-derived Sleep Variables--ANCOVA 
Full Analysis Set 
Table 14.2.2.1.1 
Summary of Insomnia Severity Index (ISI) by Study Visit and Treatment Group 
Full Analysis Set 
Table 14.2.2.1.2 
Model-based Summary of Change from Baseline in Insomnia Severity Index (ISI) --MMRM 
Full Analysis Set 
Table 14.2.2.2.1 
Summary of Subjective Total Sleep Time (sTST) (Min) by Study Visit and Treatment Group 
Full Analysis Set 
Table 14.2.2.2.2 
Model-based Summary of Change from Baseline in Subjective Total Sleep Time (sTST) 
(Min) --MMRM 
Full Analysis Set 
Table 14.2.2.3.1 
Summary of Subjective Wake After Sleep Onset (sWASO) (Min) by Study Visit and 
Treatment Group 
Full Analysis Set 
Table 14.2.2.3.2 
Model-based Summary of Change from Baseline in Subjective Wake After Sleep Onset 
(sWASO) (Min) --MMRM 
Full Analysis Set 
Table 14.2.2.4.1 
Summary of Subjective Sleep Latency (sSL) (Min) by Study Visit and Treatment Group 
Full Analysis Set 


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Table 14.2.2.4.2 
Model-based Summary of Change from Baseline in Subjective Sleep Latency (sSL) (Min) -- 
MMRM 
Full Analysis Set 
Table 14.2.2.5.1 
Summary of Subjective Number of Times Waking up (sNAW) (Num) by Study Visit and 
Treatment Group 
Full Analysis Set 
Table 14.2.2.5.2 
Model-based Summary of Change from Baseline in Subjective Number of Times Waking up 
(sNAW) (Num) --MMRM 
Full Analysis Set 
Table 14.2.2.6.1 
Summary of Subjective Sleep Quality (sSQ) by Study Visit and Treatment Group 
Full Analysis Set 
Table 14.2.2.6.2 
Summary of Change from Baseline in Sleep Quality Response, including Model-Based 
(Generalized Estimating Equations) Estimates, by Study Visit and Treatment Group 
Full Analysis Set 
Table 14.2.3.1.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study Visit and 
Treatment Group 
Full Analysis Set 
Table 14.2.3.1.2 
Model-based Summary of Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) --MMRM 
Full Analysis Set 
Table 14.2.3.2.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Subscale Scores by Study Visit 
and Treatment Group 
Full Analysis Set 
Table 14.2.3.2.2 
Model-based Summary for Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Subscale Scores by Study Visit and Treatment Group -MMRM 
Full Analysis Set 
Table 14.2.3.3.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Individual Item Scores by 
Study Visit and Treatment Group 
Full Analysis Set 
Table 14.2.3.3.2 
Model-based Summary for Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Individual Item Scores by Study Visit and Treatment Group -MMRM 
Full Analysis Set 
Table 14.2.3.4.1.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response, including Model- 
Based (Generalized Estimating Equations) Estimates, by Study Visit and Treatment Group 
Full Analysis Set 
Table 14.2.3.4.1.2 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) Response, 
including Model-Based (Generalized Estimating Equations) Estimates, by Study Visit and 
Treatment Group 
Full Analysis Set 
Table 14.2.3.5.1.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission, including Model- 
Based (Generalized Estimating Equations) Estimates by Study Visit and Treatment Group 
Full Analysis Set 
Table 14.2.3.5.1.2 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Remission, including Model-Based (Generalized Estimating Equations) Estimates by Study 
Visit and Treatment Group- 
Full Analysis Set 


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Table 14.2.4.1.1 
Summary of Clinical Global Impression (CGI) - Severity by Study Visit and Treatment Group 
Full Analysis Set 
Table 14.2.4.1.2 
Summary of Clinical Global Impression (CGI) - Improvement by Study Visit and Treatment 
Group 
Full Analysis Set 
Table 14.2.4.1.3 
Summary of Clinical Global Impression (CGI) - Improvement Response by Study Visit and 
Treatment Group 
Full Analysis Set 
Table 14.2.5.1 
Summary of Patient Health Questionnaire (PHQ-9) by Study Visit and Treatment Group 
Full Analysis Set 
Table 14.2.5.2 
Model-based Summary of Patient Health Questionnaire (PHQ-9) --MMRM 
Full Analysis Set 
Table 14.3.1.1 
Overview of Treatment Emergent Adverse Events 
Safety Set 
Table 14.3.1.2 
Summary of Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.2.1 
Summary of Double-blind Treatment Period Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.2.2.1 
Summary of Run-out Treatment Period Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.2.2.2 
Summary of Follow-up Treatment Period Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.2.3 
Summary of Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term, and Use of Anti-Depressant 
Safety Set 
Table 14.3.1.2.4 
Summary of Treatment Emergent Adverse Events by System Organ Class, Preferred Term 
and Age Group 
Safety Set 
Table 14.3.1.2.5 
Summary of Treatment Emergent Adverse Events by System Organ Class, Preferred Term 
and Gender Group 
Safety Set 
Table 14.3.1.2.6 
Summary of Treatment Emergent Adverse Events by System Organ Class, Preferred Term 
and Race Group 
Safety Set 
Table 14.3.1.3 
Summary of Treatment Emergent Adverse Events by System Organ Class, Preferred Term, 
and Maximum Severity 
Safety Set 
Table 14.3.1.4 
Summary of Treatment Emergent Adverse Events by System Organ Class, Preferred Term, 
Safety Set 


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and Maximum Relationship to Study Drug 
Table 14.3.1.5 
Summary of Treatment Emergent Adverse Events leading to Discontinuation of Study Drug 
by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.6 
Summary of Treatment Emergent leading to Withdrawal from the Study by System Organ 
Class and Preferred Term 
Safety Set 
Table 14.3.1.7.1 
Summary of Treatment Emergent Serious Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.1.7.2 
Summary of Run-out Treatment Period Treatment Emergent Serious Adverse Events by 
System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.7.3 
Summary of Follow-up Period Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.9 
Summary of Most Common (>5%) Treatment Emergent Adverse Events by Preferred Term 
Safety Set 
Table 14.3.1.10 
Adverse Events Occurred during Placebo Run-in Period by Preferred Term 
Safety Set 
Table 14.3.1.11 
Adverse Events Occurred for Subjects Not Randomized to Double-blind Treatment Period by 
Preferred Term 
Run-in Safety Set 
Table 14.3.4.1.1 
Summary of Serum Chemistry Results by Study Visit 
Safety Set 
Table 14.3.4.1.2 
Summary of Shift in Serum Chemistry Results During the Study 
Safety Set 
Table 14.3.4.1.3 
Summary of Potentially Clinically Significant Liver Function Tests Any Time Post-Baseline 
Safety Set 
Table 14.3.4.1.4 
Summary of Potentially Clinically Significant Serum Chemistry (excluding Liver Function 
Tests) Results Any Time Post-Baseline 
Safety Set 
Table 14.3.4.2.1 
Summary of Hematology Results by Study Visit 
Safety Set 
Table 14.3.4.2.2 
Summary of Shift in Hematology Results During the Study 
Safety Set 
Table 14.3.4.2.3 
Potentially Clinically Significant Hematology Results Any Time Post-Baseline 
Safety Set 
Table 14.3.4.3.1 
Summary of Urinalysis by Study Visit – Quantitative Results 
Safety Set 
Table 14.3.4.3.2 
Summary of Urinalysis by Study Visit – Qualitative Results 
Safety Set 
Table 14.3.4.4.1 
Summary of Coagulation Results by Study Visit 
Safety Set 
Table 14.3.4.5.1 
Summary of Vital Signs by Study Visit 
Safety Set 
Table 14.3.4.5.2 
Summary of Potentially Clinically Significant Vital Signs Any Time Post-Baseline 
Safety Set 
Table 14.3.4.5.3 
Difference in Supine to Standing Vital Signs (Supine minus Standing) by Study Visit 
Safety Set 
Table 14.3.4.6.1 
Summary of ECG Data by Study Visit 
Safety Set 
Table 14.3.4.6.2 
Summary of Abnormal ECG by Study Visit 
Safety Set 


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Table 14.3.4.6.3 
Summary of Potentially Clinically Significant QTcF in ECG Data Any Time Post-Baseline 
Safety Set 
Table 14.3.4.7.1 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) on Suicidal Ideation and 
Suicidal Behavior Data 
Safety Set 
Table 14.3.4.7.2 
Summary of Shift from Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidal Ideation and Suicidal Behavior Data 
Safety Set 
Table 14.3.4.7.3 
Summary of Shift from Baseline in C-SSRS Maximum Severity Score in Suicidal Ideation 
Any Time Post-Baseline 
Safety Set 
Table 14.3.5.1 
Summary of Physician Withdrawal Checklist (PWC-20) by Study Visit and Treatment Group 
Safety Set 
 
12.4.2. 
Index of Listings 
Number 
Title 
Analysis Set 
Listing 16.1.7 
Subject Randomization 
All Randomized Set 
Listing 16.2.1.1 
Subject Disposition 
Safety Set 
Listing 16.2.1.2 
Inclusion and Exclusion Criteria, Subjects randomized but Do not Meet Eligibility Criteria 
All Randomized Set 
Listing 16.2.1.3 
Premature Withdrawal from Study or Premature Discontinuation from Study Drug 
All Subjects 
Listing 16.2.1.4 
Analysis Sets 
All Randomized Set 
Listing 16.2.1.5 
Protocol Deviations 
All Subjects 
Listing 16.2.1.6 
Screen Failure/Run-in Failures 
Listing 16.2.2.1.1 
Demographics 
Safety Set 
Listing 16.2.2.1.2 
Baseline Characteristics 
Safety Set 
Listing 16.2.3.1 
Prior and Concomitant Psychotropic Medications 
Safety Set 
Listing 16.2.3.2 
Prior and Concomitant Non-Psychotropic Medications 
Safety Set 
Listing 16.2.3.3 
Listing of Use of Antidepressant Medications during the Study 
Safety Set 
Listing 16.2.3.4 
Listing of Use of Anti-insomnia Treatment 
Safety Set 
Listing 16.2.4.1.1 
Disease History 
Safety Set 
Listing 16.2.4.1.2 
History of Insomnia Disorder 
Safety Set 
Listing 16.2.4.2 
Sleep History 
Safety Set 
Listing 16.2.4.3 
Family History of Sleep Disorders 
Safety Set 
Listing 16.2.4.4 
History of Psychiatric Disorders 
Safety Set 
Listing 16.2.4.5 
Family History of Psychiatric Disorders 
Safety Set 
Listing 16.2.4.6 
Medical and Surgical History 
Safety Set 


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Listing 16.2.4.7 
Concomitant Procedures 
Safety Set 
Listing 16.2.5.1 
Study Drug Administration (Double-blind Period) 
Safety Set 
Listing 16.2.5.2 
Study Drug Exposure 
Safety Set 
Listing 16.2.5.3 
Study Drug Adherence 
Full Analysis Set 
Listing 16.2.6.1 
Polysomnography (PSG) 
Full Analysis Set 
Listing 16.2.6.2 
Sleep Diary 
Full Analysis Set 
Listing 16.2.6.3 
Hamilton Rating Scale for Depression (HAM-D) 
Full Analysis Set 
Listing 16.2.6.4 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
Full Analysis Set 
Listing 16.2.6.5 
Clinical Global Impression (CGI) – Severity 
Full Analysis Set 
Listing 16.2.6.6 
Clinical Global Impression (CGI) – Improvement 
Full Analysis Set 
Listing 16.2.6.7 
Insomnia Severity Index (ISI) 
Full Analysis Set 
Listing 16.2.6.8 
Physician Withdrawal Checklist (PWC-20) 
Full Analysis Set 
Listing 16.2.6.9 
9-Item Subject-rated Patient Health Questionnaire (PHQ-9) 
Full Analysis Set 
Listing 16.2.7.1 
Adverse Events 
Safety Set 
Listing 16.2.7.2 
Non-fatal Serious Adverse Events 
Safety Set 
Listing 16.2.7.3 
Adverse events leading to Death 
Safety Set 
Listing 16.2.7.4 
Adverse Events With Onset Prior to First Dose of Double-blind Study Drug 
Safety Set 
Listing 16.2.7.5 
Adverse Events leading to Premature Discontinuation of Study Drug 
Safety Set 
Listing 16.2.7.6 
Adverse events leading to Premature Withdrawal from the Study 
Safety Set 
Listing 16.2.8.1 
Serum Chemistry Data 
Safety Set 
Listing 16.2.8.2 
Hematology Data 
Safety Set 
Listing 16.2.8.3 
Urinalysis Data 
Safety Set 
Listing 16.2.8.4 
Coagulation Data 
Safety Set 
Listing 16.2.8.5 
Pregnancy Test 
Safety Set 
Listing 16.2.8.6 
Diagnostic Screening Laboratory Tests 
Safety Set 
Listing 16.2.9.1 
Vital Signs 
Safety Set 
Listing 16.2.10.1 
Electrocardiogram (ECG) data 
Safety Set 


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Listing 16.2.11.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Suicidal Ideation 
Safety Set 
Listing 16.2.11.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Suicidal Behavior 
Safety Set 
Listing 16.2.12.1 
Physical Examination 
Safety Set 
 
 
12.4.3. 
Index of Figures 
Figure 14.2.1.1 
Bar Plot of Mean (±SE) in Percent Sleep Efficiency (%SEFF), by Treatment and Visit 
Full Analysis Set 
Figure 14.2.1.2 
Forest Plot of Change from Baseline in Sleep Efficiency (SEFF) Overall and by Subgroup at 
the End of Double-blind Period 
Full Analysis Set 
Figure 14.2.1.3.1 
Bar Plot of Mean (±SE) in Wakefulness After Persistent Sleep (WASO) (Minutes) - Total , by 
Treatment and Visit 
Full Analysis Set 
Figure 14.2.1.3.2 
Line Plot of Mean (±SE) Change from Baseline in Wakefulness After Persistent Sleep 
(WASO) (Minutes) - by Quarter and Treatment 
Full Analysis Set 
Figure 14.2.1.4 
Bar Plot of Mean (±SE) in Total Sleep Time (TST) (Minutes) by Treatment and Visit 
Full Analysis Set 
Figure 14.2.1.5 
Bar Plot of Mean (±SE) in Latency to Persistent Sleep (LPS) (Minutes) by Treatment and 
Visit 
Full Analysis Set 
Figure 14.2.1.6.1 
Line Plot of LS Mean (±SE) Change from Baseline in Insomnia Severity Index (ISI) Over 
Time by Treatment 
Full Analysis Set 
Figure 14.2.1.6.2 
Bar Chart for Insomnia Severity Index (ISI) Total Score Categories Over Time by 
Treatment 
Full Analysis Set 
Figure 14.2.1.7.1 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score Over Time by Treatment 
Full Analysis Set 
Figure 14.2.1.7.2 
Bar Chart for Hamilton Rating Scale for Depression (HAM-D) Response Over Time by 
Treatment 
Full Analysis Set 
Figure 14.2.1.7.3 
Bar Chart for Hamilton Rating Scale for Depression (HAM-D) Remission Over Time by 
Treatment 
Full Analysis Set 
Figure 14.2.1.8.1 
Mean Clinical Global Impression (CGI) - Improvement Over Time by Treatment 
Full Analysis Set 
Figure 14.2.1.8.2 
Bar Chart for Clinical Global Impression (CGI) - Improvement Response Over Time by 
Treatment 
Full Analysis Set 
Figure 14.2.1.9 
Distribution of Subjects with Suicidal Ideation or Behavior Based on the C-SSRS scores Over 
Time 
Safety Set