Clinical trial NCT04476017
Conditions: Parkinson Disease Cognitive Dysfunction
Keywords: Parkinson's Disease Cognitive Dysfunction SAGE-718
Sponsor: Sage Therapeutics
Start date: 2020-07-31; Completion date: 2022-03-25
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary purpose of this two-part study was to evaluate the safety and tolerability of SAGE-718 and its effects on cognitive, neuropsychiatric, and motor symptoms in participants with Parkinson's disease mild cognitive impairment (PD-MCI).

Detailed description:

Arms: arm 1: Participants received SAGE-718 3 milligrams (mg) tablets, once daily with food in the morning for 14 days. arm 2: Participants received SAGE-718 3 mg tablets, once daily with food in the morning for 28 days.
Interventions: intervention 1: SAGE-718
Intervention descriptions: intervention 1: Oral tablets.

Protocol documents:
Prot_002.pdf: 
Official Title: An Open-Label Evaluation of the Safety and Tolerability of SAGE-718 
in Participants with Parkinson’s Disease Mild Cognitive Impairment 
NCT Number: NCT04476017 
Document Dates: Protocol Version 5.0: 29-April-2021 








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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-718. I have read the 
718-CNP-201 protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY) 
 
 


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CONTACT INFORMATION 
 
Table 1: 
Contact Information 
Sage Study Physician and 
24-hour emergency contact 
 MD 
215 First Street 
Cambridge, MA 02142 
Phone:
SAE Reporting 
IQVIA Lifecycle Safety 
4820 Emperor Boulevard 
Durham, NC 27703 
e-mail: Sage.Safety@iqvia.com 
Fax: 1-855-638-1674 
SAE Hotline: 1-855-564-2229  
Product Complaints 
Sage Therapeutics 
e-mail:
Phone:
 






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Day -8 to determine eligibility, including assessments of 
. 
Baseline Period 
The Baseline Period will occur from Day -7 through Day -1. During this period, each participant will 
receive dietary counseling to aid in choosing a morning meal containing approximately 30 g fat to 
consume prior to dosing. On Day -7 (±1 day), participants will visit the clinic for confirmation of 
continued eligibility and collection of baseline 
 and safety data. Additionally, participants 
will be trained on the use of a mobile data capture device to perform daily 
 
. Participants will continue to complete daily assessments of 
 
 using the mobile device at home during the Baseline Period. On Day -1, 
participants will return to the study site for confirmation of continued eligibility and collection of 
baseline 
 and safety data. 
Treatment Period 
Beginning on Day 1 and continuing through Day 14 in Part A and Day 28 in Part B, participants will 
self-administer 3.0 mg SAGE-718 (as six 0.5-mg oral tablets), once per day in the morning within 
1 hour after initiating a meal containing approximately 30 g of fat, in accordance with the guidelines 
provided in a nutritional information brochure. Participants will continue to complete daily 
assessments of 
 via mobile device either remotely (at home), or in the 
clinic at scheduled visits and will track IP dosing and predose food intake in a participant diary. 
At scheduled visits during the Treatment Period, participants will arrive at the clinic in the morning 
prior to IP dosing and completion of daily mobile device tasks. Following predose procedures, 
participants will eat a morning meal, then take the IP and complete the mobile device tasks under 
staff supervision 
At scheduled clinic visits during the Treatment Period, safety, efficacy, and 
 will be 
performed, and study staff will dispense a sufficient amount of SAGE-718 for daily administration 
until the next scheduled study visit. In addition to weekly clinic visits, study staff will contact 
participants by telephone on Day 4 to document any TEAEs and/or changes in concomitant 
medications. 
Follow-up Period 
In Part A, study staff will contact participants by telephone on Day 21 to document any AEs and/or 
changes in concomitant medications. Participants will return to the clinic on Day 28 (±2 days) for a 
follow-up visit. 
In Part B, participants will return to the clinic for follow-up visits on Day 35 and Day 42.  
Number of participants (planned): Up to 33 participants (11 in Part A and 22 in Part B) will be 
dosed to obtain up to 30 participants who complete dosing in this study. Additional participants may 
be dosed if the early discontinuation rate is >10%. 
Eligibility criteria: 
Inclusion criteria 
Each eligible participant must: 
1. Be capable of providing informed consent 
2. Have signed an informed consent form prior to any study-specific procedures being 
performed 
3. Be willing and, in the opinion of the investigator, able to comply with study procedures 
4. Be between the ages of 50 and 75 years, inclusive, at Screening 
5. Meet the following criteria for PD-MCI: 
a. Have a confirmed diagnosis of idiopathic PD according to 2015 MDS clinical diagnostic 


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criteria 
b. Meet MDS Task Force Criteria for MCI in PD (excluding requirement for UK PD Brain 
Bank diagnostic criteria) 
6. Have a score of 20 to 25 (inclusive) on the MoCA at Screening 
7. Meet criteria for Hoehn and Yahr Stage I to III (mild to moderate motor severity) at 
Screening 
8. Have an estimated premorbid IQ ≥85 (as assessed by the Test of Premorbid Functioning 
[TOPF], performed at Screening) 
9. Be willing to invite a study partner who is reliable, competent, and at least 18 years of age to 
participate in the study 
10. Be ambulatory, able to travel to the study center, and in the opinion of the investigator likely 
to be able to continue to travel to the study center to complete study visits for the duration of 
the study 
11. Have stable concomitant medication dose and frequency for at least 4 weeks prior to the first 
IP administration that is expected to remain stable for the duration of the study 
12. Have stable motor symptoms for at least 4 weeks prior to screening, in the opinion of the 
investigator 
13. Agree, if female, to use an acceptable highly effective method of contraception (as defined in 
Section 9.2.4) during participation in the study and for 30 days following the last dose of IP, 
unless she is postmenopausal (defined as no menses for 12 months without an alternative 
medical cause and confirmed by follicle stimulating hormone [FSH] > 40 mIU/mL), 
surgically sterile (hysterectomy or bilateral oophorectomy or bilateral salpingectomy), or 
does not engage in sexual relations which carry a risk of pregnancy 
14. Agree, if male, to use an acceptable method of highly effective contraception (as defined in 
Section 9.2.4) during the Treatment Period and for 2 weeks after receiving the last dose of IP, 
unless the participant does not engage in sexual relations that carry a risk of pregnancy 
15. Agree, if male, to abstain from sperm donation during the Treatment Period and for 2 weeks 
after receiving the last dose of IP 
16. Agree to refrain from drugs of abuse and alcohol for the duration of the study 
Exclusion Criteria 
Each eligible participant must not: 
1. Have participated previously in a clinical study of SAGE-718, or have used any other 
investigational drug, biologic, or device or have participated in a clinical drug, biologic, or 
device study within 30 days or 5 half-lives (whichever is longer) prior to Screening 
2. Have clinically significant comorbid medical conditions, a chronic condition that is unstable 
or requires more than 2 medications to be controlled, or be taking concomitant medications 
that, in the opinion of the investigator, may make the participant unsuitable for inclusion or 
have the potential to compromise safety and/or compliance with study requirements 
3. Have a diagnosis of dementia of any etiology, including but not limited to: Dementia 
associated with PD (probable or possible), Dementia with Lewy Bodies, Alzheimer’s 
Dementia, and Vascular Dementia 
4. Have any indication of parkinsonism other than idiopathic PD, including secondary 
parkinsonism or atypical parkinsonism 
5. In the opinion of the investigator, be experiencing unpredictable fluctuations in motor and/or 


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nonmotor symptoms associated with PD 
6. Have an ongoing central nervous system condition other than idiopathic PD, including active 
neurologic and/or nonremitted psychiatric disorders, in the opinion of the investigator 
7. Have a history of brain surgery, deep brain stimulation, a significant head injury causing loss 
of consciousness greater than 30 minutes, or hospitalization due to a brain injury 
8. Have a history, presence, and/or current evidence of intracranial abnormality (eg, stroke, 
hemorrhage, space-occupying lesion) 
9. Have experienced significant psychotic symptoms within the past 3 months, including those 
associated with PD medications, as determined by the investigator  
10. Have a history of possible or probable cerebral amyloid angiopathy according to the Boston 
Criteria (Greenberg 1995) 
11. Be receiving any of the following prohibited medications: 
a. Medications with potent effects at the N-methyl-D-aspartate (NMDA) receptor, including 
memantine, amantadine, ketamine, or related compounds 
b. Medications that inhibit cholesterol absorption (eg, ezetimibe) 
c. Bile acid sequestrants (eg, colesevelam, cholestyramine) 
d. Other medications given at doses, frequencies, or in combinations that are likely, in the 
opinion of the investigator, to have a deleterious effect on cognitive performance, as 
based on the 2019 American Geriatrics Society Updated Beers® Criteria for Potentially 
Inappropriate Medication Use in Older Adults (American Geriatrics Society 2019) 
e. Prescribed cannabis or other THC-containing substances 
12. Have an alcohol or drug use disorder within the past 12 months as per DSM-5 criteria 
13. Have a history of seizures or epilepsy, with the exception of a single episode of febrile 
seizures in childhood 
14. Have current or recent suicidality, defined as follows: 
a. Suicidal ideation within the past month, as evidenced by a score of 4 (active suicidal 
ideation with some intent to act, without specific plan) or 5 (active suicidal ideation with 
specific plan and intent) on the screening or baseline Columbia–Suicide Severity Rating 
Scale (C-SSRS) 
b. Suicidal behavior within the past year, as evidenced by a "Yes" on any of the 5 C-SSRS 
Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory 
acts, or behavior) on the C-SSRS during Screening or Baseline 
c. Present a serious risk of suicide in the opinion of the investigator 
15. Have any of the following clinically significant medical conditions: 
a. Any clinically significant finding on 12-lead ECG during Screening or Baseline 
b. Supine vital signs outside of the following ranges during Screening or Baseline; vital sign 
measurements may be repeated once if initial values exceed these ranges: 
− 
Heart rate <50 or >100 bpm 
− 
Systolic blood pressure <100 or >160 mmHg 
− 
Diastolic blood pressure <60 or >100 mmHg 
16. Have significant hepatic, renal, cardiovascular, pulmonary, gastrointestinal, hematological, 
immunologic, ophthalmologic, metabolic, or oncological disease 
17. Have a history, presence, and/or current evidence of serologic positive results for HIV-1 or 
HIV-2 


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18. Have a positive pregnancy test or be lactating at Screening or Day -1 
19. Be investigative site personnel, sponsor personnel, or an immediate member of their family 
(spouse, parent, child, or sibling whether biological or legally adopted) 
Investigational Product, Dosage and Mode of Administration: SAGE-718 3.0 mg will be self-
administered as six 0.5 mg oral tablets, once daily in the morning within 1 hour after initiating a meal 
containing approximately 30 g of fat. 
Duration of Treatment: 14 days in Part A or 28 days in Part B 
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. 
General Considerations 
Unless otherwise specified, Baseline is defined as the last measurement prior to the first dose of IP. 
Continuous endpoints will be summarized with n, mean, standard deviation, median, minimum and 
maximum, Q1, and Q3. In addition, change from baseline values will be calculated at each time point 
and will be summarized using the same summary statistics. Out of range safety endpoints may be 
categorized as low or high, where applicable. For all categorical endpoints, summaries will include 
counts and percentages. 
Analysis Sets 
Safety Set will include all participants who were administered IP and will be used to describe the 
safety data. 
Full Analysis Set will include all participants who initiate IP and have baseline and at least 
1 postbaseline efficacy evaluation. 
Safety Analysis 
AEs will be coded using Medical Dictionary for Regulatory Activities with the overall incidence of 
AEs displayed by System Organ Class and preferred term. Incidence of treatment-emergent AEs will 
also be presented by maximum severity and relationship to IP. Data from vital signs, clinical 
laboratory measures, ECGs, and C-SSRS will be summarized using descriptive statistics. 
Efficacy Analysis 
The endpoints for each of the 
 are change from baseline scores at each 
postbaseline assessment. Descriptive statistics of scores and change from baseline scores will be 
summarized based on the Full Analysis Set. These endpoints will also be analyzed using a mixed-
effects model for repeated measures. The model will include baseline 
, and 
assessment time point. Model-based point estimates (ie, least squares means, 95% confidence 
intervals, and p values) at each time point will be reported where applicable. An unstructured 
covariance structure will be used to model the within-participant errors. If there is a convergence 
issue with the unstructured covariance model, a Toeplitz or Autoregressive (1) [AR(1)] covariance 
structure will be used, following this sequence until convergence is achieved. Line plots of change 
from baseline scores will be plotted with standard error bars. Other continuous efficacy endpoints, 
including 
 will be summarized using similar 
methods. 
Sample Size Calculation: 
No formal sample size calculation was made for this study. Up to 10 participants completing 14 days 
of dosing in Part A and 20 participants completing 28 days of dosing in Part B are considered 


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sufficient to assess preliminary safety and tolerability and for signal-finding of
after 
repeated daily dosing with SAGE-718. 
Assuming a 10% dropout rate, approximately 33 total participants will be required to obtain 
30 completers. Additional participants may be dosed if the early discontinuation rate is >10%. 


















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3. 
TABLE OF CONTENTS 
 
1. 
TITLE PAGE ................................................................................................................1 
CONTACT INFORMATION ..........................................................................................................5 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS ...........................................................................................21 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................26 
5. 
INTRODUCTION ......................................................................................................27 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................28 
6.1. 
Objectives ...................................................................................................................28 
6.1.1. 
Primary Objective .......................................................................................................28 
 
28 
6.2. 
Endpoints ....................................................................................................................28 
6.2.1. 
Primary Endpoint ........................................................................................................28 
6.2.2. 
Secondary Endpoint ....................................................................................................28 
 
28 
7. 
INVESTIGATIONAL PLAN .....................................................................................30 
7.1. 
Overall Study Design ..................................................................................................30 
7.1.1. 
Screening Period .........................................................................................................30 
7.1.2. 
Baseline Period ...........................................................................................................30 
7.1.3. 
Treatment Period ........................................................................................................30 
7.1.4. 
Follow-up Period ........................................................................................................31 
7.2. 
Number of Participants ...............................................................................................31 
7.3. 
Treatment Assignment ................................................................................................31 
7.4. 
Dose Adjustment Criteria ...........................................................................................31 
7.4.1. 
Stopping Criteria .........................................................................................................31 
7.4.2. 
Dose Evaluation Committee .......................................................................................31 
7.5. 
Criteria for Study Termination ...................................................................................32 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.....................................33 
8.1. 
Participant Inclusion Criteria ......................................................................................33 
8.2. 
Participant Exclusion Criteria .....................................................................................34 
8.3. 
Screen Failures ............................................................................................................35 


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8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................36 
8.4.1. 
Investigational Product Discontinuation .....................................................................36 
8.4.2. 
Early Termination from the Study ..............................................................................36 
8.4.3. 
Loss to Follow Up ......................................................................................................36 
8.4.4. 
Replacement of Participants .......................................................................................36 
9. 
TREATMENT OF PARTICIPANTS .........................................................................37 
9.1. 
Description of Investigational Product .......................................................................37 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................37 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................37 
9.2.2. 
Prohibited Medications ...............................................................................................37 
9.2.3. 
Other Restrictions .......................................................................................................38 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................38 
9.3. 
Intervention after the End of the Study .......................................................................38 
9.4. 
Treatment Adherence ..................................................................................................38 
9.5. 
Randomization and Blinding ......................................................................................39 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............40 
10.1. 
Investigational Product ...............................................................................................40 
10.2. 
Investigational Product Packaging and Labeling .......................................................40 
10.3. 
Investigational Product Storage ..................................................................................40 
10.4. 
Investigational Product Preparation ............................................................................40 
10.5. 
Investigational Product Administration ......................................................................40 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................40 
10.7. 
Product Complaints ....................................................................................................41 
11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS ....................42 
11.1. 
Efficacy Assessments .................................................................................................42 
 
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11.1.9. 
Daily Remote Assessments.........................................................................................46 
11.2. 
Clinical Pharmacology Assessments ..........................................................................46 
 
46 
11.2.1.1. 
Blood Sample Collection ............................................................................................47 
 
47 
11.2.2. 
Pharmacodynamic Assessments .................................................................................47 
 
47 
 
47 
12. 
SAFETY ASSESSMENTS ........................................................................................49 
12.1. 
Safety Parameters .......................................................................................................49 
12.1.1. 
Demography and Medical History ..............................................................................49 
12.1.1.1. 
Screening Assessments ...............................................................................................49 


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12.1.2. 
Weight and Height ......................................................................................................49 
12.1.3. 
Physical Examination .................................................................................................49 
12.1.4. 
Vital Signs ..................................................................................................................50 
12.1.5. 
Electrocardiogram .......................................................................................................50 
12.1.6. 
Electroencephalogram ................................................................................................50 
12.1.7. 
Laboratory Assessments .............................................................................................50 
12.1.7.1. 
Pregnancy Testing ......................................................................................................51 
12.1.7.2. 
Drugs of Abuse and Alcohol ......................................................................................51 
12.1.7.3. 
Columbia–Suicide Severity Rating Scale ...................................................................51 
12.2. 
Adverse Events and Serious Adverse Events .............................................................52 
12.2.1. 
Adverse Event Definition ...........................................................................................52 
12.2.2. 
Serious Adverse Event Definition ..............................................................................52 
12.2.3. 
Relationship to Investigational Product ......................................................................53 
12.2.4. 
Recording Adverse Events .........................................................................................54 
12.2.5. 
Reporting Serious Adverse Events .............................................................................54 
12.3. 
Pregnancy ...................................................................................................................55 
12.4. 
Overdose .....................................................................................................................55 
13. 
STATISTICS ..............................................................................................................56 
13.1. 
Data Analysis Sets ......................................................................................................56 
13.2. 
Handling of Missing Data ...........................................................................................56 
13.3. 
General Considerations ...............................................................................................56 
13.4. 
Demographics and Baseline Characteristics ...............................................................56 
13.5. 
Efficacy Analysis ........................................................................................................56 
13.5.1. 
Multiplicity Adjustment..............................................................................................57 
13.5.2. 
Sensitivity Analyses ....................................................................................................57 
13.6. 
Safety Analyses ..........................................................................................................57 
13.6.1. 
Adverse Events ...........................................................................................................57 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................57 
13.6.3. 
Physical Examinations ................................................................................................57 
13.6.4. 
Vital Signs ..................................................................................................................58 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................58 
13.6.6. 
Prior and Concomitant Medications ...........................................................................58 
13.6.7. 
Columbia–Suicide Severity Rating Scale ...................................................................58 


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13.8. 
Sample Size and Power ..............................................................................................58 
13.8.1. 
Interim and Data Monitoring Committee Analysis ....................................................59 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................60 
14.1. 
Study Monitoring ........................................................................................................60 
14.2. 
Audits and Inspections ................................................................................................60 
14.3. 
Institutional Review Board or Independent Ethics Committee ..................................61 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................62 
16. 
ETHICS ......................................................................................................................63 
16.1. 
Ethics Review .............................................................................................................63 
16.2. 
Ethical Conduct of the Study ......................................................................................63 
16.3. 
Written Informed Consent ..........................................................................................63 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................64 
17.1. 
Inspection of Records .................................................................................................64 
17.2. 
Retention of Records ..................................................................................................64 
18. 
PUBLICATION POLICY ..........................................................................................65 
19. 
LIST OF REFERENCES ............................................................................................66 
 
LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................5 
Table 2: 
Schedule of Assessments (Part A) ..............................................................................13 
 
16 
Table 4: 
Schedule of Assessments (Part B) ..............................................................................17 
 
20 
Table 6: 
Summary of Clinical Laboratory Analytes .................................................................51 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol: 
Abbreviation 
Definition 
AE 
adverse event 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EEG 
electroencephalogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IP 
investigational product 
IRB 
institutional review board 
IRT 
interactive response technology 
MDS 
Movement Disorder Society 
MoCA 
Montreal Cognitive Assessment 
MRI 
magnetic resonance imaging 
NMDA 
N-methyl-D-aspartate 
PAM 
positive allosteric modulator 
PD-MCI 
Parkinson’s disease mild cognitive impairment 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
 


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5. 
INTRODUCTION 
Mild cognitive impairment is common in patients who have Parkinson’s disease, and is 
associated with decreased quality of life and impaired functioning. Moreover, patients with PD 
mild cognitive impairment (PD-MCI) are at a high risk for developing dementia (Litvan 2011). 
Preclinical data indicate that patients who have PD have reduced plasma levels of a specific 
oxysterol, 24(S)-hydroxycholesterol (24SHC; Di Natale 2018). This molecule acts as an 
endogenous positive allosteric modulator (PAM) of the NMDA receptor (Paul 2013) and has 
been correlated with performance on cognitive tasks. NMDA receptors are a subtype of 
glutamate receptors with a fundamental and well-documented role in regulating synaptic 
strength, health, and plasticity. 
SAGE-718 is a novel oxysterol-based NMDA receptor PAM that acts at the 24SHC binding site 
and modulates the response of the receptor to endogenous glutamate. SAGE-718 only affects 
receptor function in the presence of endogenous glutamate – it does not directly activate the 
receptor and is not expected to cause NMDA receptor-associated glutamatergic excitotoxicity. 
Positive modulation of NMDA receptors is hypothesized to produce beneficial effects in 
conditions associated with reduced NMDA receptor function, activity, or expression. Preclinical 
studies have shown promise for improving cognitive deficits in conditions with decreased plasma 
levels of the endogenous NMDA receptor PAM 24SHC (Collingridge 2013). 
SAGE-718 has been well tolerated in both healthy participants and a small cohort of 
Huntington’s disease participants in previous clinical studies. However, based on nonclinical 
findings, the US Food and Drug Administration imposed a median maximum concentration 
(Cmax) cap of 45 ng/mL. To date, clinical studies have used doses that resulted in exposures 
within this cap; neither SAEs nor AEs leading to discontinuation have been reported. A once-
daily 3-mg dose of SAGE-718 is not predicted to exceed a median Cmax of 45 ng/mL. For 
additional information on exposure caps, see the SAGE-718 Investigator’s Brochure. 
A direct correlation between SAGE-718 Oral Tablet exposure and fat intake has been observed 
in healthy adults, with significantly lower exposure in fasting participants than in the same 
participants after moderate and high fat-containing meals. Additionally, as fat levels increased, 
exposure variability decreased, allowing for more predictable Cmax levels. Thus, in this study 
SAGE-718 will be administered after consumption of a morning meal containing approximately 
30 g of fat. Based on the data from healthy participants, this regimen is projected to produce a 
median Cmax of approximately 35 to 40 ng/mL at steady state. 
The safety, tolerability, and
of SAGE-718 Oral Tablet will be evaluated in this 
open-label study in participants with a diagnosis of PD-MCI. Additional data on the effects of 
SAGE-718 in participants with PD-MCI will be collected throughout, including assessments of 
 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
6.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of orally 
administered SAGE-718 in participants with PD-MCI. 
 
 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
The primary endpoint of this study is the incidence of treatment-emergent adverse events 
(TEAEs). 
6.2.2. 
Secondary Endpoint 
The secondary endpoint of this study will be assessed as the change from baseline in vital signs, 
clinical laboratory analytes, electrocardiograms (ECGs), and responses on the Columbia–Suicide 
Severity Rating Scale (C-SSRS). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is an open-label study evaluating the safety and tolerability of SAGE-718 and its effects on 
 in participants with PD-MCI. Eligible 
participants with a confirmed diagnosis of idiopathic PD by 2015 Movement Disorder Society 
(MDS) criteria (Berardelli 2013) at Screening and who meet MDS Task Force Criteria for MCI 
in PD (excluding requirement for UK PD Brain Bank diagnostic criteria) will receive a 3.0 mg 
dose of SAGE-718 daily for 14 days (Part A) or for 28 days (Part B). Participants will be 
instructed to take the daily dose of investigational product (IP) in the morning within 1 hour of 
initiating a meal containing approximately 30 g of fat. Assessments will be performed as 
outlined in the Schedules of Assessments (Table 2 and Table 4) and the
In the setting of public health advisories due to COVID-19 or similar risks to patient safety, 
assessments scheduled to be conducted at the study site may be performed via telephone/video if 
feasible. For assessments that cannot be conducted by phone or video, an in-home visit may be 
conducted. 
7.1.1. 
Screening Period 
The Screening Period begins with the informed consent process for prospective participants, 
including study partners. Subsequent screening assessments will be performed between Day -21 
and Day -8 to determine eligibility, including assessments of 
. 
7.1.2. 
Baseline Period 
The Baseline Period will occur from Day -7 through Day -1. During this period, each participant 
will receive dietary counseling to aid in choosing a morning meal containing approximately 30 g 
fat to consume prior to dosing. On Day -7 (±1 day), participants will visit the clinic for 
confirmation of continued eligibility and collection of baseline 
 and safety data. 
Additionally, participants will be trained on the use of a mobile data capture device to perform 
daily 
. Participants will continue to complete daily 
assessments of 
 using the mobile device at home during the 
Baseline Period. On Day -1, participants will return to the study site for confirmation of 
continued eligibility and collection of baseline 
 and safety data. 
7.1.3. 
Treatment Period 
Beginning on Day 1 and continuing through Day 14 in Part A and Day 28 in Part B, participants 
will self-administer 3.0 mg SAGE-718 (as six 0.5-mg oral tablets), once per day in the morning 
within 1 hour after initiating a meal containing approximately 30 g of fat, in accordance with the 
guidelines provided in a nutritional information brochure. Participants will continue to complete 
daily assessments of 
 via mobile device either remotely (at 
home), or in the clinic at scheduled visits and will track IP dosing and predose food intake in a 
participant diary. 
At scheduled visits during the Treatment Period, participants will arrive at the clinic in the 
morning prior to IP dosing and completion of daily mobile device tasks. Following predose 


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procedures, participants will eat a morning meal, then take the IP and complete the mobile 
device tasks under staff supervision 
At scheduled clinic visits during the Treatment Period, safety, efficacy, and
will 
be performed, and study staff will dispense a sufficient amount of SAGE-718 for daily 
administration until the next scheduled study visit. In addition to weekly clinic visits, study staff 
will contact participants by telephone on Day 4 to document any TEAEs and/or changes in 
concomitant medications. 
7.1.4. 
Follow-up Period 
In Part A, study staff will contact participants by telephone on Day 21 to document any AEs 
and/or changes in concomitant medications. Participants will return to the clinic on Day 28 
(±2 days) for a follow-up visit. 
In Part B, participants will return to the clinic for 2 follow-up visits on Day 35 and Day 42. 
7.2. 
Number of Participants 
Up to 33 participants (11 in Part A and 22 in Part B) are planned to be dosed to obtain up to 30 
participants who complete dosing in this study. Additional participants may be dosed if the early 
discontinuation rate is greater than 10%. 
7.3. 
Treatment Assignment 
In this open-label study, all participants will receive 3.0 mg of SAGE-718 once daily for 14 days 
in Part A and for 28 days in Part B. 
7.4. 
Dose Adjustment Criteria 
Dosing may be interrupted in an individual participant due to an AE considered by the 
investigator to be related to IP, however, no individual dose reductions will be permitted. 
7.4.1. 
Stopping Criteria 
If clinical events suspicious for seizure occur after Screening, an unscheduled 
electroencephalogram (EEG) will be performed for review by an independent epileptologist to 
identify evidence of seizure activity (see Section 12.1.6). Should the independent epileptologist 
identify evidence for a subclinical or clinical seizure, dosing with SAGE-718 will be stopped for 
that participant. 
7.4.2. 
Dose Evaluation Committee 
A Dose Evaluation Committee may be convened to review
and safety data when at least 
5 participants have completed 14 days of dosing to consider adjusting the dose, administration 
schedule, or food intake recommendations for subsequent participants. The Dose Evaluation 
Committee will include, at a minimum, the Sage program medical lead, a Sage Drug Safety and 
Pharmacovigilance physician, and a clinical operations representative and will be supported by a 
Sage biostatistician. 


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7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons, including the occurrence of AEs or other findings suggesting unacceptable risk to 
participants, or for administrative reasons. In the event of study termination, Sage Therapeutics 
will provide written notification to the investigator. Investigational sites must promptly notify 
their institutional review board (IRB)/independent ethics committee (IEC), where required, and 
initiate withdrawal procedures for participants. 


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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Participant Inclusion Criteria 
To be eligible to enroll in this study, participants must: 
1. Be capable of providing informed consent 
2. Have signed an informed consent form prior to any study-specific procedures being 
performed 
3. Be willing and, in the opinion of the investigator, able to comply with study procedures 
4. Be between the ages of 50 and 75 years, inclusive, at Screening 
5. Meet the following criteria for PD-MCI: 
a. Have a confirmed diagnosis of idiopathic PD according to 2015 MDS clinical 
diagnostic criteria 
b. Meet MDS Task Force Criteria for MCI in PD (excluding requirement for UK PD 
Brain Bank diagnostic criteria) 
6. Have a score of 20 to 25 (inclusive) on the MoCA at Screening 
7. Meet criteria for Hoehn and Yahr Stage I to III (mild to moderate motor severity) at 
Screening 
8. Have an estimated premorbid IQ ≥85 (as assessed by the Test of Premorbid Functioning 
[TOPF], performed at Screening) 
9. Be willing to invite a study partner who is reliable, competent, and at least 18 years of 
age to participate in the study 
10. Be ambulatory, able to travel to the study center, and in the opinion of the investigator 
likely to be able to continue to travel to the study center to complete study visits for the 
duration of the study 
11. Have stable concomitant medication dose and frequency for at least 4 weeks prior to the 
first IP administration that is expected to remain stable for the duration of the study 
12. Have stable motor symptoms for at least 4 weeks prior to screening, in the opinion of the 
investigator 
13. Agree, if female, to use an acceptable highly effective method of contraception (as 
defined in Section 9.2.4) during participation in the study and for 30 days following the 
last dose of IP, unless she is postmenopausal (defined as no menses for 12 months 
without an alternative medical cause and confirmed by follicle stimulating hormone 
[FSH] > 40 mIU/mL), surgically sterile (hysterectomy or bilateral oophorectomy or 
bilateral salpingectomy), or does not engage in sexual relations which carry a risk of 
pregnancy 
14. Agree, if male, to use an acceptable method of highly effective contraception (as defined 
in Section 9.2.4) during the Treatment Period and for 2 weeks after receiving the last 
dose of IP, unless the participant does not engage in sexual relations that carry a risk of 
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15. Agree, if male, to abstain from sperm donation during the Treatment Period and for 
2 weeks after receiving the last dose of IP 
16. Agree to refrain from drugs of abuse and alcohol for the duration of the study  
8.2. 
Participant Exclusion Criteria 
To be eligible to enroll in this study, participants must not: 
1. Have participated previously in a clinical study of SAGE-718, or have used any other 
investigational drug, biologic, or device or have participated in a clinical drug, biologic, 
or device study within 30 days or 5 half-lives (whichever is longer) prior to Screening 
2. Have clinically significant comorbid medical conditions, a chronic condition that is 
unstable or requires more than 2 medications to be controlled, or be taking concomitant 
medications that, in the opinion of the investigator, may make the participant unsuitable 
for inclusion or have the potential to compromise safety and/or compliance with study 
requirements 
3. Have a diagnosis of dementia of any etiology, including but not limited to: Dementia 
associated with PD (probable or possible), Dementia with Lewy Bodies, Alzheimer’s 
Dementia, and Vascular Dementia 
4. Have any indication of parkinsonism other than idiopathic PD, including secondary 
parkinsonism or atypical parkinsonism 
5. In the opinion of the investigator, be experiencing unpredictable fluctuations in motor 
and/or nonmotor symptoms associated with PD 
6. Have an ongoing central nervous system condition other than idiopathic PD, including 
active neurologic and/or nonremitted psychiatric disorders, in the opinion of the 
investigator 
7. Have a history of brain surgery, deep brain stimulation, a significant head injury causing 
loss of consciousness greater than 30 minutes, or hospitalization due to a brain injury 
8. Have a history, presence, and/or current evidence of intracranial abnormality (eg, stroke, 
hemorrhage, space-occupying lesion) 
9. Have experienced significant psychotic symptoms within the past 3 months, including 
those associated with PD medications, as determined by the investigator  
10. Have a history of possible or probable cerebral amyloid angiopathy according to the 
Boston Criteria (Greenberg 1995) 
11. Be receiving any of the following prohibited medications: 
a. Medications with potent effects at the N-methyl-D-aspartate (NMDA) receptor, 
including memantine, amantadine, ketamine, or related compounds 
b. Medications that inhibit cholesterol absorption (eg, ezetimibe) 
c. Bile acid sequestrants (eg, colesevelam, cholestyramine) 
d. Other medications given at doses, frequencies, or in combinations that are likely, in 
the opinion of the investigator, to have a deleterious effect on cognitive performance, 
based on the 2019 American Geriatrics Society Updated Beers® Criteria for 


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e. Prescribed cannabis or other THC-containing substances 
12. Have an alcohol or drug use disorder within the past 12 months as per DSM-5 criteria 
13. Have a history of seizures or epilepsy, with the exception of a single episode of febrile 
seizures in childhood 
14. Have current or recent suicidality, defined as follows: 
a. Suicidal ideation within the past month, as evidenced by a score of 4 (active suicidal 
ideation with some intent to act, without specific plan) or 5 (active suicidal ideation 
with specific plan and intent) on the screening or baseline Columbia–Suicide Severity 
Rating Scale (C-SSRS) 
b. Suicidal behavior within the past year, as evidenced by a "Yes" on any of the 
5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted 
attempt, preparatory acts, or behavior) on the C-SSRS during Screening or Baseline 
c. Participant presents a serious risk of suicide in the opinion of the investigator. 
15. Have any of the following clinically significant medical conditions: 
a. Any clinically significant finding on 12-lead ECG during Screening or Baseline 
b. Supine vital signs outside of the following ranges during Screening or Baseline; vital 
sign measurements may be repeated once if initial values exceed these ranges: 
− Heart rate <50 or >100 bpm 
− Systolic blood pressure <100 or >160 mmHg 
− Diastolic blood pressure <60 or >100 mmHg 
16. Have significant hepatic, renal, cardiovascular, pulmonary, gastrointestinal, 
hematological, immunologic, ophthalmologic, metabolic, or oncological disease 
17. Have a history, presence, and/or current evidence of serologic positive results for HIV-1 
or HIV-2 
18. Have a positive pregnancy test or be lactating at Screening or Day -1 
19. Be investigative site personnel, sponsor personnel, or an immediate member of their 
family (spouse, parent, child, or sibling whether biological or legally adopted) 
8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study intervention or are not entered in the study. A minimal set of 
screen failure information will be collected, including demography, screen failure details, 
eligibility criteria, and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, with the approval of the medical monitor. Rescreened participants will be 
assigned a new participant number. 


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8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, or administrative reasons. 
The reason for IP discontinuation and/or the reason for early termination from the study must be 
documented in the participant’s study record and recorded in the participant’s electronic case 
report form (eCRF). 
The investigator must notify the sponsor and/or the medical monitor when a participant stops 
participation in the study for any reason. 
8.4.1. 
Investigational Product Discontinuation 
Participants who discontinue IP will be invited by the investigator to complete all of the 
scheduled study visits and assessments through the end of the Treatment Period. Those who 
decline to continue participation will be asked to complete an Early Termination Visit. 
8.4.2. 
Early Termination from the Study 
For participants who are terminated from the study early, if possible, an Early Termination Visit 
should be conducted as described in Table 2 or Table 4. The participant will be permanently 
discontinued both from the IP and from the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
8.4.3. 
Loss to Follow Up 
A participant will be deemed lost to follow up after 3 attempts to contact the participant have 
been unsuccessful. 
8.4.4. 
Replacement of Participants 
Participants who discontinue or withdraw from the study will not be replaced. However, 
additional participants may be dosed if the early discontinuation rate is higher than expected. 


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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Product 
SAGE-718 Oral Tablets are immediate release, white to off-white, round tablets containing 
0.5 mg of SAGE-718 Drug Substance. 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
To be eligible to participate in this study, any concomitant medications must have been taken at a 
stable dose and frequency for at least 4 weeks before the first IP administration and be expected 
to continue at that stable dose until the final study visit is complete. 
The start and end dates, route, dose/units, frequency, and indication for all relevant medications 
and/or supplements will be recorded at Screening, to include all medications and supplements 
taken within 60 days and all medications used to treat PD regardless of timing. At visits 
subsequent to Screening, all changes to any medication should be captured. All medications 
and/or supplements taken from the first dose of IP through the final study visit (including start 
and end dates, route, dose/units, frequency, and indication) will be recorded on the eCRF. 
Because this study aims to measure effects on 
, it is important to evaluate 
single or combined concomitant medications and their doses for their potential effects on 
cognition. Investigators will carefully review concomitant medications for possible 
 
 at Screening to determine participant eligibility and throughout the study. 
9.2.2. 
Prohibited Medications 
Treatment with an investigational drug or device is prohibited within the 30 days (or 5 half-lives 
of the IP, whichever is longer) prior to Screening and until the final Follow-up Visit. 
During the course of the study, adjustment of medication or addition of medications that are 
known to affect cognitive performance (eg, stimulants, benzodiazepines, antipsychotics, 
anticholinergics) is to be avoided as much as possible. Any medication determined necessary for 
the welfare of the participant may be given at the discretion of the investigator at any time during 
the study, however, the use of any prohibited medications will be captured as a protocol 
deviation. 
Use of the following medications is prohibited during the entire course of the study: 
• Medications with potent effects at the NMDA receptor, including memantine, 
amantadine, ketamine, or related compounds 
• Medications that inhibit cholesterol absorption (eg, ezetimibe) 
• Bile acid sequestrants (eg, colesevelam, cholestyramine) 
• Other medications given at doses, frequencies, or in combinations that are likely, in 
the opinion of the investigator, to have a deleterious effect on cognitive performance, 
based on the 2019 American Geriatrics Society Updated Beers® Criteria for 


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• Prescribed cannabis or other THC-containing substances 
9.2.3. 
Other Restrictions 
Participants must agree not to use alcohol or any drugs of abuse (including marijuana) during the 
study. 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal ligation or bilateral tubal occlusion (performed at least 3 months prior 
to Screening) 
• Vasectomized partner (performed at least 3 months prior to Screening) 
• Sexual abstinence (no sexual intercourse) 
Acceptable forms of contraception for male participants include: 
• Sexual abstinence (no sexual intercourse) 
• History of vasectomy (performed at least 3 months prior to Screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
9.3. 
Intervention after the End of the Study 
Not applicable. 
9.4. 
Treatment Adherence 
The investigator(s) or designated staff will observe the participant taking the first dose of IP to 
identify any potential risks to adherence (such as difficulty opening the packaging or swallowing 
the tablets). The time and dose of IP administration will be noted in the source documents. The 
clinician will provide instructions for self-administration of the IP and train the participant to 
track adherence to the IP regimen and food intake in a participant diary. At clinic visits during 
the Treatment Period, a supply of IP will be dispensed for participants to take at home once daily 
until the next scheduled visit. Participants will be required to bring all components of the IP 


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packaging, including empty bottles and unused medication, and the participant diary to the clinic 
at every visit. 
Adherence to the dosing regimen will be assessed at each in-clinic visit. Adherence will be 
assessed by reviewing the participant diary, examining the used packaging, and counting any 
tablets returned by the participant. This information will be documented in the source files and 
eCRF, along with any deviations from the prescribed dosage regimen. Details about IP 
accountability are included in Section 10.6. 
9.5. 
Randomization and Blinding 
This is an open-label study, in which all participants will received unblinded IP. 


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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
SAGE-718 Oral Tablets are immediate release, white to off-white, round tablets containing 
0.5 mg of SAGE-718 Drug Substance. The tablets are composed of SAGE-718 Drug Substance, 
mannitol, microcrystalline cellulose, sodium starch glycolate, and sodium stearyl fumarate. 
10.2. 
Investigational Product Packaging and Labeling 
SAGE-718 Oral Tablets are packaged in high density polyethylene bottles with desiccant, 
induction seal, and child-resistant closures. 
The composition and pharmaceutical quality of the oral tablet will be maintained according to 
current Good Manufacturing Practice (GMP). Labels with all required information and 
conforming to all applicable Code of Federal Regulations and GMP/Good Clinical Practice 
(GCP) guidelines and all other applicable regulations will be prepared by Sage Therapeutics. The 
site pharmacist or designee will prepare labels for individual doses. 
10.3. 
Investigational Product Storage 
SAGE-718 Oral Tablets should be stored in the supplied bottles with 1 g desiccant, capped with 
a child-resistant closure and induction seal, and stored at room temperature. Refer to the shipping 
documentation for product expiry information. 
10.4. 
Investigational Product Preparation 
The IP will be provided to the site in tablet form and will be administered orally as described 
below. 
10.5. 
Investigational Product Administration 
Each 3.0-mg dose of IP will be self-administered as 6 tablets containing 0.5 mg of SAGE-718, 
once daily in the morning within 1 hour after initiating a meal containing approximately 30 g of 
fat. Participants are to swallow the tablets whole with approximately 240 mL (8 fluid ounces) of 
water. For doses taken in the clinic, site staff will watch the participant self-administer the IP. 
10.6. 
Investigational Product Accountability, Handling, and Disposal 
Upon receipt of IP, the pharmacist will inspect the IP and complete and follow the instructions 
regarding receipt and storage in the SAGE-718 Investigator’s Brochure and in the pharmacy 
manual. A copy of the shipping documentation will be kept in the study files. The IP provided is 
for use only as directed in this protocol. 
The investigator or designee must keep a record of all IP received, used, and returned/discarded. 
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
sponsor must be notified immediately. 
Designated site staff will dispense the IP to participants at weekly clinic visits as outlined in the 
Schedules of Assessments (Table 2 and Table 4). 


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In Part B, site staff will access the interactive response technology (IRT) at the Screening Visit to 
obtain a participant identification number for each participant. On Day 1, site staff will access 
the IRT to enroll the eligible participant. During IP-dispensing clinic visits, site staff will access 
the IRT to obtain the medication identification number for the IP to be dispensed to that 
participant. The medication ID number and the number of tablets dispensed must be recorded. 
After Day 1, the participant will return all empty packaging and unused IP to the site at each 
clinic visit during the dosing period, and the number of tablets returned by the participant must 
be recorded. 
The investigator, pharmacist, or qualified designee is responsible for drug accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records). 
Sage Therapeutics or designee will be permitted access to the study supplies at any time with 
appropriate notice during or after completion of the study to perform drug accountability 
reconciliation. At the end of the study, any unused IP will be returned to Sage Therapeutics for 
destruction or destroyed locally per standard operating procedures at the site; disposition of IP 
will be documented. 
More detailed information can be found in the SAGE-718 Investigator’s Brochure and in the 
pharmacy manual. 
10.7. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness, or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution. 
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1. 
Where possible, personnel should segregate and retain any product, materials, or packaging 
associated with the product complaint until further instruction is provided by Sage or its 
designated representative(s). 


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11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS 
A variety of measures will be employed in this study to evaluate
 All assessments are to be 
completed according to the Schedules of Assessments (Table 2 and Table 4) and the
 If necessary to comply with 
local travel restrictions or to limit public health risks to study site staff and study participants, 
assessments scheduled to be conducted at the study site may be performed via telephone, video, 
or in-home visits, if feasible. 
The eligible participants in this study will be in the earliest stages of PD and are expected to be 
able to independently care for themselves. However, some of these assessments include 
information provided by caregivers. For the purposes of this study, the word “caregiver” refers to 
the participant’s study partner. 
11.1. 
Efficacy Assessments 
The assessments described below provide broad 
 
. 
 
 
 
 
During the Baseline Period, participants will be trained by study staff on the use of all software 
applications and devices necessary for the conduct of the study. 
These assessments are to be administered after the daily dose of SAGE-718 during the Treatment 
Period, and at approximately the same time of day (±2 hours) throughout the study. For 
participants receiving medication for PD symptoms, assessments are to be administered in the 
“on” state (defined as the period in which motor symptoms are mitigated due to the effects of PD 
medication). Additionally, participants should be in a fed state during 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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es 
 
 
 
 
11.1.9. 
Daily Remote Assessments 
Participants will complete daily assessments using a mobile device each morning during the 
Treatment Period within 1 hour after IP administration. At scheduled clinic visits, the task will 
be performed in the clinic under observation by study staff, otherwise the participant will 
perform this task remotely (at home). Daily reminders will be provided to complete these 
assessments (
 
). 
11.2. 
Clinical Pharmacology Assessments 
 
 
 
 
 
 
 
. 




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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedules of Assessments (Table 2 and Table 
4) and the
 
Abnormalities in physical examinations, vital signs, electrocardiograms (ECGs), and out of range 
values in laboratory test results will be interpreted by an investigator as clinically significant or 
not clinically significant in the source documents. 
Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be 
documented as part of medical history, AE collection, and prior/concomitant 
medication/procedure collection throughout the study. Questions to be asked are as follows:  
• Were you diagnosed with COVID-19 by a healthcare professional?  
− If the answer is “no”, no further questions. 
− If the answer is “yes”, the following questions are asked:  
▪ Did you have a test? If yes, was the result positive, negative or 
inconclusive?  
▪ Were you isolated? If yes, what were the dates of isolation?  
▪ Were you hospitalized? If yes, what were the dates of hospitalization? 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, ethnicity) and a full medical history will be 
documented.  
12.1.1.1. Screening Assessments 
The following assessments will be performed only at Screening to confirm participant eligibility: 
• Hoehn and Yahr Staging Scale (Goetz 2004): a scale used by clinicians to categorize 
the degree of progression of PD in an individual 
• Test of Premorbid Functioning (Wechsler 2009): a language-based 
neuropsychological tool administered to participants in order to determine their level 
of intellectual function prior to the onset of cognitive impairment 
12.1.2. 
Weight and Height 
Height and weight will be measured and documented. Body mass index will be calculated and 
documented. 
12.1.3. 
Physical Examination 
Whenever possible, the same individual should perform all physical examinations. A full 
physical examination will be performed at Screening, to include assessment of body systems 
(eg, head, eye, ear, nose and throat; heart; lungs; abdomen; and extremities) as well as
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include assessment of general appearance, cardiovascular, respiratory, gastrointestinal, and 
neurological systems, followed by a targeted physical examination as needed. Unscheduled, 
symptom-directed physical examinations may also be conducted at the investigator’s discretion. 
12.1.4. 
Vital Signs 
Vital signs comprise heart rate, respiratory rate, temperature, and blood pressure. Systolic and 
diastolic blood pressure are to be measured after the participant has been supine for at least 
5 minutes prior to the measurement. Orthostatic blood pressure and heart rate will also be 
measured after the participant has been in the supine position for at least 5 minutes and then 
repeated approximately 1 and 3 minutes after standing. 
12.1.5. 
Electrocardiogram 
A 12-lead ECG will be performed at the time points described in Table 2. At each time point, the 
ECGs will be recorded in triplicate at 1-minute intervals. The standard intervals (heart rate, PR, 
QRS, QT, and QTcF) as well as any rhythm abnormalities will be recorded. 
Electrocardiograms will be performed after the participant has been resting in a supine position 
for at least 5 minutes. When ECG measurements coincide with safety assessments, vital signs 
assessment or blood draws, procedures should be carried out in said order (vital signs, ECG, 
blood draw). 
12.1.6. 
Electroencephalogram 
During Screening, EEG monitoring using the 10 to 20 international system for EEG electrode 
placement will occur for a duration of 1 hour. The assessment may be performed on any single 
day during the Screening Period, at any time of day, but preferably while the participant is in a 
fed state. If clinical events suspicious for seizure occur after Screening (eg, episodes of altered 
consciousness and/or involuntary motor behaviors), an unscheduled 1-hour EEG will be 
performed for safety. An additional 1-hour EEG may be performed at the discretion of the 
investigator to follow up on results from any unscheduled EEG. The EEG recording will be 
reviewed by an independent epileptologist to identify evidence of seizure risk (eg, spikes or 
spike and wave discharges), subclinical seizure (eg, synchronous sharp waves and/or 
synchronous spike and wave discharges), seizure corresponding to a clinical event, or changes 
consistent with a postseizure state (eg, focal slowing and/or diffuse slowing). Should the 
independent epileptologist identify evidence for a subclinical or clinical seizure, dosing with 
SAGE-718 will be stopped for that participant. All EEG abnormalities suggestive of seizure risk 
or postseizure state will be reviewed by the study medical monitor. 
12.1.7. 
Laboratory Assessments 
Blood and urine samples will be collected for hematology, biochemistry, coagulation, urinalysis, 
and serology at the time points detailed in Table 2 and Table 4. During Screening only, samples 
for clinical laboratory assessments will be collected from participants when they are in a fasted 
state. 
Analytes to be evaluated are summarized below: 


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Table 6: 
Summary of Clinical Laboratory Analytes 
Biochemistry 
Renal Panel: glucose, calcium, phosphorus, blood urea nitrogen, 
creatinine, sodium, potassium, chloride, bicarbonate 
Hepatic Panel: albumin, ALT, AST, total bilirubin, direct bilirubin, 
indirect bilirubin, alkaline phosphatase, total protein, lactate 
dehydrogenase, gamma glutamyl transferase 
Other: triglycerides, cholesterol (low density lipoprotein [LDL], high 
density lipoprotein [HDL]), creatine phosphokinase, thyroid stimulating 
hormone  
Coagulation 
activated partial thromboplastin time, prothrombin time, and international 
normalized ratio 
Hematology 
red blood cell count (RBC), hemoglobin, hematocrit, white blood cell 
count with differential, platelet count, and if RBC indices are abnormal, 
reflex RBC morphology is indicated 
Urinalysis 
protein, glucose, pH, blood, leukocytes, leukocyte esterase, urobilinogen, 
bilirubin, ketones, nitrite 
Serology (screening only) hepatitis B surface antigen, hepatitis C IgM antibody, HIV-1 antibody, 
HIV-2 antibody 
 
Follicle stimulating hormone testing will be conducted to confirm whether a participant with 
≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being 
postmenopausal. 
12.1.7.1. Pregnancy Testing 
Serum pregnancy (human chorionic gonadotropin) tests will be conducted for all female 
participants during Screening; urine pregnancy tests will be conducted for all female participants 
that are not postmenopausal or surgically sterile at other scheduled time points. A urine 
pregnancy test will also be performed as part of the early termination assessments for 
participants who discontinue the study early. 
12.1.7.2. Drugs of Abuse and Alcohol 
Testing for selected drugs of abuse will be performed via urine dipstick at the study site 
(eg, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, THC, and opiates). 
Alcohol use will be tested by either urine dipstick or breathalyzer at the study site. 
12.1.7.3.  Columbia–Suicide Severity Rating Scale 
Suicidality will be monitored during the study using the C-SSRS (Paul 2011). This scale consists 
of a baseline evaluation that assesses the lifetime experience of the participant with suicidal 
ideation and behavior, and a postbaseline 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 
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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 outlined in Table 2 and Table 4 . 
12.2. 
Adverse Events and Serious Adverse Events 
12.2.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is defined as an AE with onset after the start of IP, or any worsening of a preexisting 
medical condition/AE with onset after the start of IP and throughout the study. The term IP 
includes any Sage IP, a comparator, or a placebo administered in a clinical study. 
Laboratory abnormalities and changes from baseline in vital signs, and ECGs are considered AEs 
if they result in discontinuation or interruption of study treatment, require therapeutic medical 
intervention, meet protocol specific criteria (if applicable) or if the investigator considers them to 
be clinically significant. Any abnormalities that meet the criteria for a SAE should be reported in 
an expedited manner. Laboratory abnormalities and changes from baseline in vital signs and 
ECGs 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 participant has signed the informed consent form (ICF) and 
throughout the duration of the study, whether or not they are related to the study, must be 
reported to Sage Therapeutics. 
Participants who discontinue the IP 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. Any AEs that are unresolved at the 
participant’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. 
12.2.2. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death 


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• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP. 
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
alternative explanation for the AE. 
Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE. 


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12.2.4. 
Recording Adverse Events 
AEs spontaneously reported by the participant and/or in response to an open question from the 
study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome and seriousness (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s) 
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.5. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage or designee. 
Additional follow-up information, if required or available, should all be sent to Sage or designee 
within 24 hours of receipt on a follow-up SAE report form and placed with the original SAE 
information and kept with the appropriate section of the eCRF and/or study file. 
SAEs occurring after the designated follow-up time for the study, should be reported to Sage or 
designee according to the timelines noted above only if the investigator considers the SAE 
related to IP. 
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all suspected unexpected serious 
adverse reactions (SUSARs) that occur during the clinical study. IRBs/IECs will be notified of 
all SAEs and/or SUSARs as required by local law. 


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In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARs to investigators in a blinded fashion. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 
pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy. The investigator will also attempt to collect pregnancy information on any 
participant’s partner who becomes pregnant after the participant has received the first 
administration of IP. After obtaining the necessary signed ICF from the pregnant partner directly, 
the investigator will follow the same pregnancy reporting procedures specified for pregnant 
participants. 
The participant or participant’s partner will be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies (eg, spontaneous abortion, elective abortion, normal 
birth) must be followed and documented even if the participant was discontinued from the study. 
The investigator will collect follow-up information on the participant or participant’s partner and 
the neonate, and the information will be forwarded to Sage or designee. Generally, follow up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination 
of pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, preeclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(ie, spontaneous abortion, stillbirth, neonatal death,), the investigator should follow the 
procedures for reporting an SAE. 
12.4. 
Overdose 
An overdose is any dose of study treatment given to a participant or taken by a participant that 
exceeds the dose described in protocol. Overdoses are not considered AEs and should not be 
recorded as an AE on the eCRF; however, all overdoses must be recorded on an overdose form 
and sent to Sage or designee within 24 hours of the site becoming aware of the overdose. An 
overdose must be reported to Sage or designee even if the overdose does not result in an AE. If 
an overdose results in an AE, the AE must be recorded. 


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13. 
STATISTICS 
Detailed description of the analyses to be performed in the study will be provided in the 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to database lock. 
Any changes/additions to the SAP following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
The Safety Set will include all participants who were administered IP and will be used to 
describe the safety data. 
The Full Analysis Set will include all participants in the Safety Set with baseline and at least 
1 postbaseline efficacy evaluations. 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All participants will be used in the analyses, 
as per the analysis populations, using all nonmissing data available. No imputation process will 
be used to estimate missing data. 
13.3. 
General Considerations 
All participant data, including those that are derived, that support the tables and figures will be 
presented in participant data listings. 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to the first dose of IP. 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, maximum, Q1, and Q3. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages. 
13.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and body mass index, will be summarized using the Safety Set. 
Pregnancy test results and drug and alcohol test results will be listed but not summarized. 
Medical history will be listed by participant. 
13.5. 
Efficacy Analysis 
The endpoints for each of the
are change from baseline scores at each 
postbaseline assessment. Descriptive statistics of scores and change from baseline scores will be 
summarized based on the Full Analysis Set. These endpoints will also be analyzed using a 
mixed-effects model for repeated measures. The model will include baseline


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and assessment time point. Model-based point estimates (ie, least squares means, 95% 
confidence intervals, and p values) at each time point will be reported where applicable. An 
unstructured covariance structure will be used to model the within-participant errors. If there is a 
convergence issue with the unstructured covariance model, a Toeplitz or Autoregressive (1) 
[AR(1)] covariance structure will be used, following this sequence until convergence is achieved. 
Line plots of change from baseline scores will be plotted with standard error bars. Other 
continuous efficacy endpoints, including
will be summarized using similar methods. 
Additional analyses will be detailed in the SAP. 
13.5.1. 
Multiplicity Adjustment 
Not applicable. 
13.5.2. 
Sensitivity Analyses 
Not applicable. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-718 will be evaluated by TEAEs and change from baseline in 
vital signs, clinical laboratory analytes, ECGs, and responses on the C-SSRS. Safety data will be 
listed by participant and summarized by treatment group. All safety summaries will be 
performed on the Safety Set. 
13.6.1. 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities version 22.0 or higher. A 
TEAE is defined as an AE with onset after the first dose of IP. The analysis of AEs will be based 
on the concept of TEAEs. The incidence of TEAEs will be summarized by System Organ Class 
and preferred term. In addition, summaries will be provided by intensity (mild, moderate, severe) 
and by causality (related, not related) to IP. 
Any TEAEs leading to discontinuation or interruption of treatment or withdrawal from the study 
and any treatment-emergent SAEs will be summarized. 
All AEs and SAEs (including those with onset or worsening before the start of IP) 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 ranges for each parameter will be provided by the 
laboratory; shift from baseline to postbaseline values in abnormality of results will be provided. 
Potentially clinically significant values will be summarized by treatment. Clinical laboratory 
results will be listed by participant and timing of collection. 
13.6.3. 
Physical Examinations 
The occurrence of a physical examination (yes/no) and the date performed will be listed by 
participant. 


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13.6.4. 
Vital Signs 
Vital sign results at each visit and mean changes from baseline will be summarized by scheduled 
visit. Potentially clinically significant values will be summarized by treatment. Vital sign results 
will be listed by participant 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 participant: 
heart rate, PR, QRS, QT, and QTcF. The derived mean of each parameter will also be listed. 
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 participant 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 and supplements taken within 60 days prior to informed consent through the 
duration of the study will be recorded, as well as all medications used to treat PD regardless of 
timing. Those medications taken prior to the first dose of IP will be denoted “Prior”. Those 
medications taken prior to the first dose of IP and continuing beyond the initiation of the IP or 
those medications started at the same time or after the initiation of the IP will be denoted 
“Concomitant”. 
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant. 
Details of prior and concomitant medications will be listed by participant, start date, and 
verbatim term. 
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 and summarized for all participants. Listings will include behavior type and/or 
category for Suicidal Ideation and Suicidal Behavior of the C-SSRS. 
13.8. 
Sample Size and Power 
No formal sample size calculation was made for this study. Ten participants completing 14 days 
of dosing in Part A and 20 completing 28 days of dosing in Part B are considered sufficient to 
assess preliminary safety and tolerability and for signal-finding of
after repeated 
dosing with of SAGE-718. Assuming a 10% dropout rate, approximately 33 total participants 


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will be required to obtain 30 completers. Additional participants may be dosed if the early 
discontinuation rate is >10%. 
13.8.1. 
Interim and Data Monitoring Committee Analysis 
Not applicable. 


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


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14.3. 
Institutional Review Board or Independent Ethics Committee 
The principal investigator must obtain IRB (or IEC) approval for the clinical study prior to 
enrolling a participant. Initial IRB (or IEC) approval, and all materials approved by the IRB (or 
IEC) for this study including the participant consent form and recruitment materials must be 
maintained by the investigator and made available for inspection. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, Sage Therapeutics 
may conduct a quality assurance audit(s) at the clinical site. Please see Section 14.2 for more 
details regarding the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Significant protocol deviations should be reported to the IRB/IEC per the IRB/IEC’s 
written procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates study-related duties and functions conducted at the study site. When the investigator 
retains the services of any individual or party to perform study-related duties and functions, the 
investigator must ensure the individual or party is qualified to perform study-related duties and 
functions and should implement procedures to ensure the integrity of the study-related duties and 
functions performed, and any data generated. 
The investigator must maintain adequate and accurate source documents and study records that 
include all pertinent observations on each of the site’s study participants. Source data must be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained, if necessary 
to provide clarification. 


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be given a written and 
dated approval or favorable opinion by an IRB or IEC as appropriate. The investigator must 
obtain and document approval before he or she can enroll any participant into the study. The IRB 
or IEC must supply to the sponsor a list of the IRB/IEC membership and a statement to confirm 
that the IRB/IEC is organized and operates according to GCP and applicable laws and 
regulations. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the IP. Sage 
Therapeutics will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. In addition, the principal investigator must 
inform the IRB/IEC and sponsor of any changes significantly affecting the conduct of the study 
and/or increasing the risk to participants (eg, violations to the protocol or urgent safety measures 
taken for participant safety). 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH and GCP guidelines, as well as all 
applicable regional or national regulatory requirements. 
16.3. 
Written Informed Consent 
Prior to enrolling a study participant, the investigator(s) will ensure that the participant is given 
full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study. Participants must also be notified that they are free to discontinue from the 
study at any time. The participant should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
When the participant decides to participate in the study, the participant (or the participant’s, 
parent or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source records. The investigator must maintain 
the original, signed ICF. A copy of the signed ICF must be given to the participant or to the 
participant’s parent or legally authorized representative. 
Throughout the study participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 
documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics or its representative(s) will be allowed to conduct site visits at the 
investigation facilities for the purpose of monitoring any aspect of the study. The investigator 
agrees to allow the monitor to inspect the facility, drug storage area, drug accountability records, 
participant charts and study source documents, and other records relative to study conduct. 
Inspection of the study by a regulatory authority may occur at any time. The investigator must 
agree to the inspection of study-related records and source documents by the regulatory authority 
representative(s). 
17.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the IP. Sage is responsible to inform the investigator/institution as to when study documents 
no longer need to be retained. 


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18. 
PUBLICATION POLICY 
All information concerning SAGE-718 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 
American Geriatrics Society Beers Criteria Update Expert Panel. J Am Geriatr Soc. 
2019 Apr;67(4):674-694. 
Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES/ENS recommendations for the 
diagnosis of Parkinson’s disease. Eur J Neurol. 2013;20:16-34. 
 
 
 
 
 
 
. 
Collingridge GL, Volianskis A, Bannister N, et al. The NMDA receptor as a target for cognitive 
enhancement. Neuropharmacology. 2013 Jan 1;64:13-26. 
Di Natale C, Monaco A, Pedone C, et al. The level of 24-hydroxycholesteryl esters decreases in 
plasma of patients with Parkinson's disease. Neurosci Lett. 2018 Apr 13;672:108-112. 
Goetz CG, Poewe W, Rascol O, et al. Movement Disorder Society Task Force Report on the 
Hoehn and Yahr Staging Scale: Status and Recommendations. Mov Disord. 2004;19(9):1020-
1028. 
Greenberg SM, Rebeck GW, Vonsattel JP, et al. Apolipoprotein E epsilon 4 and cerebral 
hemorrhage associated with amyloid angiopathy. Ann. Neurol. 1995;38(2):254-9. 
 
 
 
 
 
 
 
Litvan I, Aarsland D, Adler CH, et al. MDS Task Force on mild cognitive impairment in 
Parkinson's disease: critical review of PD-MCI. Mov Disord. 2011;26(10):1814–1824. 
Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: A 
Brief Screening Tool for Mild Cognitive Impairment. J Am Ger Soc. 2005 Mar;53(4):695-699. 
 
Paul SM, Doherty JJ, Robichaud AJ, et al. The major brain cholesterol metabolite 
24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors. 
J Neurosci. 2013;33:17290-17300. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. 


Clinical Protocol 
Sage Therapeutics, Inc. 
718-CNP-201, Version 5 
CONFIDENTIAL 
67 
 
 
 
Wechsler D. Test of premorbid functioning. San Antonio, TX: The Psychological Corporation. 
2009. 
 
 


718-CNP-201 Summary of Changes
Sage Therapeutics 
Version 5, Amendment 4
1 
Protocol  718-CNP-201, Amendment 4 
Date of Amendment: 28 April 2021 
An Open-Label Evaluation of the Safety and Tolerability of SAGE-718 in Participants with 
Parkinson’s Disease Mild Cognitive Impairment 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to add a Part B to explore the safety and 
efficacy of longer duration dosing (28 versus 14 days). Associated changes to the planned 
number of participants, planned study duration and duration of treatment, schedule of 
assessments, and sample size and power based on the addition of Part B have been incorporated. 
Other changes incorporated with this amendment include the following: 
•
Included a provision that participants who screen fail may be rescreened once, with
the approval of the medical monitor. Rescreened participants will be assigned a new
participant number.
•
Corrected text in Section 9.2.1 Prior and Concomitant Medications and/or
Supplements to align with inclusion criterion #11 to state that concomitant
medications must have been taken at a stable dose and frequency for at least 4 weeks
before the first IP administration.
•
Added text to describe IP accountability, handling, and disposal due to the addition of
Part B.
•
Added COVID-19 questions to be asked to document information regarding
diagnosis, isolation, and/or hospitalization due to COVID-19 as part of medical
history, AE collection, and prior/concomitant medication/procedure collection
throughout the study.
•
Minor textual changes have been made throughout the protocol to increase clarity on
the procedures of the study.
Corrections to typographical errors, punctuation, grammar, abbreviations, and formatting 
have been made 


718-CNP-201 Summary of Changes 
Sage Therapeutics 
Version 4, Amendment 3  
 
 
1 
718-CNP-201, Amendment 3 
Date of Amendment: 25 January 2021 
An Open-Label Evaluation of the Safety and Tolerability of SAGE-718 in Participants with 
Parkinson’s Disease Mild Cognitive Impairment  
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to broaden range of eligible participants by 
revising the participant eligibility criteria. Several additional changes are being implemented as 
outlined below: 
• Inclusion criterion 9 has been updated to allow entry to otherwise eligible participants 
who do not have an eligible study partner. 
• Inclusion criterion 10 has been revised to allow entry to participants who require the 
use of a walker or wheelchair. 
• Inclusion criterion 11 has been revised to allow entry to participants who have been 
taking any concomitant medications at stable dose and frequency for at least 4 weeks 
prior to IP administration. 
• Inclusion criterion 12 has been revised to allow entry to participants whose motor 
symptoms have been stable for at least 4 weeks prior to screening. 
• Exclusion criterion 6 has been updated to allow the investigator to determine the 
presence of ongoing central nervous system conditions, whether or not they have 
been diagnosed prior to Screening. 
• Exclusion criterion 9 has been revised to exclude participants who have experienced 
significant psychotic symptoms, as determined by the investigator. 
• Exclusion criterion 11d has been clarified to allow the investigator to assess whether 
a prospective participant’s medications could have a deleterious effect on cognitive 
performance. 
• Signatories have been updated to reflect sponsor staff changes. 
• Minor textual changes have been made throughout the protocol to increase clarity on 
the procedures of the study, and corrections to typographical errors, punctuation, 
grammar, abbreviations, and formatting have been made. 




718-CNP-201 Summary of Changes 
Sage Therapeutics 
Version 3, Amendment 2  
 
 
2 
Table 1: 
Protocol Amendment 2 Detailed Summary of Changes 
The primary section of the protocol affected by the changes in Protocol Amendment 2 is 
indicated. The corresponding related text has been revised throughout the protocol. Deleted text 
is indicated by strikeout; added text is indicated by bold font. 
Purpose: To decrease burden on sties and patients, tests for drugs of abuse will now be performed via 
urine tests at the site at all time points, instead of serum testing at a central laboratory. 
The primary change occurs in Section 12.1.7.2, Drugs of Abuse and Alcohol. 
Revised text: 
During Screening and Baseline, urine will be tested at the study site Testing for selected drugs of abuse 
will be performed via urine dipstick at the study site (eg, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, THC, and opiates). Thereafter, drug testing will be performed 
at a central laboratory using the blood samples collected for clinical laboratory assessments. Alcohol 
use will be tested viaby either urine dipstick or breathalyzer at the study site. 
Sections also affected by this change: 
Table 2, Schedule of Assessments 
Purpose: Text revisions have been added to improve clarity and readability. 
The primary change occurs in Section 7.1, Overall Study Design. 
Revised text: 
7.1.1.     Screening Period 
The Screening Period begins with the informed consent process for prospective participants, including 
study partners. Subsequent screening assessments will be performed between Day -21 and Day -8 to 
determine eligibility, including assessments of
 
7.1.2.     Baseline Period 
The Baseline Period will occur from Day -7 through Day -1. During this period, each participant will 
receive dietary counseling to aid in choosing a morning meal containing approximately 30 g fat for to 
consume prior to dosing. On Day -7 (±1 day), participants will visit the clinic for confirmation of 
continued eligibility and collection of baseline
and safety data. Additionally, participants will 
be trained on the use of a mobile data capture device to perform daily
, dosing regimen adherence, and food intake. Participants will continue to complete daily 
assessments of 
 using the mobile device at home during the Baseline 
Period. On Day -1, participants will return to the study site for confirmation of continued eligibility and 
collection of baseline 
 and safety data. 
7.1.3.     Treatment Period 
Beginning on Day 1 and continuing through Day 14, participants will self-administer 3.0 mg SAGE 
718 (as six 0.5-mg oral tablets), once per day in the morning within 1 hour after initiating a meal 
containing approximately 30 g of fat, in accordance with the guidelines provided in a nutritional 
information brochure. Participants will continue to complete daily remote assessments of 
 
 via mobile device either remotely (at home), or in the clinic at scheduled 
visits and will track IP dosing and predose food intake in a participant diary. Treatment Period 
clinic visits will occur on  
On Day 1, Day 7 (±1 day), and Day 14, participants will arrive at the clinic in the morning prior 
to IP dosing and completion of daily mobile device tasks. Following predose procedures, 


718-CNP-201 Summary of Changes 
Sage Therapeutics 
Version 3, Amendment 2  
 
 
3 
participants will eat a morning meal, then take the IP and complete the mobile device tasks under 
staff supervision. 
At scheduled clinic visits during the Treatment Period, safety, efficacy, and 
 will be 
performed, and study staff will dispense a sufficient amount of SAGE-718 for daily administration 
until the next scheduled study visit. In addition to weekly clinic visits, study staff will contact 
participants by telephone on Day 4 to document any TEAEs and/or changes in concomitant 
medications. 
7.1.4      Follow-up Period 
Study staff will contact participants by telephone on Day 21 to document any AEs and/or 
changes in concomitant medications. Participants will return to the clinic on Day 28 
(±2 days) for a follow-up visit. 
Sections also affected by this change: 
Synopsis  
Purpose: Duplicative text has been removed from the description of statistical methods. 
The primary change occurs in: Section 2, Synopsis. 
Deleted text: 
Safety Analysis 
AEs will be coded using Medical Dictionary for Regulatory Activities with the overall incidence of 
AEs displayed by System Organ Class and preferred term. Incidence of treatment-emergent AEs will 
also be presented by maximum severity and relationship to IP. Data from vital signs, clinical laboratory 
measures, ECG, and C-SSRS will be summarized using descriptive statistics. Continuous endpoints 
will be summarized with n, mean, standard deviation, median, minimum, and maximum. In addition, 
change from baseline values will be calculated at each time point and will be summarized using the 
same summary statistics. Out of range safety endpoints may be categorized as low or high, where 
applicable. For all categorical endpoints, summaries will include counts and percentages. 
Purpose: Duplicative text has been removed from the description of restricted participant activities. 
The primary change occurs in: Section 9.2.3, Other Restrictions. 
Revised text:Participants must be willing to comply with all study procedures and restrictions, 
including the following for the time frames specified: 
Consumption ofagree not to use alcohol or any drugs of abuse (including marijuana) during the study 
Purpose: Clarification has been added to ensure 
 are performed after IP dosing. 
The primary change occurs in: Section 11.1, Efficacy Assessments. 
Revised text:AtDuring the Baseline Period, participants will be trained by study staff on the use of all 
software applications and devices necessary for the conduct of the study. 
These assessments are to be administered after the daily dose of SAGE-718 during the Treatment 
Period, and at approximately the same time of day (±2 hours) throughout the study. Additionally, 
participants should be in a fed state during
 
Purpose: Text has been deleted to provide an accurate description of the version of the instrument that 
will be used in this study.  
The primary change occurs in: 
. 






718-CNP-201 Summary of Changes 
Sage Therapeutics 
Version 3, Amendment 2  
 
 
6 
Purpose: Unecessary duplicative text was removed from the planned statistical methods. 
The primary change occurs in the Section 13.3, General Considerations. 
Revised text: 
All participant data, including those that are derived, that support the tables and figures will be 
presented in participant data listings. Some data may be presented only in participant data listings and 
some may be presented with a corresponding table or figure; these will be indicated in relevant sections 
below. 
Purpose: Correct typographical errors, punctuation, grammar, abbreviations, and formatting. 
These changes are not listed individually. 


718-CNP-201 Summary of Changes 
Sage Therapeutics 
Version 2, Amendment 1  
 
 
1 
718-CNP-210 Amendment 1 
Date of Amendment: 16 April 2020 
An Open-Label Evaluation Of The Safety And Tolerability Of Sage-718 In Participants 
With Mild Cognitive Impairment Or Mild Dementia Due To Alzheimer’s Disease 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to align procedures across protocols in the 
program and to clarify the procedures to be followed in the study. Several additional changes are 
being implemented as outlined below: 
 To address changing public health advisories and the possibility of local travel 
restrictions at the time of enrolment, assessments scheduled to be conducted at the 
study site may be performed via telephone, video, or in-home visits, if necessary and 
feasible.  
 The requirement for participants to attend all clinic visits in a fasted state for clinical 
laboratory assessments has been removed to reduce the burden on participants.  
 Exclusion Criterion 2 has been expanded to exclude patients with chronic conditions 
that are unstable and /or require more than 2 medications to control, in order to 
protect patient safety and facilitate the interpretation of pharmacokinetic data. 
 A new eligibility criterion has been added to exclude those with possible or probable 
cerebral amyloid angiopathy, to protect patient safety, as this condition could increase 
exposure to the investigational product (IP). 
 Benzodiazepines have been removed from the prohibited medications list to allow 
investigators to make case-by-case decisions in the context of each patient’s medical 
history and concomitant medications using the American Geriatrics Society Beers 
Criteria® for Potentially Inapropriate Medication Use in Older Adults. 
 Positive hepatitis B/C test results have been removed from the exclusion criteria, in 
order to expand the number of patients who may safely participate in the study. 
 
 
 
 
 
 An explanation was added that study partners must provide informed consent during 
Screening to participate. 
 Descriptions of safety assessments have been expanded for clarity. 
 
 
 
 Signatories have been changed to reflect current staffing at Sage Therapeutics. 
A detailed summary of changes is provided in Table 1. Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed. 


718-CNP-201 Summary of Changes 
Sage Therapeutics 
Version 2, Amendment 1  
 
 
2 
Table 1: 
Protocol Amendment 1 Detailed Summary of Changes 
The primary section of the protocol affected by the changes in Protocol Amendment 1 is 
indicated. The corresponding related text has been revised throughout the protocol. Deleted text 
is indicated by strikeout; added text is indicated by bold font. 
Purpose: To address changing public health advisories and the possibility of local travel restrictions 
at the time of enrolment, assessments scheduled to be conducted at the study site may be performed via 
telephone, video, or in-home visits, if necessary and feasible.
The primary change occurs in Section 7.1, Overall Study Design. 
Added text: 
In the setting of public health advisories or similar risks to patient safety, assessments scheduled 
to be conducted at the study site may be performed via telephone/video if feasible. For 
assessments that cannot be conducted by phone or video, an in-home visit may be conducted. 
Sections also affected by this change: 
 
Synopsis 
 
Section 11, Efficacy and Clinical Pharmacology Assessments 
Purpose: The requirement for participants to attend all clinic visits in a fasted state for clinical 
laboratory assessments has been changed to fasting only for screening clinical laboratory assessments, 
in order to reduce the burden on participants.  
The primary change occurs in Section 7.1, Overall Study Design. 
Revised text: 
Beginning on Day 1 and continuing through Day 14, participants will self-administer 3.0 mg SAGE 
718 (as six 0.5-mg oral tablets), once per day in the morning within 1 hour after einitiating a meal 
containing approximately 30 g of fat, in accordance with the guidelines provided in a nutritional 
information brochure. Participants will complete daily remote assessments of 
 
. Treatment Period clinic visits will occur on Day 1, Day 7, (±1 
day), and Day 14. For each Treatment Period clinic visit, participants will arrive at the clinic after an 
overnight fast. Following predose procedures, participants will eat a morning meal and take the IP 
under staff supervision within 1 hour after initiating the meal.
Sections also affected by this change: 
 
Synopsis  
 
Section 12.1.7, Laboratory Assessments 
Purpose: Exclusion criterion 2 has been expanded to exclude those with chronic conditions that are 
unstable and /or require more than 2 medications to control, in order to protect patient safety and 
facilitate the interpretation of pharmacokinetic data. 
The primary change occurs in: Section 8.2, Participant Exclusion Criteria. 
Added text: 
2. Have clinically significant comorbid medical conditions, a chronic condition that is 
unstable or requires more than 2 medications to be controlled, or be taking concomitant 
medications that, in the opinion of the investigator, may make the participant unsuitable for 
inclusion or have the potential to compromise safety and/or compliance with study 
requirements 


718-CNP-201 Summary of Changes 
Sage Therapeutics 
Version 2, Amendment 1  
 
 
3 
Sections also affected by this change: 
 
Synopsis  
Purpose: A new eligibility criterion has been added to exclude those with possible or probable 
cerebral amyloid angiopathy, in order to protect patient safety, as this condition could increase 
exposure to the investigational product (IP). 
The primary change occurs in: Section 8.2, Participant Exclusion Criteria. 
Added text: 
10. Have a history of possible or probable cerebral amyloid angiopathy (CAA), according to 
the Boston Criteria  (Greenberg 1995) 
Sections also affected by this change: 
 
Synopsis  
Purpose: Specific prohibitions and allowances for benzodiazepines have been removed from the 
exclusion criteria to allow investigators to make case-by-case decisions using the American Geriatrics 
Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. 
The primary change occurs in: Section 8.2, Participant Exclusion Criteria. 
Revised text: 
12. Be receiving any of the following prohibited medications: 
a. Medications with potent effects at the N-methyl-D-aspartate (NMDA) receptor, including 
memantine, amantadine, ketamine, or related compounds 
b. Ezetimibe or similar medications that inhibit cholesterol absorption 
c. Bile acid sequestrants (eg, colesevelam, cholestyramine) 
d. Long acting benzodiazepines (eg, clonazepam). Shorter acting benzodiazepines 
(eg, lorazepam) are allowed if dose is stable for 8 weeks prior to the first IP 
administration.Other medications given at doses or in combinations that are likely to have 
a deleterious effect on cognitive performance, as described in the 2019 American 
Geriatrics Society Updated Beers Criteria® for Potentially Inappropriate Medication Use 
in Older Adults
Sections also affected by this change: 
 
Synopsis  
Purpose: The history or presence of serologic positive hepatitis B and hepatitis C have been removed 
from the exclusion criteria, in order to expand the number of patients who may safely participate in the 
study. 
The primary change occurs in Section 8.2, Participant Exclusion Criteria. 
Revised text: 
14. Have a history, presence, and/or current evidence of serologic positive results hepatitis B 
surface antigen, hepatitis C antibodies, or HIV 1 or 2 for HIV-1 or HIV-2  
Sections also affected by this change: 
 
Synopsis  


718-CNP-201 Summary of Changes 
Sage Therapeutics 
Version 2, Amendment 1  
 
 
4 
Purpose: 
 
 
 
 
 
 
 
 
 
 
 
 
Sections also affected by this change: 
 
Synopsis 
 
Section 11.1, Efficacy Assessments 
Purpose: Clarification was added that both participants and their study partners must provide 
informed consent during Screening. 
The primary change occurs in the Section 7.1, Overall Study Design. 
Revised text: 
The Screening Period begins with the informed consent process for eligible participants, including 
study partners. Subsequently, screening assessments will be performed between Day -21 and Day 
-8 Participants will undergo procedures to determine eligibility during a 14 day window, including 
assessments of 
. 
Sections also affected by this change: 
 
Synopsis 
Purpose: Revised the description of the testing procedure for drugs of abuse to align study procedures 
across the program. 
The primary change occurs in Section 12.1.7.3. 
Revised text: 
During Screening and Baseline, Uurine will be tested at the study site for selected drugs of abuse (eg, 
amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, THC, and 
opiates); these results will be confirmedthereafter, drug testing will be performed 
by blood screens at the central laboratory using the bloodsame samples collected for 
clinical laboratory assessments. 
Sections also affected by this change: Synopsis 
Purpose: New subsections for pregnancy testing and virus serology have been created within the 
Laboratory Assessments section to provide more complete descriptions of the testing procedures. 
The primary change occurs in Section 12.1.7.. 


718-CNP-201 Summary of Changes 
Sage Therapeutics 
Version 2, Amendment 1  
 
 
5 
Revised text: 
12.1.7.1     Virus Serology 
Subjects will be tested for hepatitis B surface antigen, anti-hepatitis C virus antibody or 
hepatitis C antigen (RNA), and human immunodeficiency virus (HIV-1 and HIV-2) antibody 
during Screening.  
12.1.7.2     Pregnancy ScreenTesting 
A Serum pregnancy (human chorionic gonadotropin) tests will be conducted for all female 
participants atduring Screening; a urine pregnancy tests will be conducted for all female participants 
that are not postmenopausal or surgically sterile at other scheduled time points. Follicle stimulating 
hormone testing will be conducted during Screening to confirm whether a participant with ≥12 months 
of spontaneous amenorrhea meets the protocol-defined criteria for being postmenopausal (Section 8.1). 
A urine pregnancy test will also be performed as part of the early termination assessments for 
subjects who discontinue the study early. 
If a participant becomes pregnant during the study, the process for reporting the pregnancy and 
guidance for collection of information related to the pregnancy is outlined in Section 12.3. 
Sections also affected by this change: Synopsis 
Purpose: The abbreviated physical examination has been defined to provide clarity and consistency.  
The primary change occurs in Section 12.1.3.. 
Revised text: 
Thereafter, abbreviated physical examinations will include a brief medical historyassessment of 
general appearance, cardiovascular, respiratory, gastrointestinal, and neurological systems, 
followed by a targeted physical examination as needed. 
Sections also affected by this change: Synopsis 
Purpose: Oxygen saturation has been removed from the list of vital signs to be documented, in 
alignment with other SAGE-718 protocols, as well as the specification that temperature must 
be taken orally. 
The primary change occurs in Section 12.1.4.. 
Revised text: 
Vital signs comprise heart rate, respiratory rate, oral temperature (°C), oxygen saturation, and blood 
pressure.  
Sections also affected by this change: Synopsis 
Purpose: 
 
 
The primary change occurs in Section 11.2.2, Pharmacodynamic Assessments. 
Revised text: 


718-CNP-201 Summary of Changes 
Sage Therapeutics 
Version 2, Amendment 1  
 
 
6 
11.2.2     Pharmacodynamic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
  
     
 
 
 
 
 
 
 
 
 
 
 
 
Sections also affected by this change: Synopsis 
Purpose: Correct typographical errors, punctuation, grammar, abbreviations, and formatting. 
These changes are not listed individually. 

SAP_001.pdf: 
 
Official Title: An Open-Label Evaluation of the Safety and Tolerability of SAGE-718 
in Participants with Parkinson’s Disease Mild Cognitive Impairment 
NCT Number: NCT04476017 
Document Date: SAP Version 1.0: 06-May-2022 
 
 
 


Clinical Study Report 
 
718-CNP-201 
16.1 Study Information 
 
1 
 
 
  
 
9. 
DOCUMENTATION OF STATISTICAL METHODS 
Statistical Analysis Plan (SAP) v1.0 Version Date: 05 May 2022 










Statistical Analysis Plan (SAP) V 1.0
Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
PRA-QMS-02745 9.0
Page 5 of 64
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
Purpose
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Sage Therapeutics Protocol 718-CNP-201: An Open-Label Evaluation of 
the Safety and Tolerability of SAGE-718 in Participants with Parkinson’s Disease Mild Cognitive 
Impairment 718-CNP-201.
Scope
This SAP describes the statistical methods to be used during the reporting and analyses of data collected 
from Sage Therapeutics Protocol 718-CNP-201, titled “An Open-Label Evaluation of the Safety and 
Tolerability of Sage-718-201 in Participants with Parkinson’s Disease Mild Cognitive Impairment”.
The Statistical Analysis Plan outlines the following:
x
Study Objectives
x
Study Design
x
Study Endpoints 
x
The Analysis sets
x
Applicable Study Definitions
x
Statistical Methods
Introduction
This is an open-label study evaluating the safety and tolerability of SAGE-718 and its effects on
 in participants with PD-MCI. Eligible participants
with a confirmed diagnosis of idiopathic PD by 2015 Movement Disorder Society (MDS) criteria at
Screening and who meets MDS Task Force Criteria for MCI in PD (excluding the requirement for UK PD
Brain Bank diagnostic criteria) will receive a 3.0 mg dose of SAGE-718 daily for 14 days (Part A) or 28 days 
(Part B).
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol version 5 dated 28-Apr-2021 and CRF dated 16-Oct-
2020 for Part A and CRF dated 09-Aug-2021 for Part B.
Changes to the protocol will require an SAP amendment ONLY if the changes are to a principal feature of 
the protocol.
Final approval of the SAP by the Sponsor and PRA statistician will occur prior to database lock. Any 
changes made to the SAP after the clinical database lock, along with the justification for the changes, will 
be described in the CSR. 
6.1 Changes from the Protocol 
Protocol section 13.6.6 mentions that the prior and concomitant medications will only be listed. Along with 
the listing, a summary table will also be provided.
   		
		


Statistical Analysis Plan (SAP) V 1.0
Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
PRA-QMS-02745 9.0
Page 6 of 64
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
Protocol Modifications
7.1 Modifications to the Approved Clinical Study Protocol 
Protocol versions 2 and 3 are updated to align procedures across protocols in the program and provide 
clarification on the procedures.
Version 4.0 is updated to broaden the range of eligible participants by revising the participant eligibility 
criteria.
The primary purpose of version 5.0 is to add a Part B study to explore the safety and efficacy of longer 
duration dosing for 28 days instead of 14 days in Part A. Associated changes to the planned number of 
participants, planned study duration and duration of treatment, schedule of assessments, and sample size
and power based on the Part B study have been incorporated.
7.2 Modifications to the Approved Statistical Analysis Plan
None.
7.3 Modifications to the Approved DMC Charter
Not applicable
Study Objectives
8.1 Primary Objective
x
Evaluate the safety and tolerability of orally administered SAGE-718 in participants with 
Parkinson’s disease mild cognitive impairment (PD-MCI). 
x
 
x
x
x
x
Study Endpoints
9.1 Primary Endpoint
x
Incidence of treatment-emergent adverse events (TEAEs)
9.2 Secondary Endpoints
x
Change from baseline in vital signs, clinical laboratory analytes, and electrocardiograms 
(ECGs).
x
Responses on the Columbia–Suicide Severity Rating Scale (C-SSRS).
   		
		




Statistical Analysis Plan (SAP) V 1.0
Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
PRA-QMS-02745 9.0
Page 8 of 64
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
x
 
x
x
x
x
Study Design
10.1 Overall Design
This study will enroll up to 33 (11 in Part A and 22 in Part B) participants. Part A participants complete 14 
days of dosing and Part B participants complete 28 days of dosing in the study. A total of 30 participants
are expected to complete dosing in the study. Additional participants may be dosed if the early 
discontinuation rate is >10%. 
This is an open-label study evaluating the safety and tolerability of SAGE-718 and its effects on
 
 in participants with PD-MCI. Eligible participants with a confirmed 
diagnosis of idiopathic PD by 2015 Movement Disorder Society (MDS) criteria at Screening and who meet 
MDS Task Force Criteria for MCI in PD (excluding the requirement for UK PD Brain Bank diagnostic criteria) 
will receive a 3.0 mg dose of SAGE-718 daily for 14 days (Part A) or 28 days for (Part B) within 1 hour of 
30g fat meal.
The study consists of a Screening Period, a Baseline Period, a Treatment Period, and a Follow-Up Period. 
The Screening Period begins with the informed consent process for prospective participants,
including caregivers. Subsequent screening assessments will be performed between Day -21 and
Day -8 to determine eligibility, including assessments of 
.
The Baseline Period will occur from Day -7 through Day -1. During this period, each participant will
receive dietary counseling to aid in choosing a morning meal containing approximately 30 g of fat for
dosing. On Day -7 (±1 day), participants will visit the clinic for confirmation of continued eligibility
and collection of baseline 
 and safety data.
The Treatment Period will begin on Day 1 and continue through Day 14 in Part A and Day 28 in Part B.
During this time, participants will self-administer 3.0 mg SAGE-718 (as six 0.5-mg oral tablets), once per 
   		
		


Statistical Analysis Plan (SAP) V 1.0
Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
PRA-QMS-02745 9.0
Page 9 of 64
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
day in the morning within 1 hour after initiating a meal containing approximately 30 g of fat. Participants will 
continue to complete daily assessments of 
 via a mobile device either 
remotely (at home), or in the clinic at scheduled visits and will track IP dosing and predose food intake in a 
participant diary. Participants will complete daily remote assessments of 
. 
For Part A the treatment period clinic visits will occur on Day 1, Day 7 (±1 day), and Day 14, and for Part B 
it will be on Day 1, Day 7 (±1 day), Day 14 (±1 day), Day 21(±1 day) and Day 28. Following pre-dose 
procedures, participants will eat a morning meal and take the IP under staff supervision within 1 hour after 
initiating the meal. At scheduled clinic visits during the treatment period, safety, efficacy, and
will be performed, and study staff will dispense a sufficient amount of SAGE-718 for daily administration 
until the next scheduled study visit. In addition to weekly clinic visits, study staff will contact participants by 
telephone on Day 4 in both Part A and Part B to document any TEAEs and/or changes in concomitant 
medications
The Follow-Up Period, study staff will contact participants by telephone on Day 21(±1 day) for Part A to 
document any AEs and/or changes in concomitant medications. Participants will then return to the clinic on 
Day 28 (±2 days) for a follow-up visit. In Part B, participants will return to the clinic for follow-up visits on 
Day 35(±1 day) and Day 42(±2 days). No formal interim analysis or DSMB review is planned for this study.
10.2 Sample Size Considerations
No formal sample size calculation was made for this study. Up to 10 participants completing 14 days of 
dosing in Part A and 20 participants completing 28 days of dosing in Part B are considered sufficient to 
assess preliminary safety and tolerability and for signal-finding of 
 after repeated daily 
dosing with SAGE-718. Assuming a 10% dropout rate, approximately 33 total participants will be required 
to obtain 30 completers. Additional participants may be dosed if the early discontinuation rate is >10%.
10.3 Randomization
This study does not involve any randomization of participants.
11.0 Analysis Sets
11.1 Safety Set
The Safety Set will include all participants who were administered at least one dose of an investigational 
product (IP). Safety set will be used to describe the safety data.
11.2 Full Analysis Set
The Full Analysis Set will include all participants in the Safety Set with baseline and at least one 
postbaseline efficacy evaluation.
12.0 Interim Analyses
There are no planned interim analyses for this study.
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Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
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The denominator of the percentages will be based on the Safety analysis set. A by-participant disposition 
listing will be provided. In addition, a separate listing of screening failures with the primary reason for screen 
failures will be provided.
13.4 Eligibility Criteria Violations and Protocol Deviations
Protocol deviations identified during the study will be captured and categorized by the study team review 
as major and minor deviations on an ongoing basis.  In addition, COVID-19 related protocol deviations 
such as remote telephone/video visit/assessment, home healthcare visit, missed visit/assessment, out of 
window visit/assessment, safety reporting, investigational product administration, and others will be 
documented and analyzed as appropriate.
All major protocol deviations will be summarized by using the FAS.
A by-participant listing of all protocol deviations will be provided with columns identifying the following: 
date of the deviation, type of deviation (Major/Minor), deviation category, and verbatim description.
13.5 Demographic and Baseline Characteristics
Demographic and baseline characteristics, such as sex, race, age, height (cm), baseline weight (kg), 
body mass index (BMI) (kg/m2), years since the first diagnosis of Parkinson’s disease, and Hoehn and 
Yahr stage will be summarized using the Safety analysis set. Data will be summarized using descriptive 
statistics including sample size (n), mean, std, median, Q1, Q3, minimum, and maximum for continuous 
variables and numbers and percentages of participants for categorical variables.
The baseline for weight, height and BMI is defined as the last non-missing value prior to the first dose of 
the investigational product. 
13.6 Medical and Surgical History
Medical/surgical procedure history collected at screening will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 23.0u. Medical/surgical procedures history data will be 
summarized by system organ class (SOC) and preferred term (PT) using the Safety analysis set. A 
summary of medical/surgical history that is ongoing at the time of screening will be provided separately.  
Medical/surgical procedures history will also be listed.
13.7 Physical/Neurological Examinations
The physical examination will be conducted at Screening (Day -21 to Day -8) and baseline (Day -7 and 
Day -1), as well as the end of the scheduled dose day or ET.
A full physical examination will occur at Screening and will include an assessment of body systems (eg, 
head, eye, ear, nose and throat; heart; lungs; abdomen; and extremities) as well as neurological 
examination. Thereafter abbreviated physical examinations will include an assessment of general 
appearance, cardiovascular, respiratory, gastrointestinal, and neurological systems, followed by a targeted 
physical examination as needed.
Clinically significant abnormalities found during Screening or clinic visits will be reported on the medical 
history CRF; clinically significant abnormalities or worsening conditions will be reported on the adverse 
event CRF, hence will be captured in AE displays. Therefore, no summaries will be done for physical and 
neurological examinations.
13.8 Prior and Concomitant Medications
The following analyses will use the Safety Set.
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Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
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All medications taken and procedures undergone during the study will be recorded.
Medications will be presented according to whether they are being taken prior to and/or during the study 
(concomitant). Prior medications are defined as those taken prior to the initiation of the start of the 
investigational product, and that ended prior to the IP.  Concomitant medications are defined as those with 
a start date on or after the first dose of investigational product or those with a start date before the first dose 
of investigational product that is ongoing or with a stop date on or after the first dose of investigational 
product.  
13.9 Treatments
13.9.1 Extent of Investigational Product Exposure and Treatment Adherence
The following analyses will use the Safety Set.
Total drug exposure (in mg) is defined as the total investigational product in mg for SAGE-718 that was 
taken during the study.
Total exposure duration to investigational product (in days) is defined as the date of last dose – date of first 
dose + 1. Note that this does not exclude days when the dose has been missed
The percentage of the planned exposure received is defined as the total drug exposure, divided by 
planned exposure, times 100.  For participants who complete the treatment period, planned drug
exposure is the number of days of treatment planned times 3 mg. For participants who discontinued the 
treatment early, the planned drug exposure is the number of days (last dose date – first dose date + 1), 
times 3 mg.
Investigational product adherence (%) is defined as the number of tablets taken, divided by the number of 
tablets planned to be taken, times 100.  The schedule of investigational product is six tablets per day.  
The number of tablets planned to be taken is defined as follows:
x
If the participant discontinues treatment within Day 2 and Day 14 (both inclusive), the number of 
tablets planned to be taken is the last dose day of investigational product × 6. 
x
If the Part A participant does not discontinue treatment, the number of tablets planned to be 
taken is 84 (6x14) whereas for Part B it is 168(6x28).
Investigational product exposure and adherence will be summarized descriptively and listed. The number 
and percentage of participants with investigational product adherence in categories(<80%, 80-100%, 
>100%) will be provided.  Investigational product accountability will be listed.
All investigational product exposure data will be in by-participant listings, as well as a summary of treatment 
adherence.
13.10 Visit Windows
The scheduled visits will not be windowed and will be used at nominal visit value for analysis purposes. The 
unscheduled and early termination (ET) visit will be mapped to a scheduled visit for analysis.  In order to 
accommodate as much data as possible for analysis, the windows in the table below have been widened 
compared to protocol-specified operational windows, to have no gap between them; these windows are 
used for analysis purposes only. Once analysis visit windows are assigned, all visits, including scheduled 
visits, unscheduled visits, and ET visits will be eligible for being flagged as the “analyzed record” within the 
analysis window; a participant’s individual analysis visit window could potentially contain more than 1 
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Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
PRA-QMS-02745 9.0
Page 13 of 64
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visit. In the event of multiple visits falling within an analysis window or in case of a tie, the following rules 
will be used in sequence to determine the “analyzed record” for the analysis visit window:
x
If the data from the scheduled visit is available, then the scheduled visit data will be used. 
x
If there is no data from the scheduled visit is available, the data closest to the scheduled study day 
for that window will be used. 
x
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. 
Table 1A: Visit Windows for Analysis – Part A
Scheduled Visit 
(+/1 window days) in protocol
Target Study Day 
Study Day Window for Visit in Analysis
Day 1
Day 1 (predose)
Day 1 (predose) or last non-missing 
assessment before pre-dose.
Day 7 
Day 7
Day 2 - Day 10 
Day 14 
Day 14
Day 11 - Day 17
Day 28 
Day 28 
>= Day 18
Table 1B: Visit Windows for Analysis – Part B
Scheduled Visit 
(+/1 window days) in protocol
Target Study Day 
Study Day Window for Visit in Analysis
Day 1
Day 1 (predose)
Day 1 (predose) or last non-missing assessment 
before predose.
Day 7 
Day 7
Day 2 - Day 10 
Day 14 
Day 14
Day 11 - Day 17
Day 21 
Day 21 
Day 18 - Day 24 
Day 28 
Day 28 
Day 25 - Day 31 
Day 35 
Day 35 
Day 32 - Day 38 
Day 42
Day 42 
>= Day 39 
The summary by visit will use the “analyzed records” only – at most one per participant. The data not 
flagged as the “analyzed record” will be included in listings. An unscheduled visit that does not fall under 
any analysis window will remain in the database and will be included in the listings.
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Protocol no: 718-CNP-201
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For each item above, a mixed-effects model for repeated measures will be utilized to analyze the change 
from baseline scores at all post-baseline assessments. The model will include visit as a fixed effect and 
baseline as a covariate. An unstructured covariance structure will be used to model the variance-covariance 
matrix of the repeated measurements. If estimation issues arise during the construction of covariance 
structure, Toeplitz, Autoregressive (1) [AR (1)], or Compound Symmetry (CS) covariance structure will be 
used, following this sequence until convergence is achieved. If the model still does not converge with the 
CS structure, no results will be reported. Model-based point estimates ie, least-squares [LS] means are
used as the test statistic and will be reported where applicable along with 95% confidence intervals, and p-
values.
Line plots of change from baseline scores will be plotted with standard error bars. 
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Statistical Analysis Plan (SAP) V 1.0
Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
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16.1 Adverse Events
TEAEs are defined as any AEs with an onset date on or after the date of the first dose of IP
or any 
worsening of a preexisting medical condition/AE with onset after the start of IP and throughout the study.
An AE leading to treatment discontinuation is defined as an AE with action taken of investigational product
as Drug Withdrawn. AEs will be coded using the Medical Dictionary for Regulatory Activities MedDRA 
version 23.0u. 
An overall summary of TEAEs, including the number of events, reported, the number and percentage of 
participants reporting at least one TEAE, the number and percentage of participants reporting at least one 
related TEAE, the number and percentage of participants by maximum severity, the number and 
percentage of participants discontinuing due to an adverse event, the number and percentage of 
participants with at least one serious adverse event, and the number and percentage of deaths will be 
presented. 
A breakdown of the number and percentage of participants reporting each adverse event, categorized by 
System Organ Class (SOC) and preferred term (PT), will be presented. Note that counting will be by 
participant, not event, and participants are only counted once within each SOC and PT.
A further tabulation of these data, categorized by relationship (to SAGE-718), will be presented. Participants 
with multiple events within a particular body system or preferred term will be counted under the category of 
their drug-related event (related and not related) within SOC and PT. Relationship to SAGE-718 is 
categorized as related or not related.
A summary of events reported, categorized by severity, will also be provided. Participants with multiple 
events within a particular SOC and PT will be counted under the category of their most severe event in the 
following order: severe> moderate> mild within that SOC and PT.
A summary of adverse events leading to discontinuation of SAGE-718 will be provided, grouped by body 
system and preferred term.
All adverse events (including non-treatment-emergent events) recorded on the CRF will be listed.
Handling of missing AE start dates is defined in Appendix 3. Missing data for severity or relatedness to 
treatment will not be imputed.
16.1.1 Deaths and Serious Adverse Events (SAEs)
All deaths and SAEs will be listed.
16.2 Clinical Laboratory Evaluations
Laboratory assessments for biochemistry, coagulation, hematology, urinalysis, and serology, will be
collected at screening, on Day -1, Day 7, Day 14, and Day 28 for Part A, whereas for Part B it is collected 
at screening, on Day -1, Day 14, Day 28 and Day 42. The clinical laboratory tests to be performed for 
monitoring safety are listed in Table 4. Laboratory assessments will be summarized (n, mean, std, 
median, Q1, Q3, minimum, and maximum) for Part A and Part B along with the change from baseline by 
each scheduled post-baseline visit. The International System of Unit (SI) will be used.
For the laboratory results that is “< or = x”, where x is a number as collected in the data, the numeric part 
of the result will be used in the calculation in the summary tables. The same is true if the result is 
presented as below limit of quantification (BLQ) and a lower limit of quantification (LLOQ) value is 
provided – LLOQ value will be used for calculation in the summary tables. The actual results as collected 
will be displayed in the listings.
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Statistical Analysis Plan (SAP) V 1.0
Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
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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.
Table 4 Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Coagulation
Red blood cell count
Hemoglobin 
Hematocrit 
White blood cell count 
   with differential 
Platelet count
Red Blood Cell 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 
Phosphate
Triglycerides 
Thyroid-stimulating hormone
(TSH)
pH 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial
Thromboplastin
time 
Prothrombin time 
International
normalized ratio 
If a normal range is provided for the parameter, out-of-range values will be flagged as low or high, where 
applicable, in the participant data listings
The number and percentage of participants with potentially clinically significant (PCS) values will be 
provided in separate displays in hematology, serum chemistry, and liver function tests provided for such 
occurrence by time point.
PCS values will be identified for specific laboratory parameters as outlined in Table 5.
Liver function tests will be monitored closely for PCS values, and will be summarized for an occurrence at 
any post-baseline visit for the following parameters for these PCS threshold (for conditions involving more 
than one parameter, the results need to be from the same timepoint):
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Statistical Analysis Plan (SAP) V 1.0
Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
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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, and 
hence will show up in AE displays.
Pregnancy test results will be listed. 
Table 5 Potentially Clinically Significant Values for Specific Laboratory Parameters
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
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Statistical Analysis Plan (SAP) V 1.0
Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
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Laboratory 
Parameter
Gender
Units
Criteria for PCS Values (Observed values)
High 
Low 
Serum Chemistry
Albumin 
g/L 
>70 
<28 
Blood urea nitrogen 
mmol/L
>10.71
NA
Calcium
mmol/L
>2.75
<2.0
Chloride
mmol/L
>120
<90
Creatinine
mmol/L
>3xULN or >3x 
Baseline
Gamma Glutamyl 
Transferase 
>3xULN
Glucose
mmol/L
>13.9
<2.8
Sodium 
mmol/L 
>150
<132 
Potassium 
mmol/L 
>5.4 
<3.3 
Protein 
g/L
<45
Bicarbonate 
mmol/L 
>34 
<18 
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 
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Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
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16.3 Physical/Neurological Examinations
The occurrence of a physical examination (yes/no) and the date performed and the neurological 
examination date along with the system and results will be listed by the participant.
16.4 Vital Signs
Vitals for the following parameters - respiratory rate (breaths/minute), oral temperature (degrees C), 
supine heart rate (beats/minute), supine systolic blood pressure (mmHg), supine diastolic blood pressure 
(mmHg), standing heart rate (beats/minute), standing systolic blood pressure (mmHg), standing diastolic 
blood pressure (mmHg), – are collected at Screening and on Days -7, -1, 1, 7, 14, and  28 for Part A, and 
for Part B an additional collection will be made on Days 21, 35 and 42. Descriptive summaries of 
observed values and changes from baseline will be provided for vital sign parameters along with body 
weights by scheduled assessment time points for Part A and Part B separately. Additionally, the number 
and percentage of participants with PCS and potentially clinically significant change (PCSC) values will 
be summarized for such occurrence at any post-baseline visit. Potentially clinically significant values will 
be identified for vital sign parameters as outlined in Table 6.
Table 6 Potentially Clinically Significant Values and Change for Vital Sign Parameters
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
Possible Orthostatic 
hypotension: supine –
standing SBP and DBP
mmHg
SBP ≥20 or 
DBP
≥10
The orthostatic vital sign - the change from supine to standing (Supine – Standing) in heart rate, systolic 
and diastolic blood pressure – will be summarized by scheduled assessment timepoint, at 1 and 3 
minutes.
Any vital signs result considered clinically significant by the investigator will be captured as adverse 
events, and hence will show up in AE displays. All vital sign assessments along with PCS will be listed.
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Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
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16.5 12-Lead Electrocardiogram
Supine 12-lead ECGs will be performed in triplicate, and are collected on screening, days -1, 1, 7, 14, and 
28 for Part A whereas for Part B it is performed on days -1, 14, 28, and 42. The following ECG 
parameters will be listed for each participant: heart rate (beats per minute), PR (msec), QRS (msec), QT 
(msec), and QTcF (msec).
The average of the triplicate values will be used in the summary, including baseline ECG values. The 
precision on averages is to keep only 2 decimal places. The observed value at each time point and 
change from baseline at each post-baseline scheduled time point will be summarized. Each ECG is 
evaluated as ‘normal’, ‘abnormal, not clinically significant’ and ‘abnormal, clinically significant’; the number 
and percentage of participants with at least one of the triplicate values in the categories of normal,
‘abnormal, clinically significant’ and ‘abnormal, not clinically significant’ will be provided at baseline and 
each post-baseline scheduled assessment time point.
The number and percentage of participants with PCS and PCSC values will be summarized for such 
occurrence of baseline and at any post-baseline visit. Potentially clinically significant values will be identified 
for ECG parameters as outlined in Table 7. A listing of ECG and QTcF PCS values will be provided.
Table 7 Potentially Clinically Significant Values and Change for ECG Parameters
ECG
Units
Criteria for PCS Values (Observed values)
Criteria for PCSC values 
(Change from Baseline)
High 
Low 
Increase 
Decrease 
QTcF 
Interval
msec 
>450 but <=480
>480 but <=500
>500
NA 
>=30 to 60
>60
NA 
16.6 Columbia-Suicide Severity Rating Scale (C-SSRS)  
Suicidality will be monitored during the study using the C-SSRS. The C-SSRS is a questionnaire used to 
measure the presence and intensity of suicidal ideation and behavior. The C-SSRS will be completed at 
Screening, Days -7, -1, 1, 7, 14, and 28 for Part A, and additional Day 21, Day 35, and Day 42 are
completed for Part B. 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 subsequent time 
points.
Suicidal behavior and suicidal ideation will be summarized by visit for the Safety analysis set. The proportion 
of participants who meet the criterion for each of these categories at any post-baseline visit will be 
summarized as described in Table 8.
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Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
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Table 8 C-SSRS Categories for Analysis
Category
C-SSRS Item response is “YES”
Suicidal ideation
x
Wish to be dead
x
Non-specific active suicidal thoughts
x
Active suicidal ideation with any methods (not plan) 
without intent to act
x
Active suicidal ideation with some intent to act, without 
specific plan
x
Active suicidal ideation with specific plan and intent
Suicidal behavior
x
Actual attempt
x
Interrupted attempt
x
Aborted attempt
x
Preparatory acts or behavior
x
Completed suicide [1]
Non-suicidal self-injurious behavior
x
Non-suicidal self-injurious behavior 
[1] Completed suicide is not collected at the screening visit.
16.7 Electroencephalogram (EEG)  
During Screening, EEG monitoring using the 10 to 20 international system for EEG electrode
placement will occur for a duration of 1 hour. The assessment may be performed on any single
day during the Screening Period, at any time of day, but preferably while the participant is in a
fed state. If clinical events suspicious for seizure occur after Screening (eg, episodes of altered
consciousness and/or involuntary motor behaviors), an unscheduled 1-hour EEG will be performed for 
safety. EEG will be listed by the participant.
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Version Date: 05-May-2022
Sponsor: Sage Therapeutics
Protocol no: 718-CNP-201
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19.4 Appendix-D Adverse Event Start/Stop Date Imputation
Parameter
Missing
Additional Conditions
Imputation
Start date for AEs
D
M and Y same as M and Y of investigational product
administration
Date of investigational product
administration
M and/or Y not same as date investigational product
administration
First day of month
D and M
Y same as Y of investigational product administration
Date of investigational product
administration
Y prior to Y of investigational product administration but same 
as Y of screening date
Date of screening date
D, M, Y
None - date completely missing
Date of investigational product
administration
Stop date for AEs
D
M and Y same as M and Y of investigational product
administration
Date of investigational product
administration
M and/or Y not same as date of investigational product
administration
Use last day of month
D and M
Y same as Y of investigational product administration
Date of investigational product
administration
Y not same as Y of investigational product administration
Use Dec 31
D, M, Y
None - date completely missing
No imputation, but assume ongoing
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. Similarly, if the 
estimated stop date is before a complete or imputed start date, use the last day of the start day month.
19.5 Appendix- E Calculation of years since diagnosis of Parkinson Disease
Observed 
Missing 
Formula to Calculate Duration
D,M,Y
(Date of Enrollment – Date of Diagnosis + 1)/365.25
M and Y
D
[Year (Date of Enrollment) – Year (Date of Diagnosis)] + [Month (Date 
of Enrollment) – Month (Date of Diagnosis)]/12
Y
D and M
[Year (Date of Enrollment) – Year (Date of Diagnosis)]
Note : The number of years from the date of diagnosis to the date of enrollment, which will be derived based on the table above. No 
imputation will be done for missing diagnosis date (Year, Month, Day).
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19.7 Appendix-G Tables, Figures, and Listings
Table Number       
Title
                                     Population
Table 14.1.1.1A
Subject Analysis Sets - Part A
All Screened Subjects
Table 14.1.1.1B
Subject Analysis Sets - Part B
All Screened Subjects
Table 14.1.1.2A
Subject Disposition - Part A
Safety Analysis Set
Table 14.1.1.2B
Subject Disposition - Part B
Safety Analysis Set
Table 14.1.1.3A
Major Protocol Deviations - Part A
Full Analysis Set
Table 14.1.1.3B
Major Protocol Deviations - Part B
Full Analysis Set
Table 14.1.2.1A
Demographic Characteristics - Part A
Safety Analysis Set
Table 14.1.2.1B
Demographic Characteristics - Part B
Safety Analysis Set
Table 14.1.3A
Prior Medications by ATC Classification and WHO Drug Dictionary 
Preferred Term - Part A
Safety Analysis Set
Table 14.1.3B
Prior Medications by ATC Classification and WHO Drug Dictionary 
Preferred Term - Part B
Safety Analysis Set
Table 14.1.4A
Concomitant Medications by ATC Classification and WHO Drug 
Dictionary Preferred Term - Part A
Safety Analysis Set
Table 14.1.4B
Concomitant Medications by ATC Classification and WHO Drug 
Dictionary Preferred Term – Part B
Safety Analysis Set
Table 14.1.5A
Medical and Procedures  by System Organ Class and Preferred 
Term - Part A
Safety Analysis Set
Table 14.1.5B
Medical and Procedures  by System Organ Class and Preferred 
Term - Part B
Safety Analysis Set
Table 14.1.6A
Medical and Procedures  that are Ongoing at the time of Screening 
by WHO Drug Dictionary Preferred Term - Part A
Safety Analysis Set
Table 14.1.6B
Medical and Procedures  that are Ongoing at the time of Screening 
by WHO Drug Dictionary Preferred Term - Part B
Safety Analysis Set
Table 14.1.7A
Summary of Exposure and Adherence - Part A
Safety Analysis Set
Table 14.1.7B
Summary of Exposure and Adherence - Part B
Safety Analysis Set
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Table 14.3.1.1A
Overall Summary of Treatment Emergent Adverse Events - Part A
Safety Analysis Set
Table 14.3.1.1B
Overall Summary of Treatment Emergent Adverse Events - Part B
Safety Analysis Set
Table 14.3.1.2A
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term - Part A
Safety Analysis Set
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Table 14.3.1.2B
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term - Part B
Safety Analysis Set
Table 14.3.1.3A
Treatment Emergent Adverse Events Leading to Discontinuation of the 
Study by System Organ Class and Preferred Term - Part A
Safety Analysis Set
Table 14.3.1.3B
Treatment Emergent Adverse Events Leading to Discontinuation of the 
Study by System Organ Class and Preferred Term - Part B
Safety Analysis Set
Table 14.3.1.4A
Treatment Emergent Serious Adverse Events by System Organ Class 
and Preferred Term - Part A
Safety Analysis Set
Table 14.3.1.4B
Treatment Emergent Serious Adverse Events by System Organ Class 
and Preferred Term - Part B
Safety Analysis Set
Table 14.3.1.5A
Treatment Emergent Adverse Events with Outcome of Death by 
System Organ Class and Preferred Term - Part A
Safety Analysis Set
Table 14.3.1.5B
Treatment Emergent Adverse Events with Outcome of Death by 
System Organ Class and Preferred Term - Part B
Safety Analysis Set
Table 14.3.1.6A
Treatment Emergent Adverse Events Leading to Discontinuation of 
Study Treatment by System Organ Class and Preferred Term - Part A
Safety Analysis Set
Table 14.3.1.6B
Treatment Emergent Adverse Events Leading to Discontinuation of 
Study Treatment by System Organ Class and Preferred Term - Part B
Safety Analysis Set
Table 14.3.1.7A
Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship to IP - Part A
Safety Analysis Set
Table 14.3.1.7B
Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship to IP - Part B
Safety Analysis Set
Table 14.3.1.8A
Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Maximum Severity - Part A
Safety Analysis Set
Table 14.3.1.8B
Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Maximum Severity - Part B
Safety Analysis Set
Table 14.3.3.1.1A
Hematology and Coagulation Results by Time Point - Part A
Safety Analysis Set
Table 14.3.3.1.1B
Hematology and Coagulation Results by Time Point - Part B
Safety Analysis Set
Table 14.3.3.1.2A
Potentially Clinically Significant Postbaseline Hematology Results by 
Timepoint - Part A 
Safety Analysis Set
Table 14.3.3.1.2B
Potentially Clinically Significant Postbaseline Hematology Results by 
Timepoint - Part B
Safety Analysis Set
Table 14.3.3.2.1A
Biochemistry Results by Time Point - Part A
Safety Analysis Set
Table 14.3.3.2.1B
Biochemistry Results by Time Point - Part B
Safety Analysis Set
Table 14.3.3.2.2A
Potentially Clinically Significant Postbaseline Biochemistry Results -
Part A 
Safety Analysis Set
Table 14.3.3.2.2B
Potentially Clinically Significant Postbaseline Biochemistry Results -
Part B
Safety Analysis Set
Table 14.3.3.3.1A
Urinalysis Results by Time Point Part 1 Continuous Variables - Part A
Safety Analysis Set
Table 14.3.3.3.1B
Urinalysis Results by Time Point Part 1 Continuous Variables - Part B
Safety Analysis Set
Table 14.3.3.3.2A
Urinalysis Results by Time Point Part 2 Categorical Variables - Part A
Safety Analysis Set
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Table 14.3.3.3.2B
Urinalysis Results by Time Point Part 2 Categorical Variables - Part B
Safety Analysis Set
Table 14.3.4.1A
Vital Sign Results by Time Point - Part A
Safety Analysis Set
Table 14.3.4.1B
Vital Sign Results by Time Point - Part B
Safety Analysis Set
Table 14.3.4.2A
Potentially Clinically Significant Vital Sign Results - Part A
Safety Analysis Set
Table 14.3.4.2B
Potentially Clinically Significant Vital Sign Results - Part B
Safety Analysis Set
Table 14.3.5.1A
Electrocardiogram Results - Part A
Safety Analysis Set
Table 14.3.5.1B
Electrocardiogram Results - Part B
Safety Analysis Set
Table 14.3.5.2A
Overall Electrocardiogram Interpretations by Investigator over Time 
Point - Part A
Safety Analysis Set
Table 14.3.5.2B
Overall Electrocardiogram Interpretations by Investigator over Time 
Point - Part B
Safety Analysis Set
Table 14.3.5.3A
Potentially Clinically Significant Electrocardiogram Results - Part A
Safety Analysis Set
Table 14.3.5.3B
Potentially Clinically Significant Electrocardiogram Results - Part B
Safety Analysis Set
Table 14.3.6A
Summary of Columbia–Suicide Severity Rating Scale (C-SSRS) 
Suicidal Ideation and Suicidal Behavior - Part A
Safety Analysis Set
Table 14.3.6B
Summary of Columbia–Suicide Severity Rating Scale (C-SSRS) 
Suicidal Ideation and Suicidal Behavior - Part B
Safety Analysis Set
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Listing 16.1.7
Subject Enrollment
All Screened subjects
Listing 16.2.1.1
Completion/Discontinued Subjects from Study
Safety Analysis Set
Listing 16.2.1.2
Completion / Discontinuation of Investigational Product (IP)
Safety Analysis Set
Listing 16.2.2
Protocol Deviations
Safety Analysis Set
Listing 16.2.3.1
Subject Analysis Sets 
All Enrolled Subjects
Listing 16.2.4.1
Demographic and Baseline Data
Safety Analysis Set
Listing 16.2.4.2
General Medical History
Safety Analysis Set
Listing 16.2.4.3
Prior and Concomitant Medications
Safety Analysis Set
Listing 16.2.4.4
Prior and Concomitant Procedures
Safety Analysis Set
Listing 16.2.5.1  
Administration of Investigational Product (Oral)
Safety Analysis Set
Listing 16.2.5.2
Drug Accountability
Safety Analysis Set
Listing 16.2.5.3
Treatment Adherence
Safety Analysis Set
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Listing 16.2.7.1
Adverse Events
Safety Analysis Set
Listing 16.2.7.2
Subjects with Adverse Events with Outcome of Death
Safety Analysis Set
Listing 16.2.8.1
Hematology and Coagulation Results and Change from Baseline
Safety Analysis Set
Listing 16.2.8.2
Biochemistry Results and Change from Baseline
Safety Analysis Set
Listing 16.2.8.3
Urinalysis Results and Change from Baseline
Safety Analysis Set
Listing 16.2.8.4
Pregnancy Test Results (Females of Childbearing Potential only)
Safety Analysis Set
Listing 16.8.5
Urine Drug Screen
Safety Analysis Set
Listing 16.2.9
Vital Signs
Safety Analysis Set
Listing 16.2.10.1
Electrocardiogram Results - Part 1
Safety Analysis Set
Listing 16.2.10.2
Electrocardiogram Results - Part 2
Safety Analysis Set
Listing 16.2.11.1
Physical Examinations
Safety Analysis Set
Listing 16.2.11.2
Neurological Examination
Safety Analysis Set
Listing 16.2.12
Columbia–Suicide Severity Rating Scale (C-SSRS)
Safety Analysis Set
Listing 16.2.13
Electroencephalogram (EEG) Monitoring Test
Safety Analysis Set
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