Clinical trial NCT04602624
Conditions: Alzheimer Disease Cognitive Dysfunction Mild Dementia
Sponsor: Sage Therapeutics
Start date: 2020-12-07; Completion date: 2021-09-28
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary purpose of this study is to evaluate the safety and tolerability of SAGE-718 and its effects on cognitive and neuropsychiatric symptoms in participants with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease (AD).

Detailed description:

Arms: arm 1: Participants received SAGE-718 3 mg oral tablets, once daily in the morning for 14 days.
Interventions: intervention 1: SAGE-718
Intervention descriptions: intervention 1: SAGE-718 oral tablets.

Protocol documents:
Prot_000.pdf: 
Official Title: 
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 
NCT Number: 
NCT04602624 
Document Date: 
Protocol Version 2.0: 24 September 2020 


Clinical Study Report 
SAGE-718-CNA-201 
16.1 Study Information 
 
1 
 
 
  
 
1. 
PROTOCOL AND AMENDMENTS 
 
Version Number Date 
Title 
2.0 
23 Sep 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 V 
2.0 SOC 
 
Amendment 1 Summary of Changes 
Admin. Letter #1 
19 May 2021 
Administrative Letter #1 
1.0 
11 May 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 
 






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INVESTIGATOR’S AGREEMENT 
 
 
I have received and read the Investigator’s Brochure for SAGE-718. I have read the 
718-CNA-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 
Role in Study 
Name 
Contact Details 
Sage Study Physician 
, MD 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
 
Phone: 
 
SAE Reporting  
IQVIA Lifecycle Safety 
4820 Emperor Boulevard 
Durham, NC 27703 
e-mail: 
 
Fax: 
 
SAE Hotline: 
 
Product Complaints Sage 
Therapeutics 
Product Complaints Sage 
Therapeutics 
e-mail: 
 
Phone: 
 




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Study Description: 
This is an open-label study evaluating the safety and tolerability of SAGE-718 and its effects on 
 in participants with MCI or mild dementia due to AD. 
Eligible participants will have a confirmed diagnosis of MCI or mild dementia due to AD, according 
to the National Institute on Aging-Alzheimer’s Association 2011 diagnostic guidelines, which will 
be confirmed via the Clinical Dementia Rating Dementia Staging Instrument® (CDR). Participants 
will self-administer 3.0 mg of SAGE-718 once daily in the morning for 14 days within 1 hour after 
initiating a meal containing approximately 30 g of fat. Dosing and morning food intake will be 
tracked in a participant diary. Assessments will be performed as outlined in the Schedule of 
Assessments (Table 2) 
 
In the setting of public health advisories due to COVID-19, 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.  
Screening Period 
The Screening Period will begin 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 but not limited to: assessments of 
, vital 


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signs, clinical laboratory tests, electrocardiogram (ECG), magnetic resonance imaging (MRI) of the 
brain, and C-SSRS. 
An electroencephalogram (EEG) will also be performed for all participants during Screening. 
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 of 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 
 safety data. Additionally, participants 
will be trained on the use of a mobile data capture device to perform 
 and to document 
. Participants will continue to complete these assessments daily during the Baseline 
Period, using the mobile device remotely (at home), with the support of a study partner. On Day -1, 
participants will return to the study site for confirmation of continued eligibility and collection of 
further baseline 
 safety data. 
Treatment Period 
Beginning on Day 1 and continuing through Day 14, participants will self-administer 3.0 mg of 
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. During this period, participants will continue to complete daily assessments of 
 via mobile device either remotely (at home) or in the clinic (at 
scheduled in-clinic visits) and will track investigational product (IP) dosing and predose food intake 
in a participant diary. 
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 (ie, body weight, 
vital signs, ECG, followed by blood and urine collection for clinical laboratory analyses, 
 and 
), 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, study staff will dispense a sufficient amount of 
SAGE-718 for daily administration until the next scheduled study visit. In addition to the 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 
Study staff will contact participants by telephone on Day 21 (±1 day) to document any TEAEs and/or 
changes in concomitant medications. Participants will return to the clinic on Day 28 (±2 days) for a 
follow-up visit. 
Dose Evaluation Committee 
At any time during the study, Sage may elect to form a Dose Evaluation Committee (DEC). If 
convened, this DEC will review the available data and provide recommendations for adjusting the 
dose, administration schedule, and/or food intake and make adjustments for subsequent participants, 
if appropriate (see Section 7.4.2). 
Number of Participants (planned): Up to 22 participants will be dosed to obtain up to 
20 participants that complete 14 days of 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 


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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 80 years, inclusive, at Screening 
5. Meet the following criteria for MCI or mild dementia due to AD at Screening: 
a. A memory complaint reported by the participant or his/her study partner 
b. A CDR score of 0.5 to 1.0 (inclusive) with a memory box score ≥0.5 
c. Essentially preserved activities of daily living, in the opinion of the investigator 
d. Brain MRI report, obtained within the 2 years preceding the Baseline Period, that is 
consistent with the diagnosis of AD-MCI with no clinically significant findings of non-
AD pathology that could account for the observed cognitive impairment 
6. Have a score of 15 to 24 (inclusive) on the Montreal Cognitive Assessment at Screening 
7. Have an estimated premorbid IQ ≥85 (as assessed by the Test of Premorbid Functioning, 
performed at Screening) 
8. Have a study partner who is reliable, competent, at least 18 years of age, willing to be 
available to the study center by phone, support study-specific activities, and accompany the 
participant to study visits as needed 
9. Be ambulatory (use of assistance devices such as a walker or cane is acceptable; individuals 
requiring a wheelchair are excluded), 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 
10. Have stable concomitant medication usage per the following criteria: 
a. For psychotropic medications, including acetylcholinesterase inhibitors and other 
medications that are likely to have an effect on cognitive performance, the dose and 
frequency must remain stable for at least 12 weeks prior to the first IP administration and 
be expected to remain stable for the duration of the study 
b. For all other concomitant medications, the dose and frequency must remain stable for at 
least 4 weeks prior to the first IP administration and be expected to remain stable for the 
duration of the study 
11. 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 >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 
12. Agree, if male, to use an acceptable method of highly effective contraception (as defined in 
Section 9.2.4) during the 14-day 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 
13. Agree, if male, to abstain from sperm donation during the 14-day Treatment Period and for 
2 weeks after receiving the last dose of IP 
14. Agree to refrain from drugs of abuse and alcohol for the duration of the study 
Exclusion Criteria 
Each eligible participant must not: 


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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 a condition that precludes undergoing an MRI, in accordance with standard operating 
procedures at the imaging facility (eg, ferromagnetic metal in the body, claustrophobia), in a 
participant requiring MRI during Screening 
3. 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 
4. Have any medical or neurological condition (other than AD) that might be contributing to the 
participant's cognitive impairment or history of cognitive decline 
5. 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 
6. Have a history, presence, and/or current evidence of a clinically significant intracranial 
abnormality (eg, stroke, hemorrhage, space-occupying lesion, or other non-AD pathology) 
that is likely to call into question a primary clinical diagnosis of Alzheimer’s Disease. 
7. Have a history of possible or probable cerebral amyloid angiopathy, according to the Boston 
Criteria (Greenberg 1995) 
8. Have a history of treatment with an anti-amyloid therapy (including biologics) without 
subsequent MRI demonstrating the absence of amyloid-related imaging abnormalities 
9. Be receiving any of the following prohibited medications: 
a. Medications with potent effects at the N-methyl-D-aspartate (NMDA) receptor, including 
amantadine, ketamine, cycloserine, or related compounds 
b. Memantine within the 4 weeks prior to IP administration 
c. Medications that inhibit cholesterol absorption (eg, ezetimibe) 
d. Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine) 
e. 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 
(American Geriatrics Society 2019) 
f. Prescribed cannabis or other THC-containing substances 
10. Have an alcohol or drug use disorder within the past 12 months, as per DSM-5 criteria 
11. Have a history of seizures or epilepsy, with the exception of a single episode of febrile 
seizures in childhood 
12. 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 C-SSRS during Screening or Baseline 














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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................21 
5. 
INTRODUCTION ......................................................................................................22 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................23 
6.1. 
Study Objectives .........................................................................................................23 
6.1.1. 
Primary Objective .......................................................................................................23 
 
 
6.2. 
Endpoints ....................................................................................................................23 
6.2.1. 
Primary Endpoint ........................................................................................................23 
6.2.2. 
Secondary Endpoint ....................................................................................................23 
 
 
7. 
INVESTIGATIONAL PLAN .....................................................................................24 
7.1. 
Overall Study Design ..................................................................................................24 
7.1.1. 
Screening Period .........................................................................................................25 
7.1.2. 
Baseline Period ...........................................................................................................25 
7.1.3. 
Treatment Period ........................................................................................................25 
7.1.4. 
Follow-up Period ........................................................................................................26 
7.2. 
Number of Participants ...............................................................................................26 
7.3. 
Treatment Assignment ................................................................................................26 
7.4. 
Dose Adjustment Criteria ...........................................................................................26 
7.4.1. 
Stopping Criteria .........................................................................................................26 
7.4.2. 
Dose Evaluation Committee .......................................................................................26 
7.5. 
Criteria for Study Termination ...................................................................................26 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.....................................27 
8.1. 
Participant Inclusion Criteria ......................................................................................27 
8.2. 
Participant Exclusion Criteria .....................................................................................28 
8.3. 
Screen Failures ............................................................................................................29 
8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................30 


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8.4.1. 
Investigational Product Discontinuation .....................................................................30 
8.4.2. 
Early Termination from the Study ..............................................................................30 
8.4.3. 
Loss to Follow Up ......................................................................................................30 
8.4.4. 
Replacement of Participants .......................................................................................30 
9. 
TREATMENT OF PARTICIPANTS .........................................................................30 
9.1. 
Description of Investigational Product .......................................................................30 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................31 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................31 
9.2.2. 
Prohibited Medications ...............................................................................................31 
9.2.3. 
Other Restrictions .......................................................................................................32 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................32 
9.3. 
Intervention after the End of the Study .......................................................................32 
9.4. 
Treatment Adherence ..................................................................................................32 
9.5. 
Randomization and Blinding ......................................................................................33 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............33 
10.1. 
Investigational Product ...............................................................................................33 
10.2. 
Investigational Product Packaging and Labeling .......................................................33 
10.3. 
Investigational Product Storage ..................................................................................33 
10.4. 
Investigational Product Preparation ............................................................................33 
10.5. 
Investigational Product Administration ......................................................................33 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................34 
10.7. 
Product Complaints ....................................................................................................34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12. 
SAFETY ASSESSMENTS ........................................................................................41 
12.1. 
Safety Parameters .......................................................................................................41 
12.1.1. 
Demography and Medical History ..............................................................................41 
12.1.2. 
Weight and Height ......................................................................................................41 
12.1.3. 
Physical Examination .................................................................................................41 
12.1.4. 
Vital Signs ..................................................................................................................41 
12.1.5. 
Electrocardiogram .......................................................................................................42 
12.1.6. 
Electroencephalogram ................................................................................................42 


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12.1.7. 
Laboratory Assessments .............................................................................................42 
12.1.7.1. 
Pregnancy Testing ......................................................................................................43 
12.1.7.2. 
Drugs of Abuse and Alcohol ......................................................................................43 
12.1.8. 
Columbia–Suicide Severity Rating Scale ...................................................................43 
12.1.9. 
Magnetic Resonance Imaging .....................................................................................43 
12.2. 
Adverse and Serious Adverse Events .........................................................................44 
12.2.1. 
Adverse Event Definition ...........................................................................................44 
12.2.2. 
Serious Adverse Event Definition ..............................................................................44 
12.2.3. 
Relationship to Investigational Product ......................................................................45 
12.2.4. 
Recording Adverse Events .........................................................................................46 
12.2.5. 
Reporting Serious Adverse Events .............................................................................46 
12.3. 
Pregnancy ...................................................................................................................47 
12.4. 
Overdose .....................................................................................................................47 
13. 
STATISTICS ..............................................................................................................47 
13.1. 
Data Analysis Sets ......................................................................................................48 
13.2. 
Handling of Missing Data ...........................................................................................48 
13.3. 
General Considerations ...............................................................................................48 
13.4. 
Demographics and Baseline Characteristics ...............................................................48 
 
 
 
 
 
 
13.6. 
Safety Analyses ..........................................................................................................49 
13.6.1. 
Adverse Events ...........................................................................................................49 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................49 
13.6.3. 
Physical Examinations ................................................................................................49 
13.6.4. 
Vital Signs ..................................................................................................................49 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................50 
13.6.6. 
Prior and Concomitant Medications ...........................................................................50 
13.6.7. 
Columbia–Suicide Severity Rating Scale ...................................................................50 
 
 
13.8. 
Sample Size and Power ..............................................................................................50 
13.8.1. 
Interim and Data Monitoring Committee Analysis ....................................................50 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................51 


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14.1. 
Study Monitoring ........................................................................................................51 
14.2. 
Audits and Inspections ................................................................................................51 
14.3. 
Institutional Review Board or Ethics Committee .......................................................52 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................52 
16. 
ETHICS ......................................................................................................................52 
16.1. 
Ethics Review .............................................................................................................52 
16.2. 
Ethical Conduct of the Study ......................................................................................53 
16.3. 
Written Informed Consent ..........................................................................................53 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................53 
17.1. 
Inspection of Records .................................................................................................53 
17.2. 
Retention of Records ..................................................................................................54 
18. 
PUBLICATION POLICY ..........................................................................................54 
19. 
LIST OF REFERENCES ............................................................................................55 
 
LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................12 
 
 
Table 4: 
Summary of Clinical Laboratory Analytes .................................................................42 


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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 
AD 
Alzheimer’s disease 
AE 
adverse event 
DEC 
Dose Evaluation Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EEG 
electroencephalogram 
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 
MCI 
mild cognitive impairment 
MRI 
magnetic resonance imaging 
NMDA 
N-methyl-D-aspartate 
PET 
positron emission tomography 
 
 
QTcF 
QT interval 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 


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5. 
INTRODUCTION 
Diminished ability to learn and remember new information is the clinical hallmark of 
Alzheimer’s disease (AD) and is associated with decreased quality of life and impaired 
functioning. Primary memory impairment tends to be followed by functional decline in networks 
that promote language, attention, executive functions, and visuospatial abilities 
(Weintraub 2012). SAGE-718 is hypothesized to correct disruptions in these large-scale 
neuroanatomical networks through positive allosteric activity at N-Methyl-D-aspartate (NMDA) 
receptors. 
A subtype of glutamate receptors, NMDA receptors have a fundamental and well-documented 
role in regulating synaptic strength, health, and plasticity. The NMDA receptor antagonist 
memantine is approved as a treatment for AD, targeting glutamate excitotoxicity in later stages 
of the disease. However, blockade of NMDA receptor signaling can result in impaired 
neuroplasticity and cognitive deficits (Molinuevo 2005). Administration of a short-term NMDA 
partial agonist (D-cycloserine) in a small study of AD patients improved their scores on the 
cognitive subscale of the Alzheimer's Disease Assessment Scale, suggesting that NMDA-
enhancing agents can benefit cognition in AD (Tsai 1999). 
SAGE-718 is a novel, oxysterol-based, positive allosteric modulator of NMDA receptors that 
modulates the response to endogenous glutamate (Paul 2013). SAGE-718 only affects receptor 
function in the presence of endogenous glutamate, thus it does not directly activate the receptor 
and is not expected to cause glutamatergic excitotoxicity. 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 maximum median concentration (Cmax) cap of 45 ng/mL. To date, clinical studies 
have used doses that resulted in exposures within this cap; neither serious adverse events (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 individuals meeting diagnostic criteria for mild cognitive impairment (MCI) 
or mild dementia due to AD with otherwise stable neuropsychiatric symptoms. Additional data 
on the effects of SAGE-718 will be collected throughout, including assessments of 
 
. 




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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 
 
 in participants with MCI or mild dementia due to AD. 
Eligible participants will have a confirmed diagnosis of MCI or mild dementia due to AD, 
according to the National Institute on Aging-Alzheimer’s Association 2011 diagnostic 
guidelines, which will be confirmed via the Clinical Dementia Rating Dementia Staging 
Instrument® (CDR). Participants will self-administer 3.0 mg of SAGE-718 once daily in the 
morning for 14 days within 1 hour after initiating a meal containing approximately 30 g of fat. 
Dosing and morning food intake will be tracked in a participant diary. Assessments will be 
performed as outlined in the Schedule of Assessments (Table 2) 
 
. 
At any time during the study, Sage may elect to form a Dose Evaluation Committee (DEC). If 
convened, this DEC will review the available data and provide recommendations for adjusting 


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the dose, administration schedule, and/or food intake and make adjustments for subsequent 
participants, if appropriate (see Section 7.4.2). 
In the setting of public health advisories related to COVID-19, 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 will begin 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 but not limited to: assessments of 
 
, vital signs, clinical laboratory tests, electrocardiogram (ECG), magnetic resonance 
imaging (MRI) of the brain, and C-SSRS. An electroencephalogram (EEG) will also be 
performed for all participants during Screening. 
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 
of 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 
 safety data. 
Additionally, participants will be trained on the use of a mobile data capture device 
 
 Participants will continue to complete these 
assessments daily during the Baseline Period, using the mobile device remotely (at home), with 
the support of a study partner. On Day -1, participants will return to the study site for 
confirmation of continued eligibility and collection of further baseline 
 safety data. 
7.1.3. 
Treatment Period 
Beginning on Day 1 and continuing through Day 14, participants will self-administer 3.0 mg of 
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. During this period, participants will continue to complete daily 
assessments 
 via mobile device either remotely (at home) or 
in the clinic (at scheduled clinic visits) and will track investigative product (IP) dosing and 
predose food intake in a participant diary. 
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 
(ie, body weight, vital signs, ECG, followed by blood and urine collection for clinical laboratory 
analyses, 
 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, study staff will dispense a sufficient 
amount of SAGE-718 for daily administration until the next scheduled study visit. In addition to 
the clinic visits, study staff will contact participants by telephone on Day 4 to document any 
TEAEs and/or changes in concomitant medications. 


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7.1.4. 
Follow-up Period 
Study staff will contact participants by telephone on Day 21 (±1 day) to document any TEAEs 
and/or changes in concomitant medications. Participants will return to the clinic on Day 28 
(±2 days) for a follow-up visit. 
7.2. 
Number of Participants 
Up to 22 participants are planned to be dosed to obtain up to 20 participants that complete 
14 days of 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. 
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 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 
At any time during this study, Sage may elect to form a DEC (preferably after at least 
5 participants have completed 14 days of dosing). If convened, this DEC will be responsible for 
reviewing the available data and providing recommendations for adjusting the dose, 
administration schedule, or food intake recommendations for subsequent participants. The DEC 
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. 
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 participating 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 80 years, inclusive, at Screening 
5. Meet the following criteria for MCI or mild dementia due to AD at Screening: 
a. A memory complaint reported by the participant or his/her study partner 
b. A CDR score of 0.5 to 1.0 (inclusive) with a memory box score ≥0.5 
c. Essentially preserved activities of daily living, in the opinion of the investigator 
d. Brain magnetic resonance imaging (MRI) report, obtained within the 2 years preceding 
the Baseline Period, that is consistent with the diagnosis of AD-MCI with no clinically 
significant findings of non-AD pathology that could account for the observed 
cognitive impairment 
6. Have a score of 15 to 24 (inclusive) on the Montreal Cognitive Assessment at Screening 
7. Have an estimated premorbid IQ ≥85 (as assessed by the Test of Premorbid Functioning, 
performed at Screening) 
8. Have a study partner who is reliable, competent, at least 18 years of age, willing to be 
available to the study center by phone, support study-specific activities, and accompany 
the participant to study visits as needed 
9. Be ambulatory (use of assistance devices such as a walker or cane is acceptable; 
individuals requiring a wheelchair are excluded), 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 
10. Have stable concomitant medication usage per the following criteria: 
a. For psychotropic medications, including acetylcholinesterase inhibitors and other 
medications that are likely to have an effect on cognitive performance, the dose and 
frequency must remain stable for at least 12 weeks prior to the first IP administration 
and be expected to remain stable for the duration of the study 
b. For all other concomitant medications, the dose and frequency must remain stable for 
at least 4 weeks prior to the first IP administration and be expected to remain stable 
for the duration of the study 
11. 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 


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without an alternative medical cause and confirmed by follicle stimulating hormone 
>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 
12. Agree, if male, to use an acceptable method of highly effective contraception (as defined 
in Section 9.2.4) during the 14-day 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 
13. Agree, if male, to abstain from sperm donation during the 14-day Treatment Period and 
for 2 weeks after receiving the last dose of IP 
14. 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 a condition that precludes undergoing an MRI, in accordance with standard 
operating procedures at the imaging facility (eg, ferromagnetic metal in the body, 
claustrophobia), in a participant requiring MRI during screening 
3. 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 
4. Have any medical or neurological condition (other than AD) that might be contributing to 
the participant's cognitive impairment or history of cognitive decline 
5. 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 
6. Have a history, presence, and/or current evidence of a clinically significant intracranial 
abnormality (eg, stroke, hemorrhage, space-occupying lesion, or other non-AD 
pathology) that is likely to call into question a primary clinical diagnosis of AD 
7. Have a history of possible or probable cerebral amyloid angiopathy, according to the 
Boston Criteria (Greenberg 1995) 
8. Have a history of treatment with an anti-amyloid therapy (including biologics) without 
subsequent MRI demonstrating the absence of amyloid-related imaging abnormalities 
9. Be receiving any of the following prohibited medications: 
a. Medications with potent effects at the NMDA receptor, including amantadine, 
ketamine, cycloserine, or related compounds 
b. Memantine within the 4 weeks prior to IP administration 


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c. Medications that inhibit cholesterol absorption (eg, ezetimibe) 
d. Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine) 
e. 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 (American Geriatrics Society 2019) 
f. Prescribed cannabis or other THC-containing substances 
10. Have an alcohol or drug use disorder within the past 12 months, as per DSM-5 criteria 
11. Have a history of seizures or epilepsy, with the exception of a single episode of febrile 
seizures in childhood 
12. 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 C-SSRS during Screening or Baseline 
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 
13. 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 for initial values outside these ranges: 
− Heart rate <50 or >100 bpm 
− Systolic blood pressure <100 or >160 mmHg 
− Diastolic blood pressure <60 or >100 mmHg 
14. Have a history, presence, and/or current evidence of serologic positive results for HIV-1 
or HIV-2 
15. Have a positive pregnancy test or be lactating at Screening or Day -1 
16. 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. 


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8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
8.4.1. 
Investigational Product Discontinuation 
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. 
Participants who discontinue IP will be invited by the investigator to complete all of the 
scheduled study visits and assessments (except IP administration) through the end of the 
Treatment Period (Day 14). Those who decline continued participation through Day 14 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. 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 at contacting 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. 
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. 


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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. For psychotropic 
medications, including acetylcholinesterase inhibitors and other medications that are likely to 
have an effect on cognitive performance, the dose and frequency must have been stable for at 
least 12 weeks prior to the first IP administration and be expected to remain stable for the 
duration of the study. 
The start and end dates, route, dose/units, frequency, and indication for all relevant medications 
and/or supplements will be recorded at Screening. Medications to be recorded include all 
psychotropic medications used within 12 weeks of informed consent, any other medications and 
supplements taken within 60 days of informed consent, and all medication used to treat AD, 
regardless of timing. After Screening, all changes to any medication or supplements 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 cognitive performance, 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 cognitive 
effects 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, cycloserine, or related compounds 
• Medications that inhibit cholesterol absorption (eg, ezetimibe) 
• Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine) 
• 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 


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Geriatrics Society Updated Beers® Criteria for Potentially Inappropriate Medication 
Use in Older Adults (American Geriatrics Society 2019) 
• Prescribed cannabis or other THC-containing substances 
9.2.3. 
Other Restrictions 
Participants must agree not to consume 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 the Day 1, and Day 7 
visits, 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 packaging, 


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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. 
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. It 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 


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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 
Schedule of Assessments (Table 2). 
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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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 not while the participant is in 
a fasted 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 for clinical laboratory assessments will be collected. will be collected 
for hematology, biochemistry, coagulation, urinalysis, and serology at the time points detailed in 
Table 2 and Table 3. 
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 in Table 4. 
Table 4: 
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 (LDL, HDL), creatine 
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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. 
12.1.8. 
Columbia–Suicide Severity Rating Scale 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the 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 the most severe). 
The “Baseline/Screening” C-SSRS form will be completed at Screening (lifetime history and 
past 24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points outlined in Table 2. 
12.1.9. 
Magnetic Resonance Imaging 
Participants without documented MRI results that fulfill aforementioned entry criteria will 
undergo structural MRI of the brain. This assessment will be conducted according to standard 
operating procedures at the imaging center. The results will be reviewed by a qualified 
radiologist to assess for the presence of non-AD pathology that could account for the 
participant’s observed cognitive impairment, and the site investigator will determine the clinical 
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12.2. 
Adverse 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 adverse event with onset after the start of IP, or any worsening of a 
preexisting medical condition/adverse event 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 an 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 and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage 
Therapeutics. 
Subjects 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 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 


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• 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 informed consent form (ICF) and 
throughout the duration of the study, whether or not they are related to the study, must be 
recorded on the SAE report form provided by Sage Therapeutics. Any SAE that is ongoing when 
the participant completes their final study visit, will be followed by the investigator until the 
event has resolved, stabilized, returned to baseline status, or until the participant dies or is lost to 
follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each adverse event 
(not related, related). The following definitions should be considered when evaluating the 
relationship of AEs and SAEs to the IP. 
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
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 
Adverse events spontaneously reported by the participant and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome and seriousness (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s) 
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in 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. 
Serious adverse events occurring after the designated follow-up time for the study, should be 
reported to Sage or designee according to the timelines noted above only if the investigator 
considers the SAE related to IP. 
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all suspected unexpected serious 
adverse reactions (SUSARs) that occur during the clinical study. IRBs/IECs will be notified of 
SAEs and/or SUSARs as required by local law. 


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Sage, or designee, will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies 
according to local law and investigators. 
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 informed consent 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. 
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 
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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 Independent Ethics Committee or an Institutional Review Board 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 and/or 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 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. 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit(s) at the clinical site. Please see 
Section 14.2 for more details regarding the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Significant protocol deviations should be reported to the IRB/IEC per the IRB/IEC’s 
written procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates 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. 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
given a written and dated approval or favorable opinion by an IRB or IEC as appropriate. The 
investigator must obtain and document approval before he or she can enroll any participant into 
the study. The IRB or IEC must supply to the sponsor a list of the IRB/IEC membership and a 
statement to confirm that the IRB/IEC is organized and operates according to GCP and 
applicable laws and regulations. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 


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The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. In addition, the principal investigator must 
inform the IRB/IEC and sponsor of any changes significantly affecting the conduct of the 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 Informed Consent Form. A copy of the signed Informed Consent Form must 
be given to the participant or to the participant’s parent or legally authorized representative. 
Throughout the 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. 
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 
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17.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. Sage is responsible to inform the investigator/institution as to 
when study documents no longer need to be retained. 
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. doi: 10.1111/jgs.15767. Epub 2019 Jan 29 
Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical 
practice. Psychiatry (Edgemont). 2007;4(7):28-37. Adapted from: Kay SR. Positive and negative 
symptoms in schizophrenia: Assessment and research (Monograph). Clinical and Experimental 
Psychiatry. 1991;5. Modified from Guy W, ed. ECDEU Assessment Manual for 
Psychopharmacology. US Department of Health, Education, and Welfare Public Health Service 
Alcohol, Drug Abuse, and Mental Health Administration. 1976;218-22. 
 
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. 
Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. US Department of Health, 
Education, and Welfare; Public Health Service; Alcohol, Drug Abuse, and Mental Health 
Administration. 1976. 
Jutten RJ, Peeters CF, Leijdesdorff SM, et al. Detecting functional decline from normal aging to 
dementia: Development and validation of a short version of the Amsterdam IADL Questionnaire. 
Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2017;8:26-35. 
Kaufer DI, Cummings JL, Ketchel P, et al. Validation of the NPI-Q, a brief clinical form of the 
Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci. 2000;12:233-239. 
Molinuevo J, et al. Memantine: Targeting glutamate excitotoxicity in AD and other dementias. 
Am Journal of AD & Other Dementias. 2005;77-85. 
Morris JC. The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology. 
1993;43:2412-2414 
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. 
Tsai GE, et al. Improved cognition in Alzheimer's disease with short-term D-cycloserine 
treatment. Am J Psychiatry. 1999 Mar;156(3):467-9. 
Wechsler D. Test of premorbid functioning. San Antonio, TX: The Psychological Corporation. 
2009. 
Weintraub S, et al. The neuropsychological profile of Alzheimer disease. Cold Spring Harb 
Perspect Med. 2012;2(4):a006171. 


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Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression 
screening scale: A preliminary report. J Psych Res. 1983;17:37-49. 






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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 
PROTOCOL NUMBER: 718-CNA-201 
 
Investigational Product 
SAGE-718 
Clinical Phase 
2 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact and Medical Monitor 
, MD 
 
Phone: 
 
Date of Original Protocol 
11 May 2020 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from Sage Therapeutics, 
Inc. 




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INVESTIGATOR’S AGREEMENT 
 
 
I have received and read the Investigator’s Brochure for SAGE-718. I have read the 
718-CNA-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 
Role in Study 
Name 
Contact Details 
Sage Study Physician 
 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Phone: 
 
SAE Reporting 
IQVIA Lifecycle Safety 
4820 Emperor Boulevard 
Durham, NC 27703 
e-mail: 
Fax: 
 
SAE Hotline: 
 
Product Complaints Sage 
Therapeutics 
Product Complaints Sage 
Therapeutics 
e-mail: 
Phone: 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or Sage) 
Name of Investigational Product: 
SAGE-718 Oral Tablet 
Name of Active Ingredient: 
SAGE-718 
Title of Study: 
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 
Number of Sites and Study Location: Approximately 5 sites in the US 
Phase of Development: 2 
Planned Duration for each Study Participant: Each participant’s involvement will be 
approximately 7 weeks, including a maximum 2-week Screening Period, a 1-week Baseline Period, a 
2-week Treatment Period, and a 2-week Follow-up Period.  
Objectives: 
Primary Objective 
• 
To evaluate the safety and tolerability of orally administered SAGE-718 in participants 
with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease (AD) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endpoints: 
Primary Endpoint 
• 
Incidence of treatment-emergent adverse events (TEAEs) 
Secondary Endpoint 
• 
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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Study Description: 
This is an open-label study evaluating the safety and tolerability of SAGE-718 and its effects 
 
 in participants with MCI or mild dementia due to AD. 
Eligible participants will have a confirmed diagnosis of MCI or mild dementia due to AD, according 
to the National Institute on Aging-Alzheimer’s Association 2011 diagnostic guidelines, which will be 
confirmed via the CDR® Dementia Staging Instrument. Participants will self-administer 3.0 mg of 
SAGE-718 once daily in the morning for 14 days within 1 hour after initiating a meal containing 
approximately 30 g of fat. Dosing and morning food intake will be tracked in a participant diary. 
Assessments will be performed as outlined in the Schedule of Assessments ( Table 2) 
 
 
Screening Period 
The Screening Period will begin 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 but not limited to: assessments of 
, vital 
signs, clinical laboratory tests, electrocardiogram (ECG),and C-SSRS. 
An electroencephalogram (EEG) will also be performed for all participants during Screening, 
preferably not in a fasted state. 
Baseline Period 
The Baseline Period will occur from Day -7 through Day -1. During this period, each participant will 


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receive dietary counseling to aid in choosing a morning meal containing approximately 30 g of 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 
 safety data. Additionally, participants 
will be trained on the use of a mobile data capture device 
 
 Participants will continue to complete these assessments daily during the Baseline 
Period, using the mobile device remotely (at home), with the support of a study partner. On Day -1, 
participants will return to the study site for confirmation of continued eligibility and collection of 
further baseline 
 safety data. 
Treatment Period 
Beginning on Day 1 and continuing through Day 14, participants will self-administer 3.0 mg of 
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. During this period, participants will continue to complete daily assessments 
 
 via mobile device either remotely (at home) or in the clinic (at 
scheduled in-clinic visits) and will track investigational product (IP) dosing and predose food intake 
in a participant diary. 
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 (ie, body weight, 
vital signs, ECG, followed by blood and urine collection for clinical laboratory analyses, 
 
 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, study staff will dispense a sufficient amount of 
SAGE-718 for daily administration until the next scheduled study visit. In addition to the 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 
Study staff will contact participants by telephone on Day 21 (±1 day) to document any TEAEs and/or 
changes in concomitant medications. Participants will return to the clinic on Day 28 (±2 days) for a 
follow-up visit. 
Dose Evaluation Committee 
At any time during the study, Sage may elect to form a Dose Evaluation Committee (DEC). If 
convened, this DEC will review the available data and provide recommendations for adjusting the 
dose, administration schedule, and/or food intake and make adjustments for subsequent participants, 
if appropriate (see Section 7.4.2). 
Number of Participants (planned): Up to 22 participants will be dosed to obtain up to 
20 participants that complete 14 days of 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 80 years, inclusive, at Screening


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5.
Meet the following criteria for MCI or mild dementia due to AD at Screening:
a.
A memory complaint reported by the participant or his/her study partner
b.
A CDR score of 0.5 to 1.0 (inclusive) with a memory box score ≥0.5
c.
Essentially preserved activities of daily living, in the opinion of the investigator
d.
Documented evidence of a positive molecular marker for AD (either a positive amyloid
positron emission tomography scan or β-amyloid and tau levels in cerebrospinal fluid that
are consistent with underlying AD pathology)
e.
Documented magnetic resonance imaging (MRI) report consistent with the diagnosis of
AD-MCI with no clinically significant findings of non-AD pathology that could account
for the observed cognitive impairment
6.
Have a score of 15 to 24 (inclusive) on the Montreal Cognitive Assessment at Screening
7.
Have an estimated premorbid IQ ≥85 (as assessed by the Test of Premorbid Functioning,
performed at Screening)
8.
Have a study partner who is reliable, competent, at least 18 years of age, willing to be
available to the study center by phone, support study-specific activities, and accompany the
participant to study visits as needed
9.
Be ambulatory (use of assistance devices such as a walker or cane is acceptable; individuals
requiring a wheelchair are excluded), 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
10. Have stable concomitant medication usage per the following criteria:
a.
For psychotropic medications, including acetylcholinesterase inhibitors and other
medications that are likely to have an effect on cognitive performance, the dose and
frequency must remain stable for at least 12 weeks prior to the first IP administration and
be expected to remain stable for the duration of the study
b.
For all other concomitant medications, the dose and frequency must remain stable for at
least 4 weeks prior to the first IP administration and be expected to remain stable for the
duration of the study
11. 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 >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
12. Agree, if male, to use an acceptable method of highly effective contraception (as defined in
Section 9.2.4) during the 14-day 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
13. Agree, if male, to abstain from sperm donation during the 14-day Treatment Period and for
2 weeks after receiving the last dose of IP
14. 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


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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 any medical or neurological condition (other than AD) that might be contributing to the
participant's cognitive impairment or history of cognitive decline
4.
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
5.
Have a history, presence, and/or current evidence of an intracranial abnormality (eg, stroke,
hemorrhage, space-occupying lesion)
6.
Have a history of possible or probable cerebral amyloid angiopathy, according to the Boston
Criteria (Greenberg 1995)
7.
Have a history of treatment with an anti-amyloid therapy (including biologics) without
subsequent MRI demonstrating the absence of amyloid-related imaging abnormalities
8.
Be receiving any of the following prohibited medications:
a.
Medications with potent effects at the N-methyl-D-aspartate (NMDA) receptor, including
amantadine, ketamine, cycloserine, or related compounds
b.
Memantine within the 4 weeks prior to IP administration
c.
Medications that inhibit cholesterol absorption (eg, ezetimibe)
d.
Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine)
e.
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
(American Geriatrics Society 2019)
f.
Prescribed cannabis or other THC-containing substances
9.
Have an alcohol or drug use disorder within the past 12 months, as per DSM-5 criteria
10. Have a history of seizures or epilepsy, with the exception of a single episode of febrile
seizures in childhood
11. 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 C-SSRS during Screening or Baseline
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
12. 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 for initial values outside these ranges:
−
Heart rate <50 or >100 bpm
−
Systolic blood pressure <100 or >160 mmHg
−
Diastolic blood pressure <60 or >100 mmHg


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13. Have a history, presence, and/or current evidence of serologic positive results for HIV-1 or 
HIV-2 
14. Have a positive pregnancy test or be lactating at Screening or Day -1 
15. 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 
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 
 evaluation. 
 
 
Safety Analysis 
Adverse events (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 TEAEs 
will also be presented by maximum severity, and relationship to IP. Data from vital signs, clinical 
laboratory analytes, ECGs, and C-SSRS will be summarized using descriptive statistics. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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t Daily reminders will be sent to participants to complete assessments 
 
 within 1 hour following IP administration, either remotely (at home) or in the clinic during the 
Treatment Period (with observation by study staff during scheduled clinic visits). 
u On visit days during the Treatment Period, participants will self-administer IP in the clinic under the supervision 
of study staff after the predose assessments and consumption of a morning meal. 
v Study staff will dispense sufficient IP for daily dosing at home until the next scheduled visit (see Section 9.4). 
w On Days 7 and 14, participants will return used IP packaging and any unused IP for site staff to document. 
x At Screening, include all psychotropic medications used within 12 weeks of informed consent, any other 
medications and supplements taken within 60 days of informed consent, and all medication used to treat AD, 
regardless of timing. After Screening, all changes to any medication or supplements should be captured. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................20 
5. 
INTRODUCTION ......................................................................................................21 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................22 
6.1. 
Study Objectives .........................................................................................................22 
6.1.1. 
Primary Objective .......................................................................................................22 
 
 
6.2. 
Endpoints ....................................................................................................................22 
6.2.1. 
Primary Endpoint ........................................................................................................22 
6.2.2. 
Secondary Endpoint ....................................................................................................22 
 
 
7. 
INVESTIGATIONAL PLAN .....................................................................................23 
7.1. 
Overall Study Design ..................................................................................................23 
7.1.1. 
Screening Period .........................................................................................................24 
7.1.2. 
Baseline Period ...........................................................................................................24 
7.1.3. 
Treatment Period ........................................................................................................24 
7.1.4. 
Follow-up Period ........................................................................................................25 
7.2. 
Number of Participants ...............................................................................................25 
7.3. 
Treatment Assignment ................................................................................................25 
7.4. 
Dose Adjustment Criteria ...........................................................................................25 
7.4.1. 
Stopping Criteria .........................................................................................................25 
7.4.2. 
Dose Evaluation Committee .......................................................................................25 
7.5. 
Criteria for Study Termination ...................................................................................25 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .....................................26 
8.1. 
Participant Inclusion Criteria ......................................................................................26 
8.2. 
Participant Exclusion Criteria .....................................................................................27 
8.3. 
Screen Failures ............................................................................................................28 
8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................29 


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8.4.1. 
Investigational Product Discontinuation .....................................................................29 
8.4.2. 
Early Termination from the Study ..............................................................................29 
8.4.3. 
Loss to Follow Up ......................................................................................................29 
8.4.4. 
Replacement of Participants .......................................................................................29 
9. 
TREATMENT OF PARTICIPANTS .........................................................................29 
9.1. 
Description of Investigational Product .......................................................................29 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................30 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................30 
9.2.2. 
Prohibited Medications ...............................................................................................30 
9.2.3. 
Other Restrictions .......................................................................................................31 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................31 
9.3. 
Intervention after the End of the Study .......................................................................31 
9.4. 
Treatment Adherence ..................................................................................................31 
9.5. 
Randomization and Blinding ......................................................................................32 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............32 
10.1. 
Investigational Product ...............................................................................................32 
10.2. 
Investigational Product Packaging and Labeling .......................................................32 
10.3. 
Investigational Product Storage ..................................................................................32 
10.4. 
Investigational Product Preparation ............................................................................32 
10.5. 
Investigational Product Administration ......................................................................32 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................33 
10.7. 
Product Complaints ....................................................................................................33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12. 
SAFETY ASSESSMENTS ........................................................................................39 
12.1. 
Safety Parameters .......................................................................................................39 
12.1.1. 
Demography and Medical History ..............................................................................39 
12.1.2. 
Weight and Height ......................................................................................................39 
12.1.3. 
Physical Examination .................................................................................................40 
12.1.4. 
Vital Signs ..................................................................................................................40 
12.1.5. 
Electrocardiogram .......................................................................................................40 
12.1.6. 
Electroencephalogram ................................................................................................40 
12.1.7. 
Laboratory Assessments .............................................................................................41 


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12.1.7.1. 
Pregnancy Testing ......................................................................................................41 
12.1.7.2. 
Drugs of Abuse and Alcohol ......................................................................................41 
12.1.8. 
Columbia–Suicide Severity Rating Scale ...................................................................42 
12.2. 
Adverse and Serious Adverse Events .........................................................................42 
12.2.1. 
Adverse Event Definition ...........................................................................................42 
12.2.2. 
Serious Adverse Event Definition ..............................................................................43 
12.2.3. 
Relationship to Investigational Product ......................................................................43 
12.2.4. 
Recording Adverse Events .........................................................................................44 
12.2.5. 
Reporting Serious Adverse Events .............................................................................44 
12.3. 
Pregnancy ...................................................................................................................45 
12.4. 
Overdose .....................................................................................................................46 
13. 
STATISTICS ..............................................................................................................46 
13.1. 
Data Analysis Sets ......................................................................................................46 
13.2. 
Handling of Missing Data ...........................................................................................46 
13.3. 
General Considerations ...............................................................................................46 
13.4. 
Demographics and Baseline Characteristics ...............................................................46 
 
 
 
 
 
 
13.6. 
Safety Analyses ..........................................................................................................47 
13.6.1. 
Adverse Events ...........................................................................................................47 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................48 
13.6.3. 
Physical Examinations ................................................................................................48 
13.6.4. 
Vital Signs ..................................................................................................................48 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................48 
13.6.6. 
Prior and Concomitant Medications ...........................................................................48 
13.6.7. 
Columbia–Suicide Severity Rating Scale ...................................................................48 
 
 
13.8. 
Sample Size and Power ..............................................................................................49 
13.8.1. 
Interim and Data Monitoring Committee Analysis ....................................................49 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................49 
14.1. 
Study Monitoring ........................................................................................................49 
14.2. 
Audits and Inspections ................................................................................................50 


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14.3. 
Institutional Review Board or Ethics Committee .......................................................50 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................50 
16. 
ETHICS ......................................................................................................................51 
16.1. 
Ethics Review .............................................................................................................51 
16.2. 
Ethical Conduct of the Study ......................................................................................51 
16.3. 
Written Informed Consent ..........................................................................................51 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................52 
17.1. 
Inspection of Records .................................................................................................52 
17.2. 
Retention of Records ..................................................................................................52 
18. 
PUBLICATION POLICY ..........................................................................................52 
19. 
LIST OF REFERENCES ............................................................................................53 
 


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LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................11 
 
 
Table 4: 
Summary of Clinical Laboratory Analytes .................................................................41 


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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 
AD 
Alzheimer’s disease 
AE 
adverse event 
 
 
DEC 
Dose Evaluation Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EEG 
electroencephalogram 
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 
MCI 
mild cognitive impairment 
MRI 
magnetic resonance imaging 
NMDA 
N-methyl-D-aspartate 
 
 
QTcF 
QT interval 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 


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5. 
INTRODUCTION 
Diminished ability to learn and remember new information is the clinical hallmark of 
Alzheimer’s disease (AD) and is associated with decreased quality of life and impaired 
functioning. Primary memory impairment tends to be followed by functional decline in networks 
that promote language, attention, executive functions, and visuospatial abilities 
(Weintraub 2012). SAGE-718 is hypothesized to correct disruptions in these large-scale 
neuroanatomical networks through positive allosteric activity at N-Methyl-D-aspartate (NMDA) 
receptors. 
A subtype of glutamate receptors, NMDA receptors have a fundamental and well-documented 
role in regulating synaptic strength, health, and plasticity. The NMDA receptor antagonist 
memantine is approved as a treatment for AD, targeting glutamate excitotoxicity in later stages 
of the disease. However, blockade of NMDA receptor signaling can result in impaired 
neuroplasticity and cognitive deficits (Molinuevo 2005). Administration of a short-term NMDA 
partial agonist (D-cycloserine) in a small study of AD patients improved their scores on the 
cognitive subscale of the Alzheimer's Disease Assessment Scale, suggesting that NMDA-
enhancing agents can benefit cognition in AD (Tsai 1999). 
SAGE-718 is a novel, oxysterol-based, positive allosteric modulator of NMDA receptors that 
modulates the response to endogenous glutamate (Paul 2013). SAGE-718 only affects receptor 
function in the presence of endogenous glutamate, thus it does not directly activate the receptor 
and is not expected to cause glutamatergic excitotoxicity. 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 maximum median concentration (Cmax) cap of 45 ng/mL. To date, clinical studies 
have used doses that resulted in exposures within this cap; neither serious adverse events (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, 
 of SAGE-718 Oral Tablet will be evaluated in this 
open-label study in individuals meeting diagnostic criteria for mild cognitive impairment (MCI) 
or mild dementia due to AD with otherwise stable neuropsychiatric symptoms. Additional data 
on the effects of SAGE-718 will be collected throughout, 
 
 


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6.
STUDY OBJECTIVES AND ENDPOINTS
6.1. 
Study 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 MCI or mild dementia due to AD 
 
 
 
6.2. 
Endpoints
6.2.1. 
Primary Endpoint
•
Incidence of treatment-emergent adverse events (TEAEs)
6.2.2. 
Secondary Endpoint
•
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 
 
 in participants with MCI or mild dementia due to AD. 
Eligible participants will have a confirmed diagnosis of MCI or mild dementia due to AD, 
according to the National Institute on Aging-Alzheimer’s Association 2011 diagnostic 
guidelines, which will be confirmed via the CDR® Dementia Staging Instrument. Participants 
will self-administer 3.0 mg of SAGE-718 once daily in the morning for 14 days within 1 hour 
after initiating a meal containing approximately 30 g of fat. Dosing and morning food intake will 
be tracked in a participant diary. Assessments will be performed as outlined in the Schedule of 
Assessments (Table 2) 
 
At any time during the study, Sage may elect to form a Dose Evaluation Committee (DEC). If 
convened, this DEC will review the available data and provide recommendations for adjusting 


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the dose, administration schedule, and/or food intake and make adjustments for subsequent 
participants, if appropriate (see Section 7.4.2). 
7.1.1. 
Screening Period 
The Screening Period will begin 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 but not limited to: assessments of cognitive 
function, vital signs, clinical laboratory tests, electrocardiogram (ECG),and C-SSRS. 
An electroencephalogram (EEG) will also be performed for all participants during Screening, 
preferably not in a fasted state. 
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 
of 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 
 safety data. 
Additionally, participants will be trained on the use of a mobile data capture device 
 
 Participants will continue to complete these 
assessments daily during the Baseline Period, using the mobile device remotely (at home), with 
the support of a study partner. On Day -1, participants will return to the study site for 
confirmation of continued eligibility and collection of further baseline 
 safety data. 
7.1.3. 
Treatment Period 
Beginning on Day 1 and continuing through Day 14, participants will self-administer 3.0 mg of 
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. During this period, participants will continue to complete daily 
assessments 
 via mobile device either remotely (at home) or 
in the clinic (at scheduled clinic visits) and will track investigative product (IP) dosing and 
predose food intake in a participant diary. 
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 
(ie, body weight, vital signs, ECG, followed by blood and urine collection for clinical laboratory 
analyses, 
 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, study staff will dispense a sufficient 
amount of SAGE-718 for daily administration until the next scheduled study visit. In addition to 
the clinic visits, study staff will contact participants by telephone on Day 4 to document any 
TEAEs and/or changes in concomitant medications. 


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7.1.4. 
Follow-up Period 
Study staff will contact participants by telephone on Day 21 (±1 day) to document any TEAEs 
and/or changes in concomitant medications. Participants will return to the clinic on Day 28 
(±2 days) for a follow-up visit. 
7.2. 
Number of Participants 
Up to 22 participants are planned to be dosed to obtain up to 20 participants that complete 
14 days of 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. 
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 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 
At any time during this study, Sage may elect to form a DEC (preferably after at least 
5 participants have completed 14 days of dosing). If convened, this DEC will be responsible for 
reviewing the available data and providing recommendations for adjusting the dose, 
administration schedule, or food intake recommendations for subsequent participants. The DEC 
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. 
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 participating 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 80 years, inclusive, at Screening 
5. Meet the following criteria for MCI or mild dementia due to AD at Screening: 
a. A memory complaint reported by the participant or his/her study partner 
b. A CDR score of 0.5 to 1.0 (inclusive) with a memory box score ≥0.5 
c. Essentially preserved activities of daily living, in the opinion of the investigator 
d. Documented evidence of a positive molecular marker for AD (either a positive 
amyloid positron emission tomography scan or β-amyloid and tau levels in 
cerebrospinal fluid that are consistent with underlying AD pathology) 
e. Documented magnetic resonance imaging (MRI) report consistent with the diagnosis 
of AD-MCI with no clinically significant findings of non-AD pathology that could 
account for the observed cognitive impairment 
6. Have a score of 15 to 24 (inclusive) on the Montreal Cognitive Assessment at Screening 
7. Have an estimated premorbid IQ ≥85 (as assessed by the Test of Premorbid Functioning, 
performed at Screening) 
8. Have a study partner who is reliable, competent, at least 18 years of age, willing to be 
available to the study center by phone, support study-specific activities, and accompany 
the participant to study visits as needed 
9. Be ambulatory (use of assistance devices such as a walker or cane is acceptable; 
individuals requiring a wheelchair are excluded), 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 
10. Have stable concomitant medication usage per the following criteria: 
a. For psychotropic medications, including acetylcholinesterase inhibitors and other 
medications that are likely to have an effect on cognitive performance, the dose and 
frequency must remain stable for at least 12 weeks prior to the first IP administration 
and be expected to remain stable for the duration of the study 
b. For all other concomitant medications, the dose and frequency must remain stable for 
at least 4 weeks prior to the first IP administration and be expected to remain stable 
for the duration of the study 


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11. 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 >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 
12. Agree, if male, to use an acceptable method of highly effective contraception (as defined 
in Section 9.2.4) during the 14-day 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 
13. Agree, if male, to abstain from sperm donation during the 14-day Treatment Period and 
for 2 weeks after receiving the last dose of IP 
14. 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 any medical or neurological condition (other than AD) that might be contributing to 
the participant's cognitive impairment or history of cognitive decline 
4. 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 
5. Have a history, presence, and/or current evidence of an intracranial abnormality 
(eg, stroke, hemorrhage, space-occupying lesion) 
6. Have a history of possible or probable cerebral amyloid angiopathy, according to the 
Boston Criteria (Greenberg 1995) 
7. Have a history of treatment with an anti-amyloid therapy (including biologics) without 
subsequent MRI demonstrating the absence of amyloid-related imaging abnormalities 
8. Be receiving any of the following prohibited medications: 
a. Medications with potent effects at the N-methyl-D-aspartate (NMDA) receptor, 
including amantadine, ketamine, cycloserine, or related compounds 
b. Memantine within the 4 weeks prior to IP administration 
c. Medications that inhibit cholesterol absorption (eg, ezetimibe) 


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d. Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine) 
e. 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 (American Geriatrics Society 2019) 
f. Prescribed cannabis or other THC-containing substances 
9. Have an alcohol or drug use disorder within the past 12 months, as per DSM-5 criteria 
10. Have a history of seizures or epilepsy, with the exception of a single episode of febrile 
seizures in childhood 
11. 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 C-SSRS during Screening or Baseline 
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 
12. 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 for initial values outside these ranges: 
− Heart rate <50 or >100 bpm 
− Systolic blood pressure <100 or >160 mmHg 
− Diastolic blood pressure <60 or >100 mmHg 
13. Have a history, presence, and/or current evidence of serologic positive results for HIV-1 
or HIV-2 
14. Have a positive pregnancy test or be lactating at Screening or Day -1 
15. 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. 


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8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
8.4.1. 
Investigational Product Discontinuation 
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. 
Participants who discontinue IP will be invited by the investigator to complete all of the 
scheduled study visits and assessments (except IP administration) through the end of the 
Treatment Period (Day 14). Those who decline continued participation through Day 14 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. 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 at contacting 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. 
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. 


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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. For psychotropic 
medications, including acetylcholinesterase inhibitors and other medications that are likely to 
have an effect on cognitive performance, the dose and frequency must have been stable for at 
least 12 weeks prior to the first IP administration and be expected to remain stable for the 
duration of the study. 
The start and end dates, route, dose/units, frequency, and indication for all relevant medications 
and/or supplements will be recorded at Screening. Medications to be recorded include all 
psychotropic medications used within 12 weeks of informed consent, any other medications and 
supplements taken within 60 days of informed consent, and all medication used to treat AD, 
regardless of timing. After Screening, all changes to any medication or supplements 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 
, it is important to evaluate 
single or combined concomitant medications and their doses for their potential effects 
 
 Investigators will carefully review concomitant medications for possible 
 
effects 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 
 performance 
 
 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, cycloserine, or related compounds 
• Medications that inhibit cholesterol absorption (eg, ezetimibe) 
• Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine) 
• Other medications given at doses or in combinations that are likely to have a 
deleterious effect on 
 performance, as described in the 2019 American 


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Geriatrics Society Updated Beers® Criteria for Potentially Inappropriate Medication 
Use in Older Adults (American Geriatrics Society 2019) 
• Prescribed cannabis or other THC-containing substances 
9.2.3. 
Other Restrictions 
Participants must agree not to consume 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 the Day 1, and Day 7 
visits, 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 packaging, 


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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. 
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. The pharmacist will dispense the tablets into 
unit doses to 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 


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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 
Schedule of Assessments (Table 2). 
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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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
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. 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, ethnicity) and a full medical history will be 
documented. Premorbid IQ will be estimated by administration of the Test of Premorbid 
Functioning (Wechsler 2009). 
Medical history must include a confirmed diagnosis of MCI or mild dementia due to AD 
according to the National Institute on Aging-Alzheimer’s Association 2011 diagnostic 
guidelines. This diagnosis will be confirmed via the administration of the CDR. The CDR is a 
clinician-administered 5-point scale to characterize a patient’s level of impairment due to 
dementia in 6 domains: memory, orientation, judgment and problem solving, community affairs, 
home and hobbies, and personal care (Morris 1993). The Test of Premorbid Functioning uses a 
word-reading scale to estimate premorbid 
 function in individuals with 
dementia (Wechsler 2009). In addition to full medical history, all nonpharmacological methods 
 used to treat or prevent 
 
 AD are to be recorded. 
12.1.2. 
Weight and Height 
Height and weight will be measured and documented. Body mass index will be calculated and 
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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) 
 
. Thereafter, physical examinations will include brief 
assessments 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 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 not while the participant is in 
a fasted 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. 


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12.1.7. 
Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected. will be collected 
for hematology, biochemistry, coagulation, urinalysis, and serology at the time points detailed in 
Table 2 and Table 3. 
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 in Table 4. 
Table 4: 
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 (LDL, 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. 


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12.1.8. 
Columbia–Suicide Severity Rating Scale 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the 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 the most severe). 
The “Baseline/Screening” C-SSRS form will be completed at Screening (lifetime history and 
past 24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points outlined in Table 2. 
12.2. 
Adverse 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 adverse event with onset after the start of IP, or any worsening of a 
preexisting medical condition/adverse event 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 an 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 and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage 
Therapeutics. 
Subjects 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. 


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12.2.2. 
Serious Adverse Event Definition 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the informed consent form (ICF) and 
throughout the duration of the study, whether or not they are related to the study, must be 
recorded on the SAE report form provided by Sage Therapeutics. Any SAE that is ongoing when 
the participant completes their final study visit, will be followed by the investigator until the 
event has resolved, stabilized, returned to baseline status, or until the participant dies or is lost to 
follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each adverse event 
(not related, related). The following definitions should be considered when evaluating the 
relationship of AEs and SAEs to the IP. 
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 


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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. 
12.2.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the participant and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome and seriousness (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s) 
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in 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, 
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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. 
Serious adverse events occurring after the designated follow-up time for the study, should be 
reported to Sage or designee according to the timelines noted above only if the investigator 
considers the SAE related to IP. 
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all suspected unexpected serious 
adverse reactions (SUSARs) that occur during the clinical study. IRBs/IECs will be notified of 
SAEs and/or SUSARs as required by local law. 
Sage, or designee, will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies 
according to local law and investigators. 
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 informed consent 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 
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Pregnancy test results and alcohol and drug test results will be listed but not summarized. 
Medical history will be listed by participant. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 


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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. 
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 September 2015, or later. 
At Screening, all psychotropic medications used by the participant within 12 weeks before 
informed consent, any other medications and supplements within 60 days before informed 
consent, and all medications used to treat AD, regardless of timing, will be recorded. After 
Screening, all changes to any medication or supplements should be captured. 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. 


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13.8. 
Sample Size and Power 
No formal sample size calculation was made for this study. Twenty participants completing 
14 days of dosing are considered sufficient to assess preliminary safety and tolerability and for 
signal-finding 
 after 14 days of repeated dosing with of SAGE-718. Assuming 
a 10% dropout rate, approximately 22 total participants will be required to obtain 20 completers. 
Additional participants may be dosed if the early discontinuation rate is >10%. 
13.8.1. 
Interim and Data Monitoring Committee Analysis 
Not applicable. 
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. 


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• 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 Independent Ethics Committee or an Institutional Review Board 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 and/or 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. 
14.3. 
Institutional Review Board or 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. 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit(s) at the clinical site. Please see 
Section 14.2 for more details regarding the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Significant protocol deviations should be reported to the IRB/IEC per the IRB/IEC’s 
written procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates 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 


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should be traceable, should not obscure the original entry, and should be explained, if necessary 
to provide clarification. 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
given a written and dated approval or favorable opinion by an IRB or IEC as appropriate. The 
investigator must obtain and document approval before he or she can enroll any participant into 
the study. The IRB or IEC must supply to the sponsor a list of the IRB/IEC membership and a 
statement to confirm that the IRB/IEC is organized and operates according to GCP and 
applicable laws and regulations. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. In addition, the principal investigator must 
inform the IRB/IEC and sponsor of any changes significantly affecting the conduct of the 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 Informed Consent Form. A copy of the signed Informed Consent Form must 
be given to the participant or to the participant’s parent or legally authorized representative. 


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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. 
17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics or its representative(s) will be allowed to conduct site visits at the 
investigation facilities for the purpose of monitoring any aspect of the study. The investigator 
agrees to allow the monitor to inspect the facility, drug storage area, drug accountability records, 
participant charts and study source documents, and other records relative to study conduct. 
Inspection of the study by a Regulatory Authority may occur at any time. The investigator must 
agree to the inspection of study-related records and source documents by the Regulatory 
Authority representative(s). 
17.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. Sage is responsible to inform the investigator/institution as to 
when study documents no longer need to be retained. 
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 
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symptoms in schizophrenia: Assessment and research (Monograph). Clinical and Experimental 
Psychiatry. 1991;5. Modified from Guy W, ed. ECDEU Assessment Manual for 
Psychopharmacology. US Department of Health, Education, and Welfare Public Health Service 
Alcohol, Drug Abuse, and Mental Health Administration. 1976;218-22. 
 
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. 
Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. US Department of Health, 
Education, and Welfare; Public Health Service; Alcohol, Drug Abuse, and Mental Health 
Administration. 1976. 
Jutten RJ, Peeters CF, Leijdesdorff SM, et al. Detecting functional decline from normal aging to 
dementia: Development and validation of a short version of the Amsterdam IADL Questionnaire. 
Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2017;8:26-35. 
Kaufer DI, Cummings JL, Ketchel P, et al. Validation of the NPI-Q, a brief clinical form of the 
Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci. 2000;12:233-239. 
Molinuevo J, et al. Memantine: Targeting glutamate excitotoxicity in AD and other dementias. 
Am Journal of AD & Other Dementias. 2005;77-85. 
Morris JC. The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology. 
1993;43:2412-2414 
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 
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adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. 
Tsai GE, et al. Improved cognition in Alzheimer's disease with short-term D-cycloserine 
treatment. Am J Psychiatry. 1999 Mar;156(3):467-9. 
Wechsler D. Test of premorbid functioning. San Antonio, TX: The Psychological Corporation. 
2009. 
Weintraub S, et al. The neuropsychological profile of Alzheimer disease. Cold Spring Harb 
Perspect Med. 2012;2(4):a006171. 


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Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression 
screening scale: A preliminary report. J Psych Res. 1983;17:37-49. 

SAP_001.pdf: 
 
Official Title: 
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 
NCT Number: 
 
NCT04602624 
 
Document Date: 
 
SAP Version 1.0: 01 November 2021 
 
 
 
 
 
 
 


Clinical Study Report 
 
SAGE-718-CNA-201 
16.1 Study Information 
 
1 
 
 
  
 
9. 
STATISTICAL METHODS ANALYSIS PLAN 
 
Statistical Analysis Plan (SAP) v1.0, 01 Nov 2021