Conditions: Mild Cognitive Impairment Mild Dementia Alzheimer's Disease
Keywords: SAGE-718 Cognitive dysfunction N-methyl-D-aspartate (NMDA)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 174
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to evaluate the effect of SAGE-718 on cognitive performance in participants with Alzheimer's Disease.

Detailed description:

Arms:
arm 1: Participants will receive SAGE-718, 1.2 milligrams (mg), orally, once daily (QD) for the first 6 weeks (Days 1 to 42), followed by 0.9 mg of SAGE-718 for the remainder of the treatment period up to Day 84. arm 2: Participants will receive SAGE-718-matching placebo, orally, QD, throughout the treatment period up to Day 84.

Interventions: intervention 1: SAGE-718 intervention 2: SAGE-718-matching Placebo
Intervention descriptions: intervention 1: Softgel lipid capsules. intervention 2: Softgel lipid capsules.

Protocol document:
Prot_000.pdf: 
Official Title: A Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Effects of SAGE-718 in Participants with Mild 
Cognitive Impairment or Mild Dementia Due to Alzheimer’s 
Disease 
NCT ID: NCT05619692 
Document Date: Protocol Version 2.0, 22 December 2023 
 


 
 
 
 
 
A Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Effects of SAGE-718 in Participants with Mild 
Cognitive Impairment or Mild Dementia Due to Alzheimer’s 
Disease  
PROTOCOL NUMBER: 718-CNA-202 
 
Investigational Product 
SAGE-718 
 
Clinical Phase 
2 
 
Sponsor Contact 
 
 
  
 
  
Cambridge, MA 02142 
Phone: 
 
 
 
Medical Monitor 
, MD 
 
 
Cambridge, MA 02142 
Phone: 
 
 
 
Date of Original Protocol 
Date of Amendment 1 
24 May 2022 
22 December 2023 
 
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 


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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-202 protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
Date (DD MMM YYYY) 
 
 


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CONTACT INFORMATION 
 
 
Table 1: 
Contact Information 
Sage Study Physician and 24-hour 
emergency contact  
, MD 
215 First Street 
Cambridge, MA 02142 
Phone: 
 
SAE Reporting 
IQVIA Lifecycle Safety 
4820 Emperor Boulevard 
Durham, NC 27703 
e-mail: Sage.Safety@iqvia.com 
Fax: 1-855-638-1674 
SAE Hotline: 1-855-564-2229  
Product Complaints 
Sage Therapeutics 
e-mail: 
productcomplaints@sagerx.com 
Phone: 1-833-554-7243 
Inspection Notification Contact 
Sage Therapeutics 
Email: 
InspectionNotification@sagerx.com 
 
 
 




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Study Description: 
This is a randomized, double-blind, placebo-controlled study to evaluate the effects of SAGE-718 in 
participants with mild cognitive impairment (MCI) or mild dementia due to AD. Eligible participants 
with a confirmed diagnosis and who meet the criteria for MCI or Mild Dementia due to AD at 
Screening will be randomized to receive either SAGE-718 or matching placebo. Within the SAGE-718 
treatment arm, participants will receive 1.2 mg of SAGE-718 as a softgel lipid capsule orally once 
daily for the first 6 weeks (Day 1 Visit to Day 42 Visit [±2 days]), followed by 0.9 mg of SAGE-718 
for the remainder of the Treatment Period (ie, beginning the first day after the Day 42 Visit). Dosing 
ends at the Day 84 Visit (±7 days). The placebo arm will receive placebo throughout the Treatment 
Period (12 weeks). All participants will self-administer investigational product (IP) in the morning.  




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will be performed. Participants will self-administer IP in the clinic under the supervision of study staff. 
Participants will receive a sufficient amount of IP for daily administration until the next scheduled 
clinic visit, at which time study staff will assess participants’ treatment adherence by examining used 
packaging and counting returned capsules. 
During the Treatment Period, participants will be able to receive IP if there are no dose limiting 
safety/tolerability concerns. Participants who discontinue IP should complete the remaining study visits 
as scheduled unless the participant chooses to withdraw consent or loses the capacity to grant consent. 
If a participant withdraws from the study/stops study participation early, an Early Termination Visit 
should be conducted. Treatment with SAGE-718 can be ended without down titration. Participants may 
be invited to screen for a subsequent SAGE-718 study (if available) after the Day 84 Visit. 
Follow-up Period 
After completing the Treatment Period, participants will return to the clinic for a Follow-up Visit on 
Day 112 (±7 days) to collect safety, some cognition, 
. 
Number of Participants (planned): Approximately 150 participants will be randomized to obtain up 
to 60 evaluable participants per treatment arm.  
Eligibility Criteria  
Inclusion Criteria: 
Participants must meet all of the following criteria to qualify for participation in this study: 
1. Be capable of providing informed consent 
2. Have signed an informed consent form (ICF) 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 their study partner 
b. A Clinical Dementia Rating (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 with no clinically significant findings of non-AD 
pathology that could account for the observed cognitive impairment 
6. Have a score of 15 to 25 (inclusive) on the MoCA with years of education adjustment at 
Screening 
7. Have a study partner who, in the opinion of the investigator, is willing and able to provide 
informed consent, reliably support study-specific activities including IP adherence, be 
available by phone, and accompany the participant to study visits as needed 
8. Be ambulatory (use of assistance devices such as a walker or cane is acceptable; individuals 
requiring a wheelchair are excluded) and able to travel to the study center 
9. Have stable concomitant medication usage (dose and frequency) for at least 4 weeks prior to 
the first IP administration, and which is expected to remain stable for the duration of the study  
10. Agree to refrain from drugs of abuse for the duration of the study and from alcohol during the 
48 hours preceding each study visit 
11. Agree, if female, to use an acceptable highly effective method of contraception 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 


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confirmed by follicle stimulating hormone [FSH] >40 mIU/mL), surgically sterile 
(hysterectomy or bilateral oophorectomy or bilateral salpingectomy), or does not engage in 
sexual relations which carry a risk of pregnancy 
12. Agree, if male, to use an acceptable method of highly effective contraception during the 
Treatment Period and for 21 days 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 Treatment Period and for 21 days 
after receiving the last dose of IP  
Exclusion Criteria: 
Participants who meet any of the following criteria are disqualified from participation in this study: 
1. Have participated in a previous clinical study of SAGE-718, have participated in a previous 
gene therapy study, or have received study treatment in any other drug, biologic, or device trial 
within 30 days or 5 half-lives (whichever is longer), unless the participant participated solely in 
the placebo arm of the study. Additionally, participants who have received treatment with 
antisense oligonucleotides (ASO) will be excluded 
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 (eg, hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or 
oncological disease), or a chronic condition that is unstable, or are 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, presence, and/or current evidence of 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 
6. Have a history, presence, and/or current evidence of  
a. Brain surgery, deep brain stimulation, or any history of hospitalization due to a brain 
injury 
b. Possible or probable cerebral amyloid angiopathy, according to the Boston Criteria 
(Greenberg 1995) 
c. Treatment with an anti-amyloid therapy (including biologics) without subsequent MRI 
demonstrating the absence of amyloid-related imaging abnormalities 
d. Seizures or epilepsy, with the exception of childhood febrile seizures 
7. Have an alcohol or drug use disorder within the past 12 months as per Diagnostic and 
Statistical Manual of Mental Disorders (DSM-5) criteria 
8. Be receiving any of the following prohibited medications: 
a. Medications with potent effects at the N-methyl-D-aspartate (NMDA) receptor, including 
memantine, within 4 weeks of IP administration and during the entire course of the study 
b. Medications that inhibit cholesterol absorption (eg, ezetimibe) 
c. Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine) 


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d. Other medications or supplements given at doses, frequencies, or in combinations that are 
likely, in the opinion of the investigator, to have a deleterious effect on cognitive 
performance 
e. Cannabis or other tetrahydrocannabinol (THC)-containing substances (any route of 
administration), regardless of whether or not they are prescribed 
9. Participant has a history of suicidal behavior within 2 years or answers “YES” to Questions 3, 
4, or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk of suicide in the opinion 
of the investigator.  
10. Have any of the following medical conditions: 
a. Any clinically significant finding on 12-lead ECG during Screening in the opinion of 
the investigator 
b. Any clinically significant supine vital signs (heart rate, systolic and diastolic blood 
pressure)  during Screening (note: vital sign measurements may be repeated once)  
11. Have a history, presence, and/or current evidence of serologic positive results for human 
immunodeficiency virus (HIV)-1 or HIV-2, or hepatitis B or C 
12. Have a positive pregnancy test, or be lactating, or intend to breastfeed during the study 
13. Be investigative site personnel, sponsor personnel, or an immediate member of their family 
(spouse, parent, child, or sibling whether biological or legally adopted) 
14.  Is known to be allergic to any of SAGE-718 excipients, including soy lecithin. 
15. Plans to undergo elective surgery or procedures during participation in the study. 
16. Have a history of gastric bypass 
Investigational Product Dosage and Mode of Administration:  
SAGE-718 or matching placebo, under double-blind conditions, will be self-administered as softgel 
lipid capsule orally once daily in the morning. 
Duration of Treatment: IP will be administered once daily during the 12-week Treatment Period.  
Dosing ends at the Day 84 Visit (±7 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, 
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 
The All Randomized Set will include all participants who have been randomized and will be used to 
describe participant disposition. 
The Safety Set will include all participants who were administered at least one dose of the IP and will 
be used to describe the safety data and analyses will be based on the actual treatment received. 
The Full Analysis Set (FAS) will include all participants in the Safety Set who have baseline and at 
least 1 postbaseline efficacy evaluation. The FAS will be used to describe the efficacy data. Analyses 
will be based on the randomized treatment. 


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Safety Analysis 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). The proportion of 
participants experiencing TEAEs will be displayed by treatment group and by system organ class and 
preferred term. The frequency of TEAEs will also be presented by maximum severity and relationship 
to IP and by treatment group. Vital signs, laboratory parameters, ECGs, 
 data will be 
summarized by treatment group. Additional analyses will be detailed in the SAP. 
Efficacy Analysis 
The endpoints for each cognitive test, including WAIS-IV Coding Test, 
 
 are change from baseline 
scores at each postbaseline assessment. Descriptive statistics of scores and change from baseline scores 
will be summarized based on the Full Analysis Set. These endpoints will also be analyzed using a 
mixed effects model for repeated measures. The model will include change from baseline scores as 
dependent variable; treatment, visit, and visit by treatment interaction as fixed effects; participants as 
random effects; and baseline cognitive test scores as a covariate; Model-based point estimates (ie, least 
square means, 95% confidence intervals, and associated p values) at each time point (visit) will be 
reported where applicable. Line plots of change from baseline scores will be plotted with standard error 
bars. 
 
  
  
 
 
Sample Size Calculation 
The sample size calculation is based on change from baseline in WAIS-IV Coding Test total correct 
score. Based on data in a previous study, we assume difference between placebo and the SAGE-718 
group at the end of treatment (at Day 84) for primary endpoints of WAIS-IV Coding test total correct 
score is 2.5, the standard deviation is 4.2. 
The total sample size of 120 evaluable participants will provide 90% power to detect the treatment 
difference of 2.5 in change from baseline in WAIS-IV Coding Test total correct score while allowing 
for one interim analysis and one final analysis. This sample size and power are based on a two-sided 
test using an overall significance level of 0.05.One formal interim analysis may be conducted after 
approximately 60 participants have completed Week 12. The group sequential method by O'Brien and 
Fleming for the two-sided test will be used (O’Brien 1979). The significance level will be based on the 
type I error spending function of Lan and DeMets such that the overall significance level will be 
maintained at 0.05 (Lan 1983). Assuming a 20% dropout and a 1:1 randomization ratio, approximately 
150 randomized participants (75 per treatment group) will be required to obtain 60 evaluable 
participants per treatment group. Evaluable participants are defined as those randomized participants 
who receive IP and have a valid baseline and at least 1 postbaseline WAIS-IV Coding test assessment. 
Additional participants may be randomized if the dropout rate is higher than 20%.  
The table below summarizes operating characteristics of this design based on 120 evaluable 
participants. 


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Table Group Sequential Design 
Repeated 
Analyses 
Information 
Time 
No of 
Participants 
Boundaries for Efficacy 
Boundary for Futility 
Interim 
0.5 
60 
2.796 
0.4229 
Final  
1 
120 
1.977 
 


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Table 2: 
Schedule of Assessments  
Assessments  
Screening 
Period  
Baseline 
Period 
Treatment Period 
Follow-Up 
Period 
Days 
-35 to -8 
Days 
-7 
through   
-1 
Day 1a 
Day 14 
(±2 days)  
 
Day 28 
(±2 days)  
safety  
phone callb 
Day 42 
(±2 days)c 
 
Day 63 
(±2 days)  
safety 
phone callb  
Day 84 
(±7 days)d 
or ET 
Day 112 
(±7 days) 
 
Informed consente 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
Medical history and 
demographicsf 
X 
 
 
 
 
 
 
 
 
Participant trainingg 
 
X 
 
 
 
 
 
 
 
Body weight 
X 
 
X 
 
 
X 
 
X 
X 
Body height 
X 
 
 
 
 
 
 
 
 
CDR 
X 
 
 
 
 
 
 
 
 
Vital signs (including 
orthostatic)h 
X 
 
X 
X 
 
X 
 
X 
X 
Physical examinationi 
X 
 
X 
X 
 
X 
 
X 
X 
FSH testj 
X 
 
 
 
 
 
 
 
 
Serology testk 
X 
 
 
 
 
 
 
 
 
12-lead ECGl 
X 
 
X 
X 
 
X 
 
X 
X 
MRIm  
X 
 
 
 
 
 
 
 
 
Safety laboratory 
assessmentsn 
X 
 
X 
X 
 
X 
 
X 
X 




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Assessments  
Screening 
Period  
Baseline 
Period 
Treatment Period 
Follow-Up 
Period 
Days 
-35 to -8 
Days 
-7 
through   
-1 
Day 1a 
Day 14 
(±2 days)  
 
Day 28 
(±2 days)  
safety  
phone callb 
Day 42 
(±2 days)c 
 
Day 63 
(±2 days)  
safety 
phone callb  
Day 84 
(±7 days)d 
or ET 
Day 112 
(±7 days) 
 
IP self-administrationu 
 
 
X (once daily in the morning) 
 
IP dispensationv 
 
 
X 
X 
 
X 
 
 
 
IP accountability
w 
 
 
X 
 
IP returnx 
 
 
 
X 
 
X 
 
X 
 
Safety call assessmentb 
 
 
 
 
X 
 
X 
 
 
AEs/SAEsy  
 
 
X 
Prior and concomitant 
medicationsz 
X 
Abbreviations: AD = Alzheimer’s Disease; AE = adverse event, 
 
 
 CDR = Clinical Dementia Rating; 
 
COVID-19 = coronavirus disease 2019; 
 ET = early 
termination; 
 FSH = follicle-stimulating hormone; HIV = human 
immunodeficiency virus; ICF = informed consent form; IP = investigational product; 
 MRI = magnetic resonance 
imaging; 
 
 SAE = serious adverse 
event; WAIS-IV Coding Test = Wechsler Adult Intelligence Scale-IV Coding Test.  
 
a All tests at the Day 1 Visit will be conducted predose. 


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b Phone check-in only for AEs/SAEs and changes to medical history or medications. 
c Within the SAGE-718 treatment arm, participants will receive 1.2 mg of SAGE-718 daily for the first 6 weeks (Day 1 Visit to Day 42 Visit [±2 days]), 
followed by 0.9 mg of SAGE-718 for the remainder of the Treatment Period (ie, beginning the first day after the Day 42 Visit). Dosing ends at the Day 84 Visit 
(±7 days). The placebo arm will receive matching placebo throughout the Treatment Period (12 weeks). 
d Dosing ends at the Day 84 Visit (±7 days). Participants who terminate early should perform all of the assessments that are scheduled for the Day 84 Visit 
(±7 days). 
e Both participants and their study partners will provide informed consent at screening. Participants and study partners will consent to participation in the study, 
and any optional assessments 
.  
f Includes full medical history (including family history of AD), medications and supplements taken within 30 days prior to Screening, medications used to treat 
AD regardless of timing, and nonpharmacological methods (eg, psychosocial, psychotherapeutic) used to treat or prevent 
 or 
cognitive manifestations of AD. Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be documented as part of medical 
history, AE collection, and prior/concomitant medication collection at Screening and throughout the study. 
g Participants and study partners will be trained by study staff on the use of software applications and devices necessary for the conduction of the study. 
h Vital signs include body temperature, respiratory rate, heart rate, and blood pressure. On dosing days, vital signs will be measured prior to dosing. 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 at all scheduled time points. Vital signs can be repeated once if out of range. 
i A full physical and neurological examination will be conducted during Screening and at the Day 84 Visit (±7 days; End of Treatment). At other visits, an 
abbreviated physical examination will include a brief assessment of general appearance, cardiovascular, respiratory, gastrointestinal, and neurological systems, 
followed by a targeted physical assessment as needed. A symptom directed examination may be conducted at any time at the discretion of the investigator. 
j Serum FSH test will be conducted at Screening for the female participants who are not surgically sterile and who have ≥12 months of spontaneous amenorrhea 
to confirm postmenopausal state as defined in protocol.  
k To include hepatitis B and C screening tests, HIV-1 and -2 antibody. 
l ECG will be measured after the participant has been in a supine position for at least 5 minutes. 
m Only in participants without an MRI report obtained within the 2 years preceding the Baseline Period. 
n Clinical laboratory assessments will include blood samples for hematology, biochemistry, coagulation, and urine samples for urinalysis. On dosing days 
samples will be collected prior to dosing. On nondosing days, collection may occur at any time.  
o Serum pregnancy tests will be conducted for all female participants at Screening; urine pregnancy tests will be conducted at other scheduled time points for 
female participants who do not meet the protocol definition of postmenopausal or surgically sterile. 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 


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u On Day 1, participants will self-administer IP in the clinic under the supervision of study staff. All scheduled safety assessments and cognitive tests will be 
administered prior to dosing. At Day 14 Visit (±2 days), Day 42 Visit (±2 days), and Day 84 Visit (±7 days), cognitive tests will be administered postdose. 
v Study staff will dispense enough IP for the participant to take daily at home until the next scheduled site visit. 
w IP dosing date and time will be recorded by participant remotely using mobile device.  
x Participants will bring all used packaging and unused IP to the clinic at each visit for study staff to review and document. 
y AEs/SAEs will be collected beginning with completion of ICF through end of study participation. 
z At Screening, to include all medications and supplements taken within 30 days of signing ICF and all medications used to treat AD. At visits subsequent to 
Screening, all changes to any medication should be captured.  
 


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Table 3: 
  
 
 
 
 
 
 
  
 
 
 
 


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3. 
TABLE OF CONTENTS 
 
1. 
TITLE PAGE ................................................................................................................1 
CONTACT INFORMATION ..........................................................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS ...........................................................................................19 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................25 
5. 
INTRODUCTION ......................................................................................................27 
5.1. 
Overall Risk/Benefit Assessment ...............................................................................27 
5.2. 
Dose Justification ........................................................................................................28 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................30 
7. 
INVESTIGATIONAL PLAN .....................................................................................32 
7.1. 
Overall Study Design ..................................................................................................32 
7.1.1. 
Screening Period .........................................................................................................32 
7.1.2. 
Baseline Period ...........................................................................................................32 
7.1.3. 
Treatment Period ........................................................................................................32 
7.1.4. 
Follow-up Period ........................................................................................................33 
7.2. 
Number of Participants ...............................................................................................35 
7.3. 
Treatment Assignment ................................................................................................35 
7.4. 
Dose Adjustment Criteria ...........................................................................................35 
7.4.1. 
Stopping Criteria .........................................................................................................35 
7.4.2. 
Dose Evaluation Committee .......................................................................................35 
7.4.3. 
Criteria for Study Termination ...................................................................................36 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.....................................37 
8.1. 
Inclusion Criteria ........................................................................................................37 
8.2. 
Exclusion Criteria .......................................................................................................38 
8.3. 
Screen Failures ............................................................................................................39 
8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................39 
8.4.1. 
Investigational Product Discontinuation .....................................................................39 
8.4.2. 
Early Termination from the Study ..............................................................................40 
8.4.3. 
Lost to Follow-up .......................................................................................................40 
8.4.4. 
Replacement of Participants .......................................................................................40 


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9. 
TREATMENT OF PARTICIPANTS .........................................................................41 
9.1. 
Description of Investigational Product .......................................................................41 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................41 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................41 
9.2.2. 
Prohibited Medications ...............................................................................................41 
9.2.3. 
Other Restrictions .......................................................................................................42 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................42 
9.3. 
Intervention after the End of the Study .......................................................................43 
9.4. 
Treatment Adherence ..................................................................................................43 
9.5. 
Randomization and Blinding ......................................................................................43 
9.5.1. 
Emergency Unblinding ...............................................................................................43 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............44 
10.1. 
Investigational Product ...............................................................................................44 
10.2. 
Investigational Product Packaging and Labeling .......................................................44 
10.3. 
Investigational Product Storage ..................................................................................44 
10.4. 
Investigational Product Preparation ............................................................................45 
10.5. 
Investigational Product Administration ......................................................................45 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................45 
10.6.1. 
Investigational Product Accountability, Handling, and Disposal ...............................45 
10.6.2. 
Product Complaints ....................................................................................................46 
11. 
EFFICACY 
 ....................47 
11.1. 
Cognitive Assessments ...............................................................................................47 
11.1.1. 
 .........................47 
11.1.1.1. 
 ................................................................................................................47 
11.1.1.2. 
 ........................................................................................................47 
11.1.1.3. 
 ..................................................................................48 
11.1.1.4. 
 ...........................................................................48 
11.1.1.5. 
 ......................................................................................48 
11.1.2. 
 .................................................................................48 
11.1.3. 
 ......................49 
11.1.4. 
Wechsler Adult Intelligence Scale-IV Coding Test ...................................................49 
11.2. 
 .........................................................................................49 


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11.2.1. 
 ..................................................................................49 
11.2.2. 
 .....................................................................49 
11.2.3. 
 ......................................................................................49 
11.3. 
 ..............................................................................................50 
11.3.1. 
 ................................................................................................50 
11.3.1.1. 
 ..............................................................................50 
11.3.2. 
 .............................................................................................50 
11.3.2.1. 
 
 ....................................................................................................50 
11.3.2.2. 
 .........................................................................................50 
11.3.2.3. 
 ..............................................................................50 
11.3.2.4. 
 ............................50 
11.3.3. 
 .........................................................................................51 
11.3.3.1. 
 
 .................................................................................................51 
11.3.3.2. 
 ...........................................................................51 
11.3.3.3. 
 ....................................................................51 
11.4. 
 ..........................................................................51 
11.4.1. 
 ....................................................................................51 
11.4.1.1. 
 ............................................................................................52 
11.4.1.2. 
 .........................................................................................................52 
11.4.2. 
 ..................................................................................52 
11.4.3. 
 .......................................................................52 
12. 
SAFETY ASSESSMENTS ........................................................................................53 
12.1. 
Safety Parameters .......................................................................................................53 
12.1.1. 
Demography and Medical History ..............................................................................53 
12.1.2. 
Weight and Height ......................................................................................................53 
12.1.3. 
Physical Examination .................................................................................................53 
12.1.4. 
COVID-19 Questions .................................................................................................53 
12.1.5. 
Vital Signs ..................................................................................................................54 
12.1.6. 
Electrocardiogram .......................................................................................................54 
12.1.7. 
Magnetic Resonance Imaging .....................................................................................54 
12.1.8. 
Clinical Laboratory Assessments ...............................................................................54 




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14.1. 
Study Monitoring ........................................................................................................66 
14.2. 
Audits and Inspections ................................................................................................66 
14.3. 
Institutional Review Board or Independent Ethics Committee ..................................67 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................68 
16. 
ETHICS ......................................................................................................................69 
16.1. 
Ethics Review .............................................................................................................69 
16.2. 
Ethical Conduct of the Study ......................................................................................69 
16.3. 
Written Informed Consent ..........................................................................................69 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................71 
17.1. 
Inspection of Records .................................................................................................71 
17.2. 
Retention of Records ..................................................................................................71 
18. 
PUBLICATION POLICY ..........................................................................................72 
19. 
LIST OF REFERENCES ............................................................................................73 
 
 


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LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................13 
Table 3: 
 ............................................18 
Table 4: 
Investigational Product ...............................................................................................44 
Table 5: 
Summary of Clinical Laboratory Analytes .................................................................54 
Table 6: 
Group Sequential Design ............................................................................................65 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................34 
 
 


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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 
24SHC 
24(S)-hydroxycholesterol  
AD 
Alzheimer’s Disease 
ADME 
absorption, distribution, metabolism and excretion  
AE 
adverse event 
 
 
 
ASO 
antisense oligonucleotides 
BMI 
body mass index 
 
  
 
  
 
  
CDR 
Clinical Dementia Rating 
COVID-19 
coronavirus disease 2019  
CS 
clinically significant  
DILI 
drug-induced liver injury 
 
 
ECG 
electrocardiogram 
ET 
Early Termination 
eCRF 
electronic case report form 
FAS 
Full Analysis Set 
 
 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone  
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification  


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Abbreviation 
Definition 
IEC 
independent ethics committee 
IP 
investigational product 
IRB 
institutional review board 
IRT 
interactive response technology  
LC-MS/MS 
Liquid Chromatography with tandem Mass Spectrometry  
MCI 
Mild Cognitive Impairment 
MoCA 
Montreal Cognitive Assessment 
MRI 
magnetic resonance imaging 
NCS 
not clinically significant  
 
  
NMDA 
N-methyl-D-aspartate 
 
  
 
 
 
 
 
 
 
 
QTcF 
QT corrected according to Fridericia’s formula 
 
 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
 
 
 
 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
THC 
tetrahydrocannabinol  
US 
United States  
USM 
urgent safety measure 
WAIS-IV 
Wechsler Adult Intelligence Scale-IV  


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5. 
INTRODUCTION 
Alzheimer’s disease (AD) is the most common cause of dementia and is projected to increase in 
incidence to >13 million in the United States by 2050 (Hebert 2013; Sharma 2019). Deficits in 
executive functioning (eg, problem solving) occur early in the disease, and are hypothesized to 
reflect prefrontal cortex pathology (Weintraub 2012). As AD progresses, deficits in learning and 
memory become more pronounced, and are coupled with impaired sustained attention and 
visuospatial abilities (Weintraub 2012).  
The N-methyl-D-aspartate receptor (NMDAR) is a type of glutamate receptor that has a 
fundamental and well-documented role in regulating synaptic plasticity, as well as in memory 
and learning (Danysz 1998; Ghanavati 2022; Li 2009). NMDAR functioning is affected by AD 
(Mony 2009; Prasanth 2021; Taniguchi 2022), however the nature of this relationship may be a 
function of disease severity. In later stages of AD, memantine, an NMDAR antagonist, may 
protect against glutamate excitotoxicity (Gauthier 2013). In earlier stages of AD, however, 
NMDAR functioning may be impaired (Ortiz-Sanz 2022). Indeed, administration of a short-term 
NMDA partial agonist (D-cycloserine) has been shown to improve cognition in AD patients, as 
evidenced by scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale 
(Tsai 1999).  
SAGE-718 is a novel NMDAR positive allosteric modulator that is being developed by 
Sage Therapeutics for the treatment of neurodegenerative disorders such as AD. Recently, a 
Phase 2 open-label study assessed the effects of SAGE-718 in an AD population 
(Study 718-CNA-201). In this seminal study, investigators assessed the safety and tolerability of 
SAGE‑718, as well as its effects on cognitive and neuropsychiatric symptoms in participants 
with MCI or mild dementia due to AD (n=24). SAGE-718 had a well-tolerated safety profile, 
with no unexpected safety concerns. Over 14 days of open-label dosing with SAGE-718, 
improvement was observed on cognitive test performance in several key domains, including 
Global Cognition, Executive Function, Learning and Memory, Social Cognition, and Everyday 
Function.  
The current study, 718-CNA-202, is a randomized, double-blind, placebo-controlled Phase 2 
study designed to evaluate the effects of SAGE-718 in participants with MCI or mild dementia 
due to AD. 
5.1. 
Overall Risk/Benefit Assessment 
 
In addition to the study discussed above, SAGE-718 has been shown to improve cognition in 
other neurodegenerative disorders (for details refer to SAGE-718 Investigator’s Brochure [IB]). 
The potential benefit of SAGE-718 is coupled with low risk of NMDAR-associated 
excitotoxicity. Indeed, SAGE-718 is oxysterol-based and acts on the 24(S) hydroxycholesterol 
(24SHC) binding site of NMDAR. SAGE-718 only modulates the response of NMDAR in the 
presence of endogenous glutamate. That is, SAGE-718 does not directly activate the receptor and 
thus, is not expected to cause NMDAR-associated glutamatergic excitotoxicity.  
SAGE-718 has been well characterized in a comprehensive series of in vitro and in vivo 
nonclinical studies that have defined its key pharmacology, absorption, distribution, metabolism 
and excretion (ADME), drug-drug interaction, and toxicology findings, including compound-
related effects and the reversibility of these changes. In a radiolabeled rat ADME study, there 


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was no selective distribution or retention of radioactive SAGE-718 to pigmented tissues and no 
quantifiable concentration of radioactivity was observed in the eye lens in Long Evans rats, 
implying that potential risk of phototoxicity is low. 
Due to an unexplained mortality early in the 14-day oral repeat-dose rat study at 30 mg/kg/day, a 
human maximum concentration (Cmax) cap for clinical studies was established from the Day 0 
mean Cmax (443 ng/mL) in female rats at the 15 mg/kg/day dose level. A 10-fold safety factor 
was used to derive the 45 ng/mL clinical exposure cap (see Section 5.2 Dose Justification). 
Across the nonclinical studies conducted with rats and dogs, a Cmax threshold for observation of 
convulsions occurred at exposures 20 to 40 times greater than clinically relevant exposures.  
No deaths, SAEs or TEAEs leading to discontinuation assessed as related to SAGE-718 were 
reported in the completed studies with SAGE-718. A maximum tolerated dose has not been 
identified and no characteristic safety signals have been identified to date. No clinically relevant 
mean changes from baseline have been observed in ECGs or EEGs. In addition, there were no 
SAEs or severe TEAEs reported in patients with AD that were enrolled in the completed 
Study 718-CNA-201.  
There is no contraindication for use of the coronavirus disease 2019 (COVID-19) vaccination in 
the trial setting of SAGE-718. Vaccine status will be recorded as a concomitant medication and 
COVID-19 safety protocols will be incorporated in all studies, data collection, and operating 
procedures.  
Based on the completed studies, the benefit-risk profile of SAGE-718 supports further 
development in an AD patient population. 
5.2. 
Dose Justification 
SAGE-718 has been well tolerated in both healthy participants and AD participants in previous 
clinical studies. However, based on nonclinical findings, the United States (US) Food and Drug 
Administration (FDA) imposed a median Cmax cap of 45 ng/mL. To date, clinical studies have 
used doses that resulted in exposures within this cap; no IP-related SAEs or AEs leading to 
discontinuation have been reported. For additional information on exposure caps, see the 
SAGE-718 IB. 
A daily dose of 1.2 mg from the Day 1 Visit to the Day 42 Visit (±2 days) followed by 0.9 mg 
until the Day 84 Visit (±7 days) (or ET) of SAGE-718 in a lipid-based softgel formulation or 
matching blinded placebo, will be taken by the participants each morning. The dose regimen is 
selected to provide PK exposures that are similar to those achieved in prior studies that have 
shown evidence of target engagement consistent with the NMDA hypothesis for pro-cognitive 
effects. 
 
 
 
 
 
In the completed SAGE-718 studies (718-EXM-101, 718-EXM-102 and 718-EXM-103), repeat 
doses of 1 mg and single doses of 3 mg, given as an oral solution to healthy volunteers, have 
demonstrated evidence consistent with NMDA target engagement in experimental medicine 
paradigms. A repeat dose of 1 mg daily of the oral solution in HD patients, and a solid tablet 


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taken with a moderate fat meal (containing approximately 30 g of dietary fat) in Parkinson’s 
Disease patients, has shown beneficial effects on assessments of cognition in 14-day studies. 
Based on an approximately 3-fold accumulation of SAGE-718 at steady-state, the PK exposures 
in each of these scenarios was similar, with median AUC values (AUC0-∞ for single doses, and 
AUC0-24 for repeat doses, accordingly) ranging from 315 to 444 ng·h/mL and Cmax values of 
19.7 ng/mL to 29.7 ng/mL and these levels are expected to be achieved in the present study. 
The effect of SAGE-718 will be evaluated in the current placebo-controlled study in participants 
with MCI or mild dementia due to AD. Additional data on the effects of SAGE-718 in 
participants with AD will be collected throughout, including the assessments of 
 
. 




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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled study to evaluate the effects of 
SAGE-718 in participants with mild cognitive impairment (MCI) or mild dementia due to AD. 
Eligible participants with a confirmed diagnosis and who meet the criteria for MCI or Mild 
Dementia due to AD at Screening will be randomized to receive either SAGE-718 or matching 
placebo. Within the SAGE-718 treatment arm, participants will receive 1.2 mg of SAGE-718 as 
softgel lipid capsule orally once daily in the morning for the first 6 weeks (Day 1 Visit to Day 42 
Visit [±2 days]), followed by 0.9 mg of SAGE-718 for the remainder of the Treatment Period (ie, 
beginning the first day after the Day 42 Visit). Dosing ends at the Day 84 Visit (±7 days). The 
placebo arm will receive placebo throughout the Treatment Period (12 weeks).  
Assessments will be performed as outlined in the Schedule of Assessments (Table 2) 
 
. 
7.1.1. 
Screening Period 
The Screening Period will begin with the informed consent process for prospective participants 
and their study partners. Subsequent screening assessments will be performed between Day -35 
and Day -8 to determine eligibility, including assessments of cognitive function. An adult study 
partner is required to support completion of study activities and to answer questions about the 
participant’s condition. 
7.1.2. 
Baseline Period 
The Baseline Period will occur from Day -7 through Day -1. During the Baseline Period, 
participants will visit the clinic for collection of baseline cognitive and functional data. 
Participants and study partners will receive training on the study procedures and devices. 
 
 
7.1.3. 
Treatment Period 
The blinded Treatment Period will occur from the Day 1 Visit through the Day 84 Visit 
(±7 days). Eligible participants will be randomized 1:1 to receive either SAGE-718 or matching 
placebo. Participants who are randomized to SAGE-718 will receive 1.2 mg of SAGE-718 for 
the first 6 weeks (Day 1 Visit to Day 42 Visit [±2 days]) followed by 0.9 mg of SAGE-718 for 
the remainder of the Treatment Period (ie, beginning the first day after the Day 42 Visit). Dosing 
ends at the Day 84 Visit (±7 days). All participants will receive blinded investigational product 
(IP) once per day in the morning, orally.  
At scheduled clinic visits during the Treatment Period, safety, efficacy, 
 will 
be performed. Participants will self-administer IP in the clinic under the supervision of study 
staff. Participants will receive a sufficient amount of IP for daily administration until the next 
scheduled clinic visit, at which time study staff will assess participant adherence by examining 
used packaging and counting returned capsules. 
During the Treatment Period, participants will be able to receive IP if there are no dose limiting 
safety/tolerability concerns. Participants who discontinue IP should complete the remaining 


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study visits as scheduled unless the participant chooses to withdraw their consent or loses the 
capacity to grant consent. If a participant withdraws from the study/stops study participation 
early, an Early Termination Visit will be conducted. Treatment with SAGE-718 can be ended 
without down titration.  
7.1.4. 
Follow-up Period 
After completing the Treatment Period, participants will return to the clinic for a Follow-up Visit 
on Day 112 (±7 days) to collect safety, some cognition, 
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7.2. 
Number of Participants 
Approximately 150 participants will be randomized to obtain up to 60 evaluable participants per 
treatment arm. Additional participants may be randomized if the early discontinuation rate is 
higher than expected. If the early discontinuation rate is lower than expected, enrollment may be 
closed once 120 evaluable participants have completed the study. 
7.3. 
Treatment Assignment 
Participants will be randomized to receive either SAGE-718 or matching placebo. Within the 
SAGE-718 treatment arm, participants will receive 1.2 mg of SAGE-718 as softgel lipid 
capsule(s) orally once daily in the morning for the first 6 weeks (Day 1 Visit to Day 42 Visit 
[±2 days]), followed by 0.9 mg of SAGE-718 for the remainder of the Treatment Period (ie, 
beginning the first day after the Day 42 Visit). Dosing ends at the Day 84 Visit (±7 days). The 
placebo arm will receive placebo throughout the Treatment Period (12 weeks).  
7.4. 
Dose Adjustment Criteria 
Individual dose reductions will be permitted.  
During the Treatment Period, participants will be able to receive IP as long as there are no dose 
limiting safety/tolerability concerns. Participants who cannot tolerate 1.2 mg will receive 0.9 mg 
for the remainder of the Treatment Period.  
If dose adjustment is deemed necessary by the investigator at any time during the Treatment 
Period, the participant will return to the site to return any remaining IP and for the adjusted dose 
to be dispensed. 
At the discretion of the investigator, participants who cannot tolerate the 0.9-mg dose may be 
discontinued from further IP administration refer to Section 8.4 for procedures for early IP 
discontinuation). Participants will be encouraged to continue to come in for the remaining 
study-related periodic assessments even after the IP discontinuation.  
7.4.1. 
Stopping Criteria 
If clinical events suspicious for seizure occur after Screening, IP should be discontinued 
immediately with appropriate clinical follow-up, including electroencephalogram, serum 
chemistry, urinalysis, and drug/alcohol tests.  
7.4.2. 
Dose Evaluation Committee 
A Dose Evaluation Committee (DEC) will be convened at a reasonable time after the first 
10 participants have completed the Treatment Period of the study 
 
 
 
 
 
 
 
 


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A separate DEC charter will detail the data to be reviewed and will be agreed upon and signed 
prior to administration of the first dose of IP. 
7.4.3. 
Criteria for Study Termination 
Sage Therapeutics (The Sponsor) may terminate this study or any portion of the study at any 
time for safety reasons, including the occurrence of AEs or other findings suggesting 
unacceptable risk to participants, or for administrative reasons. In the event of study termination, 
Sage Therapeutics will provide written notification to the investigator. Investigational sites must 
promptly notify their institutional review board (IRB)/independent ethics committee (IEC), 
where required, and initiate withdrawal procedures for participants. 


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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Inclusion Criteria 
Participants must meet all of the following criteria to qualify for participation in this study: 
1. Be capable of providing informed consent 
2. Have signed an informed consent form (ICF) 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 their study partner 
b. A Clinical Dementia Rating (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 with no clinically significant findings of 
non-AD pathology that could account for the observed cognitive impairment 
6. Have a score of 15 to 25 (inclusive) on the MoCA with years of education adjustment at 
Screening 
7. Have a study partner who, in the opinion of the investigator, is willing and able to 
provide informed consent, reliably support study-specific activities including IP 
adherence, be available by phone, and accompany the participant to study visits as 
needed 
8. Be ambulatory (use of assistance devices such as a walker or cane is acceptable; 
individuals requiring a wheelchair are excluded) and able to travel to the study center 
9. Have stable concomitant medication usage (dose and frequency) for at least 4 weeks prior 
to the first IP administration, and which is expected to remain stable for the duration of 
the study  
10. Agree to refrain from drugs of abuse for the duration of the study and from alcohol 
during the 48 hours preceding each study visit 
11. Agree, if female, to use an acceptable highly effective method of contraception during 
participation in the study and for 30 days following the last dose of IP, unless she is 
postmenopausal (defined as no menses for 12 months without an alternative medical 
cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL), surgically 
sterile (hysterectomy or bilateral oophorectomy or bilateral salpingectomy), or does not 
engage in sexual relations which carry a risk of pregnancy 
12. Agree, if male, to use an acceptable method of highly effective contraception during the 
Treatment Period and for 21 days 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 Treatment Period and for 
21 days after receiving the last dose of IP  


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8.2. 
Exclusion Criteria 
Participants who meet any of the following criteria are disqualified from participation in this 
study: 
1. Have participated in a previous clinical study of SAGE-718, have participated in a 
previous gene therapy study, or have received study treatment in any other drug, biologic, 
or device trial within 30 days or 5 half-lives (whichever is longer), unless the participant 
participated solely in the placebo arm of the study. Additionally, participants who have 
received treatment with antisense oligonucleotides (ASO) will be excluded  
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 (eg, hepatic, renal, 
cardiovascular, pulmonary, gastrointestinal, hematological, immunologic, 
ophthalmologic, metabolic, or oncological disease), or a chronic condition that is 
unstable, or are 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, presence, and/or current evidence of 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 
6. Have a history, presence, and/or current evidence of  
a. Brain surgery, deep brain stimulation, or any history of hospitalization due to a 
brain injury 
b. Possible or probable cerebral amyloid angiopathy, according to the Boston 
Criteria (Greenberg 1995) 
c. Treatment with an anti-amyloid therapy (including biologics) without subsequent 
MRI demonstrating the absence of amyloid-related imaging abnormalities 
d. Seizures or epilepsy, with the exception of childhood febrile seizures 
7. Have an alcohol or drug use disorder within the past 12 months as per Diagnostic and 
Statistical Manual of Mental Disorders (DSM-5) criteria 
8. Be receiving any of the following prohibited medications: 
a. Medications with potent effects at the N-methyl-D-aspartate (NMDA) receptor, 
including memantine, within 4 weeks of IP administration and during the entire 
course of the study 
b. Medications that inhibit cholesterol absorption (eg, ezetimibe) 
c. Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine) 
d. Other medications or supplements given at doses, frequencies, or in combinations 
that are likely, in the opinion of the investigator, to have a deleterious effect on 
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e. Cannabis or other tetrahydrocannabinol (THC)-containing substances (any route 
of administration), regardless of whether or not they are prescribed 
9. Participant has a history of suicidal behavior within 2 years or answers “YES” to 
Questions 3, 4, or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk of 
suicide in the opinion of the investigator.  
10. Have any of the following medical conditions: 
a. Any clinically significant finding on 12-lead ECG during Screening in the opinion 
of the investigator 
b. Any clinically significant supine vital signs (heart rate, systolic and diastolic 
blood pressure) during Screening (note: vital sign measurements may be repeated 
once)  
11. Have a history, presence, and/or current evidence of serologic positive results for human 
immunodeficiency virus (HIV)-1 or HIV-2, or hepatitis B or C 
12. Have a positive pregnancy test, or be lactating, or intend to breastfeed during the study 
13. Be investigative site personnel, sponsor personnel, or an immediate member of their 
family (spouse, parent, child, or sibling whether biological or legally adopted) 
14.  Is known to be allergic to any of SAGE-718 excipients, including soy lecithin. 
15. Plans to undergo elective surgery or procedures during participation in the study. 
16. Have a history of gastric bypass. 
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. Screen failure information will be collected, 
including, but not limited to demography, screen failure details, eligibility criteria, and any AE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, with the approval of the medical director or medical monitor. Rescreened 
participants will be assigned a new participant number. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, or administrative reasons. 
The reason for IP discontinuation and/or the reason for early termination from the study must be 
documented in the participant’s study record and in the participant’s electronic case report form 
(eCRF). 
8.4.1. 
Investigational Product Discontinuation 
Participants who discontinue IP will be invited by the investigator to complete all of the 
scheduled study visits and assessments. Those who may decline to continue participation will be 
asked to complete an Early Termination Visit. 


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8.4.2. 
Early Termination from the Study 
At the time of study withdrawal/stopping study participation, if possible, an early 
termination/end of treatment visit should be conducted. 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. 
Lost to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts by different modes (eg, phone, 
email, letter) at contacting the participant have been made and it has been at least 1 month since 
the last participant contact. All attempts at contact and the reason for discontinuation will be 
documented. If the investigator becomes aware of a change in the participant’s status or receives 
more information about a participant’s disposition, this information will be documented.  
8.4.4. 
Replacement of Participants 
Participants who discontinue or withdraw from the study will not be replaced. However, 
additional participants may be dosed if the early discontinuation rate is higher than expected. 


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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Product 
SAGE-718 softgel lipid capsules are opaque, white to off-white, oval capsules containing either 
1.2 mg or 0.9 mg of SAGE-718 Drug Substance. Placebo is matching in appearance.  
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
All medications and supplements taken within 30 days prior to Screening, all medications used 
to treat AD regardless of timing, and all nonpharmacological methods (eg, psychosocial, 
psychotherapeutic) used to treat or prevent 
 or cognitive 
manifestations of AD are to be recorded. Information regarding diagnosis, isolation, and/or 
hospitalization due to COVID-19 will be documented as part of medical history, AE collection, 
and prior/concomitant medication collection at Screening and throughout the study. 
At visits subsequent to Screening, all changes to any medication should be captured. All 
medications and/or supplements taken from the first dose of IP through the final study visit 
(including start and end dates, route, dose/units, frequency, and indication) will be recorded. Any 
concomitant medication determined necessary for the welfare of the participant may be given at 
the discretion of the Investigator at any time during the study. 
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 and throughout the study, to determine participant eligibility.  
9.2.2. 
Prohibited Medications 
Treatment with an investigational drug, biologics 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 N-methyl-D-aspartate (NMDA) receptor, including 
memantine, within 4 weeks of IP administration and during the entire course of the study 
• Medications that inhibit cholesterol absorption (eg, ezetimibe) 
• Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine) 


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• Other medications or supplements given at doses, frequencies, or in combinations that are 
likely, in the opinion of the investigator, to have a deleterious effect on cognitive 
performance 
• Cannabis or other tetrahydrocannabinol (THC)-containing substances (any route of 
administration), regardless of whether or not they are prescribed 
9.2.3. 
Other Restrictions 
Participants must agree to refrain from drugs of abuse for the duration of the study and from 
alcohol during the 48 hours preceding each study visit.  
9.2.4. 
Acceptable Forms of Contraception 
As per the Clinical Trials Facilitation and Coordination Group, a female is considered of 
childbearing potential eg, fertile, following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy.  
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and confirmed by FSH ˃40 mIU/mL. A high FSH level in the postmenopausal range may 
be used to confirm a postmenopausal state in females not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.  
A male is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Acceptable forms of highly effective contraception (eg, can achieve a failure rate of <1% per 
year when used consistently and correctly) for participants of childbearing potential or for a male 
participant’s partner of childbearing potential include: 
• Sexual abstinence 
• combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation; 
• oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation;  
• intrauterine device; 
• intrauterine hormone-releasing system; 
• bilateral tubal ligation or bilateral tubal occlusion (performed at least 3 months prior 
to Screening); 
• vasectomized partner (performed at least 3 months prior to Screening) 
(Note: vasectomy is a highly effective birth control method provided that partner is 
the sole sexual partner of the participants of childbearing potential and that the 
vasectomized partner has received medical assessment of the surgical success.) 
Acceptable forms of contraception for male participants include: 
• Sexual abstinence 


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• 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 
Beginning at the Day 1 Visit and continuing through the Day 84 Visit (±7 days), participants will 
self-administer blinded IP once per day in the morning.  
At clinic visits, participants will self-administer the IP under staff supervision, followed by 
assessments of cognitive function, 
 
. Study staff will dispense sufficient IP for daily administration until 
the next scheduled study visit. Adherence to the dosing regimen will be assessed at each in-clinic 
visit by examination of the used packaging and counting any returned capsules. This information 
will be documented along with any deviations from the prescribed dosage regimen. Details about 
IP accountability are included in Section 10.6.1. 
9.5. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Eligible participants will be 
randomized 1:1 to receive SAGE-718 or placebo for 84 days (±7 days). 
Participants, clinicians, and the study team will be blinded to treatment allocation. 
Randomization will be performed centrally via an interactive response technology (IRT) system. 
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group will be based on the randomization schedule. The randomization schedules will 
be kept strictly confidential, accessible only to authorized personnel until the time of unblinding. 
The blinding of the study will be broken after the database has been locked. 
9.5.1. 
Emergency Unblinding 
During the study, the blind can be broken by the investigator via the IRT system only when the 
safety of a participant is at risk and the treatment plan is dependent on the study treatment 
received. Unless a participant is at immediate risk, the investigator should make attempts to 
contact Sage prior to unblinding the study treatment administered to a participant. The 
responsibility to break the treatment code in emergency situations resides solely with the 
investigator. If the unblinding occurs without Sage’s knowledge, the investigator must notify 
Sage within 24 hours of breaking the blind. All circumstances surrounding a premature 
unblinding must be clearly documented in the source records. The Early Termination Visit 
should be completed after a participant’s treatment assignment has been unblinded. 


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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
SAGE-718 softgel lipid capsules are opaque, white to off-white, oval capsules containing 0.3, 
0.6, 0.9, or 1.2 mg of SAGE-718 Drug Substance. The capsules are composed of SAGE-718 
drug substance and butylated hydroxyanisole, gelatin, glycerin, glyceryl monocaprylate, glyceryl 
monolinoleate, lecithin, medium chain triglycerides, purified water, sorbitol, titanium dioxide, 
and vitamin E polyethylene glycol succinate as excipients.  
Table 4: 
Investigational Product 
Product Name: 
SAGE-718 
0.3 mg 
SAGE-718 
0.6 mg  
SAGE-718 
0.9 mga  
SAGE-718 
1.2 mga  
Placebo  
Dosage Form: 
Softgel lipid capsule 
Unit Dose 
0.3 mg 
0.6 mg 
0.9 mg 
1.2 mg 
Matching 
Placebo 
Route of 
Administration 
Oral 
Physical 
Description 
Opaque, white to off-white, oval, softgel lipid capsule 
Manufacturer 
 
 
a SAGE-718 0.9 and 1.2 mg dose and matching placebo will be administered in this study. 
10.2. 
Investigational Product Packaging and Labeling 
SAGE-718 and matching placebo oral softgel lipid capsules are packaged in blisters using 
ACLAR® rigid barrier film and heat sealable foil lidding with an additional child resistant lid 
(refer to the pharmacy manual for further details).  
The composition and pharmaceutical quality of the softgel lipid capsules 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.  
10.3. 
Investigational Product Storage  
Upon receipt of the IP, the Investigator, or the responsible pharmacist or designee, will inspect 
the product and acknowledge receipt in accordance with the study-specific process.  
The IP must be carefully stored at the temperature specified in the SAGE-718 IB and (where 
applicable) in the pharmacy manual, securely and separately from other drugs. The IP may not 
be used for any purpose other than the present study. After the study is completed, all unused IP 
must be returned per the sponsor’s instructions or destroyed locally per the site’s procedure(s). IP 


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may not be destroyed until accountability and reconciliation procedures have been completed 
and monitored. 
The Investigator or designee will be responsible for ensuring appropriate storage, compounding 
(if applicable), dispensing, inventory, and accountability of the IP. An accurate, timely record of 
the disposition of the IP must be maintained.  
10.4. 
Investigational Product Preparation 
SAGE-718 0.9 mg and 1.2 mg, or corresponding placebo will be provided as softgel lipid 
capsules for self-administration orally once daily in the morning through the Day 84 Visit 
(±7 days). 
10.5. 
Investigational Product Administration 
Each 0.9 or 1.2-mg dose of IP will be self-administered once daily in the morning.  
Participants are to swallow the softgel lipid capsules 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 
10.6.1. 
Investigational Product Accountability, Handling, and Disposal 
Upon receipt of IP, the Investigator(s), or the responsible pharmacist or designee, will inspect the 
IP and complete and follow the instructions regarding receipt and storage in the SAGE-718 IB 
and (where applicable) in the pharmacy manual. A copy of the shipping documentation will be 
kept in the study files. 
The designated site staff will dispense the supplied participant-specific kits to participants at the 
planned dispensation visit intervals outlined in Table 2.  
Site staff will access the Interactive Response Technology (IRT) at the Screening Visit to obtain 
a participant identification (ID) number for each participant that has signed an ICF. On Day 1, 
site staff will access the IRT and provide the necessary participant-identifying information, 
including the participant ID number assigned at Screening, to randomize the eligible participant 
into the study and to obtain the medication ID number for the IP to be dispensed to that 
participant. The medication ID number and the number of softgel lipid capsules dispensed must 
be recorded. 
At the subsequent IP-dispensing visits, the investigator or designee will access the IRT, 
providing the same participant ID number assigned at Screening, to obtain the medication ID 
number for the IP to be dispensed at that visit. The medication ID number, the number of softgel 
lipid capsules dispensed, and the number of softgel lipid capsules returned by the participant at 
this visit must be recorded.  
If dispensing errors or discrepancies are discovered by site staff or Sponsor’s designee, the 
Sponsor must be notified immediately. 
Sage Therapeutics will be permitted access to the study supplies at any time with appropriate 
notice during and/or after completion of the study to perform drug accountability reconciliation.  


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The investigator, pharmacist, or qualified designee is responsible for drug accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records). 
At the end of the study, any unused IP will be returned to Sage for destruction or destroyed 
locally per the site’s procedures; disposition of IP will be documented. 
More detailed information can be found in the SAGE-718 IB and (where applicable) in the 
pharmacy manual. 
10.6.2. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution.  
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1. 
Where possible, personnel should segregate and retain any product, materials, or packaging 
associated with the product complaint until further instruction is provided by Sage or its 
designated representative(s). 


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11. 
EFFICACY 
 
 cognitive function, 
. All 
assessments are to be completed according to the Schedule of Assessments (Table 2) and 
 
.  
An adult study partner is required for each participant to support completion of study activities 
and to answer questions about the participant’s condition. 
Participants will be required to take a short break (eg, 5 to 15 min) prior to beginning cognitive 
testing. The purpose of this break is to prepare for testing and to ensure maximal focus during the 
testing session. All cognitive assessments should be administered at approximately the same time 
of day (±2 hours) throughout the study in the following order: WAIS-IV Coding, 
 
. When applicable, cognitive tests should be administered predose at the 
Day 1 Visit, 
 and Day 84 Visit 
(±7 days), and pre-laboratory assessments at the Day 112 Visit (±7 days). Cognitive, 
 assessments will be administered postdose during the rest of the 
Treatment Period. For clinician administered scales, the same individual should administer the 
scale when possible. 
 
 
 It is recommended that the assessments are completed at approximately the same 
time each day, within 2 hours following IP administration. 
 
 If in conflict with clinic visit schedule, 
remote assessment may be completed in the clinic under observation by the study staff.  
11.1. 
Cognitive Assessments 
11.1.1. 
 
 
 
 
 
 
11.1.1.1. 
 
 
 
 
 
 
11.1.1.2. 
 
 
 


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11.1.1.3. 
 
 
 
 
 
 
 
11.1.1.4. 
 
 
 
 
 
 
11.1.1.5. 
  
 
 
 
 
 
11.1.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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11.3. 
  
11.3.1. 
 
11.3.1.1. 
  
 
 
 
 
 
11.3.2. 
  
11.3.2.1. 
 
 
 
 
 
 
 
 
 
 
 
 
11.3.2.2. 
  
 
 
 
 
11.3.2.3. 
  
 
 
 
 
 
11.3.2.4. 
 
 
 
 
 
 


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11.3.3. 
 
11.3.3.1. 
 
 
 
 
 
 
 
 
 
 
 
 
11.3.3.2. 
  
 
 
 
 
 
 
11.3.3.3. 
  
 
 
 
 
 
 
11.4. 
 
11.4.1. 
 
 
  
 
 


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. 
11.4.1.1. 
 
 
 
 
 
 
 
 
 
 
11.4.1.2. 
 
 
 
 
11.4.2. 
 
 
 
 
 
 
11.4.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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, ECGs, MRI, and out of range values in 
laboratory test results will be interpreted by an investigator as clinically significant (CS) or not 
clinically significant (NCS) in the source documents. 
Information about COVID-19 diagnosis, treatment, and quarantine status will be collected with 
medical history, AEs, and prior and concomitant medications. 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, ethnicity, years of education, years of employment 
and current employment status) and a full medical history will be documented.  
Full medical history of each participant will include history of AD (for participant and family), 
medications and supplements taken within 30 days prior to Screening, medications used to treat 
AD regardless of timing, and nonpharmacological methods (eg, psychosocial, psychotherapeutic) 
used to treat or prevent 
 or cognitive manifestations of AD. 
Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be 
documented as part of medical history, AE collection, and prior/concomitant medication 
collection at Screening and throughout the study.  
12.1.2. 
Weight and Height 
Height and weight will be measured and documented. Body mass index (BMI) will be derived.  
12.1.3. 
Physical Examination 
Whenever possible, the same individual should perform all physical examinations.  
A full physical examination will be conducted during Screening and at the Day 84 Visit 
(±7 days; End of Treatment). At other visits (Table 2), an abbreviated physical examination will 
include a brief assessment of general appearance, cardiovascular, respiratory, gastrointestinal, 
and neurological systems, followed by a targeted physical assessment as determined by the 
investigator. Unscheduled, symptom directed examinations may be conducted at any time at the 
discretion of the investigator. 
Any abnormality in physical examinations will be interpreted by the investigator as abnormal, 
NCS, or abnormal, CS, in source documents. 
12.1.4. 
COVID-19 Questions  
Detailed information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 and 
COVID-19 vaccine history will be documented as part of medical history. In addition, 
information focused on COVID-19 (eg, AE collection, and prior/concomitant medication) will 
be collected at Screening and throughout the study. 


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12.1.5. 
Vital Signs 
Vital signs include body temperature, respiratory rate, heart rate, and blood pressure. On dosing 
days vital signs will be measured prior to dosing. 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 at all scheduled time points. 
Any abnormality in vital signs will be interpreted by an investigator as abnormal, NCS; or 
abnormal, CS in source documents. 
12.1.6. 
Electrocardiogram  
A 12-lead electrocardiogram (ECG) will be performed at the time points described in Table 2. 
The standard intervals (heart rate, PR, QRS, QT, and QT corrected according to Fridericia’s 
formula [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). 
All abnormal ECGs will be interpreted by the investigator as CS or NCS in source documents. 
12.1.7. 
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 the standard 
operating procedures (SOP) 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 
significance of these findings. 
12.1.8. 
Clinical Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected. Analytes to be 
evaluated are summarized in Table 5. 
Table 5: 
Summary of Clinical Laboratory Analytes 
Biochemistry 
Renal Panel: glucose, calcium, phosphorus, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate 
Hepatic Panel: albumin, alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, total bilirubin, direct bilirubin, indirect bilirubin, total protein, 
lactate dehydrogenase, gamma glutamyl transferase 
Other: triglycerides, cholesterol (low density lipoprotein [LDL], high density 
lipoprotein [HDL]), creatine phosphokinase, thyroid stimulating hormone [TSH] 
and reflex to free triiodothyronine (T3) and thyroxine (T4) if TSH is abnormal. 
Hematology 
Red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell count with 
differential, platelet count, RBC indices (mean corpuscular volume [MCV], mean 
corpuscular hemoglobin [MCH], and mean corpuscular hemoglobin concentration 
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A TEAE is defined as an AE with onset after the start of IP, or any worsening of a pre-existing 
medical condition/AE with onset after the start of IP and throughout the study. The term IP 
includes any Sage IP, a comparator, or a placebo administered in a clinical study.  
Laboratory abnormalities and changes from baseline in vital signs, and ECGs are considered AEs 
if they result in discontinuation or interruption of IP, require therapeutic medical intervention, 
meet protocol specific criteria (if applicable) or if the Investigator considers them to be CS. Any 
abnormalities that meet the criteria for a SAE should be reported in an expedited manner. 
Laboratory abnormalities and changes from baseline in vital signs and ECGs that are clearly 
attributable to another AE do not require discrete reporting (eg, electrolyte disturbances in the 
context of dehydration, chemistry and hematologic disturbances in the context of sepsis). 
All AEs that occur after any participant has signed the informed consent and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage 
Therapeutics. 
Participants who discontinue the IP due to an AE, regardless of Investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the Investigator 
determines the event is no longer CS. 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 participant with ongoing AE(s)/SAE(s) at the end of the 
study, if judged necessary. 
12.2.2. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the Investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 


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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. 
Definition of Urgent Safety Measure and Unanticipated Problem  
In accordance with Article 10(b) of Directive 2001/20/EC, some reported events may result in an 
urgent safety measure, defined as an action that the sponsor and investigator may take in order to 
protect the participants of a study against any immediate hazard to their health or safety. 
Examples of USMs include: 
• suspension of enrollment due to significantly higher incidence of death at one site 
• additional clinical or non-clinical investigations performed due to increased 
frequency of AEs 
• halting a clinical study for safety reasons 
In accordance with Food and Drug Administration Guidance 21 Code of Federal Regulations 
Part 312.66, some reported events may qualify as an unanticipated problem, defined as any 
incident, experience, or outcome that meets all of the following criteria: 
• unexpected (in terms of nature, severity, or frequency) given (i) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (ii) the 
characteristics of the population being studied; related or possibly related to an 
individual’s participation in the study; and 
• suggests the study may place the participant or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the study 
than was previously known or recognized. 
Any unanticipated problem must be reported within 24 hours via email to 
sage.safety@IQVIA.com upon discovery due to the urgent reporting requirements to regulators 
and IRB(s)/ECs(s). 
12.2.4. 
Relationship to Investigational Product 
The Investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP.  
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 


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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. 
12.2.5. 
Recording Adverse Events 
AEs spontaneously reported by the participant and/or in response to an open question from the 
study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the Investigator will evaluate and report the onset date (and time, where 
applicable), resolution date (and time, where applicable), intensity, causality, action taken, 
outcome and seriousness (if applicable), and whether or not it caused the participant to 
discontinue the IP or withdraw early from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s)  
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.6. 
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 and designee (see Table 1) 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.  


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Additional follow-up information, if required or available, should all be sent to Sage and 
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 and designee according to the timelines noted above only if the investigator 
considers the SAE related to IP.  
Sage or designee, are 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, as required by local law. Investigators will also be notified of all 
suspected unexpected serious adverse reactions (SUSARs) that occur during the clinical study. 
IRBs/IECs will be notified of SAEs and/or SUSARs as required by local law. 
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARS to Investigators in a blinded fashion.  
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the Pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 
pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy. The 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, pre-eclampsia) 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.  


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The investigator will permanently withdraw the participant from IP if the participant becomes 
pregnant. 
12.4. 
Special Considerations 
Drug abuse is the persistent or sporadic, intentional excessive use of IP which is accompanied by 
harmful physical or psychological effects in the participant. If an event of drug abuse occurs 
during the study, it must be reported to the sponsor and designee (see Table 1) using the Special 
Considerations Form within 24 hours of the site becoming aware of the event(s). If the drug 
abuse results in an AE or SAE, the AE or SAE must also be recorded and reported as described 
in Section 12.2.5 and Section 12.2.6, respectively. 
Drug misuse refers to situations where IP is intentionally and inappropriately used not in 
accordance with the intended use as specified in the protocol. If an event of drug misuse occurs 
during the study, it must be reported to the sponsor and designee using the Special 
Considerations Form within 24 hours of the site becoming aware of the event(s). If the drug 
misuse results in an AE or SAE, the AE or SAE must also be recorded and reported as described 
in Section 12.2.5 and Section 12.2.6, respectively. 
An overdose is any dose of IP given to a participant or taken by a participant that exceeds the 
dose described in the protocol. Overdoses are not considered AEs and should not be recorded as 
an AE on the CRF; however, all overdoses must be recorded on the Special Considerations Form 
and sent to Sage and designee within 24 hours of the site becoming aware of the overdose. An 
overdose must be reported to Sage and designee even if the overdose does not result in an AE. If 
an overdose results in an AE or SAE, the AE or SAE must also be recorded and reported as 
described in Section 12.2.5 and Section 12.2.6, respectively. 
A medication error is any preventable event that may cause or lead to inappropriate medication 
use or participant harm while the medication is in the control of the healthcare professional, 
participant, or consumer. All medication errors must be recorded on the Special considerations 
form and sent to the sponsor and designee within 24 hours of the site becoming aware of the 
medication error. The medication error must be reported to the sponsor and/or designee even if 
the medication error does not result in an AE. If a medication error results in an AE or SAE, the 
AE or SAE must also be recorded and reported as described in Section 12.2.5 and Section 12.2.6, 
respectively. 
 


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13. 
STATISTICS 
Detailed description of the analyses to be performed in the study will be provided in the 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to database lock. 
Any changes/additions to the SAP following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
The All Randomized Set will include all participants who have been randomized and will be 
used to describe participant disposition. 
The Safety Set will include all participants who were administered at least one dose of the IP and 
will be used to describe the safety data and analyses will be based on the actual treatment 
received. 
The Full Analysis Set (FAS) will include all participants in the Safety Set who have baseline and 
at least 1 postbaseline efficacy evaluation. The FAS will be used to describe the efficacy data. 
Analyses will be based on the randomized treatment. 
 
  
 
 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All participants will be used in the analyses, 
as per the analysis populations, using all nonmissing data available. No imputation process will 
be used to estimate missing data. However, a sensitivity analysis will be used to investigate the 
impact of missing data if >5% of participants in any treatment group have missing data in the 
primary endpoint. 
13.3. 
General Considerations 
All participant data, including those that are derived, that support the tables and figures will be 
presented in the participant data listings. Some data may be presented only in participant data 
listings, some may be presented with a corresponding table or figure; these will be indicated in 
relevant sections below. All summaries will be provided by treatment – either by randomized 
treatment or actual treatment received.  
If a participant takes any dose of SAGE-718, the participant’s actual treatment is considered as 
SAGE-718, regardless of the treatment to which the participant has been randomized. 
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,  
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. 


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Descriptive summary statistics will be provided for demographics, baseline characteristics, and 
total disposition, including the number of participants enrolled and the percentage of participants 
who discontinued from the study, along with reasons for discontinuations. 
13.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, years of education, years of employment, 
current employment status, and baseline characteristics, such as height, weight, and body mass 
index (BMI), will be summarized using the Safety Set. 
Pregnancy test results and drug and alcohol test results will be listed but not summarized. 
Medical history will be summarized and listed by participant. 
13.5. 
Efficacy Analysis 
Descriptive statistics of scores and change from baseline scores at each postbaseline assessment 
will be summarized based on the Full Analysis Set according to randomized treatment. Cognitive 
test scores endpoints will also be analyzed using a mixed effects model for repeated measures. 
The model will include change from baseline scores as dependent variable; treatment, visit, and 
visit by treatment interaction as fixed effects; participants as random effects; and baseline 
cognitive test scores as a covariate. An unstructured covariance matrix will be used to model the 
within-subject correlation. If the convergence criteria are not met, other covariance matrix will 
be used and more details will be described in the SAP. Model-based point estimates (ie, least 
square means, 95% confidence intervals, and associated p values) at each time point (visit) will 
be reported where applicable. Line plots of change from baseline scores will be plotted with 
standard error bars. 
 
  
The estimand for the primary efficacy analysis is defined as follows: 
1) The treatment regimen for participants is placebo or SAGE-718 for 84 days. 
2) The target population is participants with MCI or mild dementia due to AD. 
3) The variable of interest is the change from baseline in WAIS-IV Coding Test total correct 
score at Day 84.  
4) The intercurrent events could be: 
a) The premature discontinuation of treatment for any reason, thus not having a Day 84 
WAIS-IV Coding Test total correct score available. The treatment policy strategy will 
be used.  
b) Certain medications including, but not limited to, medications with potent effects at 
the NMDA receptor, including memantine, medication that inhibit cholesterol 
absorption, bile acid sequestrants or other medications, given at doses, frequencies, or 
in combinations that are likely, in the opinion of the investigator, to have a deleterious 
effect on cognitive performance, or prescribed cannabis or other tetrahydrocannabinol 
(THC)-containing substances. 


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5) The population summary level deals with the difference between SAGE-718 and placebo 
treatments in mean change from baseline in WAIS-IV Coding Test total correct score at 
Day 84. 
Additional analyses will be detailed in the SAP. 
13.5.1. 
Multiplicity Adjustment 
Not applicable. 
13.5.2. 
Sensitivity Analyses 
Sensitivity analysis is planned based on multiple imputation of missing values for different 
reason of discontinuation if >5% participants in any treatment group have missing data in 
primary endpoint, details will be provided in SAP. 
13.6. 
Safety Analyses 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 
or higher. The proportion of participants experiencing TEAEs will be displayed by treatment 
group and by system organ class and preferred term. The frequency of TEAEs will also be 
presented by maximum severity and relationship to IP and by treatment group. Observed and 
change from baseline in vital signs, laboratory parameters, ECGs, 
 data will be 
summarized by treatment group. All safety summaries will be performed on the Safety Set.  
Additional analyses will be detailed in the SAP. 
13.6.1. 
Adverse Events 
A TEAE is defined as an AE with onset after the first dose of IP. The analysis of AEs will be 
based on the concept of TEAEs. The incidence of TEAEs will be summarized by system organ 
class and preferred term. In addition, summaries will be provided by intensity (mild, moderate, 
severe) and by causality (related, not related) to IP. 
Any TEAEs leading to discontinuation or interruption of treatment or withdrawal from the study 
and any treatment-emergent SAEs will be summarized. 
All AEs and SAEs (including those with onset or worsening before the start of IP) through the 
end of the study will be listed. 
13.6.2. 
Clinical Laboratory Evaluations 
Results of clinical laboratory parameters in each scheduled visit and mean changes from baseline 
will be summarized in standard units. Normal ranges for each parameter will be provided by the 
laboratory; shift from baseline to postbaseline values in abnormality of results will be provided. 
Potentially CS values will be summarized by treatment. Clinical laboratory results will be listed 
by participant and timing of collection. 
13.6.3. 
Physical Examinations 
The occurrence of a physical examination (yes/no) and the date performed will be listed by 
participant. 




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The total sample size of 120 evaluable participants will provide 90% power to detect the 
treatment difference of 2.5 in change from baseline in WAIS-IV Coding Test total correct score 
while allowing for one interim analysis and one final analysis. This sample size and power are 
based on a two-sided test using an overall significance level of 0.05. One formal interim analysis 
may be conducted after approximately 60 participants have completed Week 12. The group 
sequential method by O'Brien and Fleming for the two-sided test will be used. The significance 
level will be based on the type I error spending function of Lan and DeMets such that the overall 
significance level will be maintained at 0.05. Assuming a 20% dropout and a 1:1 randomization 
ratio, approximately 150 randomized participants (75 per treatment group) will be required to 
obtain 60 evaluable participants per treatment group. Evaluable participants are defined as those 
randomized participants who receive IP and have a valid baseline and at least 1 postbaseline 
WAIS-IV Coding test assessment. Additional participants may be randomized if the dropout rate 
is higher than 20%. 
Table 6 summarizes operating characteristics of this design based on 120 evaluable participants. 
Table 6: 
Group Sequential Design 
Repeated 
Analyses 
Information 
Time 
No of 
Participants 
Boundaries for 
Efficacy 
Boundary for 
Futility 
Interim 
0.5 
60 
2.796 
0.4229 
Final  
1 
120 
1.977 
 
13.8.1. 
 
  


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Unless otherwise waived or addressed in another forum (eg, investigator meeting), before an 
investigational site can enter a participant into the study, a representative of Sage will visit the 
investigational study site to: 
• Confirm the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, IP management, GCP/ICH GCP compliance, and the responsibilities 
of Sage or its representatives. Agreed upon site responsibilities will be documented in a 
Clinical Trial Agreement between Sage and the investigator. 
During the study, a monitor from Sage 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 eCRF, and that IP accountability checks are being performed 
• Perform source data verification. This includes a comparison of the data in the eCRF 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, 
medical records, source documents, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage Therapeutics. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Sage Therapeutics and those SAEs that met criteria for 
reporting have been forwarded to the IRB or IEC. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Sage Therapeutics or authorized representatives of Sage Therapeutics, a regulatory authority, or 
an IEC/IRB may visit the site to perform an audit(s) or inspection(s), including source data 
verification. The purpose of a Sage Therapeutics audit or a regulatory authority inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP/ICH GCP guidelines, and any applicable 
regulatory requirements. The investigator should contact Sage Therapeutics immediately at 
InspectionNotification@sagerx.com if contacted by a regulatory agency or IRB/IEC about an 
inspection. 


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


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, Sage Therapeutics 
may conduct a quality assurance audit(s) at the clinical site. Please see Section 14.2 for more 
details regarding the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Protocol deviations that harm or increase the possibility of harm to the rights and 
welfare of a participant, or a deviation made without prior IRB/IEC approval to eliminate an 
immediate hazard to the participant should be reported to the IRB/IEC per the IRB/IEC’s written 
procedures.  
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates study-related duties and functions conducted at the study site. When the investigator 
retains the services of any individual or party to perform study-related duties and functions, the 
investigator must ensure the individual or party is qualified to perform study-related duties and 
functions and should implement procedures to ensure the integrity of the study-related duties and 
functions performed, and any data generated. 
The investigator must maintain adequate and accurate source documents and study records that 
include all pertinent observations on each of the site’s study participants. Source data must be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained, if necessary 
to provide clarification. 


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


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documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 


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


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18. 
PUBLICATION POLICY 
All information concerning SAGE-718 is considered confidential and shall remain the sole 
property of Sage Therapeutics. The investigator agrees to use this information only in conducting 
the study and shall not use it for any other purposes without written approval from Sage 
Therapeutics. No publication or disclosure of study results will be permitted except as specified 
in a separate, written, agreement between Sage Therapeutics and the investigator. 


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19. 
LIST OF REFERENCES 
 
 
 
  
 
 
 
Danysz W, Parsons CG. Glycine and N-methyl-D-aspartate receptors: physiological significance 
and possible therapeutic applications. Pharmacol Rev. 1998;50(4):597. 
Erdodi LA, Abeare CA. Stronger Together: The Wechsler Adult Intelligence Scale-Fourth 
Edition as a Multivariate Performance Validity Test in Patients with Traumatic Brain Injury. 
Arch Clin Neuropsychol. 2020;35(2):188-204.  
Gauthier S, Molinuevo J L. Benefits of combined cholinesterase inhibitor and memantine 
treatment in moderate-severe Alzheimer's disease. Alzheimers Dement. 2013;9(3):326-331.  
Girard TA, Axelrod BN, Patel R, et al. Wechsler Adult Intelligence Scale-IV Dyads for 
Estimating Global Intelligence. Assessment. 2015;22(4):441-8.  
Ghanavati E, Salehinejad MA, De Melo L et al. NMDA receptor-related mechanisms of 
dopaminergic modulation of tDCS-induced neuroplasticity. Cereb Cortex. 2022; Epub ahead of 
print. PMID: 35165699.  
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. 
 
 
 
Hebert LE, Weuve J, Scherr PA, et al. Alzheimer disease in the United States (2010-2050) 
estimated using the 2010 census. Neurology. 2013;80(19):1778-83.  
SAGE-718 Investigator’s Brochure, Edition 8, 2022.  
 
 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70:659–63. 
Li F, Tsien JZ. Memory and the NMDA receptors. N. Engl J Med. 2009;361:302–3. 
Mony L, Kew JN, Gunthorpe M J, et al. Allosteric modulators of NR2B-containing NMDA 
receptors: molecular mechanisms and therapeutic potential. Br J Pharmacol, 2009;157(8), 1301-
1317.  
 
 


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O’Brien, P. C. and Fleming, T. R. (1979), “A Multiple Testing Procedure for Clinical Trials,” 
Biometrics. 35; 549–56. 
Ortiz-Sanz C, Balantzategi U, Quintela-López T, et al. Amyloid β / PKC-dependent alterations in 
NMDA receptor composition are detected in early stages of Alzheimer´s disease. Cell Death Dis. 
2022;13(3):253.  
 
  
 
 
 
Prasanth, N. V., Pandian, P., & Balasubramanian, T. Role of NMDA Receptors in Alzheimer's 
Disease Pathology and Potential NMDA Receptor Blockers from Medicinal Plants - A Review. 
Asian Journal of Pharmaceutical Research and Health Care, 2021;13(4). 
https://doi.org/10.18311/ajprhc/2021/28351 
 
 
  
Sharma K. Cholinesterase inhibitors as Alzheimer's therapeutics (Review). Mol Med Rep. 
2019;20(2):1479-1487.  
 
  
 
 
Taniguchi K, Yamamoto F, Amamo A et al. Amyloid-beta oligomers interact with NMDA 
receptors containing GluN2B subunits and metabotropic glutamate receptor 1 in primary cortical 
neurons: Relevance to the synapse pathology of Alzheimer's disease. Neurosci Res. 2022; in 
press.  
Tsai GE, Falk WE, Gunther J et al. Improved cognition in Alzheimer's disease with short-term 
D-cycloserine treatment. Am J Psychiatry. 1999;156(3):467-9. 
Wechsler, D. "Subtest Administration and Scoring. WAIS–IV: Administration and Scoring 
Manual." San Antonio, TX: The Psychological Corporation. 2009;87-93. 
Weintraub S, et al. The neuropsychological profile of Alzheimer disease. Cold Spring Harb 
Perspect Med. 2012;2(4):a006171 
 
 
 
 






718-CNA-202 Summary of Changes 
Sage Therapeutics 
Version 2.0, Amendment 1  
 
 
3 
• The statement that body mass index “will be calculated” was changed to “will be 
derived” to indicate it will be done as part of the analyses (Section 12.1.4). 
• The Overdose section was replaced with the Special Considerations section, which 
was implemented via Administrative Letter #1, and it is being formally added to the 
protocol with this amendment (Section 12.4). 
• The Efficacy Analysis section was revised to simplify the list of endpoints and add a 
description of the covariance matrix (Section 13.5). 
• Sunwoo et al, included in error, was removed from the list of references (Section 19). 
• Minor textual changes have been made throughout the protocol to increase clarity on 
the procedures of the study. 
• Study personnel and related administrative changes have been made based on 
changes to the study team. 
Corrections to typographical errors, punctuation, grammar, abbreviations, and formatting have 
been made. 

SAP_001.pdf: 
Official Title: A Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Effects of SAGE-718 in Participants with Mild 
Cognitive Impairment or Mild Dementia Due to Alzheimer’s 
Disease 
NCT Number: NCT05619692 
Document Date: SAP Version 1.0, 10 September 2024 
 


STATISTICAL ANALYSIS PLAN 
METHODS 
PROTOCOL NUMBER: 718-CNA-202 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Effects of SAGE-718 in Participants with Mild Cognitive Impairment or Mild 
Dementia Due to Alzheimer’s Disease  
Author of SAP: 
 
Version: Version 1.0 
Version Date of SAP: 10SEP2024 
Sponsor: 
Sage Therapeutics, Inc. 
55 Cambridge Parkway 
Cambridge, Massachusetts 02142 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure 
without the prior written consent of Sage Therapeutics, Inc. is strictly prohibited except to the 
extent required under applicable laws or regulations.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 


 
 
 
 
AUTHORIZATION SIGNATURE PAGE 
Protocol Number: 718-CNA-202 
Study Title: A Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Effects of SAGE-718 in Participants with Mild Cognitive Impairment or Mild Dementia 
Due to Alzheimer’s Disease 
 
 
Author: 
 
 
 
 
 
 
 
 
Date 
 
 
 
  
 
Approved by:  
 
 
 
 
 
 
 
 
Date 
Parexel International  
 
 
 
 
 
 
 
 
 
 
Date 
  
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
____________________________________________ 
 
__________________ 
 
 
 
Date 


Statistical Analysis Plan Methods Version 1.0 10 September 2024 
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Protocol Number: 718-CNA-202 (Version 2.0 22 December 2023) 
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TABLE OF CONTENTS 
AUTHORIZATION SIGNATURE PAGE.................................................................. 2 
1. 
LIST OF ABBREVIATIONS................................................................... 6 
2. 
INTRODUCTION .................................................................................... 8 
3. 
STUDY OBJECTIVES ............................................................................ 9 
3.1. 
Primary Objective ..................................................................................... 9 
3.2. 
Secondary Objectives ............................................................................... 9 
3.3. 
 ....................................................................................... 9 
4. 
STUDY ENDPOINTS ............................................................................ 10 
4.1. 
Efficacy Endpoint ................................................................................... 10 
4.1.1. 
Primary Efficacy Endpoint ..................................................................... 10 
4.1.2. 
 ....................................................................... 10 
4.2. 
Safety Endpoints ..................................................................................... 11 
4.3. 
 ...................................................................................... 11 
5. 
STUDY DESIGN ................................................................................... 12 
5.1. 
Overall Design ........................................................................................ 12 
5.1.1. 
Screening Period ..................................................................................... 12 
5.1.2. 
Baseline Period ....................................................................................... 12 
5.1.3. 
Treatment Period .................................................................................... 12 
5.1.4. 
Follow-up Period .................................................................................... 13 
5.2. 
Sample Size and Power .......................................................................... 13 
5.3. 
Randomization ........................................................................................ 14 
5.4. 
Blinding and Unblinding ........................................................................ 14 
6. 
MODIFICATIONS ................................................................................. 16 
6.1. 
Modifications from the Approved Clinical Study Protocol .................... 16 
6.2. 
Modifications from the Approved Statistical Analysis Plan .................. 16 
6.3. 
Modifications from the Approved DMC Charter ................................... 16 
7. 
ANALYSIS SETS .................................................................................. 17 
7.1. 
Randomized Set ...................................................................................... 17 
7.2. 
Safety Set ................................................................................................ 17 
7.3. 
Full Analysis Set ..................................................................................... 17 


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7.4. 
 ...................................................................................... 17 
7.5. 
 ............................................................................... 17 
8. 
STATISTICAL ANALYSIS .................................................................. 18 
8.1. 
General Considerations ........................................................................... 18 
8.2. 
Background Characteristics .................................................................... 19 
8.2.1. 
Participant Disposition ............................................................................ 19 
8.2.2. 
 ................................................................................ 20 
8.2.3. 
Demographics and Baseline Characteristics ........................................... 20 
8.2.4. 
Medical/Surgical History ........................................................................ 21 
8.2.5. 
Prior and Concomitant Medications/Procedures .................................... 21 
8.2.6. 
Investigational Product Exposure ........................................................... 22 
8.2.7. 
Investigational Product Adherence ......................................................... 23 
8.3. 
Efficacy Analysis .................................................................................... 24 
8.3.1. 
Definition of Efficacy Variable(s) .......................................................... 24 
8.3.1.1. 
Primary Efficacy Assessment ................................................................. 24 
8.3.1.2. 
 ................................................................... 24 
8.3.2. 
Visit Windows for Efficacy Analyses .................................................... 34 
8.3.3. 
Analysis of Primary Efficacy Variable(s) ............................................... 35 
8.3.3.1. 
Primary Analysis and Estimand .............................................................. 35 
8.3.3.2. 
Multiplicity Adjustment.......................................................................... 37 
8.3.3.3. 
 .............................................. 37 
8.3.3.4. 
 .............................................. 39 
8.3.3.5. 
Subgroup Analyses of Primary Analysis ................................................ 39 
8.3.4. 
Analysis of Secondary Efficacy Variables ............................................. 39 
8.3.5. 
 ..................................................... 39 
8.3.5.1. 
 ............................... 40 
8.3.5.2. 
 ..... 40 
8.3.5.3. 
 ............................................................. 40 
8.3.5.4. 
 .... 40 
8.3.5.5. 
 ............................................. 41 
8.3.5.6. 
 ................................... 41 
8.3.5.7. 
 ....................................................... 41 


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8.3.5.8. 
 ........ 41 
8.3.5.9. 
 .................................................................... 42 
8.3.5.10. 
 ................................................................. 42 
8.3.5.11. 
 ..................................................................... 42 
8.4. 
Safety Analysis ....................................................................................... 43 
8.4.1. 
Adverse Events ....................................................................................... 44 
8.4.2. 
Clinical Laboratory ................................................................................. 46 
8.4.3. 
Electrocardiogram ................................................................................... 48 
8.4.4. 
Vital Signs .............................................................................................. 49 
8.4.5. 
Physical Examination ............................................................................. 50 
8.4.6. 
Magnetic Resonance Imaging ................................................................. 50 
8.4.7. 
 ................................................ 50 
8.4.8. 
Other Safety Analysis ............................................................................. 51 
8.5. 
Other Analysis ........................................................................................ 52 
8.5.1. 
 ............................................................................ 52 
9. 
 .......................... 53 
9.1. 
 ...................................................................................... 53 
9.2. 
 ........................................................................................ 53 
10. 
REFERENCES ....................................................................................... 54 
APPENDIX A. SCHEDULE OF ASSESSMENTS ............................................... 55 
APPENDIX B. 
 ...................... 61 
APPENDIX C. 
............................................ 64 
APPENDIX D. LIST OF DISPLAYS .................................................................... 66 
 
 
 


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1. 
LIST OF ABBREVIATIONS 
The following abbreviations and specialist terms are used in this Statistical Analysis Plan.  
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation 
Definition 
AD 
Alzheimer’s Disease 
AE 
adverse event 
 
 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical code 
BMI 
Body Mass Index 
BLQ 
Below Limit of Quantification 
 
  
CDR 
Clinical Dementia Rating 
 
 
 
 
CI 
Confidence Intervals 
COVID-19 
Coronavirus Disease 2019 
CS 
Clinically Significant 
 
 
 
 
 
 
ET  
Early Termination  
eCRF 
electronic Case Report Form 
 
 
FAS 
Full Analysis Set 
 
 
IA 
Interim Analysis 
IP 
Investigational Product 
IRT 
Interactive Response Technology 
 
 
LSM 
Least Squares Means 
MAR 
Missing At Random 
MCI 
Mild Cognitive Impairment 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed-effects Model for Repeated Measures 


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Abbreviation 
Definition 
MNAR 
Missing Not At Random 
 
 
 
  
 
  
 
 
NMDA 
N-methyl-D-aspartate 
 
 
 
  
PCS 
Potentially Clinically Significant 
 
 
 
 
 
 
PMM 
Pattern Mixture Model  
 
 
 
  
PT 
Preferred Term 
 
 
 
 
Q1 
25th percentile 
Q2 
75th percentile 
 
  
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
 
 
 
 
 
  
TEAE 
Treatment-Emergent Adverse Events 
WAIS-IV 
Wechsler Adult Intelligence Scale Fourth Edition-IV  


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis, and is based on the following 
approved study documents: 
• Study Protocol, Version 2.0 (22 December 2023) 
• electronic Case Report Form (eCRF), Version 7.0  on 29 April 2024 
This SAP addresses the objectives of the study and describes the planned statistical analyses 
and data presentations. All analyses and data presentations will be generated using the SAS 
Software Version 9.4 or higher (SAS Institute, Cary, North Carolina, USA). This SAP will 
be finalized and approved before the clinical database lock. Any changes made to the SAP 
after the clinical database lock will be documented and discussed in the clinical study report 
for this study. 
 


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3. 
STUDY OBJECTIVES  
3.1. 
Primary Objective 
• To evaluate the effect of SAGE-718 on cognitive performance in participants with 
Alzheimer’s Disease (AD) 
3.2. 
Secondary Objectives  
•  To evaluate the safety and tolerability of SAGE-718 softgel lipid capsule in 
participants with AD 
3.3. 
 
• To evaluate the safety and tolerability of SAGE-718 softgel lipid capsule on other 
safety parameters 
 
 
 
 
 
 
 
 
 
 
 


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4. 
STUDY ENDPOINTS 
4.1. 
Efficacy Endpoint 
4.1.1. 
Primary Efficacy Endpoint 
The primary endpoint is the change from baseline to Day 84 in the Wechsler Adult 
Intelligence Scale Fourth Edition-IV (WAIS-IV) Coding Test, total correct score.  
4.1.2. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 


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4.2. 
Safety Endpoints 
• To evaluate the safety and tolerability of SAGE-718 softgel lipid capsule in 
participants with AD  
o Proportion of participants experiencing treatment-emergent adverse events 
(TEAEs) and severity of TEAEs 
o Number of participants who withdraw due to adverse events (AEs) 
• To evaluate the safety and tolerability of SAGE-718 softgel lipid capsule on other 
safety parameters 
o Change from baseline in vital signs, clinical laboratory parameters, 
electrocardiograms (ECGs), 
 
4.3. 
 
 
   
 
 
 
 
 
 
 


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5. 
STUDY DESIGN  
5.1. 
Overall Design  
This is a randomized, double-blind, placebo-controlled study to evaluate the effects of 
SAGE-718 in participants with MCI or mild dementia due to AD. Eligible participants with a 
confirmed diagnosis and who meet the criteria for MCI or Mild Dementia due to AD at 
Screening will be randomized to receive either SAGE-718 or matching placebo. Within the 
SAGE-718 treatment arm, participants will receive 1.2 mg of SAGE-718 as a softgel lipid 
capsule orally once daily for the first 6 weeks (Days 1 Visit to 42 Visit [±2 days]), followed 
by 0.9 mg of SAGE-718 for the remainder of the Treatment Period (i.e., beginning the first 
day after the Day 42 Visit). Dosing ends at the Day 84 Visit (±7 days). The placebo arm will 
receive placebo throughout the Treatment Period (12 weeks). 
5.1.1. 
Screening Period 
The Screening Period will begin with the informed consent process for prospective 
participants and their study partners. Subsequent screening assessments will be performed 
between Day -35 and Day -8 to determine eligibility, including assessments of cognitive 
function. An adult study partner is required to support completion of study activities and to 
answer questions about the participant’s condition. 
5.1.2. 
 Baseline Period 
The Baseline Period will occur from Day -7 through Day -1. During the Baseline Period, 
participants will visit the clinic for collection of baseline cognitive, 
 
 data. Participants and their study partners will receive training on the study 
procedures and devices. 
 
  
5.1.3. 
 Treatment Period 
The blinded Treatment Period will occur from the Day 1 Visit through the Day 84 Visit (±7 
days). Eligible participants will be randomized 1:1 to receive either SAGE-718 or matching 
placebo. Participants who are randomized to SAGE-718 will receive 1.2 mg of SAGE-718 
for the first 6 weeks (Days 1 Visit to 42 Visit [±2 days]) followed by 0.9 mg of SAGE-718 
for the remainder of the Treatment Period (i.e., beginning the first day after the Day 42 
Visit). Dosing ends at the Day 84 Visit (±7 days). All participants will self-administer 
blinded IP once per day in the morning, orally. 
At scheduled clinic visits during the Treatment Period, safety, efficacy, 
 
 will be performed. Participants will self-administer IP in the clinic under the 
supervision of study staff. Participants will receive a sufficient amount of IP for daily 
administration until the next scheduled clinic visit, at which time study staff will assess 
participant adherence by examining used packaging and counting returned capsules. 
During the Treatment Period, participants will be able to receive IP if there are no dose- 
limiting safety/tolerability concerns. Participants who discontinue IP should complete the 




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may be conducted after approximately 60 participants as total have completed Day 84 (Week 
12). The group sequential method by O'Brien and Fleming for the two-sided test will be used. 
The significance level will be based on the type I error spending function of Lan and 
DefsMets such that the overall significance level will be maintained at 0.05. Assuming a 20% 
dropout and a 1:1 randomization ratio, approximately 150 randomized participants (75 per 
treatment group) will be required to obtain 60 evaluable participants per treatment group. 
Evaluable participants are defined as those randomized participants who receive IP and have 
a valid baseline and at least 1 postbaseline WAIS-IV Coding test assessment. Additional 
participants may be randomized if the dropout rate is higher than 20%. Table 2 summarizes 
operating characteristics of this design based on 120 evaluable participants. 
Table 2: 
Group Sequential Design 
Repeated 
Analyses 
 Information 
Time 
Number of 
Participants 
Boundaries for 
Efficacy (Z-score) 
Boundary for 
Futility (Z-score) 
Interim 
0.5 
60 
2.796 
0.4229 
Final 
1 
120 
1.977 
 
* Using the SAS Software Version 9.4 
5.3. 
Randomization 
This is a randomized, double-blind, placebo-controlled study. Eligible participants will be 
randomized 1:1 to receive SAGE-718 or placebo for 84 days (±7 days). 
Randomization will be performed centrally via an interactive response technology (IRT) 
system. Randomization schedules will be generated by an independent statistician. The 
allocation to treatment group will be based on the randomization schedule.  
5.4. 
Blinding and Unblinding 
Participants, clinicians, and the study team will be blinded to treatment allocation. The 
randomization schedules will be kept strictly confidential, accessible only to authorized 
personnel until the time of unblinding. The blinding of the study will be broken after the 
database has been locked for the final analysis. In addition, only the designated personnel 
approved by Sage will be unblinded to the treatment allocation for the participants included 
in the IA, should one occur. 
During the study, the blind can be broken by the investigator via the IRT system only when 
the safety of a participant is at risk and the treatment plan is dependent on the study treatment 
received. Unless a participant is at immediate risk, the investigator should make attempts to 
contact Sage prior to unblinding the study treatment administered to a participant. The 
responsibility to break the treatment code in emergency situations resides solely with the 
investigator. If the unblinding occurs without Sage’s knowledge, the investigator must notify 
Sage within 24 hours of breaking the blind. All circumstances surrounding a premature 
unblinding must be clearly documented in the source records. In the case of emergency 


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unblinding, the Early Termination Visit should be completed after a participant’s treatment 
assignment has been unblinded. 
If a participant becomes unblinded to the participant’s treatment assignment before database lock, 
the participant will be excluded 
, but will be included 
in the Full Analysis Set (FAS) (see Section 7.3) 
 


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6. 
MODIFICATIONS  
6.1. 
Modifications from the Approved Clinical Study Protocol 
Not applicable 
6.2. 
Modifications from the Approved Statistical Analysis Plan 
This is the first version of the SAP.  
6.3. 
Modifications from the Approved DMC Charter 
Not applicable 


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7. 
ANALYSIS SETS 
7.1. 
Randomized Set 
The Randomized Set will include all participants who have been randomized to the 
investigational product (IP) and will be used to describe participant’s background 
characteristics. 
7.2. 
Safety Set 
The Safety Set will include all participants who were administered at least 1 dose of the IP. 
The Safety Set will be used to describe the safety data and analyses will be based on the 
actual treatment received.  
7.3. 
Full Analysis Set 
The Full Analysis Set (FAS) will include all participants in the Safety Set who have baseline 
and at least 1 post-baseline efficacy evaluation. FAS will be used to describe the efficacy 
data, which is based upon the Intent-to-Treat principle. Analyses will be based on the 
randomized treatment. 
 
 
  
 
  
 
  
 
  
 
 
 
  
7.5. 
 
 
 
 
 
  


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8. 
STATISTICAL ANALYSIS 
8.1. 
General Considerations 
Continuous data will be summarized in terms of the number of participants, mean, standard 
deviation (SD), minimum value (min), maximum value (max), median, 25th percentile (Q1), 
and 75th percentile (Q3). The minimum and maximum will be reported with the same number 
of decimal places as the source (raw) data. Mean, Least squares Means (LSM), median, Q1 
and Q3 will be reported to 1 decimal place more than the source (raw) data. SD and standard 
error (SE), if applicable, will be reported to 2 decimal places more than the source (raw) data. 
Any values that require transformation to standard units (metric or SI) will be converted with 
the appropriate corresponding precision. Confidence intervals (CI) will be presented to one 
more decimal place than the associated parameter estimate. In general, the maximum number 
of decimal places reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of participants providing data at 
the relevant time point (n), frequency counts, and percentages. Percentages will be presented 
to 1 decimal place unless otherwise specified. Any planned collapsing of categories will be 
detailed in the SAP text and the data displays. 
Percentages will not be presented for zero counts. Percentages will be calculated using the 
number of participants (n) as the denominator. A missing category shall be included only for 
categorical variables where no data is available. The missing category will be omitted if there 
are no missing values for that variable. 
Participants who are randomized to 1.2 mg treatment and received 0.9 mg dose due to dose 
reduction will be summarized under the same SAGE-718 treatment group. For efficacy data 
analysis, participants’ data are analyzed by randomized treatment. For safety data analysis, 
participants’ data are analyzed per the actual treatment received, and this is determined as 
follows: if a participant received any dose of SAGE-718 at any point of time, the participant is 
assigned to actual treatment of SAGE-718, regardless of the treatment to which the participant 
has been randomized. 
All participant data, including those that are derived, that support the tables and figures will be 
presented in the participant data listings. Some data may be presented only in participant data 
listing, some may be presented with a corresponding table or figure; these will be indicated in 
relevant sections below. All summaries will be provided by treatment – either by randomized 
treatment or actual treatment received.  
P-values will be reported to four decimal places, with p-values less than 0.0001 reported as 
“<0.0001”. P-values larger than 0.9999 will be reported as “>0.9999”. 
Every attempt will be made to avoid missing data. All participants will be used in the analyses, 
as per the analysis populations, using all non-missing data available. No imputation process 
will be used to estimate missing data unless otherwise specified. 
General definitions are defined as below: 
• Baseline is defined as the last non-missing measurement prior to the first dose of IP, 
unless stated otherwise. If the time of an assessment is collected, baseline will be the 


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latest assessment prior to first dose of IP administration time; if the time of an 
assessment is not collected, the assessment on Day 1 is assumed to be prior to dosing 
as the protocol mentions that this assessment needs to be before dosing, or it is collected 
as “pre-dose”. 
• Study day 1 is defined as the date of randomization for untreated randomized 
participants or the date of first dose for treated participants. 
• Study day will be calculated relative to the date of randomization for untreated 
randomized participants and relative to the date of first dose for treated participants. 
o If event is prior to randomization or the first dose, then study day is calculated as: 
Date of Event – Date of Randomization or First Dose 
o If event is on or after date of randomization or the first dose, then study day is 
calculated as: 
Date of Event – Date of Randomization or First Dose + 1  
8.2. 
Background Characteristics  
8.2.1. 
Participant Disposition 
This analysis will be based on all screened participants (i.e., all participants who have signed 
an informed consent). 
Summaries will be provided for participants enrolled in the study including: 
• Participants screened 
• Participants screen-failed 
• Participants screened but  neither screen failed nor randomized 
Note: Due to enrolment closed, participants were discontinued from the study prior to 
inclusions/exclusions criteria reviewed 
• Participants randomized 
• Participants randomized but not dosed 
• Participants received at least 1 dose of IP 
• Number of participants randomized to placebo but received SAGE-718 
• Participants who had dose reduction before Visit Day 42 
• Participants completed IP 
• Participants discontinued from IP and primary reasons for discontinuing IP 
• Participants completed the study 
• Participants discontinued from the study and primary reasons for early 
discontinuation 
Numbers of participants and percentages for study or treatment completion or 
discontinuation as well as the reason for discontinuation will be based on the participants 


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who were randomized and received IP. Treatment arm assignment will be according to the 
randomized treatment. 
In addition, summary of analysis sets including Safety Set, FAS, 
 will be 
provided for participants randomized. Treatment arm assignment will be summarized 
according to the randomized treatment. 
If a participant is rescreened because the participant has been a screen failure the first time, 
the status of the participant will be determined from the second screening. In the count of 
screened participants, this participant will be counted only once.  
Listings by treatment group will be provided for disposition of participants: screen failures 
and inclusion/exclusion criteria for all screened participants, and completion and 
discontinuation from study treatment and study participation, and inclusion in analysis sets 
for Randomized Set. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.3. 
Demographics and Baseline Characteristics 
This analysis will be based on the Safety Set and FAS. 
Demographic data, such as age at randomization (continuous and categorical: ≤65, >65), sex, 
childbearing status, race (both from CRF and derived categorical: Black or African American, 
White, Other), and ethnicity, years of education, years of employment, current employment 
status, and baseline characteristics, such as height, weight, and body mass index (BMI) will be 
summarized using descriptive statistics by treatment group and overall.  
Baseline characteristics will also be summarized for: 
• WAIS-IV Coding test score (continuous) 


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• WAIS-IV total correct Score (<Median, ≥Median) 
• Clinical Dementia Rating (CDR) score (continuous) 
• Clinical Dementia Rating (CDR) score (categorical: 0.5, 1 ) 
 
 
 
 
 
 
 
 
•  BMI (categorical: ≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
• Years of Education (<Median, ≥Median) 
Median categories are calculated from the overall baseline value and rounded to the nearest 
integer.  
By-participant listing of all demographics and baseline characteristics will also be provided 
by treatment group for Randomized Set. 
8.2.4. 
Medical/Surgical History  
This analysis will be based on the Safety Set. 
Medical history collected at screening will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 24.1 or higher. Medical history data will be 
summarized by system organ class (SOC) and preferred term (PT).  
Medical history will be listed by treatment group. Also, by-participant listing of AD history 
will be provided separately. Listings will be provided for Randomized Set.  
8.2.5. 
Prior and Concomitant Medications/Procedures  
This analysis will be based on the Safety Set. 
Medications and procedures will be recorded at each study visit during the study and will be 
coded using the World Health Organization Drug dictionary September 2021 B3, or later and 
MedDRA Version 24.1 or higher, respectively.  
All medications/procedures taken within 30 days prior to Screening, all medications used to 
treat AD regardless of timing, and all nonpharmacological methods used to treat or prevent 
, or cognitive manifestations of AD are to be recorded. Those 
medications/procedures taken and ended prior to the first dose of IP will be denoted “Prior”. 
Those medications/procedures taken prior to the first dose of IP and continuing beyond the 
initiation of the IP or those medications/procedures started at the same time or after the 
initiation of the IP will be denoted “Concomitant”. 
Medications/procedures will be presented according to whether they are “Prior” or 
“Concomitant” as defined above.  If medication/procedures dates are incomplete and it is not 


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clear whether the medication/procedures are concomitant, it will be assumed to be 
concomitant. 
Missing or partial dates will be imputed for medication/procedures.  Algorithm for missing or 
partial start /end date is documented in Appendix C. 
Concomitant medications/procedures are further categorized as on-treatment and post-
treatment as follows: 
• On-treatment concomitant medications/procedures are those that have been used 
between first and last dose of IP (both inclusive) as well as medications started prior to 
first dose of IP and continue beyond the initiation of IP. 
• Post-treatment medications/procedures are those that have been started after the last 
dose of IP. 
Concomitant medications will be summarized on the Safety Set using Anatomical 
Therapeutic Chemical (ATC) level 1 and Standard Medication Name by actual treatment 
group. Concomitant procedures will be summarized on Safety Set using System Organ Class 
(SOC) and preferred term by actual treatment group. By-participant listings of prior and 
concomitant (on-treatment and post-treatment) medications as well as procedures will also be 
provided for Randomized Set. 
8.2.6. 
Investigational Product Exposure  
Total drug exposure (in mg), total exposure duration to IP (in days), and percent of planned 
exposure received (in %) will be summarized for the Safety Set by actual treatment group. 
Total drug exposure (in mg) is defined as the total IP in mg for SAGE-718 that was taken 
during the study. Total drug exposure for participants randomized to placebo is zero unless 
the participant has taken SAGE-718 by mistake, in which case the total exposure comes from 
SAGE-718 exposure and is summarized under SAGE-718 as the actual treatment. If a 
participant skips a dose on any of the days, the dose taken is 0 mg. 
Total exposure duration to IP (in days) is defined as the date of the last dose minus the date 
of first dose plus 1. Note that this does not exclude days when the dose has been missed. 
Percent of the planned exposure received is defined as the total drug exposure, divided by 
planned exposure, times 100. 
• For participants who complete the treatment period, planned exposure is (Date of Day 
42 visit – First Dose Date of 1.2 mg + 1) times 1.2 mg for participants randomized to 
SAGE-718 plus (Date of Day 84 visit – Date of Day 42 visit) times 0.9 mg for 
participants randomized to SAGE-718. For 0.9 mg exposure, with consideration of 
the Day 84 visit windows (+/- 7 days), 
o If Study Day of Day 84 Visit > 91, use the First Dose Date of 1.2 mg + 90 
instead of Date of Day 84 visit. i.e. (Date of Day 84 visit – Date of Day 42 
visit) = First Dose Date of 1.2 mg + 90 – Date of Day 42 visit. 


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o  If Study Day of Day 84 Visit < 77, use the First Dose Date of 1.2 mg + 76 
instead of Date of Day 84 visit. i.e. (Date of Day 84 visit – Date of Day 42 
visit) = First Dose Date of 1.2 mg +76 – Date of Day 42 visit. 
• For participants who discontinue the treatment prior to Day 42 visit, the planned 
exposure is (Last Dose Date – First Dose Date + 1) times 1.2 mg for participants 
randomized to SAGE-718. 
• For participants who discontinue the treatment on or after Day 42 visit but prior to 
Day 84 visit, the planned exposure is (Date of Day 42 visit – First Dose Date of 1.2 
mg + 1) times 1.2 mg plus (Last Dose Date of 0.9 mg – Date of Day 42 visit) times 
0.9 mg for participants randomized to SAGE-718. 
• For participants who cannot tolerate 1.2 mg prior to Day 42 visit therefore received 
0.9 mg for the remainder of the treatment period, the planned exposure is (First Dose 
Date of 0.9 mg – First Dose Date of 1.2 mg) times 1.2 mg plus (Date of Day 84 visit 
– First Dose Date of 0.9 mg + 1) times 0.9 mg for participants randomized to SAGE-
718. For 0.9 mg exposure, refer to the first bullet for participants who complete the 
treatment period. 
• For participants who never received SAGE-718, this measure is not applicable. 
By-participant listings of IP administration and exposure will also be provided including 
participant ID, date of dose, planned exposure (mg), and actual exposure (mg). 
8.2.7. 
Investigational Product Adherence  
This analysis will be based on the FAS. 
IP adherence (%) is defined as the number of capsules taken, divided by the number of capsules 
planned to be taken, times 100%. The planned number of capsules taken is defined as similar 
way as planned exposure, with consideration of the Day 84 visit windows (+/- 7 days). 
• For participants who complete the treatment period, the planned number of capsules 
taken is defined as follows:  
o 77 if Study Day of Day 84 Visit < 77 
o (Date of Day 84 visit – First Dose Date + 1) if Study Day of Day 84 Visit is 
between 77 and 91 (inclusive) 
o 91 if Study Day of Day 84 Visit > 91 
•  For participants who discontinue the treatment earlier than Day 84 Visit, the planned 
exposure is (Last Dose Date – First Dose Date + 1). 
Number and percentage of participants with IP adherence in categories (<80%, 80-100%, 
>100%) will be provided. By-participant listing of IP adherence will be provided. 


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8.3. 
Efficacy Analysis  
The FAS will be used for all efficacy summary and analysis tables. 
 
 
 
8.3.1. 
Definition of Efficacy Variable(s) 
8.3.1.1. 
Primary Efficacy Assessment 
The WAIS-IV Coding Test is a valid and sensitive measure of cognitive dysfunction 
impacted by many domains. In-clinic administration of the WAIS-IV Coding Test will use 
the traditional paper-and-pen format, in which the participant is required to identify the 
symbols matched to numbers using a key and write in the symbol beneath the associated 
number. The score is based on the total number of codes correctly completed over a 120 
second time limit. The WAIS-IV Coding Test will be performed as outlined in Table 12. 
8.3.1.2. 
  
8.3.1.2.1. 
 
8.3.1.2.1.1. 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
8.3.1.2.1.2. 
 
 
 
 
 


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8.3.1.2.1.3. 
 
 
 
 
 
 
8.3.1.2.1.3.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.3.1.2.1.3.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.3.1.2.1.3.3. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
8.3.1.2.1.3.4. 
 
 
 
 


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8.3.1.2.1.3.5. 
 
 
 
 
 
 
 
 
 
 
 
 


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8.3.1.2.2. 
 
 
 
 
 
 
 
Table 3. 
 
   
 
  
 
  
 
 
 
 
  
 
 
 
 
 
8.3.1.2.2.1. 
 
 
 
 
 
 
 
 
 
 
 
  


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8.3.1.2.2.2. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.1.2.2.3. 
 
 
 
 
 
 
 


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8.3.1.2.3. 
 
8.3.1.2.3.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.1.2.3.2. 
 
 
 
 
 
 
 
8.3.1.2.3.3. 
 
 
 
 
 
 
 
 
  
 
 
 


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8.3.1.2.3.4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.1.2.3.5. 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.1.2.3.6. 
 
 
 


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8.3.2. 
Visit Windows for Efficacy Analyses 
The scheduled visits will not be windowed and will be used at nominal visit value for analysis 
purposes. The unscheduled and early termination (ET) visit will be mapped to a scheduled visit 
for analysis. In order to accommodate as much data as possible into analysis, the executive 
windows have been defined as shown in below tables, which have been widened, compared to 
protocol-specified operational windows. These windows will be used for analysis purposes 
only. Once analysis visit windows are assigned, all visits, including scheduled visits, 
unscheduled visits, and ET visits will be eligible for being flagged as the “analyzed record” 
within the analysis window; a participant’s individual analysis visit window could potentially 
contain more than 1 visit. In the event of multiple visits falling within an analysis window or 
in case of a tie, the following rules will be used in sequence to determine the “analyzed record” 
for the analysis visit window: 
• If the data from the scheduled visit is available, then the scheduled visit data will be used.  
• If no data from the scheduled visit is available, the data from unscheduled visit closest to 
the scheduled study day for that window will be used.  
• If there is a tie before and after the scheduled day, the later data will be used. 
 
Table 4. Analysis Visit Windows for WAIS-IV Coding Test  
Scheduled Visit   
 
Target Study Day   Study Day Window for Visit in 
Analysis 
Baseline  
Day 1 (pre-dose)  
Day 1 (pre-dose) or last non-
missing assessment before the 
first dose of IP  
Day 84 (±7 days) 
Day 84 
Day 64 – Day 98  


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Table 5. 
 
 
Table 6. 
 
 
Table 7. 
 
8.3.3. 
Analysis of Primary Efficacy Variable(s) 
8.3.3.1. 
Primary Analysis and Estimand 
The estimand for the primary efficacy analysis is defined as follows: 
1) The treatment regimen for participants is placebo or SAGE-718 for 84 days. 
2) The target population is adult participants with Mild Cognitive Impairment or Mild 
Dementia Due to Alzheimer’s Disease. 


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3) The variable of interest is the change from baseline in WAIS-IV Coding test score at 
Day 84. 
4) The intercurrent events could be: 
a) The premature discontinuation of treatment for any reason. The treatment 
policy strategy will be used. 
b) Taking certain medications including, but not limited to, medications with 
potent effects at the NMDA receptor, including memantine, amantadine, 
ketamine, or related compounds or other medications, given at doses, 
frequencies, or in combinations that are likely, in the opinion of the 
investigator, to have a deleterious effect on cognitive performance, or 
prescribed cannabis or other THC-containing substances. The treatment 
policy strategy will be used.  
5) The population summary level deals with the difference between SAGE-718 and 
placebo treatments in mean change from baseline in WAIS-IV Coding test score at 
Day 84. 
Participants will be analyzed according to randomized treatment. Descriptive statistics of 
WAIS-IV Coding test score, percent change from baseline and change from baseline will be 
summarized by treatment group and by visit. 
The primary endpoint is change from baseline to Day 84 in the WAIS-IV Coding test and this 
primary endpoint will be analyzed using a mixed-effects model for repeated measures 
(MMRM). The model will include baseline WAIS-IV Coding test score as a continuous 
explanatory variable, treatment, visit, and visit-by-treatment interaction as categorical 
explanatory variables. The Kenward-Roger correction to degrees of freedom will be applied. 
All explanatory variables will be treated as fixed effects in the model, and all post-baseline 
time points will be included in the model. An unstructured (UN) covariance matrix with the 
default Newton-Raphson algorithm as implemented in the SAS procedure PROC MIXED will 
be used to model the within-subject correlation. If this model fails to converge, the Fisher 
Scoring algorithm (via the SCORING option of the PROC MIXED statement), the no-diagonal 
factor analytic structure (via the TYPE=FA0(T) option of the REPEATED statement, where T 
is the total number of time points), Toeplitz (TOEP), Autoregressive (1) [AR (1)], Compound 
symmetry (CS) covariance structure will be used, following this sequence until convergence 
is achieved. If the model still does not converge with CS structure, no results will be reported. 
When the covariance structure is not UN, the sandwich estimator for the variance-covariance 
matrix will be derived, using the EMPIRICAL option in the PROC MIXED statement in SAS. 
The primary comparison will be between SAGE-718 and placebo at the Day 84. The LSM and 
SE with 95% CI for each treatment group as well as difference in LSM and SE with 95% CI 
will be summarized, and the p-value from the hypothesis test of no difference between the 
treatment groups will be also presented.  
Descriptive statistics of WAIS-IV Coding test score, percent change from baseline and change 
from baseline will be summarized by treatment group and by visit. 
Line plots with LSM and SE bars of change from baseline in WAIS-IV Coding test score over 
time by treatment group will be provided. 


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By-participant listing of WAIS-IV Coding test score by treatment group and by visit will be 
produced. 
8.3.3.2. 
Multiplicity Adjustment 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.3.3.4. 
Supportive Analysis of Primary Endpoint 
The primary analysis will be repeated 
. The WAIS-IV coding score after 
taking the prohibited medication will not be included in the analysis. No sensitivity analysis 
will be performed 
. 
8.3.3.5. 
Subgroup Analyses of Primary Analysis 
Primary endpoint will be analyzed using a similar MMRM model in Section 8.3.3.1 for the 
following subgroups: 
• Baseline MoCA: 15-17, ≥18 
• Baseline CDR: 0.5, 1  
• Age: ≤65, >65 
• Race (Black or African American, White, Other) 
• Sex (Male, Female) 
• Baseline WAIS-IV (<Median, >=Median) 
• Baseline RBANS (<Median, >=Median) 
• Years of Education (<Median, >=Median) 
Median categories are calculated from the overall baseline value and rounded to the nearest 
integer.  
A summary using descriptive statistics on observed values, percent change from baseline and 
change from baseline by treatment group and subgroup will be provided. The primary 
endpoint by subgroup will be analyzed using MMRM only if there are at least 10 participants 
per subgroup. A forest plot showing the LSM and 95% CI bar at Day 84 within each 
subgroup and treatment group will be provided. 
8.3.4. 
Analysis of Secondary Efficacy Variables 
Not applicable.  
8.3.5. 
 
 
 
 
 
 


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8.3.5.1. 
 
 
 
 
8.3.5.2. 
  
 
 
 
 
 
 
 
 
 
 
  
8.3.5.3. 
   
 
 
 
 
 
 
 
 
 
 
 
 
8.3.5.4. 
 
 
 
 
 
 
 


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8.3.5.5. 
 
 
 
 
  
 
 
 
8.3.5.6. 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
8.3.5.7. 
  
 
 
 
 
 
 
 
8.3.5.8. 
  
 
  
 


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8.3.5.9. 
 
 
 
 
 
 
 
8.3.5.10. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
8.3.5.11. 
 
 
 
 
 
  
 
 
 


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8.4. 
Safety Analysis 
All safety summaries will be performed on the Safety Set using treatment received.  
Safety and tolerability of SAGE-718 softgel lipid capsule 
 in participants with AD is the secondary objective of this study and will be evaluated by the 
frequency and severity of TEAEs, and withdrawal due to AEs. Other safety endpoints include 
change from baseline in vital signs, clinical laboratory analytes, ECGs, 
 
.  
The safety endpoints evaluated at scheduled visits are taken as done in nominal visit, without 
any windowing. If a value is available for a nominal scheduled visit, that value will be used in 
summary by visit. For the summary of the scheduled visits, unscheduled measurements and 
ET measurement, unless specified, will be included only if a scheduled measurement is not 
available, and the unscheduled measurement and ET measurement falls within the visit 
window for the scheduled visit (same as WAIS-IV Coding Test in Table 4). If there are two or 
more measurements in a visit window, the measurement taken closest to the study day target 
will be used in analysis. If the two have same distance from the target study day, the latter one 
will be used. 
Anytime on treatment, last value on treatment and last value on study will be included in the 
summaries, unless specified. Anytime on treatment is defined as measurement on or after first 
dose, on or before the date of last dose. Last value on treatment is defined as the last post-
baseline value between first dose of IP and up to the date of last dose of IP. Last value on study 
is defined as the last post-baseline value on or after the first dose of IP and on or before the last 
date of the study. 
No statistical hypothesis testing will be conducted. 
Safety data will be listed by participant and summarized by treatment group.  
Table 8. Summary of Safety Analysis 
Safety 
Evaluation 
Incidence   Source 
Data 
Change 
from 
Baseline 
Shift 
from 
Baseline 
Potentially 
Clinically 
Significant 
Abnormality/
Clinical 
Significance 
AEs 
X 
 
 
 
 
 
Clinical 
Laboratory 
 
X 
X  
X 
X  
* 
ECG 
 
X 
X 
 
X 
* 
Vital Signs 
 
X 
X  
 
X 
 
Physical 
Exam 
 
* 
 
 
 
 


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Safety 
Evaluation 
Incidence   Source 
Data 
Change 
from 
Baseline 
Shift 
from 
Baseline 
Potentially 
Clinically 
Significant 
Abnormality/
Clinical 
Significance 
ECG = Electrocardiograms; 
 
X = Safety Assessment will be summarized in tables 
* = Safety Assessment will be listed in individual participant data listings 
8.4.1. 
Adverse Events  
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 
24.1. Intensity and relationship of AE will be evaluated by the investigator. 
A TEAE is defined as any AE on or after the first dose of IP or any worsening of a pre-existing 
medical condition/AE with onset after the start of IP and throughout the study. The analysis of 
AEs will be based on the concept of TEAEs. Where the AE start date is missing, adverse events 
will be assumed to be treatment-emergent, unless there is clear evidence (through comparison 
of partial dates) to suggest that the adverse event started prior to the first dose of study 
treatment. Partial dates will be imputed for AE. The algorithm for missing or partial start /end 
date is documented in Appendix C. 
Adverse events are assigned an AE period based on the onset date/time. AE periods are defined 
as follows: 
•  Pre-treatment AE: AE onset date/time before first IP dosing date/time  
• TEAE: AE onset date/time on or after the first IP dose date/time (If an AE start 
date same as IP first dose date, but no time either in AE start or treatment start, 
then consider this AE to be in treatment period TEAE.)   
•  On-treatment TEAE: AE onset date/time on or after first IP dose date/time and on 
or before IP last dose date + 30 days (Note that time does not matter for the end of 
this period. i.e., if AE occurred after the last dose but on the same date of last 
dose, it is considered as on-treatment TEAE) 
•  Post-treatment TEAE: AE onset date on or after IP last dose date + 31 days 
An overall summary of TEAEs will include the number and percentage of participants in the 
following categories: 
• Any TEAEs (On-treatment, Post-treatment) 
• TEAEs by maximum severity (severe>moderate>mild) 
• Any related TEAEs 
• Any related TEAEs by maximum severity  
• Any serious TEAEs 


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• Any serious related TEAEs 
• Any TEAEs leading to death 
• Any TEAEs leading to IP withdrawal 
• Any TEAEs leading to withdrawal from the study 
• Any TEAEs leading to IP interruption 
• Any TEAEs leading to dose reduction before Day 42 
Incidence of TEAEs in following categories will be provided by SOC and PT. A participant is 
counted only once under each SOC and PT in case of multiple occurrences of the same AE. 
These tables will be sorted by decreasing frequency of System Organ Class (SOC) in SAGE-
718 group, then in placebo group, then alphabetically first within SOC then within preferred 
term.  
• TEAEs 
• On-treatment TEAEs 
• Post-treatment TEAEs 
• TEAEs by maximum severity 
• TEAEs by causality (related, not related) to IP 
• TEAE by maximum severity and causality to IP 
• Serious TEAEs 
• TEAEs leading to IP withdrawal 
• TEAEs leading to withdrawal from the study  
• TEAEs leading to IP interruption 
Additionally, incidence of TEAEs will be summarized by PT.  Most frequent TEAEs reported 
>5% in PT of any treatment group will also be summarized by PT. 
For maximum severity, participants will be counted only once within each SOC and PT at the 
maximum severity in the following order: severe > moderate > mild; an AE with missing 
severity will be omitted from severity presentation and will not be imputed. For relationship to 
IP, participant will be counted only once within each SOC and PT with the strongest 
relationship to IP in the following order: related > not related; an AE with relationship missing 
is treated as related. For seriousness, an AE with missing seriousness will not be imputed. The 
incidences will be presented by descending frequency of SOC and then, within a SOC, by 
descending frequency of PT based on the participant count, and in alphabetical order of PT if 
the incidence within a PT is a tie. 
In addition, TEAE summary by SOC/PT will also be presented by the following subgroups: 
• Race (Black or African American, White, Other) 
• Sex (Male, Female) 


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• BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2; categories are defined after rounding) 
• Age group (≤65, >65 years) 
A by-participant listing of all AEs, SAEs (including those with onset or worsening before the 
start of IP), AEs leading to death, AEs leading to IP withdrawal through the end of the study, 
and most frequent (5%) TEAEs will be provided. 
8.4.2. 
Clinical Laboratory 
Any lab results considered clinically significant by the investigator will be captured as adverse 
events, hence will show up in AE displays. 
Laboratory values contain ‘≥ x’ or ‘x ≤’ will be taken as the value of x in the analysis. If a 
laboratory value is reported as ‘<y’ then y minus the minimum value with the same precision 
as y (ex. if y = 1.345, then use y - 0.001) will be used for the analysis. If a laboratory value is 
reported as ‘>y’ then y plus the minimum value with the same precision as y will be used for 
the analysis. The same is true if the result is presented as below limit of quantification (BLQ) 
and a lower limit of quantification (LLOQ) value is provided – LLOQ value will be used for 
calculation in the summary tables. The actual results as collected will be displayed in the 
listings. 
Results of continuous clinical laboratory parameters for hematology, biochemistry, 
coagulation, and urine samples for urinalysis at each scheduled visit and mean changes from 
baseline will be summarized in standard units. In addition, it will also include the summary of 
the last value on treatment and the last value on study. 
Normal ranges for each parameter will be provided by the laboratory. Shift from baseline to 
post-baseline values in abnormality of hematology and biochemistry results will be 
summarized. In addition, shift from baseline to post-baseline values in abnormality of results 
at anytime on treatment where the worst value is used, the last value on treatment  and the last 
value on study will be summarized. If a participant has both low and high post-baseline records, 
the participant will be counted twice for each low and high cell. 
Clinical laboratory results will be listed by participant and timing of collection for each 
treatment group. 
The number and percentage of participants with potentially clinical significance (PCS) values 
for each laboratory parameter will be summarized by treatment for anytime on treatment, the 
last value on treatment and the last value on study. Sponsor determined PCS values will be 
identified for specific laboratory parameters as outlined in Table 9 below. 


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Table 9. Potentially Clinically Significant (PCS) Values for Specific Laboratory 
Parameters 
Laboratory  
Parameter 
Sex 
Units 
Criteria for PCS Values (Observed 
values) 
 
 
 
High  
Low  
Hematology 
Hemoglobin                 Male 
g/L  
>185  
<115 
 
Female 
g/L  
>170 
<100 
Hematocrit    
Male 
Fraction of 1 
>0.55  
<0.385  
 
Female 
Fraction of 1 
>0.49 
<0.345 
Platelet count  
 
10^9/L  
>600 
<125 
White blood cell 
 
10^9/L  
>15  
<2.5  
Basophils  
 
10^9/L  
>0.5 
NA 
Eosinophils 
 
10^9/L  
>1.5 
NA 
Neutrophils  
 
10^9/L  
NA  
<1.5  
Lymphocytes  
 
10^9/L  
>6.0  
<0.5  
Monocytes  
 
10^9/L  
>1.4 
NA 
Chemistry 
Albumin  
 
g/L  
>70  
<28  
Blood urea nitrogen  
 
mmol/L 
>10.71 
NA 
Calcium 
 
mmol/L 
>2.75 
<2.0 
Chloride 
 
mmol/L 
>120 
<90 
Creatinine 
 
mmol/L 
>3xULN or >3x Baseline 
 
Gamma Glutamyl 
Transferase  
 
 
>3xULN 
 
Glucose 
 
mmol/L 
>13.9 
<2.8 
Sodium  
 
mmol/L  
>150 
<132  
Potassium  
 
mmol/L  
>5.4  
<3.3  
Protein  
 
g/L 
 
<45 
Bicarbonate  
 
mmol/L  
>34  
<18  
Phosphorus  
 
mmol/L 
>1.94 
<0.61 
Coagulation 
Prothrombin time 
 
second 
>=1.11 x ULN 
NA  


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Laboratory  
Parameter 
Sex 
Units 
Criteria for PCS Values (Observed 
values) 
 
 
 
High  
Low  
Partial 
thromboplastin time 
 
second  
>1.5 x ULN 
NA  
Liver function tests will be monitored closely for PCS values, and will be summarized for 
occurrence any time post-baseline for the following parameters for these PCS threshold (for 
condition involving more than one parameter, the results need to be from the same timepoint): 
• 
Alanine Aminotransferase: >3xULN, >5xULN, >10xULN 
• 
Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
• 
Alanine Aminotransferase or Aspartate Aminotransferase: >3xULN, >5xULN, 
>10xULN 
• 
Alkaline Phosphatase: >1.5xULN, >2xULN 
• 
Total Bilirubin: >1.5xULN, >2xULN 
• 
Total Bilirubin >2xULN AND (Alanine Aminotransferase or Aspartate 
Aminotransferase >3xULN) [any time post-baseline, does not need to be measured at 
the same time point of assessment] 
• 
[(Total Bilirubin >2xULN) AND Alkaline Phosphatase <2xULN (any time post-
baseline, measured at the same time point of assessment)] AND [(ALT or AST 
>3xULN) AND Alkaline Phosphatase <2xULN, any time post-baseline, measured at 
the same time point of assessment] 
By-participant listing of FSH and serology test results at screening will be provided. 
By-participant listing of urine drug screen and alcohol breath test will also be provided. 
8.4.3. 
Electrocardiogram 
A 12-Lead ECG will be performed after the participant has been resting in the supine 
position for at least 5 minutes. If there are both scheduled visit and unscheduled visit on the 
same date, all the assessments on that date are considered as the scheduled visit for the 
summary. A summary of raw values and change from baseline values will be summarized by 
each scheduled visit for the following ECG parameters: heart rate, PR, QRS, QT, and QTcF 
interval.  This summary will also include the last values on treatment and on study. A by-
participant listing of 12 lead ECG will also be provided for each of the ECG measurements. 
ECG is evaluated by investigator as ‘normal’, ‘abnormal, not clinically significant’ and 
‘abnormal, clinically significant’. The number and percentage of participants with each 
category will be provided at baseline and each post-baseline scheduled assessment time 
point. If there are more than one evaluation at the same time point, the latest assessment from 
ECG vendor will be used for the summary. 


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Potentially clinically significant values of QTcF as outlined in Table 10 will be summarized 
by treatment for anytime on treatment, the last value on treatment and the last value on study.   
Table 10. Potentially Clinically Significant (PCS) Values for 12-Lead ECG Parameters 
12-Lead ECG 
Units 
Criteria for PCS Values 
(Observed values) 
Criteria for PCSC values 
(Change from Baseline) 
High  
Low  
Increase 
Decrease 
QTcF 
msec 
>450 but ≤480 
>480 but ≤500 
>500 
NA 
≥30 to 60 
>60 
NA 
8.4.4. 
Vital Signs 
Vital signs will include height, weight, oral temperature(˚C), respiratory rate (breaths per 
minute), heart rate (beats per minute [bpm]), and blood pressures (mmHg). Heart rate and 
blood pressure were collected in supine position and standing position at all scheduled time 
points. 
Vital sign results and mean changes from baseline will be summarized by scheduled visit.  It 
will also include the summary of last values on treatment and on study assessments. Potentially 
clinically significant values as outlined in Table 11 will be summarized by treatment for 
anytime on treatment, the last value on treatment and the last value on study.  By-participant 
listing of vital signs will also be provided. 
Table 11. Potentially Clinically Significant (PCS) Values for Vital Sign Parameters 
Vital Sign 
Units 
Criteria for PCS 
Values (Observed 
values) 
Criteria for PCS 
values (Change from 
Baseline values) 
High  
Low  
Increase  
Decrease 
Heart rate (supine and standing) 
Beats/min  >120  
<40  
NA 
NA 
Respiratory Rate 
Beats/min >20 
<8 
 
 
Systolic blood pressure (supine 
and standing)  
mmHg  
>180 
<90  
≥30 
≥30 
Diastolic blood pressure (supine 
and standing)  
mmHg  
>110 
<50  
≥20 
≥20 
Supine – Standing* Systolic Blood 
Pressure 
mmHg  
≥20 
 
 
 
Supine – Standing* Diastolic 
Blood Pressure 
mmHg  
≥10 
 
 
 
Orthostatic hypotension: supine – 
standing* SBP and DBP 
mmHg  
SBP ≥20 
and DBP 
≥10 
 
 
 


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Vital Sign 
Units 
Criteria for PCS 
Values (Observed 
values) 
Criteria for PCS 
values (Change from 
Baseline values) 
High  
Low  
Increase  
Decrease 
Possible orthostatic hypotension: 
supine – standing* SBP and DBP 
mmHg  
SBP ≥20 
or DBP 
≥10 
 
 
 
* Supine – Standing means the difference of results between supine and standing positions. 
8.4.5. 
Physical Examination  
A full physical examination and neurological examination are to be conducted during 
Screening and at Day 84 (End of Treatment). At other visits, an abbreviated physical 
examination will include a brief assessment of general appearance, cardiovascular, respiratory, 
gastrointestinal, and neurological systems, followed by a targeted physical assessment as 
needed. A symptom directed examination may be conducted at any time at the discretion of 
the investigator. Unscheduled, symptom directed examinations may be conducted at any time 
at the discretion of the investigator. Any baseline abnormalities will be recorded on the medical 
history form. Any post-baseline abnormalities or baseline conditions that worsened post-
baseline will be recorded on the adverse events form. 
The occurrence of a physical examination (yes/no) and the date performed will be listed by 
participant to confirm the examination was done. A separate listing for the neurological 
examination will be provided. 
8.4.6. 
Magnetic Resonance Imaging  
By-participant listing of MRI at screening will be provided. 
8.4.7. 
 
 
 
 
 
   
 
  
 
 
  
 
 
 
 


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8.4.8. 
Other Safety Analysis 
Not applicable. 


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8.5. 
Other Analysis 
 will be 
described and reported separately. 
8.5.1. 
 
 
 
 
 
 
 


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10. 
REFERENCES 
SAS® Version 9.4 of the SAS System for Personal Computers. Copyright ©2013. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A. SCHEDULE OF ASSESSMENTS 
Table 12. Schedule of Assessment 
Assessments  
Screenin
g Period  
Baseline 
Period 
Treatment Period 
Follow-Up 
Period 
Days 
-35 to -8 
Days 
-7 
through   
-1 
Day 
1a 
Day 14 
(±2 days)  
 
Day 28 
(±2 days)  
safety  
phone callb 
Day 42 
(±2 days)c 
 
Day 63 
(±2 days)  
safety 
phone callb  
Day 84 
(±7 days)d 
or ET 
Day 112 
(±7 days) 
 
Informed consente 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
Medical history and 
demographicsf 
X 
 
 
 
 
 
 
 
 
Participant trainingg 
 
X 
 
 
 
 
 
 
 
Body weight 
X 
 
X 
 
 
X 
 
X 
X 
Body height 
X 
 
 
 
 
 
 
 
 
CDR 
X 
 
 
 
 
 
 
 
 
Vital signs (including 
orthostatic)h 
X 
 
X 
X 
 
X 
 
X 
X 
Physical examinationi 
X 
 
X 
X 
 
X 
 
X 
X 
FSH testj 
X 
 
 
 
 
 
 
 
 
Serology testk 
X 
 
 
 
 
 
 
 
 






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Abbreviations: AD = Alzheimer’s Disease; AE = adverse event, 
 
 
 CDR = Clinical Dementia Rating; 
 
 COVID-19 = coronavirus disease 2019; 
 
ECG = electrocardiogram; ET = early termination; 
 FSH = follicle-
stimulating hormone; HIV = human immunodeficiency virus; ICF = informed consent form; IP = investigational product; 
 
 MRI = magnetic resonance imaging; 
 
 
 SAE = serious adverse event; WAIS-IV Coding Test = Wechsler Adult Intelligence Scale-IV Coding Test.  
 
a All tests on Day 1 will be conducted predose. 
b Phone check-in only for AEs/SAEs and changes to medical history or medications. 
c Within the SAGE-718 treatment arm, participants will receive 1.2 mg of SAGE-718 daily for the first 6 weeks (Day 1 Visit to Day 42 Visit [±2 days]), 
followed by 0.9 mg of SAGE-718 for the remainder of the Treatment Period (Days 43 to 84 [±7 days]). The placebo arm will receive matching placebo 
throughout the Treatment Period (12 weeks). 
d Dosing ends on Day 84 (±7 days). Participants who terminate early should perform all of the assessments that are scheduled for Day 84. 
e Both participants and their study partners will provide informed consent at screening. Participants and study partners will consent to participation in the 
study, and any optional assessments 
.  
f Includes full medical history (including family history of AD), medications and supplements taken within 30 days prior to Screening, medications used to 
treat AD regardless of timing, and nonpharmacological methods (e.g., psychosocial, psychotherapeutic) used to treat or prevent 
 
, or cognitive manifestations of AD. Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be documented as 
part of medical history, AE collection, and prior/concomitant medication collection at Screening and throughout the study. 
g Participants and study partners will be trained by study staff on the use of software applications and devices necessary for the conduction of the study. 
h Vital signs include body temperature, respiratory rate, heart rate, and blood pressure. On dosing days, vital signs will be measured prior to dosing. 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 at all scheduled time points. Vital signs can be repeated once if out of range. 
i A full physical and neurological examination will be conducted during Screening and at Day 84 (End of Treatment). At other visits, an abbreviated 
physical examination will include a brief assessment of general appearance, cardiovascular, respiratory, gastrointestinal, and neurological systems, 
followed by a targeted physical assessment as needed. A symptom directed examination may be conducted at any time at the discretion of the investigator. 
j Serum FSH test will be conducted at Screening for the female participants who are not surgically sterile and who have ≥12 months of spontaneous 
amenorrhea to confirm postmenopausal state as defined in protocol.  
k To include hepatitis B and C screening tests, HIV-1 and -2 antibody. 
l ECG will be measured after the participant has been in a supine position for at least 5 minutes. 
m Only in participants without an MRI report obtained within the 2 years preceding the Baseline Period. 
n Clinical laboratory assessments will include blood samples for hematology, biochemistry, coagulation, and urine samples for urinalysis. On dosing days 
samples will be collected prior to dosing. On nondosing days, collection may occur at any time.  


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o Serum pregnancy tests will be conducted for all female participants at Screening; urine pregnancy tests will be conducted at other scheduled time points for 
female participants who do not meet the protocol definition of postmenopausal or surgically sterile. 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
u On Day 1, participants will self-administer IP in the clinic under the supervision of study staff. All scheduled safety assessments and cognitive tests will be 
administered prior to dosing. On Days 14, 42, and 84, cognitive tests will be administered postdose. 
v Study staff will dispense enough IP for the participant to take daily at home until the next scheduled site visit. 
w IP dosing date and time will be recorded by participant remotely using mobile device.  
x Participants will bring all used packaging and unused IP to the clinic at each visit for study staff to review and document. 
y AEs/SAEs will be collected beginning with completion of ICF through end of study participation. 
z At Screening, to include all medications and supplements taken within 30 days of signing ICF and all medications used to treat AD. At visits subsequent to 
Screening, all changes to any medication should be captured. 


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Table 13: 
  
 
 
 
 
 
 
  
 
 
 
 
 


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APPENDIX B. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX D. LIST OF DISPLAYS 
Type 
Number 
Title 
Table 
14.1.1  
Summary of Dispositions (All Screened Participants) 
Table 
14.1.2  
Summary of Analysis Sets (All Randomized Set) 
Table 
14.1.3  
Summary of Major Protocol Deviations (Full Analysis Set) 
Table 
14.1.4.1.1  
Summary of Demographics and Baseline Characteristics (Full Analysis Set) 
Table 
14.1.4.1.2  
Summary of Demographics and Baseline Characteristics (Safety Set) 
Table 
14.1.5.1  
Summary of Medical History (Safety Set) 
Table 
14.1.6.1  
Summary of Concomitant Medications (Safety Set) 
Table 
14.1.6.2  
Summary of Concomitant Procedures (Safety Set) 
Table 
14.1.7  
Summary of Investigational Product Exposure (Safety Set) 
Table 
14.1.8  
Summary of Investigational Product Adherence (Full Analysis Set) 
Table 
14.2.1.1  
Analysis of Change from Baseline on the Wechsler Adult Intelligence Scale – IV 
(WAIS-IV) Coding Test Score by Visit (Full Analysis Set) 
Table 
14.2.1.2.4  
Analysis of Change from Baseline on the Wechsler Adult Intelligence Scale – IV 
(WAIS-IV) Coding Test Score by Visit 
 
Table 
14.2.1.3.1  
Analysis of Change from Baseline on the Wechsler Adult Intelligence Scale – IV 
(WAIS-IV) Coding Test Score by Visit and Subgroup Baseline MoCA (Full 
Analysis Set) 
Table 
14.2.1.3.2  
Analysis of Change from Baseline on the Wechsler Adult Intelligence Scale-IV 
(WAIS-IV) Coding Test Score by Visit and Subgroup Baseline CDR (Full 
Analysis Set) 
Table 
14.2.1.3.3  
Analysis of Change from Baseline on the Wechsler Adult Intelligence Scale-IV 
(WAIS-IV) Coding Test Score by Visit and Subgroup Age (Full Analysis Set) 
Table 
14.2.1.3.4  
Analysis of Change from Baseline on the Wechsler Adult Intelligence Scale-IV 
(WAIS-IV) Coding Test Score by Visit and Subgroup Sex (Full Analysis Set) 
Table 
14.2.1.3.5  
Analysis of Change from Baseline on the Wechsler Adult Intelligence Scale-IV 
(WAIS-IV) Coding Test Score by Visit and Subgroup Race (Full Analysis Set) 
Table 
14.2.1.3.6  
Analysis of Change from Baseline on the Wechsler Adult Intelligence Scale-IV 
(WAIS-IV) Coding Test Score by Visit and Subgroup Baseline WAIS-IV Total 
Score (Full Analysis Set) 
Table 
14.2.1.3.7  
Analysis of Change from Baseline on the Wechsler Adult Intelligence Scale-IV 
(WAIS-IV) Coding Test Score by Visit and Subgroup Baseline RBANS Total 
Score (Full Analysis Set) 
Table 
14.2.1.3.8  
Analysis of Change from Baseline on the Wechsler Adult Intelligence Scale-IV 
(WAIS-IV) Coding Test Score by Visit and Subgroup Years of Education (Full 
Analysis Set) 




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Type 
Number 
Title 


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Type 
Number 
Title 
Table 
14.3.1.1  
Overall Summary of Treatment-Emergent Adverse Events (Safety Set) 
Table 
14.3.1.2.1  
Summary of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Set) 
Table 
14.3.1.2.2  
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Subgroup Race (Safety Set) 
Table 
14.3.1.2.3  
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Subgroup Sex (Safety Set) 
Table 
14.3.1.2.4  
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Subgroup BMI (Safety Set) 
Table 
14.3.1.2.5  
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Subgroup Age (Safety Set) 
Table 
14.3.1.2.6  
Summary of On-Treatment Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term (Safety Set) 
Table 
14.3.1.2.7  
Summary of Post-Treatment Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Set) 
Table 
14.3.1.3  
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, Maximum Severity and Causality to IP (Safety Set) 
Table 
14.3.1.4  
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Causality to IP (Safety Set) 
Table 
14.3.1.5  
Summary of Treatment-Emergent Adverse Events by Preferred Term (Safety Set) 
Table 
14.3.1.6  
Summary of Most Frequent (>5%) Treatment-Emergent Adverse Events by 
Preferred Term (Safety Set) 
Table 
14.3.2.1  
Summary of Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term (Safety Set) 
Table 
14.3.2.2  
Summary of Treatment-Emergent Adverse Events Leading to Investigational 
Product Withdrawal by System Organ Class and Preferred Term (Safety Set) 


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Type 
Number 
Title 
Table 
14.3.2.3  
Summary of Treatment-Emergent Adverse Events Leading to Withdrawal from the 
Study by System Organ Class and Preferred Term (Safety Set) 
Table 
14.3.2.4  
Summary of Treatment-Emergent Adverse Events Leading to Investigational 
Product Interruption by System Organ Class and Preferred Term (Safety Set) 
Table 
14.3.4.1.1  
Summary of Hematology Laboratory Parameters (Safety Set) 
Table 
14.3.4.1.2  
Summary of Biochemistry Parameters (Safety Set) 
Table 
14.3.4.1.3  
Summary of Quantitative Urinalysis Laboratory Parameter (Safety Set) 
Table 
14.3.4.1.4  
Summary of Quantitative Coagulation Laboratory Parameters (Safety Set) 
Table 
14.3.4.2.1  
Summary of Potentially Clinically Significant Hematology Laboratory Parameters 
(Safety Set) 
Table 
14.3.4.2.2  
Summary of Potentially Clinically Significant Biochemistry Laboratory 
Parameters (Safety Set) 
Table 
14.3.4.2.3  
Summary of Potentially Clinically Significant Liver Function Tests (Safety Set) 
Table 
14.3.4.3.1  
Summary of Abnormality Shift from Baseline in Hematology Laboratory 
Parameters (Safety Set) 
Table 
14.3.4.3.2  
Summary of Abnormality Shift from Baseline in Biochemistry Laboratory 
Parameters (Safety Set) 
Table 
14.3.5.1  
Summary of 12-Lead Electrocardiograms (ECG) (Safety Set) 
Table 
14.3.5.2  
Summary of Potentially Clinically Significant QTcF (Safety Set) 
Table 
14.3.5.3  
Summary of Electrocardiograms Interpretations by Investigator (Safety Set) 
Table 
14.3.6.1  
Summary of Vital Signs (Safety Set) 
Table 
14.3.6.2  
Summary of Potentially Clinically Significant Vital Signs (Safety Set) 
Figure 
14.2.1.1  
Plot of LS Means +/- SE in Change from Baseline on the Wechsler Adult 
Intelligence Scale-IV Coding Test Score by Visit (Full Analysis Set) 
Figure 
14.2.1.2 
Forest Plot of Difference in LS Means (95% CI) for Change from Baseline on the 
Wechsler Adult Intelligence Scale-IV (WAIS-IV) Coding Test Score  by Visit and 
by Subgroup    (Full Analysis Set) 


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Type 
Number 
Title 
Listing 
16.1.7  
Participant Randomization (Randomized Set) 
Listing 
16.2.1.1  
Participant Disposition (Randomized Set) 
Listing 
16.2.1.2  
Participants who Discontinued Treatment and/or Study (Randomized Set) 
Listing 
16.2.1.3  
Participant/Study Partner Consent on Optional Assessments (Randomized Set) 
Listing 
16.2.2.1  
Protocol Deviations (Safety Set) 
 
 
 
Listing 
16.2.3.1  
Assignment to Analysis Sets (Randomized Set) 
Listing 
16.2.3.2  
Inclusion/Exclusion Criteria Violations and Re-screening (All Screened 
Participants) 
Listing 
16.2.4.1  
Demographics (Randomized Set) 
Listing 
16.2.4.2  
Baseline Characteristics (Randomized Set) 
Listing 
16.2.4.3  
Alzheimer’s Disease History (Safety Set) 
Listing 
16.2.4.4  
Medical History (Safety Set) 
Listing 
16.2.4.5  
Prior and Concomitant Medications (Safety Set) 
Listing 
16.2.4.6  
Prior and Concomitant Procedures (Safety Set) 
Listing 
16.2.5.1  
Investigational Product Administration (Safety Set) 
Listing 
16.2.5.2  
Investigational Product Exposure (Safety Set) 
Listing 
16.2.5.3  
Investigational Product Accountability (Safety Set) 
Listing 
16.2.6.1  
Wechsler Adult Intelligence Scale – IV (WAIS-IV) Coding Test (Full Analysis 
Set) 


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Type 
Number 
Title 
Listing 
16.2.7.1  
Adverse Events (Safety Set) 
Listing 
16.2.7.2  
Serious Adverse Events (Safety Set) 
Listing 
16.2.7.3  
Treatment-Emergent Adverse Events Leading to Death (Safety Set) 
Listing 
16.2.7.4  
Treatment-Emergent Adverse Events Leading to Investigational Product 
Withdrawal and/or Study (Safety Set) 
Listing 
16.2.7.5  
Most Frequent (>5%) Treatment-Emergent Adverse Events (Safety Set) 
Listing 
16.2.8.1.1  
Hematology Laboratory Parameters (Safety Set) 
Listing 
16.2.8.1.2  
Biochemistry Laboratory Parameters (Safety Set) 
Listing 
16.2.8.1.3  
Urinalysis Laboratory Parameters (Safety Set) 
Listing 
16.2.8.1.4  
Coagulation Laboratory Parameters (Safety Set) 
Listing 
16.2.8.2.1  
Potentially Clinically Significant Hematology Laboratory Parameters (Safety Set) 
Listing 
16.2.8.2.2  
Potentially Clinically Significant Biochemistry Laboratory Parameters (Safety Set) 
Listing 
16.2.8.2.3  
Potentially Clinically Significant Liver Function Tests (Safety Set) 
Listing 
16.2.8.3  
Pregnancy Test (Safety Set) 
Listing 
16.2.8.4  
FSH and Serology/HIV/Hepatitis (Safety Set) 
Listing 
16.2.8.5  
Urine Drug Screen and Breath Alcohol Test (Safety Set) 
Listing 
16.2.9.1.1  
12-Lead Electrocardiogram (ECG) (Safety Set) 
Listing 
16.2.9.1.2  
Potentially Clinically Significant QTcF Values (Safety Set) 
Listing 
16.2.9.2.1  
Vital Signs (Safety Set) 
Listing 
16.2.9.2.2  
Potentially Clinically Significant Vital Signs (Safety Set) 
Listing 
16.2.9.3.1  
Physical Examinations (Safety Set) 
Listing 
16.2.9.3.2  
Neurological Examinations (Safety Set) 
Listing 
16.2.9.3.3  
Magnetic Resonance Imaging (MRI) (Safety Set)