A Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Effect of SAGE-718 on Cognitive Function in Participants With Huntington's Disease
Phase: PHASE2
Conditions: Huntington's Disease
Sponsor: Supernus Pharmaceuticals, Inc.

 
Official Title: A Randomized, Placebo-Controlled, Double-Blind Study to Evaluate 
the Effect of Sage-718 on Cognitive Function in Participants With 
Huntington’s Disease 
NCT Number: NCT05107128 
Document Date: Protocol Version 6.0, 20 August 2024 
 
 

Clinical Protocol 
Sage Therapeutics, Inc. 
718-CIH-201, Version 6
CONFIDENTIAL 
 
 
A RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-
BLIND STUDY TO EVALUATE THE EFFECT OF SAGE-718 
ON COGNITIVE FUNCTION IN PARTICIPANTS WITH 
HUNTINGTON’S DISEASE 
SHORT TITLE: A STUDY TO EVALUATE THE EFFECT OF 
SAGE-718 ON COGNITIVE FUNCTION IN PARTICIPANTS 
WITH HUNTINGTON’S DISEASE  
PROTOCOL NUMBER: 718-CIH-201 
IND NUMBER: 145563 
EUDRACT NUMBER: 2021-005577-16 
Investigational Product: SAGE-718 
Clinical Phase: 2 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street* 
Cambridge, MA 02142 
Sponsor Contact  
, PhD 
 
 
Cambridge, MA 02142 
Phone: 
 
Medical Monitor 
, MD 
 
Cambridge, MA 02142 
Phone: 
 
Date of Original Protocol - 26 May 2021 
Date of Amendment 3 - 21 June 2022 
Date of Amendment 1 - 1 September 2021 
Date of Amendment 4 - 03 November 2023 
Date of Amendment 2 – 04 October 2021 
Date of Amendment 5 – 19 August 2024  
Date of Amendment 2 
[United Kingdom] – 14 April 2022 
*Sponsor address effective 01 September 2024 will be: 55 Cambridge Parkway, Cambridge, MA 02142
Confidentiality Statement 
The confidential information in this document is provided to you as an investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from Sage 
Therapeutics, Inc.  

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718-CIH-201, Version 6 
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INVESTIGATOR’S AGREEMENT 
I have read the 718-CIH-201 protocol and agree to conduct the study as outlined. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD Month YYYY) 

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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sage Study Physician 
and 24-Hour Emergency 
Contact 
, MD 
 
215 First Street* 
Cambridge, MA 02142 
Phone: 
 
e-mail: 
 
 Medical Monitor 
(Global and North 
America)  
, MD 
 
Phone: 
  
e-mail: 
NorthAmerica_Medical@
 
 
 Regional 
Medical Monitor 
(EU and Australia) 
, MD 
Phone: 
 
Email: 
 
 
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 
 MD 
 
215 First Street* 
Cambridge, MA 02142 
Phone: 
 
e-mail: 
 
, MD 
e-mail: 
 
, MD 
e-mail: 
 
Product Complaints Sage 
Therapeutics 
Product Complaints Sage 
Therapeutics 
Phone: 1-833-554-7243 
e-mail: 
productcomplaints@sagerx.com 
*Sponsor address effective 01 September 2024 will be: 55 Cambridge Parkway, Cambridge, MA 02142 

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Sage Therapeutics, Inc. 
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Clinical Protocol 
Sage Therapeutics, Inc. 
718-CIH-201, Version 6 
CONFIDENTIAL 
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following daily administration of 
SAGE-718 
• 
To evaluate additional safety and 
tolerability parameters of SAGE-718 in 
participants with HD 
• 
CFB in vital signs, clinical laboratory analyses, 
electrocardiograms (ECGs), 
 
 
 
• 
 
 
a Applicable only to the subgroup of participants who can complete Trail Making Part B within the allowable 
time limit at baseline. 
 
Study Description: 
This is a randomized, placebo-controlled, double-blind study to evaluate the cognitive effects, safety, 
tolerability, 
 of SAGE-718 in participants with premanifest or early manifest HD. 
Participants will be adults with genetically confirmed expansion of the Huntingtin (HTT) gene 
cytosine, adenine, and guanine (CAG) trinucleotide repeat at Screening who meet diagnostic criteria 
detailed in the inclusion criteria below (including UHDRS scores and CAG-Age-Product [CAP] scores 
within specific ranges). 
An adult study partner is optional but highly recommended for each participant to support completion 
of study activities and to answer questions about the participant’s condition. For prospective 
participants and study partners (if applicable), the study will begin with the informed consent process. 
Screening, safety, and efficacy assessments will be performed according to the schedule presented in 
Table 2, 
 will be performed according to the schedule presented in Table 3. 
Screening assessments will be performed to determine eligibility. Participants and study partners (if 
applicable) will receive training on the study procedures and devices. 
Eligible participants will be randomized 1:1 to receive either SAGE-718, or placebo for 84 days. 
Beginning on Day 1 and continuing through Day 84, participants will self-administer blinded 
investigational product (IP) once per day in the morning. IP administration will be monitored via a 
medication adherence monitoring platform used on smartphones to visually confirm IP ingestion. At 
clinic visits, participants will take 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 review of the medication adherence 
monitoring platform, examination of the used packaging, and counting any returned tablets. 

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3. Agree to adhere to the study requirements. 
4. Be capable of complying with study procedures, in the opinion of the investigator. 
5. Be at least 25 years old but no older than 65 years of age at Screening.  
6. Meet all the following criteria for HD at Screening (Days -28 to -2): 
a. Genetically confirmed disease with CAG expansion ≥36. 
b. At Screening, UHDRS-TFC score >6 and <13, suggesting no more than a moderate level 
of functional impairment 
c. No features of juvenile HD  
7.  CAP score >70, as calculated using the CAP formula: AGE × (CAG – 30) / 6.49. 
8. Score of 15 to 25 (inclusive) on the MoCA at Screening indicating the presence of cognitive 
impairment.  
9. Be willing to invite a study partner, if available, who is reliable, competent, and at least 
18 years of age to participate in the study. 
10. Be ambulatory (use of assistance devices such as a walker or cane is acceptable, as is 
occasional use of wheelchair, as judged by the investigator. Individuals requiring a wheelchair 
on a regular basis are excluded), able to travel to the study center, and, judged by the 
investigator, is likely to be able to continue to travel to the study center to complete study 
visits for the duration of the study. 
11. Agree, if female, to use at least one method of highly effective contraception (refer to 
Section 9.2.4 for further details on acceptable forms of contraception) during participation in 
the study and for 30 days following the last dose of study drug, unless they are 
postmenopausal (defined as no menses for 12 months without an alternative medical cause and 
confirmed by follicular stimulation hormone [FSH] >40 mIU/mL), permanently sterile 
(hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), or does not engage in 
sexual relations which carry a risk of pregnancy.  
12. Agree, if male, to use an acceptable method of effective contraception for the duration of study 
and for 21 days after receiving the last dose of the IP, unless the participant does not engage in 
sexual relations which carry a risk of pregnancy. Acceptable methods of effective 
contraception are listed in Section 9.2.4. 
13. Agree, if male, to abstain from sperm donation during the Treatment Period and for 21 days 
after receiving the last dose of IP. 
14. Agree to refrain from drugs of abuse for the duration of the study and from alcohol during the 
48 hours preceding each study visit. 
15. Completion of HD-CAB Trail Making-B Test in <240 seconds at Screening (Days -28 to -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 previous exposure to gene 
therapy; have participated in any Huntington’s Disease (HD) investigational drug, biologic, or 
device trial within 180 days, or a non-HD drug, biologic, or device trial within 30 days or 
5 half-lives (whichever is longer).  
(Note: Participants with confirmation of enrollment in the placebo arm of these trials would 
not be excluded.) 
2. Have a diagnosis of an ongoing neurodegenerative condition other than HD, including but not 
limited to Alzheimer’s Disease, vascular dementia, dementia with Lewy bodies, or Parkinson’s 
Disease. 

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3. Have been diagnosed with and/or treated for any type of cancer (excluding successfully treated 
locally excised basal cell carcinoma and melanoma in situ) within the past year prior to 
Screening. 
4. Had gastric bypass surgery, has a gastric sleeve or lap band, or has had any related procedures 
that interfere with gastrointestinal transit. 
5. Plans to undergo elective surgery during participation in the study. 
6. Receive any of the following prohibited medications within 30 days of screening and during 
participation in the study: 
a. Medications with potent effects at the N-methyl-D-aspartate (NMDA) receptor, including 
memantine, amantadine, ketamine, cycloserine, or related compounds. 
b. Medications that inhibit cholesterol absorption (eg, ezetimibe). 
c. Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine). 
d. Other medications given at doses or in combinations that are likely to have a deleterious 
effect on cognitive performance, as determined by the investigator. 
e. Tetrahydrocannabinol (THC)-containing substances (any route of administration). 
7. Have current or recent suicidality, defined as follows: 
a. Suicidal ideation within the past month, as evidenced by a “Yes” on question 4 (active 
suicidal ideation with some intent to act, without specific plan) or question 5 (active 
suicidal ideation with specific plan and intent) on the C-SSRS. 
b. Suicidal behavior within the past year, as evidenced by a "Yes" on any of the 5 C-SSRS 
Suicidal Behavior items (actual attempt, interrupted attempt, aborted attempt, preparatory 
acts or behavior, or suicidal behavior) on the C-SSRS. 
c. Presenting a serious risk of suicide in the opinion of the investigator. 
8. Take any psychotropic medications, including antidepressants and anxiolytics, unless the dose 
and frequency have been stable for at least 30 days prior to the first IP administration and are 
expected to remain stable for the duration of the study. 
9. Have an ongoing medical or psychiatric condition that, in the opinion of the investigator, may 
compromise the participant’s safety or compliance with study requirements. 
10. Have supine vital signs outside of the following ranges at Screening or Baseline (vital sign 
measurements may be repeated once for initial values outside these ranges): 
a. Heart rate <50 or >100 bpm, 
b. Systolic blood pressure <100 or >160 mmHg, 
c. Diastolic blood pressure <60 or >100 mmHg. 
11. Have an alcohol or drug use disorder within the past 2 years, as assessed by the investigator. A 
positive urine drug screen is exclusionary unless deemed by the investigator to reflect a 
prescribed medication. 
12. Have a history of significant hand injury that would preclude either writing or rapid bimanual 
computerized responding. 
13. Have a history of seizures or epilepsy, with the exception of a single episode of febrile seizures 
in childhood. 
14. Have a history, presence, and/or current evidence of serologic positive results for human 
immunodeficiency virus (HIV)-1 or HIV-2, hepatitis B, or hepatitis C. 
15. Have a history of brain surgery, a significant head injury causing loss of consciousness greater 
than 30 minutes, or hospitalization due to a brain injury. 
16. Have a history, presence, and/or current evidence of intracranial abnormality (eg, stroke, 
hemorrhage, space-occupying lesion). 

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17. Have a positive pregnancy test, be pregnant, is lactating, or intend to breastfeed during the 
study. 
18. Be investigative site personnel, sponsor personnel, or an immediate member of their family 
(spouse, parent, child, or sibling whether biological or legally adopted). 
19. Is known to be allergic to any of SAGE-718 excipients, including soy lecithin. 
Investigational Product, Dosage, and Mode of Administration: SAGE-718 or placebo will be 
provided as oral softgel lipid capsule for self-administration once daily in the morning. 
Reference Therapy, Dosage, and Mode of Administration: None. 
Duration of Treatment: 84 days. 
Statistical Methods: 
Detailed methodology for summary and statistical analyses of the data collected in this study will be 
documented in a statistical analysis plan (SAP), which will be finalized and approved prior to database 
lock. 
Database lock will occur in two parts. The first database lock will include all data from all participants 
who have completed Day 84 or the ET visit. The second database lock will include all the data from all 
participants through the follow-up visit (Day 112).  
General Considerations: 
For the purpose of all analyses where applicable, baseline is defined as the last measurement prior to 
the first dose of IP, unless stated otherwise. 
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. 
Continuous data will be summarized in terms of the number of participants, mean, standard deviation 
(SD), minimum value, median,  and maximum value. Categorical data will be summarized using 
frequency counts and percentages. 
Analysis Sets 
The Randomized Set will include all participants who have been randomized. 
The Safety Set will include all participants who were administered IP and will be used to describe the 
safety data.  
The Full Analysis Set (FAS) will include all participants who initiate IP and have baseline and at least 
1 postbaseline efficacy evaluation. 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 

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Efficacy Analysis 
The change from baseline in cognitive assessments will be analyzed using a mixed-effects model for 
repeated measures; the model will include treatment, baseline scores, assessment time point, and time 
point-by-treatment as explanatory variables. All postbaseline time points will be included in the model. 
The primary comparison will be between SAGE-718 and placebo at the Day 84 time point. 
Model-based point estimates (eg, least squares means), 95% confidence intervals, and p-values will be 
reported. An unstructured covariance structure will be used to model the within-participant errors. 
Other continuous efficacy endpoints, including 
, functional outcomes, and 
, will be analyzed using similar methods. Additional analyses will be detailed in the 
SAP. 
Safety Analysis 
Adverse events (AEs) will be coded using Medical Dictionary for Regulatory Activities (MedDRA™) 
Version 22.0 or higher. The proportion of participants experiencing treatment-emergent adverse events 
(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. 
 
 
  
 
 
Sample Size 
The study is designed to detect a difference between placebo and the SAGE-718 group in the change 
from baseline to Day 84 for the primary endpoint, SDMT score. Using a 2-sided test at an alpha level 
of 0.05, a sample size of approximately 71 evaluable participants per treatment group would provide 
90% power to detect a difference of 4 points between SAGE-718 and placebo arms in the change from 
baseline to Day 84 in SDMT values, assuming that the SD of the change from baseline in SDMT is 
7.3 points.  
Assuming a 20% dropout and a 1:1 randomization ratio, approximately 178 randomized participants 
(89 per treatment group) will be required to obtain 71 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 SDMT assessment. Additional participants may be randomized to 
ensure a sufficient number of evaluable participants or if the dropout rate is higher than 20%. 
 

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Table 2: 
Schedule of Assessments 
Assessments  
Screening Period 
Treatment Period 
Follow-Up 
Days -28 
to -2 
Day -1 
Day 1 
Day 14 
(±2 days) 
Day 28 
(±2 days) 
Day 56 
(±2 days) 
Day 84 
(±2 days) 
Day 98 
(±2 days) 
Day 112 
(±2 days) 
 or ET 
Informed consenta 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
Family/Medical history and 
demographicsb 
X 
X 
 
 
 
 
 
 
 
Participant trainingc 
X 
X 
 
 
 
 
 
 
 
Body weight 
X 
 
X 
 
X 
X 
X 
 
X 
Body height 
X 
 
 
 
 
 
 
 
 
Vital signs (including orthostatics)d 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical examinatione 
X 
 
 
 
X 
 
X 
 
X 
CAG testf (if not collected as part of 
medical history) 
X 
 
 
 
 
 
 
 
 
FSH testg 
X 
 
 
 
 
 
 
 
 
Serology testh 
X 
 
 
 
 
 
 
 
 
12-lead ECGi 
X 
 
 
 
X 
 
X 
 
X 
Clinical laboratory assessmentsj 
X 
 
X 
 
X 
 
X 
 
X 
Urine drug test 
X 
 
X 
X 
X 
X 
X 
X 
X 
Alcohol testk 
X 
 
X 
X 
X 
X 
X 
X 
X 
Cigarette/tobacco use assessmentl 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testm 
X 
 
X 
 
X 
 
X 
 
X 

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Assessments  
Screening Period 
Treatment Period 
Follow-Up 
Days -28 
to -2 
Day -1 
Day 1 
Day 14 
(±2 days) 
Day 28 
(±2 days) 
Day 56 
(±2 days) 
Day 84 
(±2 days) 
Day 98 
(±2 days) 
Day 112 
(±2 days) 
 or ET 
Randomization 
 
 
X 
 
 
 
 
 
 
IP self-administrationv 
 
 
X (once daily in the morning) 
 
 
IP dispensationw 
 
 
X 
X 
X 
X 
 
 
 
IP Adherencex 
 
 
X 
 
 
IP Accountability/Returny 
 
 
X 
X 
X 
X 
X 
 
 
AEs/SAEs 
X  
(from time of ICF throughout the duration of participation)  
Prior and concomitant medications 
X 
Abbreviations: AE = adverse event, ASO = anti-sense oligonucleotide; COVID-19 = coronavirus disease 2019; C-SSRS = Columbia–Suicide Severity Rating Scale; 
ECG = electrocardiogram; ET = early termination; FSH = follicle-stimulating hormone; HD = Huntington’s Disease; Hi-DEF = Huntington’s Disease Everyday Functioning Scale; 
HIV = human immunodeficiency virus; ICF = informed consent form; IP = investigational product; 
; 
; 
; SAE = serious adverse event; UHDRS = Unified Huntington’s 
Disease Rating Scale. 
Note: If needed, participant-reported outcomes and study partner-reported outcomes can be completed remotely/at home via the web.  
a. 
Both participants and study partners (if applicable) will be consented during the Screening Period. 
 
 
b. In addition to full medical history, all medications and supplements taken within 8 weeks prior to Screening, all medications used to treat HD (including 
ASO therapies) regardless of timing, and all nonpharmacological methods (eg, psychosocial, psychotherapeutic) used to treat or prevent neuropsychiatric, 
functional, and cognitive manifestations of HD 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/procedure collection at screening and throughout the study. 
Confirmed (genetically tested) or suspected family history of HD will be collected. 
c. 
Participants and study partners (if applicable) will be trained by study staff on the use of software applications and devices necessary for the conduct of the 
study. 
d. Vital signs to 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 per visit if out of range. 
e. 
A full physical examination is to be conducted during Screening and at Day 112. At other visits, physical examinations will include a brief assessment of 
general appearance, cardiovascular, respiratory, gastrointestinal, and neurological systems and followed by a targeted physical assessment as needed. A 
symptom-directed examination may be conducted at any time at the discretion of the investigator. 
f. 
Test results of genetically confirmed disease with CAG expansion ≥36 collected as part of medical history is acceptable in lieu of central laboratory 
confirmation. For any genetic counseling, the study sites should follow the local practice. 

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g. Serum FSH test will be conducted at Screening for the female participants to confirm whether a female participant with ≥12 months of spontaneous 
amenorrhea meets the protocol-defined criteria for being postmenopausal. 
h. To include hepatitis B and C screening tests, HIV-1 and -2 antibody. 
i. 
Single ECG will be measured after the participant has been in the supine position for at least 5 minutes. When ECG measurements coincide with safety 
assessments, vital signs assessment or blood draws, blood draws should be carried out after ECG and vital signs. 
j. 
Clinical laboratory assessments will include blood samples for hematology, clinical chemistry, biochemistry, coagulation, serology, genetic testing, and 
urinalysis. Samples will be collected ≤2 hours prior to dosing on dosing days. On non-dosing days, collection may occur at any time. 
k. A breath test for alcohol will be performed. 
l. 
Data on cigarette use will be collected using the question: “How many packs of cigarettes did you smoke over the past 7 days?” at the time points 
specified. 
m. 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 that are not postmenopausal or permanently sterile. 
 
 
 
 
 
 
 
  
p. Total Functional Capacity 
 scores will be collected at Screening, 
. Independence Scale will be 
conducted at 
 84 
. 
 
 
r. 
Cognitive tests at all time points are to be performed at the same time of day (±2 hours) and postdose on dosing days. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
v. On visit Days 1, 14, 28, 56, and 84, participants will self-administer IP in the clinic under the supervision of study staff. All scheduled safety assessments 
will be conducted prior to dosing and all scheduled cognitive tests will be administered post dosing.  
w. Study staff will dispense enough IP for the participant to take daily at home until the next scheduled visit. 
x. IP administration will be monitored using the 
. Participants will complete the training within the application. Thereafter 
participants should use the application each time they take IP and sites should regularly use the dashboards to follow up on instances of non-adherence 
with IP. IP adherence will not be captured after participants discontinue IP. 
y. Participants will bring all used packaging and unused IP to the clinic at each visit for study staff to review and document.  

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Table 3: 
 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................23 
5. 
INTRODUCTION ......................................................................................................26 
5.1. 
Overall Risk/Benefit Assessment ...............................................................................26 
5.2. 
Dose Justification ........................................................................................................27 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................28 
7. 
INVESTIGATIONAL PLAN .....................................................................................30 
7.1. 
Overall Study Design ..................................................................................................30 
7.1.1. 
Screening Period .........................................................................................................30 
7.1.2. 
Treatment Period ........................................................................................................31 
7.1.3. 
Follow-up Period ........................................................................................................31 
7.1.4. 
End of Study ...............................................................................................................31 
7.2. 
Number of Participants ...............................................................................................33 
7.3. 
Treatment Assignment ................................................................................................33 
7.4. 
Dose Adjustment Criteria ...........................................................................................33 
7.4.1. 
Stopping criteria ..........................................................................................................33 
7.4.2. 
Dose Evaluation Committee .......................................................................................33 
7.4.3. 
Safety Criteria for Adjustment or Stopping Doses .....................................................34 
7.5. 
Criteria for Study Termination ...................................................................................34 
7.6. 
End of Study Definition ..............................................................................................34 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.....................................35 
8.1. 
Participant Inclusion Criteria ......................................................................................35 
8.2. 
Participant Exclusion Criteria .....................................................................................36 
8.3. 
Screen Failures ............................................................................................................37 
8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................38 
8.4.1. 
Investigational Product Discontinuation .....................................................................38 

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8.4.2. 
Early Termination from the Study ..............................................................................38 
8.4.3. 
Loss to Follow-up .......................................................................................................39 
8.4.4. 
Replacement of Participants .......................................................................................39 
9. 
TREATMENT OF PARTICIPANTS .........................................................................40 
9.1. 
Description of Investigational Product .......................................................................40 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................40 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................40 
9.2.2. 
Prohibited Medications ...............................................................................................40 
9.2.3. 
Other Restrictions and Recommendations..................................................................41 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................41 
9.3. 
Intervention After the End of the Study .....................................................................42 
9.4. 
Treatment Adherence ..................................................................................................42 
9.5. 
Randomization and Blinding ......................................................................................42 
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 
10.5.1. 
Medication Adherence and Reminder System ...........................................................45 
10.5.1.1. 
Registration in the 
 ...........................................................................45 
10.5.1.2. 
Ongoing Use and Monitoring of Medication Adherence ...........................................45 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................46 
10.7. 
Product Complaints ....................................................................................................47 
10.8. 
Ancillary Supplies ......................................................................................................47 
11. 
SCREENING, EFFICACY, 
 
ASSESSMENTS.........................................................................................................48 
11.1. 
Screening Assessments ...............................................................................................48 
11.1.1. 
Montreal Cognitive Assessment .................................................................................48 
11.1.2. 
Cigarette and(or) Tobacco Use Assessment ...............................................................48 
11.2. 
Efficacy Assessments .................................................................................................49 

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11.2.1. 
Symbol Digit Modalities Test .....................................................................................49 
11.2.2. 
Unified Huntington’s Disease Rating Scale – Independence Scale ...........................49 
11.2.3. 
 .........49 
11.2.3.1. 
One Touch Stockings of Cambridge ...........................................................................50 
11.2.3.2. 
Trail Making ...............................................................................................................50 
11.2.3.3. 
 .....................................................................50 
11.2.3.4. 
Paced Tapping Test .....................................................................................................51 
11.2.3.5. 
 .........................................................................................51 
11.2.4. 
 
 ................................................................................................................51 
11.2.4.1. 
) ..............................................................................................51 
11.2.4.2. 
 ......................................................................................51 
11.2.4.3. 
 ..................................................................................51 
11.2.4.4. 
 ...............................................................................................51 
11.2.4.5. 
.......................................................................52 
11.2.5. 
 ..............................52 
11.2.6. 
 .................52 
11.2.7. 
Patient-Reported Outcomes ........................................................................................52 
11.2.7.1. 
 ..................................52 
11.2.7.2. 
........................................................................................................52 
11.2.7.3. 
Huntington’s Disease Everyday Functioning Scale ...................................................53 
11.2.7.4. 
 ............................................................................................53 
11.2.7.5. 
..................................................................................53 
11.2.7.6. 
 ..............................................................53 
11.2.7.7. 
 ...................................................................................................54 
11.2.7.8. 
 .....................................................................54 
11.2.7.9. 
 ........................................................................................................54 
11.2.8. 
 ............................................................54 
11.2.8.1. 
 .....................................................54 
11.2.8.2. 
 ........................................................................................................54 
11.2.8.3. 
 .................................................................55 
11.2.9. 
Clinical Global Impression Severity 
 .......................................................55 
11.2.10. 
 ...............................................55 

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11.2.11. 
 ........................................................55 
11.2.12. 
 ..................................................................................56 
11.3. 
 ..........................................................................56 
11.3.1. 
 ....................................................................................56 
11.3.1.1. 
 ............................................................................................56 
11.3.1.2. 
 .........................................................................................................56 
11.3.2. 
 .................................................................................57 
11.3.2.1. 
 .................................................................................57 
11.3.2.2. 
 .......................................................................57 
12. 
SAFETY ASSESSMENTS ........................................................................................58 
12.1. 
Safety Parameters .......................................................................................................58 
12.1.1. 
Demography and Medical History ..............................................................................58 
12.1.2. 
Weight and Height ......................................................................................................58 
12.1.3. 
Physical Examination .................................................................................................58 
12.1.4. 
COVID-19 Questions .................................................................................................58 
12.1.5. 
Vital Signs ..................................................................................................................58 
12.1.6. 
Electrocardiogram .......................................................................................................59 
12.1.7. 
Laboratory Assessments .............................................................................................59 
12.1.7.1. 
Drugs of Abuse, Alcohol ............................................................................................60 
12.1.7.2. 
Pregnancy Testing ......................................................................................................60 
12.1.8. 
 ....................................................................60 
12.1.9. 
 .................................................................................60 
12.2. 
Adverse and Serious Adverse Events .........................................................................60 
12.2.1. 
Adverse Event Definition ...........................................................................................60 
12.2.2. 
Serious Adverse Event Definition ..............................................................................61 
12.2.3. 
Definition of Urgent Safety Measure and Unanticipated Problem .............................62 
12.2.4. 
Relationship to Investigational Product ......................................................................62 
12.2.5. 
Recording Adverse Events .........................................................................................63 
12.2.6. 
Reporting Serious Adverse Events .............................................................................63 
12.2.7. 
Assessment of Liver Biochemistry for Hy’s Law Screening, or Hy’s Law 
Laboratory Criteria .....................................................................................................64 
12.3. 
Pregnancy ...................................................................................................................65 
12.4. 
Special Considerations ................................................................................................65 

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19. 
LIST OF REFERENCES ............................................................................................79 
20. 
APPENDICES ............................................................................................................82 
Appendix 1: Country-Specific Changes ........................................................................................82 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................12 
Table 3: 
 ............................................16 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................23 
Table 5: 
Investigational Product ...............................................................................................44 
Table 6: 
Summary of Clinical Laboratory Analytes .................................................................59 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................32 
 
  

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms  
Abbreviation 
Definition 
AE 
adverse event 
 
 
ASO 
anti-sense oligonucleotide 
ECG 
electrocardiogram 
 
 
BMI 
body mass index  
CAG 
cytosine, adenine, and guanine 
 
 
 
 
 
 
 
 
CAP 
CAG-Age-Product  
CFR 
Code of Federal Regulations 
 
  
CGI-S 
Clinical Global Impression Severity 
COVID-19 
coronavirus disease 2019 
Cmax  
maximum concentration 
CS 
clinically significant 
C-SSRS 
Columbia–Suicide Severity Rating Scale  
eCRF 
electronic case report form 
 
  
DEC 
Dose Evaluation Committee  
ET  
Early Termination  
 
 
 
 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 

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Abbreviation 
Definition 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
GMP 
Good Manufacturing Practice 
 
 
HD 
Huntington’s Disease  
HD-CAB 
Huntington’s Disease Cognitive Assessment Battery  
 
Hi-DEF  
Huntington’s Disease Everyday Functioning  
HIV 
human immunodeficiency virus 
HTT 
Huntingtin gene 
ICF 
informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IP 
investigational product 
IRB 
institutional review board 
IRT 
interactive response technology 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoCA 
Montreal Cognitive Assessment 
NCS 
not clinically significant 
NMDA 
N-methyl-D-aspartate 
 
 
OTS 
One Touch Stockings of Cambridge 
PAM 
positive allosteric modulator 
 
 
 
  
 
PK 
pharmacokinetic 
 
 
PRO 
patient-reported outcome 

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Abbreviation 
Definition 
PTAP 
Paced Tapping Test 
 
 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDMT 
Symbol Digit Modalities Test 
 
 
Study partner 
synonymous with care partner 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TFC 
Total Functional Capacity  
THC 
tetrahydrocannabinol  
UHDRS 
Unified Huntington’s Disease Rating Scale  
UP 
unanticipated problem 
US 
United States 
USM 
urgent safety measure  
VAS 
Visual Analogue Scale  
 
  

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5. 
INTRODUCTION 
Huntington’s disease (HD) is a rare hereditary neurodegenerative disease characterized by 
specific motor symptoms, including chorea and rigidity, and deterioration of psychiatric and 
cognitive function. The motor symptoms can manifest at any age, after which disease 
progression leads to incapacitation and death. Before the appearance of motor symptoms, 
psychiatric and cognitive dysfunction predominate (Tabrizi 2012). Cognitive impairment is 
always present in the course of the disease, even in premanifest gene carriers (Cardoso 2017). 
The mechanisms of cognitive changes in HD have not been fully described, but changes in 
glutamatergic neurotransmission appear to be involved. Reduced glutamate in the posterior 
cingulate cortex has been correlated with cognitive dysfunction in early manifest HD 
(Unschuld 2012). N-methyl-D-aspartate (NMDA) receptors are a subtype of glutamate receptor 
with a fundamental and well documented role in regulating synaptic strength, health, and 
plasticity (Vyklicky 2014, Yao 2017). NMDA receptors have been found to be dysfunctional in 
the postmortem brains of HD patients (Albin 1990). Together, these data suggest that lowered 
NMDA receptor tone may contribute to cognitive dysfunction in HD (Paul 2013). 
Preclinical data illustrate that HD patients have reduced plasma levels of a specific oxysterol, 
24(S)-hydroxycholesterol (Leoni 2013). This molecule acts as an endogenous positive allosteric 
modulator (PAM) of the NMDA receptor (Paul 2013) and has been correlated with performance 
on several cognitive tasks in HD (Lewis 2019). SAGE-718 is a novel oxysterol-based PAM of 
NMDA receptors with the potential to restore NMDA receptor tone to ameliorate cognitive 
deficits in HD. SAGE-718 only affects receptor function in the presence of endogenous 
glutamate, thus it does not directly activate the receptor and is not expected to cause NMDA 
receptor-associated excitotoxicity. 
Sage believes that pre-clinical findings, combined with our early-stage clinical data in patients 
with HD, support the hypothesis that SAGE-718 may work to restore aberrant NMDA receptor 
activity in patients with early HD and thereby help to ameliorate cognitive deficits seen in these 
patients. 
5.1. 
Overall Risk/Benefit Assessment 
Currently, there are no therapies approved to treat the cognitive or psychiatric changes associated 
with HD.  
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, drug-drug interaction, and toxicology findings, including compound-related 
effects and the reversibility of these changes. 
In a radiolabeled rat absorption, distribution, metabolism and excretion study, there 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 

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was used to derive the 45 ng/mL clinical exposure cap (see Section 5.2). Across rat and dog 
nonclinical studies a Cmax threshold for observation of convulsions occurred at exposures 20 to 
40 times greater than clinically relevant exposures.  
No deaths, serious adverse events (SAEs) or treatment emergent adverse events (TEAEs) leading 
to discontinuation were reported in the completed studies with SAGE-718. A maximum tolerated 
dose has not been identified yet and no characteristic safety signals have been identified to date. 
No clinically relevant mean changes from baseline were observed in electrocardiograms (ECGs) 
or electroencephalograms (EEGs). In addition, there were no treatment-emergent adverse events 
reported in patients with Huntington’s disease that were enrolled in the completed SAGE-718 
open label study (718-CLP-102). 
Based on the completed studies, the benefit-risk profile of SAGE-718 supports further 
development in an HD patient population. 
The effect of SAGE-718 on cognitive function in participants with Huntington’s disease will be 
evaluated in this randomized, placebo-controlled, double-blind study. Additional data on the 
effects of SAGE-718 in participants with HD will be collected throughout, 
 
.  
5.2. 
Dose Justification 
SAGE-718 has been well tolerated in both healthy participants and a small cohort of participants 
with HD in previous clinical studies. However, based on nonclinical findings, the United States 
Food and Drug Administration (FDA) imposed a median maximum concentration (Cmax) cap of 
45 ng/mL. To date, clinical studies with SAGE-718 have used doses that resulted in exposures 
within this cap and no related adverse events (AEs) leading to discontinuation have been 
reported. For additional information on exposure caps, see the SAGE-718 Investigator’s 
Brochure. 
From a previous study of SAGE-718 administered as an oral solution in healthy participants, 
repeat doses of 1 mg and a single dose of 3 mg demonstrated evidence consistent with NMDA 
target engagement. From a 14-day study of SAGE-718 administered as an oral solution in 
participants with HD, repeat doses of 1 mg showed beneficial effects on cognition assessments. 
Similarly, from a 14-day study of SAGE-718 administered as a solid tablet in participants with 
Parkinson’s Disease, repeat doses of 3 mg when taken with a meal containing approximately 
30 g of dietary fat showed beneficial effects on cognition assessments. The PK exposures in the 
above scenarios were similar, with individual Cmax values ranging from 19.7 to 29.7 ng/mL. 
In the present study, SAGE-718 will be administered as a lipid based softgel formulation at a 
daily dose of 1.2 mg. The lipid formulation has improved bioavailability characteristics 
compared to solution and tablet forms. The dose is selected to provide pharmacokinetic (PK) 
exposures similar to those achieved in prior studies that have shown evidence consistent with 
NMDA target engagement and beneficial effects on assessments of cognition. 
 
 
 

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• To evaluate additional safety and 
tolerability parameters of SAGE-718 in 
participants with HD 
• CFB in vital signs, clinical laboratory 
analyses, electrocardiograms (ECGs), and 
suicidal ideation 
 
 
 
• 
 
 
a Applicable only to the subgroup of participants who can complete Trail Making Part B within the allowable time 
limit at baseline. 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, placebo-controlled, double-blind study to evaluate the cognitive effects, 
safety, tolerability, 
 of SAGE-718 in participants with premanifest or early manifest 
HD. Participants will be adults with genetically confirmed expansion of the Huntingtin (HTT) 
gene cytosine, adenine, and guanine (CAG) trinucleotide repeat at screening who meet diagnostic 
criteria detailed in the inclusion criteria below (including UHDRS scores and CAG-Age-Product 
[CAP] scores within specific ranges). 
An adult study partner is optional but highly recommended for each participant to support 
completion of study activities and to answer questions about the participant’s condition. For 
prospective participants and study partners (if applicable), the study will begin with the informed 
consent process. 
Screening, safety, and efficacy will be performed according to the schedule presented in Table 2, 
 will be performed according to the schedule presented in and Table 3. 
Screening assessments will be performed to determine eligibility. Participants and study partners 
(if applicable) will receive training on the study procedures and devices. 
Eligible participants will be randomized 1:1 to receive either SAGE-718 (1.2 mg at Day 1 visit 
through the day prior to Day 28 visit and 0.9 mg from Day 28 visit until End of 
Treatment [EOT]) or placebo for 84 days. Beginning on Day 1 and continuing through Day 84, 
participants will self-administer blinded investigational product (IP) once per day in the morning. 
IP administration will be monitored via a medication adherence monitoring platform used on 
smartphones to visually confirm IP ingestion. At clinic visits, participants will take 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 review of the medication adherence monitoring platform, 
examination of the used packaging, and counting any returned tablets.  
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. At the discretion of the investigator, participants who 
cannot tolerate the 0.9 mg dose will be discontinued from IP. Participants who discontinue IP 
early should complete the remaining study visits as scheduled unless the participant withdraws 
consent or loses the capacity to grant consent. If a participant withdraws from the study/stops 
study participation early, an early termination (ET) visit should be conducted. Treatment with 
SAGE-718 can be ended without down titration.  
7.1.1. 
Screening Period 
The Screening Period begins with the informed consent process for prospective participants, 
including study partners. Subsequent screening assessments will be performed between Day -28 
and Day -1 to determine eligibility, including assessments of cognitive function and safety data.  

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7.1.2. 
Treatment Period 
Eligible participants will be randomized 1:1 to receive either SAGE-718, or placebo for 84 days. 
Beginning on Day 1 and continuing through the 12-week treatment period, participants will 
self-administer SAGE-718 or placebo once per day in the morning. Participants who utilize the 
±2-day window at Day 84 should continue to self-administer IP within the visit window. IP 
administration will be monitored using the 
. 
At clinic visits, participants will take the IP under staff supervision, followed by assessments of 
cognitive function, 
 as 
outlined in Table 2 and Figure 1. 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 review of the medication adherence monitoring platform, examination of the 
used packaging, and counting any returned tablets. 
 
 
 
7.1.3. 
Follow-up Period 
Follow-up period starts after Day 84 and continuing through Day 112. After completing the 
Treatment Period, participants will return to the clinic for follow-up visits on Days 98 and 112 
(or ET) to collect continued safety and efficacy data. 
7.1.4. 
End of Study 
End of study will be achieved when last study participant completes Follow-Up Visit at Day 112 
(or ET) or as defined by local country specific requirements, see Section 20 (Appendix 1). 
 

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7.2. 
Number of Participants 
Approximately 178 participants will be randomized in the study to obtain 142 evaluable 
participants. Additional participants may be randomized and dosed to ensure a sufficient number 
of evaluable participants or if the early discontinuation rate is higher than expected. 
7.3. 
Treatment Assignment 
Eligible participants will be randomized 1:1 to receive either SAGE-718, or placebo for 84 days. 
Additional details on randomization and blinding are provided in Section 9.5. 
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 will be 
discontinued from IP (refer to Section 8.4 for procedures for early IP discontinuation). 
Participants are encouraged to continue to come in for assessments following IP discontinuation.  
7.4.1. 
Stopping criteria 
If clinical events suspicious for seizure occur after Screening, study drug should be discontinued 
immediately with appropriate clinical follow-up, including EEG, repeat serum chemistry, 
urinalysis, and drug/alcohol tests.  
7.4.2. 
Dose Evaluation Committee 
A Dose Evaluation Committee (DEC) will be convened as needed 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  

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7.4.3. 
Safety Criteria for Adjustment or Stopping Doses 
Dose Modification in Potential Hy’s Law Cases 
Dosing with IP for study participants meeting potential Hy’s Law criteria (described in 
Section 12.2.7) should be interrupted until drug-induced living injury (DILI) is ruled out. 
Participants should be treated accordingly if hepatic laboratory elevations are due to other causes 
(eg, viral hepatitis, alcohol ingestion, congestive heart failure). If DILI is not ruled out, IP should 
be permanently discontinued; if DILI is ruled out and upon liver biochemistry returning to 
normal or baseline levels, dosing with IP may resume, if clinically appropriate and with 
agreement from the sponsor. 
7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings, suggesting unacceptable risk to 
participants, or for administrative reasons. In the event of study termination, Sage Therapeutics 
will provide written notification to the investigator. Investigational sites must promptly notify 
their institutional review board (IRB)/independent ethics committee (IEC), where required, and 
initiate withdrawal procedures for participating participants.  
7.6. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. A 
participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit. See Section 20 (Appendix 1) for country-specific requirements. 
 

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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Participant Inclusion Criteria 
Participants must meet all of the following criteria to qualify for participation in this study: 
1. Be capable of providing informed consent, in the opinion of the investigator. 
2. Have signed an informed consent form (ICF) prior to any study-specific procedures being 
performed. 
3. Agree to adhere to the study requirements. 
4. Be capable of complying with study procedures, in the opinion of the investigator.  
5. Be at least 25 years old but no older than 65 years of, at the time informed consent is 
obtained.  
6. Meet all the following criteria for HD at Screening (Days -28 to -2): 
a. Genetically confirmed disease with CAG expansion ≥36. 
b. At Screening, UHDRS-TFC score >6 and <13, suggesting no more than a moderate 
level of functional impairment. 
c. No features of juvenile HD.  
7. CAP score >70, as calculated using the CAP formula: AGE × (CAG – 30) / 6.49. 
8. Score of 15 to 25 (inclusive) on the Montreal Cognitive Assessment (MoCA) at 
Screening. 
9. Be willing to invite a study partner, if available, who is reliable, competent, and at least 
18 years of age to participate in the study. 
10. Be ambulatory (use of assistance devices such as a walker or cane is acceptable, as is 
occasional use of wheelchair, as judged by the investigator. Individuals requiring a 
wheelchair on a regular basis are excluded), able to travel to the study center, and, judged 
by the investigator, is likely to be able to continue to travel to the study center to 
complete study visits for the duration of the study. 
11. Agree, if female, to use at least one method of highly effective contraception (refer to 
Section 9.2.4 for further details on acceptable forms of contraception) during 
participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative 
medical cause and confirmed by follicular stimulation hormone [FSH] >40 mIU/mL), 
permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), 
or does not engage in sexual relations which carry a risk of pregnancy.  
12. Agree, if male, to use an acceptable method of effective contraception for the duration of 
study and for 21 days after receiving the last dose of the IP, unless the participant does 
not engage in sexual relations which carry a risk of pregnancy. Acceptable methos of 
effective contraception are listed in Section 9.2.4.  
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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14. Agree to refrain from drugs of abuse for the duration of the study and from alcohol 
during the 48 hours preceding each study visit. 
15. Completion of HD-CAB Trail Making-B Test in <240 seconds at Screening (Days -28 
to -2).  
8.2. 
Participant 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 previous exposure to 
gene therapy; have participated in any HD investigational drug, biologic, or device trial 
within 180 days, or a non-HD drug, biologic, or device trial within 30 days or 5 half-lives 
(whichever is longer).  
(Note: Participants with confirmation of enrollment in the placebo arm of these trials 
would not be excluded.) 
2. Have a diagnosis of an ongoing neurodegenerative condition other than HD, including 
but not limited to Alzheimer’s Disease, vascular dementia, dementia with Lewy bodies, 
or Parkinson’s Disease.  
3. Have been diagnosed with and/or treated for any type of cancer (excluding successfully 
treated locally excised basal cell carcinoma and melanoma in situ) within the past year 
prior to screening. 
4. Had gastric bypass surgery, has a gastric sleeve or lap band, or has had any related 
procedures that interfere with gastrointestinal transit. 
5. Plans to undergo elective surgery during participation in the study. 
6. Receive any of the following prohibited medications within 30 days of screening and 
during participation in the study: 
a. Medications with potent effects at the NMDA receptor, including memantine, 
amantadine, ketamine, cycloserine, or related compounds. 
b. Medications that inhibit cholesterol absorption (eg, ezetimibe). 
c. Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine). 
d. Other medications given at doses or in combinations that are likely to have a 
deleterious effect on cognitive performance, as determined by the investigator. 
e. Tetrahydrocannabinol (THC)-containing substances (any route of administration), 
regardless of whether or not they are prescribed.  
7. Have current or recent suicidality, defined as follows: 
a. Suicidal ideation within the past month, as evidenced by a “Yes” on question 4 
(active suicidal ideation with some intent to act, without specific plan) or question 5 
(active suicidal ideation with specific plan and intent) on the C-SSRS. 
b. Suicidal behavior within the past year, as evidenced by a “Yes” on any of the 
5 C-SSRS Suicidal Behavior items (actual attempt, interrupted attempt, aborted 
attempt, preparatory acts, or behavior, or suicidal behavior) on the C-SSRS. 
c. Presenting a serious risk of suicide in the opinion of the investigator. 

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8. Take any psychotropic medications, including antidepressants and anxiolytics, unless the 
dose and frequency have been stable for at least 30 days prior to the first IP 
administration and are expected to remain stable for the duration of the study. 
9. Have an ongoing medical or psychiatric condition that, in the opinion of the investigator, 
may compromise the participant’s safety or compliance with study requirements. 
10. Have supine vital signs outside of the following ranges at Screening or Baseline (vital 
sign measurements may be repeated once for initial values outside these ranges): 
a. Heart rate <50 or >100 bpm, 
b. Systolic blood pressure <100 or >160 mmHg, 
c. Diastolic blood pressure <60 or >100 mmHg. 
11. Have an alcohol or drug use disorder within the past 2 years, as assessed by the 
investigator. A positive urine drug screen is exclusionary unless deemed by the 
investigator to reflect a prescribed medication. 
12. Have a history of significant hand injury that would preclude either writing or rapid 
bimanual computerized responding. 
13. Have a history of seizures or epilepsy, with the exception of a single episode of febrile 
seizures in childhood. 
14. Have a history, presence, and/or current evidence of serologic positive results for human 
immunodeficiency virus (HIV)-1 or HIV-2, hepatitis B, or hepatitis C. 
15. Have a history of brain surgery, a significant head injury causing loss of consciousness 
greater than 30 minutes, or hospitalization due to a brain injury. 
16. Have a history, presence, and/or current evidence of intracranial abnormality (eg, stroke, 
hemorrhage, space-occupying lesion). 
17. Have a positive pregnancy test, be pregnant, is lactating, or intend to breastfeed during 
the study. 
18. Be investigative site personnel, sponsor personnel, or an immediate member of their 
family (spouse, parent, child, or sibling whether biological or legally adopted). 
19. Is known to be allergic to any of SAGE-718 excipients, including soy lecithin. 
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/entered in the study. A minimal set of screen 
failure information will be collected, including demography, screen failure details, eligibility 
criteria, and any AE or SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, with the approval of the medical monitor. Rescreened participants will be 
assigned a new participant number. 

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8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, administrative reasons. When a participant is discontinued from IP, the 
participant should continue, if willing, to participate in the remainder of the study by attending 
all scheduled visits per the SOA. 
The reason for IP discontinuation and/or the reason for early termination from the study must be 
documented in the participant’s study record and recorded in the participant’s electronic case 
report form (eCRF).  
The investigator must notify the sponsor and/or the medical monitor when a participant stops 
participation in the study for any reason.  
8.4.1. 
Investigational Product Discontinuation 
Participants who discontinue IP will be invited by the investigator to complete all of the 
scheduled study visits and assessments through the end of the Treatment Period. Those who 
decline to continue participation will be asked to complete an ET Visit. 
8.4.2. 
Early Termination from the Study 
At the time of study withdrawal/stopping study participation, if possible, an ET 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. 
Possible reasons for study discontinuation include but are not limited to the following:  
• AE 
• Pregnancy 
• Protocol deviation 
• Non-compliance with study drug 
• Lost to follow-up 
• Withdrawal by subject 
• Screen failure 
• Study terminated by sponsor 
• Physician decision 
• Other 

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8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been 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 randomized and dosed to ensure a sufficient number of evaluable 
participants or if the early discontinuation rate is higher than expected. 

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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Product 
SAGE-718 oral softgel lipid capsules are opaque, white to off-white, oval capsules containing 
either 0.3, 0.6, 0.9, or 1.2 mg of SAGE-718 drug substance. 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
All medications and supplements taken within 8 weeks prior to Screening, all medications used 
to treat HD (including anti-sense oligonucleotide [ASO] therapies) regardless of timing, and all 
nonpharmacological methods (eg, psychosocial, psychotherapeutic) used to treat or prevent 
neuropsychiatric, functional, and cognitive manifestations of HD are to be recorded.  
Information regarding diagnosis, isolation, and/or hospitalization due to coronavirus 
disease 2019 (COVID-19) will be documented as part of medical history, AE collection, and 
prior/concomitant medication/procedure 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 on 
the. 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 to determine participant eligibility and throughout the study. 
9.2.2. 
Prohibited Medications 
Prohibited medications prior to and during the study include: 
• Gene therapy 
• HD investigational drug, biologic, or device within 180 days prior to Screening and 
until the final visit  
• Non-HD investigational drug, biologic, or device within 30 days or 5 half-lives 
(whichever is longer) prior to Screening and until the final visit 
Use of the following medications is prohibited within 30 days of screening and during the entire 
course of the study: 
• Medications that inhibit cholesterol absorption (eg, ezetimibe). 
• Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine). 
• Medications with potent effects at the NMDA receptor, including memantine, 
amantadine, cycloserine, ketamine, or related compounds. 

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• THC-containing substances (any route of administration), regardless of whether or 
not they are prescribed  
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. 
9.2.3. 
Other Restrictions and Recommendations 
Participants must agree to refrain from drugs of abuse for the duration of the study (unless 
deemed by the investigator to reflect a prescribed medication) and from alcohol during the 48 
hours preceding each study visit. 
Psychotropic medications and medications that are known to affect cognitive performance (eg, 
antidepressants, anxiolytics, stimulants, benzodiazepines, antipsychotics, anticholinergics) must 
be at a stable dose for at least 30 days prior to the first IP administration. Additions and/or 
modifications to these medications should be minimized throughout the course of the study. 
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 are to be avoided as 
much as possible.  
Any additions or modifications to medications during the course of the study will be recorded in 
the concomitant medications log and source documentation.  
9.2.4. 
Acceptable Forms of Contraception 
As per the Clinical Trials Facilitation and Coordination Group (CTFG), a female is considered of 
childbearing potential (FOCBP) 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 follicle-stimulating hormone (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; 

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• 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: 
vasectomized partner 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; 
• 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 on Day 1 and continuing through Day 84, participants will self-administer blinded IP 
once per day in the morning. IP administration will be monitored via a medication adherence 
monitoring platform used on smartphones to visually confirm IP ingestion. At clinic visits, 
participants will take 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 review of the 
medication adherence monitoring platform, examination of the used packaging, and counting any 
returned tablets. This information will be documented in the source files and eCRF, along with 
any deviations from the prescribed dosage regimen. Details about IP accountability are included 
in Section 10.6. 
9.5. 
Randomization and Blinding 
This is a randomized, placebo-controlled, double-blind study. Eligible participants will be 
randomized 1:1 to receive either SAGE-718, or placebo for 84 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 in a secure place, accessible only to authorized personnel until the time of study 
unblinding. The blinding of the study will be broken after the database has been locked. 

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Database lock will occur in 2 parts (see Section 13). A selected team of Sponsor personnel will 
be unblinded after Part 1 of database lock to conduct Part 1 data analyses, but site personnel, 
participants, and other Sponsor personnel will remain blinded until after Part 2 of database lock.  
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.  
In all cases where the study personnel are unblinded, pertinent information (including the reason 
for unblinding) must be documented in the participant’s source documentation and on the eCRF. 
At the time of withdrawal from the study/stopping participation, if possible, an ET visit should 
be conducted. 

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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, 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 5: 
Investigational Product 
Product Name: 
SAGE-718 
0.3 mga 
SAGE-718 
0.6 mg  
SAGE-718 
0.9 mg  
SAGE-718 
1.2 mg  
Placebo  
 
Dosage Form: 
Softgel lipid capsule 
Unit Dose 
0.3 mg 
0.6 mg 
0.9 mg 
1.2 mg 
Placebo 
 0.3, 0.6, 0.9 
and 1.2 mg 
Route of 
Administration 
Oral 
Physical 
Description 
Opaque, white to off-white, oval, softgel lipid capsule 
Manufacturer 
 
 
a US only 
10.2. 
Investigational Product Packaging and Labeling 
SAGE-718 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 oral softgel lipid capsule will be maintained 
according to current Good Manufacturing Practice (GMP). Labels with all required information 
and conforming to all applicable Code of Federal Regulations and GMP/Good Clinical Practice 
(GCP) guidelines and all other applicable regulations will be prepared by Sage Therapeutics. The 
site pharmacist or designee will prepare labels for individual doses. 
10.3. 
Investigational Product Storage 
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 Pharmacy Manual.  
The IP must be carefully stored at the temperature specified in the investigator’s brochure and 
Pharmacy Manual. 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 

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destroyed locally per the site’s procedure(s) in accordance with the study-specific Pharmacy 
Manual.  
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 1.2 mg or placebo will be provided as oral softgel lipid capsule for 
self-administration once daily in the morning through the day prior to the Day 28 visit.  
Beginning at the Day 28 visit, SAGE-718 0.9 mg or placebo will be provided as an oral softgel 
lipid capsule for self-administration once daily in the morning for the remainder of the Treatment 
Period. 
10.5. 
Investigational Product Administration 
Each 0.9 mg or 1.2-mg dose of IP will be self-administered once daily in the morning.  
Participants are to swallow the 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. 
SAGE-718 or placebo will be self-administered by participants once daily in the morning. Sites 
will dispense a 2-week or 4-week supply of IP to the participants to take at home with 
instructions for use (see Table 2).  
This study will use a medication adherence monitoring platform for all participants in the study. 
The platform is provided on the 
. Built-in reminders and a 
communication system allow real-time intervention in case of missed doses. Use of the platform 
is required for all participants in the study to reinforce the proper dosing schedule and improve 
data integrity (Section 10.5.1). 
In addition, the participant will be instructed to bring their dosing kit to the site as outlined in 
Table 2. All participants should be reinstructed about the dosing requirement during study 
contacts. The authorized study personnel conducting the re-education must document the process 
in the participant source records.  
10.5.1. 
Medication Adherence and Reminder System 
10.5.1.1. Registration in the 
 
The platform may be downloaded as an app on the participant’s personal smartphone. If a 
participant does not own a smartphone or prefers not to use his/ her personal smartphone, one of 
the backup provisioned devices should be provided.  
• Participants will be registered in the platform. 
• Participant training is automated within the application.  
10.5.1.2. Ongoing Use and Monitoring of Medication Adherence  
Participants should use the application to record each intake of study medication throughout the 
study, both at home between visits and during the visits when study drug is taken at the site.  

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Site personnel should regularly check the dashboard to ensure consistent medication adherence 
throughout the study. In cases of missed doses or pending data, site personnel should follow up 
with the participant as soon as possible to assess the reason for nonadherence and reinforce the 
importance of complying with the study drug dosing schedule. If the participant reports that a 
dose was taken but not logged in the app, site personnel should reclassify this dose to “site 
reported” using the dashboard.  
Participants who are consistently noncompliant with study medication should be discussed with 
the Medical Monitor. 
10.6. 
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 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 IRT during screening 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 obtain the dosing kit 
number for the IP to be dispensed to that participant. The medication ID number and the number 
of capsules dispensed must be recorded. 
At the subsequent IP-dispensing visit, 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 capsules 
dispensed, and the number of 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 or after completion of the study to perform drug accountability reconciliation.  
The investigator, pharmacist, or qualified designee is responsible for drug accountability, 
reconciliation, and record maintenance (eg, receipt, reconciliation, and final disposition records). 
At the end of the study, any unused IP will be returned to Sage Therapeutics for destruction or 
destroyed locally per the site’s procedures in accordance with study-specific Pharmacy Manual; 
disposition of IP will be documented. 
More detailed information can be found in the SAGE-718 Investigator’s Brochure and in the 
Pharmacy Manual. 

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10.7. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution.  
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the emergency 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). 
10.8. 
Ancillary Supplies 
Not applicable. 

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11. 
SCREENING, EFFICACY, 
 
ASSESSMENTS 
A variety of measures will be employed in this study to evaluate cognitive function, 
. All assessments are to be 
completed according to the SOA (Table 2) 
 
 (Table 3).  
The eligible participants in this study will be in the earliest stages of HD and are expected to be 
able to independently care for themselves. However, some of these assessments include 
information provided by caregivers. For the purposes of this study, the word “caregiver” refers to 
the participant’s study partner. 
11.1. 
Screening Assessments  
11.1.1. 
Montreal Cognitive Assessment  
The MoCA is a measure designed as a cognitive screening instrument that is widely used in 
clinical settings. This 1 page, 30-point questionnaire assesses several different cognitive 
domains, including attention and concentration, executive functions, memory, language, 
visuospatial skills, conceptual thinking, calculations, and orientation. 
The MoCA Memory Total Score includes all cognitive domains measured and represented global 
cognitive function. This assessment is expected to take approximately 10 minutes to complete. 
The test is scored from zero to 30, with scores 26 or higher indicating normal cognition 
(Nasreddine 2005). 
A subset of MoCA will be audio recorded and reviewed with the goal of minimizing the 
variability in assessment data. Personal participant identifiers should not be included in the 
recordings.  
The recorded study interviews will be encrypted and stored on the study devices with 
password-protected access for authorized users only. Recordings will be removed from the study 
devices once they are transferred via secure portal to the study server, where they will remain 
until study completion when Sage Therapeutics provides destruction authorization or other 
instructions. 
Note: In addition to Screening this assessment is also performed 
 
, as outlined in Table 2. 
Refer to Table 2 and Table 3 for a listing of screening assessments. 
11.1.2. 
Cigarette and(or) Tobacco Use Assessment 
Data on cigarette use will be collected using the question: “How many packs of cigarettes did 
you smoke over the past 7 days?”. 
Note: In addition to Screening, this assessment is also performed at Days 1, 14, 28, 56, 84, 98 
and Day 112 (or ET), as outlined in Table 2. 

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11.2. 
Efficacy Assessments 
The assessments described below provide broad neurocognitive evaluation across the domains of 
executive function, 
. 
During the Baseline Period, participants will be trained by study staff on the use of all software 
applications and devices necessary for the conduct of the study. 
These assessments are to be administered after the daily dose of SAGE-718 during the Treatment 
Period, and at approximately the same time of day (±2 hours) throughout the study. 
11.2.1. 
Symbol Digit Modalities Test 
The SDMT is a widely utilized tool for tracking cognitive function over time and for the early 
detection of cognitive impairment. This paper-and-pencil test assesses sustained attention, 
processing speed, visual scanning, and psychomotor speed (Smith 1991). The test requires 
participants to use a reference key to match numbers with geometric figures, with the total score 
reflecting the number of correct pairings (out of 110 possible) completed within 90 seconds. 
The SDMT is considered one of the most sensitive and broadly accepted measures of cognitive 
performance in multiple sclerosis (Strober 2019) and has been used in numerous therapeutic 
trials (Mohammadian Nejad 2023; Rezaeimanesh 2024; Morrow 2013; De Giglio 2019). It has 
also been used in Parkinson’s disease research as a sensitive measure of progression of the 
disease, particularly at early stages (Cao 2024; Han 2021; Bayram 2019). In HD, the SDMT has 
been designated as a Stage 2 cognitive landmark in the HD Integrated Staging System (HD-ISS) 
(Tabrizi 2022). This was due to its prevalence in clinical research, robust psychometric 
properties (such as consistency, test-retest reliability, sensitivity, and validity), and minimal 
susceptibility to practice effects (Stout 2014a; Braisch 2019). The National Institute of 
Neurological Disorders and Stroke (NINDS) - Common Data Elements project deemed the 
SDMT to be supplemental - highly recommended for cognitive assessments in HD studies 
(NINDS 2024). 
The SDMT has been employed in several registries, including PREDICT-HD, TRACK-HD, and 
ENROLL-HD, where it has proven sensitive to disease progression across various TFC stages 
(Siesling 1998; Dorsey 2013; Tabrizi 2013; Hamilton 2023). In a study analyzing datasets from 
IMAGE, TRACK, and PREDICT, the SDMT was identified as the most effective marker for 
describing longitudinal changes across CAG-Age Product (CAP) groups (Abeyasinghe 2021). 
11.2.2. 
Unified Huntington’s Disease Rating Scale – Independence Scale 
The UHDRS was developed as a multi-domain clinical rating scale for assessment of functional 
capacity in HD.  
Part V of the UHDRS is the Independence Scale, which is intended to assess the ability of the 
participant to function independently in activities of daily living across the full spectrum of the 
disease. A single independence rating is provided on a scale ranging from 10 to 100, with higher 
scores reflecting better functioning. 
11.2.3. 
 
 

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11.2.3.1. One Touch Stockings of Cambridge  
The OTS is a computerized test of executive function. For this task, participants must imagine 
stacking a set of colored balls to match an example by moving 1 ball at a time into 1 of 2 
possible locations. The goal is to imagine the fewest number of moves needed to perform the 
task. The participant selects that number from the response options on the screen. The primary 
measure for analysis is time to correct response 
11.2.3.2. Trail Making  
The Trail Making test is a speeded graphomotor test of visual attention and task switching, 
 
 Part B includes an additional set-switching 
component, requiring the examinee to connect a series of alternating numbers and letters in order 
from lowest to highest, as in 1-A-2-B-3-C..., in the shortest time possible. The primary measure 
for analysis is time to completion.  
Standard administration of Part B uses a 300 second time limit, at which point the test is stopped 
and scored using the maximum allowable time if not yet completed. The developers of the 
HD-CAB have adopted a briefer limit of 240 seconds to reduce overall duration of testing, 
fatigue, and frustration (Stout 2014b). However, a floor effect is an acknowledged concern that 
reduces Part B’s ability to distinguish impairment levels among individuals unable to complete 
within the standard time limit (Smith Watts 2019; Abreu 2021). This shorter time limit used by 
the HD-CAB may further compromise the test’s sensitivity to measure drug effects when scored 
using the maximum allowable time. For this reason, inclusion criterion #15 was added to the 
study protocol (in effect since Amendment 4, Version 5). Accordingly, scores of 240 at baseline 
are considered unevaluable for purposes of this study and the key secondary endpoint will be 
tested within a subgroup of participants who were able to complete the test within the allowable 
time. 
11.2.3.3. 
  
 
 
 
 
 
 

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11.2.3.4. Paced Tapping Test 
In the PTAP, examinees are presented with auditory pacing tones and instructed to harmonize 
their fingertaps with the pacing tones. A self-paced phase follows, in which the auditory pacing 
cue is removed, and ends with another auditory cue demarking the end of the test. The primary 
measure of analysis is paced tapping consistency, calculated as 1/standard deviation (SD) of the 
intertap interval (1/msec). 
11.2.3.5. 
 
 
 
 
 
  
11.2.4. 
 
11.2.4.1. 
 
 
 
 
 
 
11.2.4.2. 
 
 
 
 
 
11.2.4.3. 
 
 
 
 
 
 
 
11.2.4.4. 
 
 
 
 
 

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11.2.4.5. 
 
 
 
 
 
 
11.2.5. 
  
 
 
 
 
 
 
 
 
11.2.6. 
 
 
 
 
 
 
  
11.2.7. 
Patient-Reported Outcomes 
11.2.7.1. 
 
 
 
 
 
 
 
11.2.7.2. 
 
 
 
 
 
 
 
 
 

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11.2.7.3. Huntington’s Disease Everyday Functioning Scale 
The Hi-DEF Scale is a self-reported measure to capture difficulties experienced in daily life due 
to HD across four different areas of functioning, including (1) At home, (2) At work, (3) Driving, 
and (4) Relationships. The 47-item questionnaire asks patients to rate their functioning difficulty 
using a 5-point Likert scale from 1 (No Difficulty) to 5 (Cannot do this anymore) on the first 
three domains, and a 4-point scale from 1 (Never) to 4 (Always) for Relationships. The measure 
was developed from qualitative interviews with HD patients and study partners who were still 
functionally independent and often working but reported cognitive changes that impacted their 
daily life tasks. The Hi-DEF Scale is currently undergoing psychometric validation, and the 
scoring will be available following that outcome.  
11.2.7.4. 
 
 
 
 
 
 
 
11.2.7.5. 
 
 
 
 
 
 
 
 
11.2.7.6. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

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11.2.7.7. 
 
 
 
 
 
 
11.2.7.8. 
 
 
 
 
 
). 
11.2.7.9.  
 
 
 
 
 
 
 
 
11.2.8. 
 
11.2.8.1. 
 
 
 
 
 
 
 
 
 
 
11.2.8.2. 
 
 
 

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11.2.8.3. 
 
 
 
 
 
 
 
 
 
  
 
 
 
11.2.9. 
Clinical Global Impression Severity 
 
The Clinical Global Impressions Severity 
 (CGI-S 
) scales 
are validated instruments developed by the National Institute of Mental Health specifically for 
use in clinical studies. For global impression severity scales, clinicians, participants, and study 
partners separately rate the severity of the participant’s condition over the past 7 days (including 
the day of the clinic visit) (Guy 1976, Busner 2007). For this study, 
 
, cognitive status, 
.  
 
 
11.2.10. 
 
 
 
 
 
 
 
 
 
11.2.11. 
 
 
 
 
 
 
 
  

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11.2.12. 
 
 
  
 
 
 
 
 
 
 
 
 
 
11.3. 
 
11.3.1. 
 
 
 
 
 
 
 
 
 
11.3.1.1. 
 
 
 
 
 
 
 
 
 
 
11.3.1.2. 
 
 
 
 

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11.3.2. 
 
 
 
 
 
 
 
11.3.2.1. 
 
 
 
 
 
 
 
11.3.2.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2) 
 
 (Table 3). 
Abnormalities in physical examinations, vital signs, electrocardiograms (ECGs), and out of range 
values in laboratory test results will be interpreted by an investigator as clinically significant 
(CS) or not clinically significant (NCS) in the source documents. 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, ethnicity, highest level of education, employment 
history, and current employment status) and a full medical history will be documented. 
Confirmed (genetically tested) or suspected family history of HD will also be documented.  
12.1.2. 
Weight and Height 
Height and weight will be measured and documented. Body mass index (BMI) will be calculated 
and documented.  
12.1.3. 
Physical Examination 
Whenever possible, the same individual should perform all physical examinations. Full physical 
examinations will be performed at Screening and Day 112 (or ET), and include assessment of 
body systems (eg, head, eye, ear, nose and throat; heart; lungs; abdomen; and extremities) as 
well as cognitive and neurological examination, and mental status examination. Unscheduled 
physical examinations may also be conducted per the investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by an investigator as abnormal, not 
clinically significant (NCS); or abnormal, clinically significant (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, regardless of timing. 
In addition, information focused on COVID-19 (eg, AE collection and prior/concomitant 
medication/procedures) will be collected at Screening and throughout the study. 
12.1.5. 
Vital Signs 
Vital signs comprise heart rate, respiratory rate, temperature, and blood pressure. Systolic and 
diastolic blood pressure are to be measured after the participant has been supine for at least 
5 minutes prior to the measurement. Orthostatic blood pressure and heart rate will also be 
measured after the participant has been in the supine position for at least 5 minutes and then 
repeated approximately 1 and 3 minutes after standing.  
Any abnormality in vital signs will be interpreted by an investigator as abnormal, NCS; or 
abnormal, CS in source documents. 

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12.1.6. 
Electrocardiogram 
A 12-lead ECG will be performed at the time points described in Table 2. At each time point, a 
single ECG will be recorded. 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, blood draws should be carried out after ECG and vital signs. 
All abnormal ECGs will be interpreted by an investigator as CS or NCS in source documents. 
12.1.7. 
Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected. Analytes to be 
evaluated are summarized in Table 6. 
Table 6: 
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, TSH and reflex to free T3/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 
[MCHC]).  
Urinalysis 
Protein, glucose, pH, blood, leukocyte esterase, leukocytes (reflex to leukocytes 
via microscopy if urinalysis is abnormal) urobilinogen, bilirubin, ketones, nitrite 
Coagulation 
Activated partial thromboplastin time, prothrombin time, and international 
normalized ratio 
Serology 
(screening only) 
Hepatitis B and C screening tests, HIV-1 and -2 antibody 
Genetic test 
(screening only) 
CAG testa 
a Genetically confirmed disease with CAG expansion ≥36 collected as part of medical history is acceptable in lieu 
of central laboratory confirmation. For any genetic counseling, the study sites should follow their local practice. 
 
All clinical laboratory test results outside the reference range will be interpreted by the 
investigator as abnormal, NCS; or abnormal, CS in source documents. 
Serum FSH test will be conducted at Screening for the female participants who are not 
permanently sterile to confirm whether a female participant with ≥12 months of spontaneous 
amenorrhea meets the protocol-defined criteria for being postmenopausal. 

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12.1.7.1. Drugs of Abuse, Alcohol 
Separate urine samples for assessment of drugs of abuse (including amphetamines, barbiturates, 
benzodiazepines, cocaine, THC, and opiates) will be collected. A breath test for alcohol will be 
performed. 
12.1.7.2. Pregnancy Testing 
A serum pregnancy tests will be conducted for all female participants at Screening; a urine 
pregnancy tests will be conducted at other scheduled time points for female participants that are 
not postmenopausal or permanently sterile. 
12.1.8. 
  
 
 
 
 
 
  
 
 
  
12.1.9. 
  
 
 
 
 
 
 
 
 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A treatment-emergent adverse event (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 

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throughout the study. The term IP includes any Sage IP, a comparator, or a placebo administered 
in a clinical study. 
Laboratory abnormalities and changes from baseline in vital signs, and ECGs are considered AEs 
if they result in discontinuation or interruption of study treatment, require therapeutic medical 
intervention, meet protocol specific criteria (if applicable) or if the investigator considers them to 
be CS. Any abnormalities that meet the criteria for an SAE should be reported in an expedited 
manner. Laboratory abnormalities and changes from baseline in vital signs and ECGs that are 
clearly attributable to another AE do not require discrete reporting (eg, electrolyte disturbances 
in the context of dehydration, chemistry, and hematologic disturbances in the context of sepsis). 
All AEs that occur after any participant has signed the informed consent and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage 
Therapeutics. 
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 in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all of the following: 

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• 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 (USM), defined as an action that the sponsor and investigator may take 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 FDA Guidance 21 CFR Part 312.66, some reported events may qualify as an 
unanticipated problem (UP), 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 USM or UP 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)/IECs(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.  

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Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
alternative explanation for the AE. 
Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE. 
12.2.5. 
Recording Adverse Events 
Adverse events spontaneously reported by the participant and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome and seriousness (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s)  
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized  
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria 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 Therapeutics and designee within 24 hours of the study site staff becoming 
aware of the SAE(s). The investigator must complete, sign and date the SAE report form, verify 

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the accuracy of the information recorded on the SAE report form with the corresponding source 
documents, and send a copy to Sage Therapeutics and designee.  
Additional follow-up information, if required or available, should all be sent to Sage 
Therapeutics 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. 
SAEs occurring after the designated follow up time for the study, should be reported to Sage 
Therapeutics and designee according to the timelines noted above only if the investigator 
considers the SAE related to IP.  
Sage Therapeutics, or designee, is responsible for notifying the relevant regulatory authorities of 
certain events. It is the principal investigator’s responsibility to notify the IRB/IEC of all SAEs 
that occur at his or her site. Investigators will also be notified of all suspected unexpected serious 
adverse reactions (SUSARs) that occur during the clinical study. IRBs/IECs will be notified of 
SAEs and/or SUSARs as required by local law. 
In addition, appropriate personnel in Sage Therapeutics Drug Safety and Pharmacovigilance or 
designee will unblind SUSARs for the purpose of regulatory reporting. Sage Therapeutics or 
designee will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies according 
to local law (See Section 20 [Appendix 1]). Sage, or designee, will submit SUSARS to 
investigators in a blinded fashion.  
12.2.7. 
Assessment of Liver Biochemistry for Hy’s Law Screening, or Hy’s Law 
Laboratory Criteria  
Hy’s Law is a principle outlining specific criteria to indicate when an individual is at high risk of 
a severe drug-induced liver injury (DILI) as a result of incurring hepatocellular injury sufficient 
to impair bilirubin excretion.  
Potential Hy’s Law is defined as an elevated alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) >3× upper limit of normal (ULN) and an elevated total bilirubin 
≥2× ULN with alkaline phosphatase <2× ULN at any time during the study. Hy’s Law criteria 
are met if there is no alternative explanation for the elevations in liver biochemistry other than 
DILI caused by the IP. The elevations of transaminases and bilirubin may occur together or at 
different time points during the study, therefore, to identify cases of potential Hy’s Law, a 
comprehensive review of liver biochemistry must be performed.  
The investigator is responsible for determining whether a participant meets potential Hy’s Law 
criteria at any point during the study. If a participant has elevations in liver biochemistry, further 
evaluation may be required and, if elevations meet the potential Hy’s Law criteria, it must be 
reported as an SAE within 24 hours of Investigator awareness (see Section 12.2.6 for procedure 
on reporting an SAE). All results of laboratory tests including alkaline phosphatase testing 
should also be appended to the SAE form. The investigator must continue to follow the 
participant until liver biochemistry returns to normal or baseline levels, or for as long as 
clinically indicated. In addition, the investigator should perform any necessary diagnostic 
evaluations to investigate the etiology of the event and update the SAE report accordingly.  
These events must also be recorded as an SAE in the eCRF with the investigator’s assessment of 
seriousness, severity, and causality, and a detailed narrative must be provided on the SAE form. 

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The investigator is responsible for recording data pertaining to potential Hy’s Law/Hy’s Law 
cases and for reporting AEs and SAEs in line with standard safety reporting procedures (see 
Section 12.2.5 and Section 12.2.6). 
IP dose modifications for participants who meet potential Hy’s Law criteria should be made 
according to Section 7.4. 
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 (eg, 
spontaneous abortion, stillbirth, neonatal death,), the investigator should follow the procedures 
for reporting an SAE.  
See Section 20 (Appendix 1) for country-specific requirements. 
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/or designee 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 

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during the study it must be reported to the sponsor and/or 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 a 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 study treatment given to a participant or taken by a participant that 
exceeds the dose described in protocol. Overdoses are not considered AEs and should not be 
recorded as an AE on the CRF; however, all overdoses must be recorded on the Special 
Considerations form and sent to Sage or designee within 24 hours of the site becoming aware of 
the overdose. An overdose must be reported to Sage or designee even if the overdose does not 
result in an AE. If an overdose results in an AE or SAE, the AE or SAE must 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/or 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 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. 
Database lock will occur in two parts. The first database lock will include all data from all 
participants who have completed Day 84 or the ET visit. The second database lock will include 
all the data from all participants through the follow-up visit (Day 112). 
13.1. 
Data Analysis Sets 
The Randomized Set will include all participants who have been randomized. 
The Safety Set will include all participants who were administered IP and will be used to describe 
the safety data. 
The Full Analysis Set (FAS) will include all participants who initiate IP and have baseline and at 
least 1 postbaseline efficacy evaluation. 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
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 non-missing data available. 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 
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.  

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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. 
For the purpose of all analyses, where applicable, baseline is defined as the last measurement prior 
to the first dose of IP, unless stated otherwise. 
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. 
Continuous data will be summarized in terms of the number of participants, mean, SD, minimum 
value, median, and maximum value. Categorical data will be summarized using frequency counts 
and percentages. 
13.4. 
Demographics and Baseline Characteristics 
Demographic characteristics (age, race, sex, ethnicity, highest level of education, total years of 
employment, and current employment status) and baseline characteristics, such as height, weight, 
and BMI will be summarized using the Safety Set.  
Pregnancy test results and drug screen results will be listed but not summarized.  
Medical history will be listed by participant.  
13.5. 
Efficacy Analysis  
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods, where applicable; participant listings will be provided for all efficacy data. 
Participants will be analyzed according to randomized treatment.  
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 premanifest or early manifest HD. 
3. The variable of interest is the change from baseline in SDMT 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 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 SDMT score at Day 84. 
The change from baseline in cognitive assessments will be analyzed using a mixed-effects model 
for repeated measures; the model will include treatment, baseline scores, assessment time point, 
and time point-by-treatment as explanatory variables. All postbaseline time points will be included 

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in the model. The primary comparison will be between SAGE-718 and placebo at the Day 84 time 
point. Model-based point estimates (eg, least squares means), 95% confidence intervals, and p-
values will be reported. An unstructured covariance structure will be used to model the within-
participant errors. Other continuous efficacy endpoints, including 
 
functional outcomes, 
, will be analyzed using similar methods. 
Generalized estimating equation (GEE) methods will be used for the analysis of Clinical Global 
Impression response. GEE models will include terms for treatment, baseline CGI-S assessment, 
time point, and time point-by-treatment as explanatory variables. The comparison of interest will 
be the difference between SAGE-718 and matching placebo at the Day 84 time point. 
Model-based point estimates (eg, odds ratios), 95% confidence intervals, and p-values will be 
reported.  
Additional analyses will be detailed in the SAP. 
13.5.1. 
Multiplicity Adjustment for Primary and Key Secondary Endpoints 
The statistical comparisons for the primary and the key secondary endpoints will be carried out 
using a fixed-sequence procedure which tests hypotheses in a hierarchical order to control the 
familywise type I error rate. This means that statistically significant results for the comparison in 
the higher rank (primary) for no difference between SAGE-718 versus placebo is required to 
initiate the testing of the next comparison in the lower rank (key secondary) for no difference 
between SAGE-718 versus placebo. The hierarchical testing of key secondary endpoints will 
follow the order shown in Section 6. Details will be provided in the study SAP. Since a 
hierarchical procedure is used, each comparison will be tested at a significance level of 0.05 and 
an overall alpha level of 0.05 will be preserved. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-718 will be evaluated by the frequency of TEAEs and change 
from baseline in vital signs, clinical laboratory analytes, ECGs, 
. 
 Safety data will be listed by 
participant and summarized by treatment group, maximum severity and relationship to IP. Vital 
signs, laboratory parameters, ECGs, 
 data will be listed by participant and 
summarized by treatment group. All safety summaries will be performed on the Safety Set. 
13.6.1. 
Adverse Events 
AEs/SAEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 
22.0 or higher. A TEAE is defined as an AE with onset after the first dose of IP. The analysis of 
AEs will be based on the concept of TEAEs. The incidence of TEAEs will be summarized by 
System Organ Class (SOC) and Preferred Term (PT). In addition, summaries will be provided by 
intensity (mild, moderate, severe) and by causality (related, not related) to IP.  
Any TEAEs leading to discontinuation of treatment or withdrawal from the study and any 
treatment emergent SAEs will be summarized.  
All AEs and SAEs (including those with onset or worsening before the start of IP) through the 
end of the study will be listed.  

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13.6.2. 
Clinical Laboratory Evaluations 
Clinical laboratory assessments will include blood samples for hematology, clinical chemistry, 
and urinalysis. Samples will be collected ≤2 hours prior to dosing on dosing days. On non-dosing 
days, collection may occur at any time. 
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 
A full physical examination is to be conducted during Screening and at Day 112. At other visits, 
physical examinations will include a brief assessment of general appearance, cardiovascular, 
respiratory, gastrointestinal, and neurological systems and followed by a targeted physical 
assessment as needed. A symptom-directed examination may be conducted at any time at the 
discretion of the investigator. The occurrence of a physical examination (yes/no) and the date 
performed will be listed by participant. 
13.6.4. 
Vital Signs 
Vital signs will include body temperature, respiratory rate, heart rate, and blood pressure. Heart 
rate and blood pressure to be collected in supine position and standing position at all scheduled 
time points. Vital sign results at each visit and mean changes from baseline will be summarized 
by scheduled visit. Potentially CS values will be summarized by treatment. Vital sign results will 
be listed by participant and timing of collection. 
13.6.5. 
12-Lead Electrocardiogram 
A single ECG will be measured after the participant has been in the supine position for at least 
5 minutes. The following ECG parameters will be listed for each participant: heart rate, PR, 
QRS, QT, and QTcF. ECG data will be summarized by visit. Potentially CS values of QTcF will 
be summarized by treatment. ECG findings will be listed by participant and visit. 
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
All medications and supplements taken within 8 weeks prior to Screening, all medications used 
to treat HD (including ASO therapies) regardless of timing, and all nonpharmacological methods 
(eg, psychosocial, psychotherapeutic) used to treat or prevent neuropsychiatric, functional, and 
cognitive manifestations of HD will be recorded. Those medications taken prior to the initiation 
of the start of IP will be denoted “Prior”. Those medications taken prior to the initiation of the IP 
and continuing beyond the initiation of the IP or those medications started at the same time or 
after the initiation of the IP will be denoted “Concomitant”. Medications will be presented 
according to whether they are “Prior” or “Concomitant” as defined above. If medication dates 

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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 Therapeutics 
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 Therapeutics or its representatives. Agreed upon site 
responsibilities will be documented in a Clinical Trial Agreement between Sage 
Therapeutics and the investigator. 
During the study, a monitor from Sage Therapeutics or representative will have regular contacts 
with the investigational site, for the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the 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 IRB/IEC 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 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 Good Clinical Practice and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit(s) at the clinical site. Please see 
Section 14.2 for more details regarding the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. 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 Informed Consent Form, must be 
given a written and dated approval or favorable opinion by an IRB or IEC as appropriate. The 
investigator must obtain and document approval before he or she can enroll any participant into 
the study. The IRB or IEC must supply to the sponsor a list of the IRB/IEC membership and a 
statement to confirm that the IRB/IEC is organized and operates according to GCP and 
applicable laws and regulations. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the 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 must provide signed and 
dated informed consent. The written consent must be obtained before conducting any study 
procedures. The investigator must document the consent process in the participant’s source 
documentation. The investigator must maintain the original, signed ICF. A copy of the signed 
ICF must be given to the participant.  
Throughout the study participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 
documented in the participant’s source records, and when applicable, an updated ICF will be 

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provided. 
 
 
16.4. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
• The participant must be informed that his/her personal study-related data (including 
but not limited to, retained biological samples, images and/or recordings) will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Sage Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 

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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 visits at the investigation 
site and/or supporting 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 medical records 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. The retention of records must be in accordance with local regulations (Section 20 
[Appendix 1]) and Sage Therapeutics 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. 
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Handley O, Anderson KE, Stout JC, Sampaio C. Utility of Huntington's Disease Assessments by 
Disease Stage: Floor/Ceiling Effects. Front Neurol. 2021 Jul 15;12:595679 
Albin RL, Young AB, Penney JB, et al. Abnormalities of striatal projection neurons and 
N-methyl-D-aspartate receptors in presymptomatic Huntington's disease. N Engl J Med. 
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Bayram E, Kaplan N, Shan G, Caldwell JZK. The longitudinal associations between cognition, 
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Investigators of the European Huntington's Disease Network and COHORT Investigators of the 
Huntington Study Group. Identification of symbol digit modality test score extremes in 
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Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical 
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Cao LX, Kong WL, Chan P, Zhang W, Morris MJ, Huang Y. Assessment tools for cognitive 
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Cardoso F. Nonmotor Symptoms in Huntington Disease. Int Rev Neurobiol. 
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De Giglio L, De Luca F, Gurreri F, et al. Effect of dalfampridine on information processing 
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Dorsey ER, Beck CA, Darwin K, et al; Huntington Study Group COHORT Investigators. 
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Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. US Department of Health, 
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Hamilton JL, Mills JA, Stebbins GT, et al. Defining clinical meaningfulness in Huntington's 
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Leoni V, Long JD, Mills JA, et al. PREDICT-HD study group. Plasma 24Shydroxycholesterol 
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atomoxetine on cognitive function in patients with multiple sclerosis. Curr J Neurol. 2023 Jul 
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20. 
APPENDICES 
Appendix 1: Country-Specific Changes 
Country 
Section 
Number 
Original Language in Country-Specific Amendment 
Updated Language for Country-Specific Amendment 
United 
Kingdom 
(UK) 
Section 
7.1.4 
End of study will be achieved when last study participant 
completes Follow-Up Visit at Day 112 (or ET). 
End of study will be achieved when last study participant 
completes Follow-up Visit at Day 112 (or ET). Additionally, for 
UK participants, end of study will be achieved when all sample 
analyses are completed, with the exception of any consented 
exploratory analyses as described in Informed Consent Form 
and in adherence with local regulation. 
Australia 
Section 
12.3 
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. 
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. For participants in Australia, pregnancy follow-up 
will be required for not less than 12 months. Any termination of 
pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for the procedure. 
Australia 
Section 
17.2 
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 IP. 
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 IP. The sponsor will maintain all data relating to the study for 
a period of 50 years after the completion of the study. 
 
 
. 
 
 

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Country 
Section 
Number 
Original Language in Country-Specific Amendment 
Updated Language for Country-Specific Amendment 
Canada 
Section 
12.2.6 
IRBs/IECs will be notified of SAEs and/or SUSARs as required 
by local law. 
IRBs/IECs will be notified of SAEs and/or SUSARs as required 
by local law. The sponsor will report all SUSARs to Health 
Canada within 7 days (if fatal or life threatening) or 15 days (if 
neither fatal nor life threatening) after becoming aware of the 
information. 
Canada 
Section 
17.2 
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 IP. 
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 IP. The sponsor will maintain all documentation relating to 
the study for a period of 15 years after the completion of the 
study as outlined in Section C.05.012 (4) of the Food and Drug 
Regulations. 
Abbreviations: ET = early termination; ICH = International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; 
IRB = institutional review board; IEC = independent ethics committee; IP = investigational product; 
; SAE = serious adverse event; 
SUSAR = suspected unexpected serious adverse reaction; UK = United Kingdom 

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