Clinical trial NCT05173012
Conditions: Essential Tremor
Keywords: Essential Tremor SAGE-324
Sponsor: Sage Therapeutics
Start date: 2022-01-05; Completion date: 2024-05-16
Enrollment: 146 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to evaluate the dose-response relationship of different doses of SAGE-324 on upper extremity tremor in participants with essential tremor (ET) in the monotherapy cohort.

Detailed description:

Arms: arm 1: Participants will receive SAGE-324 matched placebo, stratified by baseline propranolol use.

Monotherapy:

Participants will receive SAGE-324 matched placebo, oral tablets, once daily (QD), in the evening, from Day 1 to Day 90 in a double-blind treatment period.

Adjunct therapy:

Participants will receive SAGE-324 matched placebo, oral tablets, QD, in the evening, from Day 1 to Day 90 along with a stable dose of up to 320 milligrams (mg) of propranolol from 3 months prior to Screening up to Day 90 in a double-blind treatment period. arm 2: Participants will receive SAGE-324, 15 mg, stratified by baseline propranolol use.

Monotherapy:

Participants will receive SAGE-324, 15 mg, oral tablets, QD, in the evening, from Day 1 to Day 90 in a double-blind treatment period.

Adjunct therapy:

Participants will receive SAGE-324, 15 mg, oral tablets, QD, in the evening, from Day 1 to Day 90 along with a stable dose of up to 320 mg of propranolol from 3 months prior to Screening up to Day 90 in a double-blind treatment period. arm 3: Participants will receive SAGE-324, 30 mg, stratified by baseline propranolol use.

Monotherapy:

Participants will receive SAGE-324, 30 mg, oral tablets, QD, in the evening, from Day 1 to Day 90 in a double-blind treatment period.

Adjunct therapy:

Participants will receive SAGE-324, 30 mg, oral tablets, QD, in the evening, from Day 1 to Day 90 along with a stable dose of up to 320 mg of propranolol from 3 months prior to Screening up to Day 90 in a double-blind treatment period. arm 4: Participants will receive SAGE-324: 15 mg, 30 mg, 45 mg, and 60 mg, stratified by baseline propranolol use.

Monotherapy:

Participants will receive SAGE-324, 15 mg from Day 1 to 14, followed by up-titration to 30 mg from Day 15 to 28, then to 45 mg from Day 29 to 42, and then to 60 mg from Day 43 to 90, oral tablets, QD, in the evening, from Day 1 to Day 90 in a double-blind treatment period.

Adjunct therapy:

Participants will receive SAGE-324, 15 mg from Day 1 to 14, followed by up-titration to 30 mg from Day 15 to 28, then to 45 mg from Day 29 to 42, and then to 60 mg from Day 43 to 90, oral tablets, QD, in the evening, from Day 1 to Day 90 along with a stable dose of up to 320 mg of propranolol from 3 months prior to Screening up to Day 90 in a double-blind treatment period.
Interventions: intervention 1: SAGE-324 intervention 2: SAGE-324 Matched Placebo
Intervention descriptions: intervention 1: SAGE-324 oral tablets. intervention 2: SAGE-324 matched placebo oral tablets.

Protocol documents:
Prot_000.pdf: 
Official Title:  A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Dose-Response  
                       Study of SAGE-324 for the Treatment of Essential Tremor
              NCT ID:   NCT05173012
Document Date:     Protocol Version 6.0: 08 November 2023


Clinical Protocol 
 
Sage Therapeutics, Inc. 
Study 324-ETD-202, version 6.0 
 
CONFIDENTIAL 
 
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A PHASE 2, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, DOSE-RESPONSE STUDY OF 
SAGE-324 FOR THE TREATMENT OF ESSENTIAL TREMOR 
PROTOCOL NUMBER: 324-ETD-202 
IND NUMBER: 144989 
Investigational Product 
SAGE-324 Oral Tablet 
Clinical Phase 
Phase 2 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
 
Phone: 
 
Email: 
 
 
Sponsor Medical Monitor 
MD 
 
Phone/text: 
 
E-mail: 
 
Date of Original Protocol 
Date of Amendment 1 
Date of Amendment 2 
Date of Amendment 3 
Date of Amendment 4 
Date of Amendment 5 
03 September 2021 
04 March 2022 
04 May 2022 
07 October 2022 
10 January 2023 
02 November 2023  
Confidentiality Statement 
The confidential information in this document is provided to you as an investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from Sage Therapeutics, 
Inc. 


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INVESTIGATOR’S AGREEMENT 
I have received and read the SAGE-324 Investigator’s Brochure. I have read the 324-ETD-202 
protocol and agree to conduct the study as outlined. I agree to maintain the confidentiality of all 
information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY) 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sage Study Physician  
MD 
  
Phone: 
  
Email: 
 
 
24-Hour Emergency Contact 
 
MD, MPH 
E-mail: 
 
Phone: 
 
Serious Adverse Event (SAE) 
Reporting Contact 
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  
Sage Study Physician 
MD 
 
E-mail: 
 
 
 
MD, MPH 
E-mail: 
 
Product Complaint Contact 
Sage Therapeutics 
E-mail: productcomplaints@sagerx.com 
Phone: +1-833-554-7243 
 


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Study 324-ETD-202, version 6.0 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or Sage) 
Name of Investigational Product: 
SAGE-324 Oral Tablet 
Name of Active Ingredient: 
SAGE-324 
Title of Study: 
A Phase 2 Double-Blind, Randomized, Placebo-Controlled, Dose-Response Study of SAGE-324 for 
the Treatment of Essential Tremor   
Number of Sites and Study Location: This study will take place at approximately 60 sites 
worldwide 
Phase of Development: 2 
Planned Duration for each Study Participant: 
The duration of participation (from Screening through the final Follow-up Visit) for each participant 
is estimated to be up to approximately 132 days. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary  
 
• 
To evaluate the dose-response 
relationship of different doses of 
SAGE-324 on upper extremity tremor 
in the monotherapy cohort  
• 
Change from baseline in The Essential Tremor 
Rating Assessment Scale (TETRAS) 
Performance Subscale Item 4 (upper limb) total 
score on Day 91 in the monotherapy cohort  
Secondary  
 
• 
To evaluate the dose-response 
relationship of different doses of 
SAGE-324 on specified activities of 
daily living (ADL) in the monotherapy 
cohort  
• 
Change from baseline in TETRAS ADL 
composite score in the monotherapy cohort  


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• 
To assess the safety and tolerability of 
SAGE-324 
• 
Incidence of treatment-emergent adverse events 
(TEAEs)  
• 
To evaluate the effect of SAGE-324 on 
other safety parameters 
• 
Change from baseline in vital signs, 
electrocardiogram (ECG), clinical laboratory 
parameters
 
 
 
 


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Study Description: 
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the 
efficacy, safety, and tolerability of SAGE-324 in participants with ET. Participants, site staff, and 
sponsor personnel will be blinded to treatment allocations. The study is presented schematically in 
Figure 1. 
Figure 1: 
Study Design 
 
Abbreviation: TETRAS = The Essential Tremor Rating Assessment Scale. 
Note: The Screening Period may be extended for an additional 14 days (total of 42 days) for subjects requiring 
additional time to taper ET medication (other than propranolol), after approval from the sponsor. 
 
This study includes a Screening Period of up to 28 days, a 90-day double-blind Treatment Period 
(90 days of dosing), and a 14-day Follow-up Period. After providing informed consent, participants 
will undergo screening assessments to determine eligibility as outlined in Table 2.  
• 
Screening Period: The Screening Period begins with the signing of the informed consent 
form (ICF). Eligible participants will visit the study center on Day 1 and complete additional 
eligibility and baseline assessments, as specified in the Schedule of Assessments (Table 2). 
The Screening Period may be extended for an additional 14 days (total of 42 days) for 
subjects requiring additional time to taper ET medication (other than propranolol), after 
approval from the sponsor. Following completion of screening and Day 1 eligibility 
assessments, participants will be randomized to 1 of 4 treatment groups (matching placebo or 
SAGE-324: 15 mg, 30 mg, or 60 mg, oral daily) in a 1:1:1:1 ratio, stratified by baseline 
propranolol use (adjunct therapy).  
• 
Double-Blind Treatment Period: Starting on Day 1, after randomization, participants will 
receive a single dose of investigational product (IP) once daily for 90 days on an outpatient 
basis, to be taken before bed, with a snack if bedtime is not within 2 hours of the evening 
meal. Guidance on suitable snacks will be provided. During the Treatment Period, 
participants will return to the study center for efficacy and safety assessments as specified in 
Table 2. In addition, safety phone call study visits will be conducted according to Table 2, or 
more often as deemed appropriate by the investigator, to review the current status of the 


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participant. Participants will be trained on the use of software applications and devices 
necessary to complete questionnaires or self-rated study assessments.  
Participants should gain experience with the study drug to see how it affects them 
before engaging in potentially hazardous activities requiring mental alertness, such as 
driving.  If participants experience any sleepiness, dizziness, or feelings of relaxation, 
or have other sedative effects, they should not engage in potentially hazardous 
activities requiring mental alertness, such as driving, until any sleepiness/sedative 
effects from the study drug have dissipated.  This is important because study 
participants may not be able to judge how these sedative effects will affect their ability 
to perform potentially hazardous activities requiring mental alertness, including 
driving. 
• 
Follow-Up Period: Follow-up visits will be conducted on an outpatient basis on Days 97 and 
104. Participants will continue to complete questionnaires as indicated in Table 2 and will 
return to the clinic approximately 6 days after the last dose of IP (ie, Day 97) for efficacy and 
safety monitoring. Participants will return to the study center for an End of Study (EOS) Visit 
approximately 13 days following the last dose of IP (ie, Day 104); the Early Termination 
Visit (ETV) will be conducted at the time of discontinuation if this occurs any time before 
Day 104. 
No dose reductions of SAGE-324 will be permitted. 
All participants who conclude the study will be offered the opportunity to enroll in a SAGE-324 
long-term open-label study, as per the long-term open-label study’s eligibility criteria. 
Number of Participants (planned): Approximately 160 participants, with at least 104 (65%, 
26 participants per dose group) monotherapy participants and up to 56 (35%, 14 participants per dose 
group) adjunct therapy participants, will be randomized to ensure at least 22 participants per arm in 
the monotherapy cohort will complete the study.   
Eligibility Criteria:  
Inclusion Criteria: 
1. 
Participant has signed an ICF before any study-specific procedures or washout of drugs is 
started. 
2. 
Participant is ambulatory and is 18 to 80 years of age, inclusive, at the time informed consent is 
obtained. 
3. 
Participant is in good physical health and has no clinically significant findings (excluding ET), 
as determined by the investigator, on physical examination, including neurologic and mental 
status examinations, 12-lead ECG, or clinical laboratory tests.  
4. 
Participant has a diagnosis of ET, as defined by all of the following criteria: 
a. 
Isolated tremor syndrome consisting of bilateral upper limb action tremor  
b. 
At least 3 years duration  
c. 
With or without tremor in other locations (eg, head, voice, or lower limbs). 
5. 
Absence of other neurological signs, such as dystonia, ataxia, or parkinsonism, isolated focal 
tremors (eg, voice, head), task- and position-specific tremors, sudden tremor onset or evidence 
of stepwise deterioration of tremor 
6. 
Participant has the following: 
a. 
Scores at least 12 in the combined TETRAS Performance Subscale Item 4 (upper limb 
tremor) at both Screening and predose on Day 1 


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b. 
Scores at least 6 in the total TETRAS Performance Subscale Item 4 score for the 
dominant upper limb (the sum of the three items for either the right or left upper limb, 
whichever is dominant) at both Screening and predose on Day 1. 
7. 
Participant has a baseline TETRAS ADL Subscale score of at least 20 at Screening. 
8. 
Participant is willing to discontinue medications taken for the treatment of ET except 
propranolol, at least 14 days or 5 half-lives (whichever is longer) prior to receiving 
IP. Medications taken for the treatment of ET that were discontinued prior to receiving IP may 
be resumed following Day 97. Participants in the adjunct therapy cohort must be on a stable 
dose of propranolol for the treatment of ET (maximum total daily propranolol dose up to 
320 mg allowed) from 3 months prior to Screening through Day 97 of the study.  
9. 
Participant is willing to limit use of alcohol to 2 units per day for males and 1 unit per day for 
females starting at least 1 week prior to Day 1 and through Day 97 of the study.  
A unit of alcohol is defined as: 12 ounces of regular beer, 5 ounces of wine, or 1.5 ounces of 
distilled spirits.  
Participant will limit alcohol use to at least 2 hours before self-administration of IP in the 
evening.  
Participant will not use alcohol starting 24 hours prior to the scheduled in-clinic study visits 
until all assessments have been completed.  
10. 
Female participant agrees to use at least one method of highly effective contraception as listed 
in Section Section 9.2.4 during participation in the study and for 30 days following the last 
dose of study drug, unless she is postmenopausal (at least 12 months of spontaneous 
amenorrhea without an alternative medical cause, with confirmatory follicle stimulating 
hormone [FSH] >40 mIU/mL), and/or surgically sterile (bilateral oophorectomy, hysterectomy, 
and/or bilateral salpingectomy), or does not engage in sexual relations which carry a risk of 
pregnancy (does include abstinence).  
11. 
Male participant agrees to use an acceptable method of effective contraception for the duration 
of the study and for 13 weeks after receiving the last dose of study drug, unless the participant 
does not engage in sexual relation(s) which carry a risk of pregnancy. Acceptable methods of 
effective contraception are listed in Section 9.2.4.  
12. 
Male participant is willing to abstain from sperm donation for the duration of the study and for 
13 weeks after receiving the last dose of study drug. 
13. 
Participant is willing to maintain prestudy consumption of products that contain nicotine 
starting at least 1 week prior to Day 1 and through Day 97 of the study.  
Exclusion Criteria: 
1. 
Participant has presence of known causes of enhanced physiological tremor.  
2. 
Participant has had newly administered tremorgenic drugs (14 days or 5 half-lives [whichever 
is longer] prior to Day 1) or presence of alcohol withdrawal state.  
3. 
Participant has had direct or indirect injury or trauma to the nervous system within 3 months 
before the onset of tremor.  
4. 
Participant has had a previous procedure for the treatment of ET, deep brain stimulation, brain 
lesioning, or magnetic resonance (MR) guided procedure, eg, MR-guided focused ultrasound. 
Use of Cala Trio bracelet for the treatment of ET from two weeks prior to Day 1 through Day 
97 is prohibited. 
5. 
Participant has had botulinum toxin for treatment of ET within 6 months of Screening.   
6. 
Participant has historical or clinical evidence of tremor with functional neurological syndrome 
origin.  


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7. 
Participant has currently active and medically significant or uncontrolled hepatic, renal, 
cardiovascular, pulmonary, gastrointestinal, hematological, immunologic, metabolic disease 
(hypothyroidism with stable thyroid replacement is acceptable).  
8. 
Participant has a body weight >140 kg or a body mass index (BMI) ≥50 kg/m2 at Screening.  
9. 
Participant currently requires propranolol treatment for a medical condition other than ET.  
10. 
Participant has a clinically relevant history within 3 years of Screening or ongoing oncologic 
disease, in the judgement of the investigator, excluding skin cancers (squamous or basal cell 
carcinoma) for which treatment has been completed or any carcinoma in situ.  
11. 
Participant has history of substance abuse or dependence prior to Screening has a positive 
screen for drugs of abuse at Screening or predose on Day 1. Participants with nicotine use 
disorder that impacts their tremor are excluded. 
12. 
Participant has a known allergy to any IP excipient.  
13. 
Female participant has a positive pregnancy test or confirmed pregnancy or is breastfeeding. 
14. 
Participant has had exposure to another investigational drug or device within 30 days or 5 half-
lives of the investigational drug, whichever is longer, prior to the Day 1 visit. 
 
 
16. 
Participant has donated 1 or more units (1 unit = 450 mL) of blood or experienced acute loss of 
an equivalent amount of blood within 60 days prior to Day 1.  
17. 
Participant has night shift work. 
18. 
Participant has any condition or comorbidity that in the opinion of the investigator would limit 
or interfere with the participant’s ability to complete or partake in the study. 
19. 
Participant is unwilling or unable to comply with study procedures and required training. 
20. 
Participant has used any known moderate or strong cytochrome P450 3A4 inhibitors and/or 
inducers within 14 days or 5 half-lives (whichever is longer) prior to Day 1 or consumed 
grapefruit juice, grapefruit, Seville oranges, pomegranates, tangelos, or St. John’s Wort or 
products containing these within 30 days prior to Day 1 and is unwilling to refrain from taking 
these medications or foods for the duration of dosing. Use of mild cytochrome inhibitors and/or 
inducers may be permitted.  
21. 
Participant has concurrent or recent exposure (14 days or five half-lives, whichever is longer, 
prior to the Day 1 visit) to sedative/hypnotic drugs, stimulants, highly caffeinated beverages, or 
dietary supplements containing high doses of caffeine, or recent increase above regular daily 
consumption of caffeine. 
22. 
Participant plans to undergo elective surgery during participation in the study. 
23. 
Participant is unable to complete participation in the study, eg, due to preplanned event. 
24. 
Participant is investigative site personnel or a member of their immediate families (spouse, 
parent, child, or sibling whether biological or legally adopted).  
25. 
Participant has previously participated in a SAGE-324 clinical study. 


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Investigational Product Therapy Dosage and Mode of Administration: 
SAGE-324 will be administered orally once daily, to be taken before bed, with a snack if bedtime is 
not within 2 hours of the evening meal.  
The 15-mg dose group will receive 15 mg of SAGE-324 from Day 1 to Day 90. 
The 30-mg dose group will receive 30 mg of SAGE-324 from Day 1 to Day 90. 
The 60-mg dose group will receive 15 mg of SAGE-324 from Day 1 to Day 14, then 30 mg from 
Day 15 to Day 28, then 45 mg from Day 29 to Day 42, and then 60 mg from Day 43 to Day 90. 
Reference Therapy Dosage and Mode of Administration:  
Placebo will be administered orally once daily for 90 days. 
Duration of Treatment: 
Each participant will receive SAGE-324 or matching placebo oral tablets for 90 days. 
Statistical Methods:  
A separate statistical analysis plan (SAP) will provide a detailed description of the data analyses to be 
performed in the study. The SAP will be finalized and approved prior to database lock.  
General Considerations 
For the purpose of all efficacy and safety analyses where applicable, baseline is defined as the last 
measurement prior to the start of IP administration. 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each time 
point and summarized descriptively. For categorical endpoints, descriptive summaries will include 
counts and percentages.   
Analysis Sets 
The Randomized Set is defined as all participants who are randomized. 
The Safety Set will include all participants who were administered IP.  
The Full Analysis Set will include all randomized participants who received any amount of IP and 
have a baseline and at least one postbaseline total TETRAS Performance Subscale Item 4 upper limb 
tremor score.  
 
 
The Per Protocol Set will include all participants in the Full Analysis Set without any major protocol 
deviations that could affect efficacy. The review of major protocol deviations will be completed, and 
the decision on whether the deviation affects efficacy will be documented before database unblinding. 
Determination of Sample Size 
The planned sample size is 160 participants, randomized in a 1:1:1:1 ratio to each of the dose groups 
(matching placebo and SAGE-324: 15 mg, 30 mg, and 60 mg), stratified by baseline propranolol use, 
with at least 104 (65%, 26 participants per dose group) monotherapy participants and up to 56 (35%, 
14 participants per dose group) adjunct therapy participants.  
The sample size of 104 participants for the monotherapy cohort assumes a change from baseline at 
Day 91 in TETRAS upper limb Item 4 score for the placebo group of -1.2 points, a maximum 
decrease of -3.2 points from baseline for a dose response in the 15-mg to 60-mg dose groups with a 
standard deviation of 2.5. Under these assumptions with a few prespecified candidate dose-response 
models, including linear, loglinear, quadratic, exponential, logistic, Emax, sigEmax and beta, a 
sample size of 22 evaluable participants per group would provide 80% power for demonstrating a 
nonflat dose-response relationship by Multiple Comparisons and Modeling (MCP-Mod) approach, 


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using a 1-sided type I error rate of 0.05. Assuming a nonevaluable rate of 15% across all treatment 
groups, approximately 104 participants (26 per treatment group) will be randomized. Additional 
monotherapy participants may be enrolled if the overall nonevaluable rate is higher than 20%.  
The sample size for adjunct therapy cohort is not based on statistical significance, but clinical 
considerations. Up to 56 adjunct therapy participants (14 per dose group) are to provide some adjunct 
therapy directional data on both efficacy and safety measures.  
Additional participants may be randomized if the variances during the blinded interim analysis are 
larger than the assumptions above. However, no more than 200 participants, including adjunct therapy 
participants, will be randomized.  
Statistical Analysis of Primary Efficacy Endpoint 
The estimand for the primary and secondary efficacy endpoint is defined as follows: 
1. There are 4 treatment groups for the monotherapy participants to be evaluated: SAGE-324 
(15 mg, 30 mg, 60 mg) and placebo.  
2. The target population consists of the monotherapy participants ages 18 to 80 years and have a 
diagnosis of ET with combined total upper limb TETRAS Performance Subscale Item 4 of at 
least 12 with the dominant upper limb score of at least 6 and baseline TETRAS ADL score of 
at least 20.  
3. The outcome for the primary efficacy endpoint is the change from baseline in TETRAS 
Performance Subscale Item 4 score on Day 91. 
4. The population-level summary measure is the dose-response of different doses of SAGE-324 
and placebo for the monotherapy cohort.  
5. The treatment/hypothetical policy strategy will be adopted for the primary and secondary 
endpoint. For data collected after the intercurrent events, such as rescue medication, the 
treatment policy strategy will be used. For data not available after the intercurrent events, like 
premature discontinuation of study treatment, the hypothetical policy strategy will be 
adopted. This means that the dose-responses of different dose groups will be analyzed using 
all observed on-study data, regardless of the occurrence of the intercurrent event, including 
use of additional medication, premature discontinuation of treatment for any reason, or other 
protocol violations.  
This will first be analyzed using a mixed-effects model for repeated measures (MMRM); the model 
will include treatment, baseline TETRAS Performance Subscale Item 4 upper limb tremor score, 
assessment timepoint, and timepoint-by-treatment as explanatory variables. All explanatory variables 
will be treated as fixed effects. All postbaseline clinic visits will be included in the model. An 
unstructured covariance structure will be used to model the within-participant errors. If there is a 
convergence issue with the unstructured covariance model, Toeplitz or Autoregressive (1) [AR(1)] 
covariance structure will be used, following this sequence until convergence is achieved. If the model 
still does not converge with AR(1) structure, no results will be reported. When the covariance 
structure is not unstructured, the sandwich estimator for the variance covariance matrix will be 
derived, using the EMPIRICAL option in the PROC MIXED statement in SAS. 
After the MMRM analysis by PROC MIXED, the estimated mean and covariance matrix will be 
passed to the MCP-Mod analysis to test the dose-response relationship. In the analysis, multiple 
dose-response candidate models will be prespecified. The actual dose-response relationship will be 
assessed using the estimated means and covariance matrix from MMRM analysis. A critical value 
will be determined from the joint multivariate normal distribution of the contrast test statistics at the 
overall one-sided alpha level of 0.05. If the test statistic exceeds this critical value, a nonflat 
dose-response relationship will be demonstrated. 
Secondary efficacy endpoints will be analyzed similarly to the primary endpoint. 


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Safety Analysis 
Safety and tolerability of study drug will be evaluated in each stratum (monotherapy cohort and 
adjunct therapy cohort) and overall using incidence of TEAEs/serious adverse events 
 
and changes from baseline in vital signs, clinical laboratory evaluations, 12-lead ECG
. 
Safety 
data will also be listed by participant using the Safety Set. 
 
 
Interim Analysis 
A blinded interim look at the primary and secondary endpoint data may be conducted to evaluate the 
sample size assumptions.  
 








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g A videographer will record TETRAS administration at Screening.  
h Washout of prestudy ET drug(s) except propranolol after the ICF was signed (Section 9.2.2.1) must be completed prior to Screening TETRAS assessment.  
i Participants will be trained by study personnel on the use of software applications, IP diary, and devices necessary for the conduct of the study.  
j Will be administered once daily, to be taken before bed, with a snack if bedtime is not within 2 hours of the evening meal. The 60-mg dose group will receive 
15 mg SAGE-324 from Day 1 to Day 14, then 30 mg from Day 15 to Day 28, then 45 mg from Day 29 to Day 42, and then 60 mg from Day 43 to Day 90. 
k A phone call to follow up on any AE(s) will be conducted, if deemed appropriate by the investigator, to review the current status of the participant.  
l Including all medications and supplements taken within the 30 days prior to signing the ICF through the first dose of IP, as well as a complete history of all 
treatments for ET since the year of diagnosis.  
 


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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.............................22 
5. 
INTRODUCTION ......................................................................................................24 
5.1. 
Dose Justification ........................................................................................................25 
5.2. 
Benefit/Risk Assessment ............................................................................................25 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................27 
7. 
INVESTIGATIONAL PLAN .....................................................................................29 
7.1. 
Overall Study Design ..................................................................................................29 
7.2. 
Number of Participants ...............................................................................................30 
7.3. 
Treatment Assignment ................................................................................................30 
7.4. 
Dose Adjustment Criteria ...........................................................................................30 
7.5. 
Criteria for Study Termination ...................................................................................31 
7.6. 
End of Study Definition ..............................................................................................31 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.....................................32 
8.1. 
Participant Inclusion Criteria ......................................................................................32 
8.2. 
Participant Exclusion Criteria .....................................................................................33 
8.3. 
Screen Failures ............................................................................................................35 
8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................35 
8.4.1. 
Investigational Product Discontinuation .....................................................................35 
8.4.2. 
Early Termination from the Study ..............................................................................35 
8.4.3. 
Loss to Follow-up .......................................................................................................36 
8.4.4. 
Replacement of Participants .......................................................................................36 
9. 
TREATMENT OF PARTICIPANTS .........................................................................37 
9.1. 
Description of Investigational Product .......................................................................37 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................37 


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9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................37 
9.2.2. 
Prohibited Medications ...............................................................................................37 
9.2.2.1. 
Prestudy Essential Tremor Medications Washout ......................................................38 
9.2.3. 
Other Restrictions .......................................................................................................38 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................39 
9.3. 
Intervention after the End of the Study .......................................................................40 
9.4. 
Treatment Adherence ..................................................................................................40 
9.5. 
Randomization and Blinding ......................................................................................40 
9.5.1. 
Emergency Unblinding ...............................................................................................40 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............42 
10.1. 
Investigational Product ...............................................................................................42 
10.2. 
Investigational Product Packaging and Labeling .......................................................42 
10.3. 
Investigational Product Storage ..................................................................................42 
10.4. 
Investigational Product Preparation ............................................................................43 
10.5. 
Investigational Product Administration ......................................................................43 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................43 
10.7. 
Product Complaints ....................................................................................................43 
11. 
EFFICACY 
 ....................45 
11.1. 
Efficacy Assessments .................................................................................................45 
11.1.1. 
The Essential Tremor Rating Assessment Scale ........................................................45 
 
45 
 
46 
 
46 
 
46 
 
47 
 
47 
 
48 
 
48 
 
48 
 
48 
 
48 
11.2.2. 
Pharmacodynamic Assessments .................................................................................48 
 
49 


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49 
12. 
SAFETY ASSESSMENTS ........................................................................................50 
12.1. 
Safety Parameters .......................................................................................................50 
12.1.1. 
Demography and Medical History ..............................................................................50 
12.1.2. 
Weight and Height ......................................................................................................50 
12.1.3. 
Physical Examination .................................................................................................50 
12.1.4. 
Vital Signs ..................................................................................................................50 
12.1.5. 
Electrocardiogram .......................................................................................................50 
12.1.6. 
Laboratory Assessments .............................................................................................51 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................51 
12.1.6.2. 
Pregnancy Screen ........................................................................................................51 
 
51 
 
51 
 
52 
12.1.10. 
COVID-19 Questions .................................................................................................52 
12.2. 
Adverse and Serious Adverse Events .........................................................................53 
12.2.1. 
Adverse Event Definition ...........................................................................................53 
12.2.2. 
Serious Adverse Event Definition ..............................................................................53 
12.2.3. 
Relationship to Investigational Product ......................................................................54 
12.2.4. 
Definition of Urgent Safety Measure and Unanticipated Problem .............................54 
12.2.5. 
Recording Adverse Events .........................................................................................55 
12.2.6. 
Reporting Serious Adverse Events .............................................................................56 
12.3. 
Pregnancy ...................................................................................................................56 
12.4. 
Special Considerations ................................................................................................57 
13. 
STATISTICS ..............................................................................................................58 
13.1. 
Data Analysis Sets ......................................................................................................58 
13.2. 
Handling of Missing Data ...........................................................................................58 
13.3. 
General Considerations ...............................................................................................58 
13.4. 
Demographics and Baseline Characteristics ...............................................................58 
13.5. 
Efficacy Analysis ........................................................................................................59 
13.6. 
Safety Analyses ..........................................................................................................60 
13.6.1. 
Adverse Events ...........................................................................................................60 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................60 




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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................13 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................22 
Table 4: 
Investigational Product ...............................................................................................42 
Table 5: 
Summary of Clinical Laboratory Analytes .................................................................51 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................6 
Figure 2: 
Study Design ...............................................................................................................29 
Figure 3: 
Prespecified Dose-response Models ...........................................................................62 
 
 


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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 3: 
Abbreviations and Specialist Terms 
Abbreviation 
Definition 
AE 
adverse event 
ADL 
activities of daily living 
AR(1) 
Autoregressive (1) 
BMI 
body mass index 
 
 
 
 
 
 
COVID-19 
coronavirus disease 2019  
 
 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
End of Study 
EOT 
End of Treatment 
 
 
 
 
 
 
ET 
essential tremor 
ETV 
Early Termination Visit 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GABAA 
γ-aminobutyric acid-gated chloride channel  
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Conference for Harmonisation 
ID 
identification 
IEC 
Independent Ethic Committee 
IP 
investigational product 
IRB 
Institutional Review Board  
IRT 
interactive response technology 


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Abbreviation 
Definition 
MCP-Mod 
Multiple Comparisons and Modeling 
MMRM 
mixed-effects model for repeated measures 
MR 
magnetic resonance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QTcF 
QT corrected according to Fridericia’s formula 
SAP 
statistical analysis plan  
SAE 
serious adverse event 
SUSAR 
suspected unexpected serious adverse reaction  
TEAE 
treatment-emergent adverse event 
TETRAS 
The Essential Tremor Rating Assessment Scale 
UP 
Unanticipated Problem 
USM 
Urgent Safety Measure 
 
 
WOCBP 
woman of childbearing potential 


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5. 
INTRODUCTION 
SAGE-324 is a positive allosteric modulator of A-type γ-aminobutyric acid-gated chloride 
channel (GABAA) receptors, the major class of inhibitory neurotransmitter receptors in the brain. 
SAGE-324 is planned to be evaluated for multiple indications affected by activity at the GABAA 
receptor, including essential tremor (ET). 
Clinical studies of SAGE-324 in healthy adults and in adults with ET, in addition to preclinical 
studies of SAGE-324, are detailed in the SAGE-324 investigator’s brochure as well as a detailed 
description of the chemistry, pharmacology, efficacy, and safety of SAGE-324. 
ET is a common, permanently debilitating, neurologically determined movement disorder 
characterized by involuntary rhythmic oscillation of a body part due to intermittent muscle 
contractions. This shaking typically occurs during voluntary movement (ie, when not at rest), 
thus interfering with fine motor skills associated with daily activities (Olanow 2008, Deuschl 
2011, Hopfner 2016, NIH 2019). Although the pathophysiology and etiology of ET is not fully 
understood, it is postulated that approximately 50% of ET patients feature an autosomal 
dominant pattern of familial inheritance and that non-inherited cases may have toxin-based or 
other causality (Olanow 2008, Hopfner 2016). ET is the most common movement disorder in the 
United States and worldwide, with prevalence estimated to be approximately 2.2% of the 
population, representing a substantial societal medical burden with over an estimated 7 million 
ET patients in the US alone (Louis 2014). 
In general, active tasks of daily life are adversely impacted by ET, including but not limited to 
speech, handwriting, household tasks, and occupational demands, contributing negatively to 
psychosocial well-being, general anxiety, and overall quality of life (Koller 1989). Although 
benign in terms of its effect on life expectancy, ET is a progressive neurodegenerative condition 
whose symptoms are typically disabling, often forcing patients to change jobs or seek early 
retirement (Zappia 2013). In some cases, serious disability may ensue.  
Current first-line therapies, propranolol and primidone, are the most commonly used medications 
for the treatment of ET. These therapies reduce tremor by >50% in 40% of people (Koller 1994), 
while up to 30% of patients do not respond to first-line therapy or experience intolerable adverse 
effects (Koller 1989). The only Food and Drug Administration (FDA)-approved pharmacological 
treatment for ET is propranolol, a β-adrenergic receptor antagonist. Because of its non-selective 
mechanism of action, not all individuals with ET are able to take propranolol due to 
contraindications such as asthma, heart failure, and diabetes (propranolol Prescribing 
Information). In addition, propranolol is not always well tolerated, mainly due to fatigue and 
similar adverse reactions, as well as rare serious adverse reactions (Olanow 2008, Wyeth 2010). 
Secondary pharmacologic approaches to the treatment of ET have included off-label use of 
anticonvulsants with limited GABA activity (eg, topiramate, gabapentin) and the use of alcohol 
(Rajput 2014). Notably, tolerability is a key limiting factor of propranolol, primidone, and 
similar therapies utilized by ET patients. 
Five clinical pharmacology studies (324-CLP-101, 324-CLP-102, 324-CLP-104, 324-CLP-105, 
and 324-CLP-106) and 1 efficacy study (324-ETD-201) are complete. The results of these 
clinical studies suggest that SAGE-324 may safely ameliorate symptoms in patients suffering 
from ET.  


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With a GABAA receptor-based mechanism of action featuring positive allosteric modulation 
capability, SAGE-324 represents a novel approach to the treatment of ET, which may help 
address the unmet medical need of the ET population, warranting further study of SAGE-324 as 
a potential treatment for this common movement disorder. Hence, this double-blind, 
placebo-controlled efficacy and safety study of SAGE-324 will be conducted in adults and is 
designed to assess the effect of 15, 30, and 60 mg doses of SAGE-324 on outcome measures 
specific to ET 
. 
5.1. 
Dose Justification 
Sage has completed 2 studies of SAGE-324 in participants with ET with promising results: a 
Phase 1 open-label, single, ascending-dose study (324-CLP-101) and a Phase 2 double-blind 
study (324-ETD-201) of once daily 60 mg of SAGE-324 or placebo for 28 days.  
One dose (60 mg), the highest dose from the 324-CLP-101 study, was evaluated in 
Study 324-ETD-201 to maximize the chance of seeing a pharmacodynamic effect. 
Study 324-ETD-201 met its prespecified primary endpoint while somnolence was the most 
common adverse event (AE) reported.  
The present study (324-ETD-202) is a 90-day, placebo-controlled, dose-ranging study of 15, 30, 
and 60 mg of SAGE-324 in participants with moderate to severe ET. Given the safety and 
efficacy profile of SAGE-324 to date, the widest possible exposure range of doses over a 90-day 
period will be administered in order to determine the optimal balance of efficacy and tolerability 
over a wide range of doses. 
In order to mitigate the AE of somnolence that was observed in Study 324-ETD-201, nighttime 
dosing will be employed for all 3 doses as well as an up-titration to the 60 mg dose (Section 7.3). 
Up-titration is a standard practice that is designed to allow participants to accommodate to the 
AE as plasma concentrations rise more slowly than they would if the target dose was 
administered from the start.  
5.2. 
Benefit/Risk Assessment 
Potential benefits and risks anticipated in this study are based on available data from 5 completed 
clinical pharmacology studies (324-CLP-101, 324-CLP-102, 324-CLP-104, 324-CLP-105, and 
324-CLP-106) and 1 completed efficacy study (324-ETD-201), as well as toxicology studies of 
SAGE-324. Available nonclinical and clinical data are summarized in the SAGE-324 
investigator’s brochure. 
Based on the mechanism of action of SAGE-324 and the results of completed nonclinical and 
clinical studies of SAGE-324, participants receiving SAGE-324 may have tremor reduction and 
improved quality of life. There is also currently no evidence of any interaction(s) (drug-drug or 
other, including propranolol) except for those outlined in the inclusion/exclusion criteria. 
In a Phase 2, randomized, double-blind, placebo-controlled study (324-ETD-201), a statistically 
significant treatment difference for SAGE-324 versus placebo was observed for the primary 
efficacy endpoint (-1.07; 95% confidence interval: -2.14 to 0.00; p = 0.0491), and clinically 
meaningful effects were reported by participants. In addition, the sensitivity analyses showed 
consistency of the primary endpoint results, and subgroup analyses demonstrated a treatment 
difference for SAGE-324 versus placebo for most subgroups. Also, a statistically significant 


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reduction from baseline in The Essential Tremor Rating Assessment Scale (TETRAS) 
Performance Subscale item 4 upper limb tremor score at Day 29 was observed in a population 
with baseline upper limb tremor score of ≥12 (p = 0.0066). Overall, the primary endpoint 
analyses have demonstrated potentially positive and therapeutic effects of SAGE-324 in 
participants suffering from ET. 
In clinical experience to date, treatment-emergent adverse events (TEAEs) of somnolence, 
feeling of relaxation, and dizziness have been most frequently reported. Most of the somnolence, 
dizziness, and feeling of relaxation events were mild or moderate. Severe serious adverse events 
(SAEs) of mental status changes were considered related to investigational product (IP) by the 
investigators. Some of reported events required dose reduction or study discontinuation but all 
events resolved without sequalae or requiring treatment. Participants in the current study will be 
dosed at nighttime and a blinded up-titration to the highest dose (60 mg) will be employed to 
mitigate the most commonly reported AE of somnolence in previous studies. Study participants 
will be closely monitored during scheduled visits, via phone calls in between clinic visits, or 
more frequently for AE monitoring as appropriate.  
Given the outcome of the Phase 2 study and the unmet need in the treatment of ET, further 
investigation of SAGE-324 in patients with ET is justified based on a favorable benefit-risk 
profile. 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary  
 
• 
To evaluate the dose-response 
relationship of different doses of 
SAGE-324 on upper extremity tremor in 
the monotherapy cohort  
• 
Change from baseline in The Essential Tremor 
Rating Assessment Scale (TETRAS) Performance 
Subscale Item 4 (upper limb) total score on Day 91 
in the monotherapy cohort  
Secondary  
 
• 
To evaluate the dose-response 
relationship of different doses of SAGE-
324 on specified activities of daily living 
(ADL) in the monotherapy cohort  
• 
Change from baseline in TETRAS ADL composite 
score in the monotherapy cohort  


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Objectives 
Endpoints 
• 
To assess the safety and tolerability of 
SAGE-324 
• 
Incidence of treatment-emergent adverse events 
(TEAEs)  
• 
To evaluate the effect of SAGE-324 on 
other safety parameters 
• 
Change from baseline in vital signs, 
electrocardiogram (ECG), clinical laboratory 
parameters
 
 
 
 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study is a Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to 
evaluate the efficacy, safety, and tolerability of SAGE-324 in participants with ET. Participants, 
site staff, and sponsor personnel will be blinded to treatment allocations. The study is 
schematically presented in Figure 2. 
Figure 2: 
Study Design 
 
Abbreviation: R = TETRAS = The Essential Tremor Rating Assessment Scale 
Note: The Screening Period may be extended for an additional 14 days (total of 42 days) for subjects requiring 
additional time to taper ET medication (other than propranolol), after approval from the sponsor. 
 
This study includes a Screening Period of up to 28 days, a 90-day double-blind Treatment Period 
(90 days of dosing), and a 14-day Follow-up Period. After providing informed consent, 
participants will undergo screening assessments to determine eligibility as outlined in Table 2. 
Screening Period: The Screening Period begins with the signing of the informed consent form 
(ICF). Eligible participants will visit the study center on Day 1 and complete additional 
eligibility and baseline assessments, as specified in the Schedule of Assessments (Table 2). The 
Screening Period may be extended for an additional 14 days (total of 42 days) for subjects 
requiring additional time to taper ET medication (other than propranolol), after approval from the 
sponsor. Following completion of screening and Day 1 eligibility assessments, participants will 
be randomized to 1 of 4 treatment groups (placebo or SAGE-324: 15 mg, 30 mg, or 60 mg, oral 
daily) in a 1:1:1:1 ratio, stratified by baseline propranolol use (adjunct therapy).  
Double-Blind Treatment Period: Starting on Day 1, after randomization, participants will 
receive a single dose of IP once daily for 90 days on an outpatient basis, to be taken before bed, 
with a snack if bedtime is not within 2 hours of the evening meal. Guidance on suitable snacks 
will be provided. During the Treatment Period, participants will return to the study center for 
efficacy and safety assessments as specified in Table 2. In addition, safety phone call study visits 
will be conducted according to Table 2, or more often as deemed appropriate by the investigator, 
to review the current status of the participant. Participants will be trained on the use of software 
applications and devices necessary to complete questionnaires or self-rated study assessments.  


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Participants should gain experience with the study drug to see how it affects them before 
engaging in potentially hazardous activities requiring mental alertness, such as driving.  If 
participants experience any sleepiness, dizziness, or feelings of relaxation, or have other sedative 
effects, they should not engage in potentially hazardous activities requiring mental alertness, 
such as driving, until any sleepiness/sedative effects from the study drug have dissipated.  This is 
important because study participants may not be able to judge how these sedative effects will 
affect their ability to perform potentially hazardous activities requiring mental alertness, 
including driving. 
Follow-up Period: Follow-up visits will be conducted on an outpatient basis on Days 97 and 
104. Participants will continue to complete questionnaires as indicated in Table 2 and will return 
to the clinic approximately 6 days after the last dose of IP (ie, Day 97) for efficacy and safety 
monitoring. Participants will return to the study center for an End of Study (EOS) visit 
approximately 13 days following the last dose of IP (ie, Day 104); the EOS visit will be 
conducted at the time of discontinuation if this occurs any time before Day 104. 
No dose reductions of SAGE-324 will be permitted. 
All participants who conclude the study will be offered the opportunity to enroll to a SAGE-324 
long-term open-label study, as per the long-term open-label study’s eligibility criteria. 
7.2. 
Number of Participants 
Approximately 160 participants, with at least 104 (65%, 26 participants per dose group) 
monotherapy participants and up to 56 (35%, 14 participants per dose group) adjunct therapy 
participants, will be randomized to ensure at least 22 participants per arm in the monotherapy 
cohort will complete the study.  
7.3. 
Treatment Assignment 
This is a randomized, double-blind, placebo-controlled study. Participants will be randomized in 
a 1:1:1:1 ratio to treatment groups (15 mg, 30 mg, 60 mg SAGE-324, or placebo), stratified by 
baseline propranolol use. 
SAGE-324 or matching placebo will be administered orally once daily, to be taken before bed, 
with a snack if bedtime is not within 2 hours of the evening meal.  
The placebo dose group will receive matching placebo from Day 1 to Day 90. 
The 15-mg SAGE-324 dose group will receive 15 mg of SAGE-324 from Day 1 to Day 90. 
The 30-mg SAGE-324 dose group will receive 30 mg of SAGE-324 from Day 1 to Day 90. 
The 60-mg SAGE-324 dose group will receive 15 mg of SAGE-324 from Day 1 to Day 14, then 
30 mg from Day 15 to Day 28, then 45 mg from Day 29 to Day 42, and then 60 mg from Day 43 
to Day 90. 
7.4. 
Dose Adjustment Criteria 
Dose adjustments are not allowed in this study. 


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7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs/SAEs 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 Day 104 visit. 


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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. Participant has signed an informed consent form (ICF) before any study-specific 
procedures or washout of drugs is started. 
2. Participant is ambulatory and is 18 to 80 years of age, inclusive, at the time informed 
consent is obtained. 
3. Participant is in good physical health and has no clinically significant findings (excluding 
ET), as determined by the investigator, on physical examination, including neurologic 
and mental status examinations, 12-lead ECG, or clinical laboratory tests.  
4. Participant has a diagnosis of ET, as defined by all of the following criteria: 
a. Isolated tremor syndrome consisting of bilateral upper limb action tremor  
b. At least 3 years duration  
c. With or without tremor in other locations (eg, head, voice, or lower limbs). 
5. Absence of other neurological signs, such as dystonia, ataxia, or parkinsonism, isolated 
focal tremors (eg, voice, head), task- and position-specific tremors, sudden tremor onset 
or evidence of stepwise deterioration of tremor. 
6. Participant has the following: 
a. Scores at least 12 in the combined TETRAS Performance Subscale Item 4 (upper 
limb tremor) at both Screening and predose on Day 1 
b. Scores at least 6 in the total TETRAS Performance Subscale Item 4 score for the 
dominant upper limb (the sum of the three items for either the right or left upper 
limb, whichever is dominant) at both Screening and predose on Day 1. 
7. Participant has a baseline TETRAS ADL Subscale score of at least 20 at Screening. 
8. Participant is willing to discontinue medications taken for the treatment of ET except 
propranolol at least 14 days or 5 half-lives (whichever is longer) prior to receiving IP. 
Medications taken for the treatment of ET that were discontinued prior to receiving IP 
may be resumed following Day 97. Participants in the adjunct therapy cohort must be on 
a stable dose of propranolol (maximum total daily propranolol dose up to 320 mg 
allowed) for the treatment of ET from 3 months prior to Screening through Day 97 of the 
study. 
9. Participant is willing to limit use of alcohol to 2 units per day for males and 1 unit per 
day for females starting at least 1 week prior to Day 1 and through Day 97 of the study.  
A unit of alcohol is defined as: 12 ounces of regular beer, 5 ounces of wine, or 1.5 ounces 
of distilled spirits.  
Participant will limit alcohol use to at least 2 hours before self-administration of IP in the 
evening.  


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Participant will not use alcohol starting 24 hours prior to the scheduled in-clinic study 
visits until all assessments have been completed.   
10. Female participant agrees to use at least one method of highly effective contraception as 
listed in Section 9.2.4 during participation in the study and for 30 days following the last 
dose of study drug, unless she is postmenopausal (at least 12 months of spontaneous 
amenorrhea without an alternative medical cause, with confirmatory follicle stimulating 
hormone [FSH] >40 mIU/mL), and/or surgically sterile (bilateral oophorectomy, 
hysterectomy, and/or bilateral salpingectomy), or does not engage in sexual relations 
which carry a risk of pregnancy (does include abstinence).  
11. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 13 weeks after receiving the last dose of study drug, unless 
the participant does not engage in sexual relation(s) which carry a risk of pregnancy. 
Acceptable methods of effective contraception are listed in Section 9.2.4. 
12. Male participant is willing to abstain from sperm donation for the duration of the study 
and for 13 weeks after receiving the last dose of study drug.  
13. Participant is willing to maintain prestudy consumption of products that contain nicotine 
starting at least 1 week prior to Day 1 and through Day 97 of the study.  
8.2. 
Participant Exclusion Criteria 
Participants who meet any of the following criteria are disqualified from participation in this 
study: 
1. Participant has presence of known causes of enhanced physiological tremor.  
2. Participant has had newly administered tremorgenic drugs (14 days or 5 half-lives 
[whichever is longer] prior to Day 1) or presence of alcohol withdrawal state.   
3. Participant has had direct or indirect injury or trauma to the nervous system within 
3 months before the onset of tremor.  
4. Participant has had a previous procedure for the treatment of ET, deep brain stimulation, 
brain lesioning, or magnetic resonance (MR) guided procedure, eg, MR-guided focused 
ultrasound. Use of Cala Trio bracelet for the treatment of ET from two weeks prior to 
Day 1 through Day 97 is prohibited. 
5. Participant has had botulinum toxin for treatment of ET within 6 months of Screening.  
6. Participant has historical or clinical evidence of tremor with functional neurological 
syndrome origin.  
7. Participant has currently active and medically significant or uncontrolled hepatic, renal, 
cardiovascular, pulmonary, gastrointestinal, hematological, immunologic, metabolic 
disease (hypothyroidism with stable thyroid replacement is acceptable).  
8. Participant has a body weight >140 kg or a body mass index (BMI) ≥50 kg/m2 at 
Screening.  
9. Participant currently requires propranolol treatment for a medical condition other than 
ET. 


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10. Participant has a clinically relevant history within 3 years of Screening or ongoing 
oncologic disease, in the judgement of the investigator, excluding skin cancers 
(squamous or basal cell carcinoma) for which treatment has been completed or any 
carcinoma in situ.  
11. Participant has history of substance abuse or dependence prior to Screening has a positive 
screen for drugs of abuse at Screening or predose on Day 1. Participants with nicotine use 
disorder that impacts their tremor are excluded. 
12. Participant has a known allergy to any IP excipient.  
13. Female participant has a positive pregnancy test or confirmed pregnancy or is 
breastfeeding. 
14. Participant has had exposure to another investigational drug or device within 30 days or 
5 half-lives of the investigational drug, whichever is longer, prior to the Day 1 visit. 
 
16. Participant has donated 1 or more units (1 unit = 450 mL) of blood or experienced acute 
loss of an equivalent amount of blood within 60 days prior to Day 1.  
17. Participant has night shift work. 
18. Participant has any condition or comorbidity that in the opinion of the investigator would 
limit or interfere with the participant’s ability to complete or partake in the study. 
19. Participant is unwilling or unable to comply with study procedures and required training. 
20. Participant has used any known moderate or strong cytochrome P450 3A4 inhibitors 
and/or inducers within 14 days or 5 half-lives (whichever is longer) prior to Day 1 or 
consumed grapefruit juice, grapefruit, Seville oranges, pomegranates, tangelos, or 
St. John’s Wort or products containing these within 30 days prior to Day 1 and is 
unwilling to refrain from taking these medications or foods for the duration of dosing. 
Use of mild cytochrome inhibitors and/or inducers may be permitted.  
21. Participant has concurrent or recent exposure (14 days or five half-lives, whichever is 
longer, prior to the Day 1 visit) to sedative/hypnotic drugs, stimulants, highly caffeinated 
beverages, or dietary supplements containing high doses of caffeine, or recent increase 
above regular daily consumption of caffeine. 
22. Participant plans to undergo elective surgery during participation in the study. 
23. Participant is unable to complete participation in the study, eg, due to preplanned event. 
24. Participant is investigative site personnel or a member of their immediate families 
(spouse, parent, child, or sibling whether biological or legally adopted). 
25. Participant has previously participated in a SAGE-324 clinical study. 


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8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized in the study. A minimal set of screen failure information will be 
collected, including demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened if reason for screen failure was not due to ineligible TETRAS score. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, or administrative reasons. 
The reason for IP discontinuation and/or the reason for early termination from the study must be 
documented in the participant’s study record and recorded in the participant’s electronic case 
report form (eCRF). 
The investigator must notify the sponsor and/or the medical monitor when a participant stops 
participation in the study for any reason. 
8.4.1. 
Investigational Product Discontinuation 
A participant may discontinue IP at any time at his/her own request for any reason. The 
investigator may discontinue a participant from IP for safety, behavioral, compliance, or 
administrative reasons. Participants who discontinue IP will be encouraged by the investigator to 
remain on study and complete the End of Treatment (EOT) Visit, the Follow-up Visit 7 days 
later, and then, after a further 7 days, the EOS/Early Termination Visit (ETV), as specified in the 
Schedule of Assessments (Table 2). If the participant withdraws consent to collect protected 
health information, the EOS/ETV will be conducted. 
The reason for IP discontinuation must be documented in the participant’s source documentation 
and recorded in the participant’s eCRF.  
The investigator must notify the sponsor and/or the medical monitor when a participant stops IP 
for any reason.  
Participants who discontinue IP due to an AE, regardless of investigator-determined causality, 
should be followed until the event is resolved, considered stable, or the investigator determines 
the event is no longer clinically significant. 
8.4.2. 
Early Termination from the Study 
At the time of study withdrawal, if possible, an ETV should be conducted. Regardless of period, 
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. 


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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. 
Reasons for study discontinuation include, but are not limited to, the following:  
• Adverse event 
• Pregnancy 
• Protocol deviation 
• Lost to follow-up 
• Withdrawal by participant 
• Screen failure 
• Study terminated by sponsor 
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after unsuccessful documented attempts to contact 
the participant  
8.4.4. 
Replacement of Participants 
Participants will not be replaced. 
Additional monotherapy participants may be enrolled at the discretion of the sponsor to achieve 
at least 22 evaluable participants per dose group.  


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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Product 
SAGE-324 is an orally administered tablet provided in 15-mg dose strengths. Participants will 
receive IP (15 mg, 30 mg, or 60 mg total dose of SAGE-324 tablets, or appearance-matched 
placebo tablets) according to the randomization schedule. Additional details regarding IP 
preparation, formulation, and storage are included in Section 10. 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route, dose/units, frequency, and indication for all medications and/or 
supplements taken within 30 days prior to signing the informed consent will be recorded. In 
addition, all psychotropic medications taken in the previous 30 days prior to Screening will be 
recorded. The start and end dates, route, dose/units, and frequency for all medications for ET 
taken at any time prior to signing the informed consent are also recorded. 
All medications and/or supplements taken from the dosing of IP on Day 1 through the end of the 
study (including start and end dates route, dose/units, frequency, and indication) will be recorded 
on the eCRF. 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. 
9.2.2. 
Prohibited Medications 
Use or consumption of the following is prohibited for the timeframes specified:  
• Any estrogen-containing products that are widely absorbed into the systemic 
circulation (eg, oral, transdermal, transvaginal, etc.), used for any indication, are 
prohibited from Day -14 and during the study. 
• Treatment with an investigational drug or device during the 30 days or 5 half-lives (if 
known) of the investigational drug, whichever is longer, prior to Day 1 or during the 
study.  
• New treatment with tremorgenic drugs within 14 days or 5 half-lives (whichever is 
longer) of Day 1 or during the study. Continued use of established treatment with 
tremorgenic drugs is permitted if there is no evidence of previous or current concerns 
for these medications to cause or exacerbate tremor as determined by investigator. 
• Use of agents known to affect SAGE-324 drug metabolism (any known moderate or 
severe cytochrome P450 3A4 inhibitors and/or inducers) within 14 days or 5 half-
lives (whichever is longer) of Day 1 and through Day 90 of the study period. Use of 
mild cytochrome inhibitors and/or inducers may be permitted. 
• Concomitant use of sedative/hypnotic drugs for 14 days or 5 half-lives prior to Day 1 
and during the 90-day dosing period. 
• As needed [PRN] propranolol use during the study. 


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9.2.2.1. 
Prestudy Essential Tremor Medications Washout 
• Any prior ET medications other than propranolol must be discontinued prior to the 
Screening TETRAS: 
− There must be at least 14 days or 5 half-lives (whichever is longer) washout 
period prior to the Day 1 (baseline) visit.   
− For drugs requiring down-titration, there must be the required number of days for 
down-titration plus 14 days or 5 half-lives (whichever is longer) prior to the Day 1 
(baseline) visit.  
− If necessary, screening assessments may be split between 2 visits in order to allow 
enough time for washout or down-titration and washout of prior ET therapy 
during the screening period. 
• Prior ET medications may be restarted following Day 97 of the study.  
• Participants in the adjunct therapy cohort must be on a stable dose of propranolol 
(maximum total daily propranolol dose up to 320 mg allowed) from 3 months prior to 
Screening through Day 97 of the study (no additional propranolol as needed [PRN] is 
allowed). 
9.2.3. 
Other Restrictions  
• Use of any drugs of abuse during the study period is prohibited. Note: participants 
with a history of drug abuse prior to Screening should not be enrolled in the study. 
• Use of alcohol is limited to 2 units per day for males and 1 unit per day for females 
starting at least 1 week prior to Day 1 and through Day 97 of the study.  
A unit of alcohol is defined as: 12 ounces of regular beer, 5 ounces of wine, or 
1.5 ounces of distilled spirits.  
Participant will limit alcohol use to at least 2 hours before self-administration of IP in 
the evening.  
Participant will not use alcohol starting 24 hours prior to the scheduled in-clinic study 
visits until all assessments have been completed.  
• Participants should gain experience with the study drug to see how it affects them 
before engaging in potentially hazardous activities requiring mental alertness, such as 
driving.  If participants experience any sleepiness, dizziness, or feelings of relaxation, 
or have other sedative effects, they should not engage in potentially hazardous 
activities requiring mental alertness, such as driving, until any sleepiness/sedative 
effects from the study drug have dissipated.  This is important because study 
participants may not be able to judge how these sedative effects will affect their 
ability to perform potentially hazardous activities requiring mental alertness, 
including driving. 
• Use of products that contain nicotine is maintained at prestudy levels starting at least 
1 week prior to Day 1 and through Day 97 of the study period. Participants with 
nicotine use disorder that impacts their tremor are excluded. 


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• Consumption of grapefruit juice, grapefruit, Seville oranges, pomegranates, tangelos, 
or St. John’s Wort or products containing these within 30 days prior to Day 1 and 
through Day 90 of the study period is prohibited.  
• Use of stimulants, highly caffeinated beverages, or dietary supplements containing 
high doses of caffeine within 14 days or five half-lives, whichever is longer, prior to 
the Day 1 visit and through Day 90 of the study period is prohibited. Note: 
participants should not increase their regular daily consumption of caffeine during the 
study period. 
• The use of medications other than fexofenadine for chronic allergies is recommended 
during participation in the study. 
• Use of Cala Trio bracelet for the treatment of ET from two weeks prior to Day 1 
through Day 97 is prohibited. 
9.2.4. 
Acceptable Forms of Contraception 
As per the Clinical Trials Facilitation and Coordination Group (CTFG), a woman is considered 
of childbearing potential (WOCBP), ie, 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. A high follicle stimulating hormone (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 (ie, can achieve a failure rate of <1% per year 
when used consistently and correctly) for participants of childbearing potential or for partners of 
male participants who are of childbearing potential include the following list.  
• Progestogen-only oral, injectable, intravaginal, implantable, or transdermal hormonal 
contraception associated with inhibition of ovulation. The use of estrogen-containing 
contraceptives that are widely absorbed into the systemic circulation are prohibited. 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion or bilateral tubal ligation (performed at least 3 months prior 
to screening) 
• Vasectomized partner (performed at least 3 months prior to screening) 
• Sexual abstinence (no sexual intercourse) 
Acceptable forms of contraception for male participants include: 
• Sexual abstinence (no sexual intercourse) 
• History of vasectomy (performed at least 3 months prior to screening) 


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• 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) 
Acceptable forms of contraception which may not be considered as highly effective include: 
• Oral progestogen-only hormonal contraception, where inhibition of ovulation is not 
the primary mode of action  
• Male or female condom with or without spermicide  
• Cap, diaphragm, or sponge with spermicide  
• A combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double barrier methods) are also considered acceptable 
9.3. 
Intervention after the End of the Study 
All participants who conclude the study will be offered the opportunity to enroll in a SAGE-324 
long-term open--label study, as per the long-term open-label study’s eligibility criteria. 
9.4. 
Treatment Adherence 
Participants will be dispensed IP starting on Day 1 and at each clinic visit for use at home prior 
to the next clinic visit with instructions specifying that IP is to be administer before bed, with a 
snack if bedtime is not within 2 hours of the evening meal. Treatment adherence will be 
monitored by the site staff at each in-clinic visit by direct questioning and counting returned 
tablets and will be documented. Details on drug accountability are included in Section 10. 
Patients will be asked to record the dates and times of their IP dose administrations at home in a 
diary. They will also record the number of tablets taken and if it was taken with food.  
9.5. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Participants will be randomized in 
a 1:1:1:1 ratio to treatment groups (15 mg, 30 mg, 60 mg SAGE-324, or placebo) stratified by 
baseline propranolol use (adjunct therapy). Participants, site staff, and the sponsor will be 
blinded to treatment allocation (see study schematic in Figure 2).  
Randomization schedules will be generated by an independent statistician. The randomization 
schedules will be kept strictly confidential, accessible only to authorized personnel until the time 
of unblinding. The blinding of the study will be broken after the database has been locked. 
9.5.1. 
Emergency Unblinding 
During the study, the blind is to be broken 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 diligent attempts to contact the sponsor prior to unblinding the 
IP administered to a participant. Requests from the investigator about the treatment administered 
to study participants should be discussed with the medical monitor. If the unblinding occurs 
without the sponsor’s knowledge, the investigator must notify the sponsor within 24 hours of 
breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records.  


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In all cases where study personnel are unblinded, pertinent information (including the reason for 
unblinding) must be documented in the participant’s source documentation and in the IRT. At 
the time of withdrawal from the study/stopping participation, if possible, an EOT and/or ETV 
should be conducted.  


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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
Table 4: 
Investigational Product 
 
Investigational Product 
Product Name: 
SAGE-324 
Placebo 
Dosage Form: 
Tablet 
Tablet 
Tablet Strength 
15 mg 
0 mg, appearance-matched to 
15 mg, respectively 
Route of Administration 
Oral 
Oral 
Physical Description 
Immediate release white to off-
white-, round, film-coated tablet 
containing 15 mg of SAGE-324 
drug substance, and composed 
of SAGE-324, lactose, 
microcrystalline cellulose, 
croscarmellose sodium, sodium 
stearyl fumarate and fumed 
silica, featuring Opadry® II 
white as the coating agent. 
White to off-white, round, 
film-coated tablet containing no 
drug substance, composed of 
lactose, microcrystalline 
cellulose, croscarmellose 
sodium, sodium stearyl fumarate 
and fumed silica, featuring 
Opadry® II white as the coating 
agent.  
Manufacturer 
Sage Therapeutics, Inc. 
10.2. 
Investigational Product Packaging and Labeling 
Oral SAGE324 and placebo tablets will be packaged in blinded, high-density polyethylene 
containers. The containers used for SAGE-324 and placebo will be identical in appearance. The 
package labeling conforms to FDA and Good Manufacturing Practice requirements. 
10.3. 
Investigational Product Storage 
Upon receipt of the IP, the investigator, or the responsible pharmacist or designee, will inspect 
the product and acknowledge receipt in accordance with the study-specific process. 
The IP must be carefully stored at the temperature specified in the Investigator’s Brochure, 
securely and separately from other drugs. The IP may not be used for any purpose other than the 
present study. After the study is completed, all unused IP must be returned per the sponsor’s 
instructions or destroyed locally per the site’s procedure(s). IP may not be destroyed until 
accountability and reconciliation procedures have been completed and monitored. 
The investigator or designee will be responsible for ensuring appropriate storage, compounding 
(if applicable), dispensing, inventory, and accountability of the IP. An accurate, timely record of 
the disposition of the IP must be maintained. 


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10.4. 
Investigational Product Preparation 
The IP will be in tablet form and provided in blinded packaging. No preparation is required for 
the tablet, which is administered orally as described below. 
10.5. 
Investigational Product Administration 
The IP will be administered at home as specified in the Schedule of Assessments (Table 2). All 
participants will take 4 tablets per day in a mix of active and placebo tablets to achieve a dose of 
15 mg (1 SAGE-324 tablet and 3 placebo tablets per dose), 30 mg (2 SAGE-324 tablets and 
2 placebo tablets per dose), or 60 mg (4 SAGE-324 tablets). IP will be orally administered once 
daily before bed, with a snack if bedtime is not within 2 hours of the evening meal.  
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 investigator’s 
brochure and (where applicable) in the pharmacy manual. A copy of the shipping documentation 
will be kept in the study files. 
Site staff will access the interactive response technology (IRT) at the Screening Visit to obtain a 
participant identification (ID) number for each participant that has signed an ICF. On Day 1, site 
staff will access the IRT and provide the necessary participant-identifying information, including 
the participant ID number assigned at Screening, to randomize the eligible participant into the 
study and obtain the IP ID number for the IP to be dispensed to that participant. The IP ID 
number and the number of tablets dispensed must be recorded. 
At subsequent IP-dispensing visits, the investigator or designee will access the IRT, providing 
the same participant ID number assigned at Screening, to obtain the IP ID number for the IP to 
be dispensed at that visit. The IP ID number, the number of tablets dispensed, and the number of 
tablets returned by the participant at each visit must be recorded.  
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
sponsor must be notified immediately. 
The IP provided is for use only as directed in this protocol. The Investigator or designee must 
keep a record of all IP received, used, and returned/discarded.  
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 (ie, 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; disposition of IP will be documented. 
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. 


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In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1 and in 
the pharmacy manual. Where possible, personnel should segregate and retain any product, 
materials, or packaging associated with the product complaint until further instruction is 
provided by Sage or its designated representative(s). 


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11. 
EFFICACY 
 
11.1. 
Efficacy Assessments 
11.1.1. 
The Essential Tremor Rating Assessment Scale 
TETRAS is a validated, comprehensive clinical assessment of ET (Elble 2013).  
The TETRAS ADL Subscale and the TETRAS Performance Subscale will both be assessed at 
each clinic visit as specified in the Schedule of Assessments under TETRAS (Table 2).  
The Performance Subscale assesses overall rating of tremor in the voice, limbs, head, face, trunk, 
while performing prespecified tasks, and also measures functional task capabilities, ie, 
handwriting, spirography, and holding a pen over a dot. Each of these items is rated on a scale 
from 0 (no tremor) to 4 (severe tremor). Collectively, the performance items generate an overall 
performance score from 0 to 64.  
For Item 4 upper limb tremor of the Performance Subscale, all 3 maneuvers in the upper limb 
assessments (subscale items 4a, 4b, and 4c) will be completed for both arms, first for the right 
arm and then for the left. Item 4 subscale ordinally rates postural (limbs extended forward 
maneuver, and wing-beating [elbows flexed] maneuver), and kinetic (finger-nose-finger 
maneuver) tremor on a 0 to 4 severity scale in 0.5-point increments.  
The ADL Subscale assesses how ET affects typical ADL (ie, speech, eating, drinking, dressing, 
personal hygiene, writing, occupational impairment, social impact, and activities affected by 
upper limb tremor). It consists of 12 items that are each rated on a scale from 0 (normal activity) 
to 4 (severe abnormality). The overall ADL score range is 0 to 48. 
The ADL composite endpoint comprises Items 1 to 11 of the ADL Subscale and Item 6 of the 
Performance Subscale.  
Responses of 0 and 1 in TETRAS ADL Subscale item 1 to 11 and performance Subscale 6 will 
be collapsed and analyzed as a single response of 0 = normal/slightly abnormal such that the 
scale becomes:  
0 = Normal/slightly abnormal 
1 = Mildly abnormal 
2 = Moderately abnormal 
3 = Severely abnormal 
In this study, a videographer will videotape TETRAS administration at Screening. 
Every effort should be made for the same rater to perform all TETRAS assessments for an 
individual participant and where possible, other assessments conducted by a separate site 
personnel. 
Prior medications for ET must be discontinued prior to Screening TETRAS ratings (see 
Section 9.2.2.1 for washout periods). 
 
 


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11.2.2. 
Pharmacodynamic Assessments 
Not applicable. 


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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
Any abnormality in physical examinations, vital signs, ECGs, or clinical laboratory test results 
outside of the normal range will be interpreted by an investigator as clinically significant or not 
clinically significant in source documents. 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, ethnicity) and a full medical history, including 
concomitant medications and supplements, products that contain nicotine, and alcohol use, will 
be documented. 
12.1.2. 
Weight and Height 
Height and weight will be measured and documented. BMI will be calculated and documented. 
12.1.3. 
Physical Examination 
Complete physical examinations and a comprehensive neurological examination, including 
mental state examinations, should be performed at Screening and EOT and as clinically 
necessary. Whenever possible, the same individual should perform all physical examinations. 
Complete physical examinations will include assessment of body systems (eg, head, eyes, ears, 
nose, and throat; heart; lungs; abdomen; and extremities) as well as cognitive and neurological 
examination and mental status examination. Targeted physical and neurological examinations 
should be performed at other times as indicated by AEs, per the investigator’s discretion. 
12.1.4. 
Vital Signs 
Vital signs comprise heart rate, respiratory rate, temperature, and blood pressure. Systolic and 
diastolic blood pressure are to be measured after the participant has been supine for at least 
5 minutes prior to the measurement. Orthostatic blood pressure and heart rate will also be 
measured after the participant has been in the supine position for at least 5 minutes and then 
repeated approximately 1 and 3 minutes after standing. On Day 1, supine and standing blood 
pressure and heart rate will be collected in triplicate at least 15 minutes apart. 
12.1.5. 
Electrocardiogram  
A 12-lead ECG will be performed. 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. ECGs will be performed after the participant has been resting in a supine position for 
at least 5 minutes. ECG may be repeated once for confirmatory purposes if initial values 
obtained exceed the limits specified.  
When ECG measurements coincide with safety and efficacy assessments, vital signs assessment 
or blood draws, procedures should be carried out in the following order: vital signs, TETRAS, 
ECG, blood sample collection for 
 clinical laboratory assessments, and questionnaires. 


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12.1.6. 
Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected at the visits and 
timepoints specified in Table 2. Analytes to be evaluated are summarized in Table 5. 
Table 5: 
Summary of Clinical Laboratory Analytes 
Biochemistry 
Renal Panel: glucose, calcium, phosphorus, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate 
Hepatic Panel: albumin, alanine aminotransferase, aspartate aminotransferase, total 
bilirubin, direct bilirubin, indirect bilirubin, alkaline phosphatase, total protein, 
lactate dehydrogenase, gamma glutamyl transferase, creatine kinase (MB and MM) 
Other: Full lipid profile/panel, creatine phosphokinase, thyroid stimulating 
hormone, alcohol level, HbA1c 
Coagulation 
activated partial thromboplastin time, prothrombin time, and international 
normalized ratio 
Hematology 
red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell count with 
differential, platelet count, and if RBC indices are abnormal, reflex RBC 
morphology is indicated 
Urinalysis 
protein, glucose, pH, blood, leukocytes, leukocyte esterase, urobilinogen, bilirubin, 
ketones, nitrite, myoglobin 
Note: Myoglobin (urinalysis) and serum creatine kinase (biochemistry) at Screening and at other timepoints at the 
discretion of the investigator. HbA1c will be collected at Screening and EOS/ETV Visit only. 
12.1.6.1. Drugs of Abuse and Alcohol 
A urine sample will be collected for assessment of selected drugs of abuse (amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine metabolites, and opiates).  
A serum sample will be collected for assessment of blood alcohol level. 
12.1.6.2. Pregnancy Screen 
A serum pregnancy test will be conducted for all female participants at Screening (Table 2); a 
urine pregnancy test will be conducted for all participants of childbearing potential at all other 
scheduled timepoints. 
 
 
 
  
 
 
 


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12.1.10. 
COVID-19 Questions 
Information regarding diagnosis, isolation, and/or hospitalization due to coronavirus disease 
2019 (COVID-19) will be documented at the time points indicated in the Schedule of 
Assessments (Table 2) and will be repeated as appropriate if a participant reports a COVID-19 
diagnosis during the study. The site will be allowed to follow procedures already in place for 
screening participants for prior potential COVID-19 exposure. As a result, additional questions 
may be asked of the participant. 
Questions to be asked are as follows: 
26. Were you diagnosed with COVID-19 by a healthcare professional? 
• If the answer is “no”, no further questions. 
• If the answer is “yes”, the following questions are asked: 
− Did you have a test? If yes, was the result positive, negative, or inconclusive? 
− Were you isolated? If yes, what were the dates of isolation? 
− Were you hospitalized? If yes, what were the dates of hospitalization? 
27. Did you receive the COVID-19 vaccine? 
• If the answer is “no”, no further questions. 
• If the answer is “yes”, the following questions are asked: 
− What is the reported name of the COVID-19 vaccine you received? 
− Who is the manufacturer of the COVID-19 vaccine you received? 
− On what date(s) did you receive the COVID-19 vaccine? 


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12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is defined as an AE with onset after the start of IP, or any worsening of a pre-existing 
medical condition/AE with onset after the start of IP and throughout the study. The term IP 
includes any Sage IP, a comparator, or a placebo administered in a clinical study. 
Laboratory abnormalities and changes from baseline in vital signs and ECGs are considered AEs 
if they result in discontinuation or interruption of study treatment, require therapeutic medical 
intervention, meet protocol specific criteria (if applicable) or if the investigator considers them to 
be clinically significant. Any abnormalities that meet the criteria for an SAE should be reported 
in an expedited manner. Laboratory abnormalities and changes from baseline in vital signs and 
ECGs that are clearly attributable to another AE do not require discrete reporting (eg, electrolyte 
disturbances in the context of dehydration, chemistry, and hematologic disturbances in the 
context of sepsis). 
All AEs that occur after any participant has signed the informed consent and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage 
Therapeutics. 
Participants who discontinue the IP due to an AE, regardless of investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the investigator 
determines the event is no longer clinically significant. Any AEs that are unresolved at the 
participant’s last AE assessment in the study are followed up by the investigator for as long as 
medically indicated, but without further recording in the eCRF. The sponsor or its representative 
retains the right to request additional information for any patient with ongoing AE(s)/SAE(s) at 
the end of the study, if judged necessary. 
12.2.2. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 


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An SAE may also be any other medically important event that, in the opinion of the investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow-up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP. 
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
alternative explanation for the AE 
Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include, but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and the 
event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the drug 
and the AE, or a lack of alternative explanation for the AE 
12.2.4. 
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 in 


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order to protect the participants of a study against any immediate hazard to their health or safety. 
Examples of USMs include: 
• Suspension of enrollment due to significantly higher incidence of death at one site 
• Additional clinical or non-clinical investigations performed due to increased 
frequency of AEs 
• Halting a clinical study for safety reasons 
In accordance with FDA Guidance 21 Code of Federal Regulations 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 UP must be reported within 24 hours of awareness via email to Sage and designee upon 
discovery due to the urgent reporting requirements to regulators and IRB(s)/IECs(s). 
12.2.5. 
Recording Adverse Events 
AEs spontaneously reported by the participant and/or in response to an open question from the 
study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
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 
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It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.6. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage and designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage and designee. 
Additional follow-up information, if required or available, should all be sent to Sage and 
designee within 24 hours of receipt on a follow-up SAE report form and placed with the original 
SAE information and kept with the appropriate section of the eCRF and/or study file. 
SAEs occurring after the designated follow-up time for the study, should be reported to Sage and 
designee according to the timelines noted above only if the investigator considers the SAE 
related to IP. 
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB 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 will be notified of SAEs and/or 
SUSARs as required by local law. 
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARs to investigators in a blinded fashion. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the Pregnancy Form and submitted to the Sage and designee 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 and designee within 24 hours of 


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awareness. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, pre-eclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death), the investigator should follow the procedures 
for reporting an SAE. 
12.4. 
Special Considerations 
Drug abuse is the persistent or sporadic, intentional excessive use of IP which is accompanied by 
harmful physical or psychological effects in the participant. If an event of drug abuse occurs 
during the study, it must be reported to the sponsor and designee (see Table 1) using the Special 
Considerations Form within 24 hours of the site becoming aware of the event(s). If the drug 
abuse results in an AE or SAE, the AE or SAE must also be recorded and reported as described 
in Section 12.2.5 and Section 12.2.6, respectively. 
Drug misuse refers to situations where IP is intentionally and inappropriately used not in 
accordance with the intended use as specified in the protocol. If an event of drug misuse occurs 
during the study, it must be reported to the sponsor and designee using the Special 
Considerations Form within 24 hours of the site becoming aware of the event(s). If the drug 
misuse results in an AE or SAE, the AE or SAE must also be recorded and reported as described 
in Section 12.2.5 and Section 12.2.6, respectively. 
An overdose is any dose of IP given to a participant or taken by a participant that exceeds the 
dose described in the protocol. Overdoses are not considered AEs and should not be recorded as 
an AE on the CRF; however, all overdoses must be recorded on the Special Considerations Form 
and sent to Sage and designee within 24 hours of the site becoming aware of the overdose. An 
overdose must be reported to Sage and designee even if the overdose does not result in an AE. If 
an overdose results in an AE or SAE, the AE or SAE must also be recorded and reported as 
described in Section 12.2.5 and Section 12.2.6, respectively. 
A medication error is any preventable event that may cause or lead to inappropriate medication 
use or participant harm while the medication is in the control of the healthcare professional, 
participant, or consumer. All medication errors must be recorded on the Special considerations 
form and sent to the sponsor and designee within 24 hours of the site becoming aware of the 
medication error. The medication error must be reported to the sponsor and/or designee even if 
the medication error does not result in an AE. If a medication error results in an AE or SAE, the 
AE or SAE must also be recorded and reported as described in Section 12.2.5 and Section 12.2.6, 
respectively. 


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13. 
STATISTICS 
A detailed description of the analyses to be performed in the study will be provided in the 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to database lock. 
Any changes/additions to the SAP following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
The Randomized Set is defined as all participants who are randomized. 
The Safety Set will include all participants who were administered IP.  
The Full Analysis Set will include all randomized participants who received any amount of IP 
and have a baseline and at least one postbaseline total TETRAS Performance Subscale Item 4 
upper limb tremor score.  
 
 
The Per Protocol Set will include all participants in the Full Analysis Set without any major 
protocol deviations that could affect efficacy. The review of major protocol deviations will be 
completed, and the decision on whether the deviation affects efficacy will be documented before 
database unblinding. 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All participants will be used in the analyses, 
as per the analysis populations, using all nonmissing data available. Sensitivity analyses will be 
conducted by imputing missing data to evaluate the treatment effect.  
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 group. 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to the start of IP administration. 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
quartile, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include frequency counts and percentages. 
13.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized by stratum (monotherapy cohort and adjunct therapy 
cohort) using the Safety Population. 


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Medical history will be listed by participant. 
Pregnancy test results and drug screen results will be listed but not summarized. 
13.5. 
Efficacy Analysis 
The estimand for the primary and secondary efficacy endpoint is defined as follows: 
1. There are 4 treatment groups for the monotherapy participants to be evaluated: 
SAGE-324 (15 mg, 30 mg, 60 mg) and placebo.  
2. The target population consists of the monotherapy participants ages 18 to 80 years and 
have a diagnosis of ET with combined total upper limb TETRAS Performance Subscale 
Item 4 of at least 12 with the dominant upper limb score of at least 6 and baseline 
TETRAS ADL score of at least 20.  
3. The outcome for the primary efficacy endpoint is the change from baseline in TETRAS 
Performance Subscale Item 4 score on Day 91. 
4. The population-level summary measure is the dose-response of different doses of 
SAGE-324 and placebo for the monotherapy cohort.  
5. The treatment/hypothetical policy strategy will be adopted for the primary and secondary 
endpoint. For data collected after the intercurrent events, such as rescue medication, the 
treatment policy strategy will be used. For data not available after the intercurrent events, 
like premature discontinuation of study treatment, the hypothetical policy strategy will be 
adopted. This means that the dose-responses of different dose groups will be analyzed 
using all observed on-study data, regardless of the occurrence of the intercurrent event, 
including use of additional medication, premature discontinuation of treatment for any 
reason, or other protocol violations.  
This will first be analyzed using a mixed-effects model for repeated measures (MMRM); the 
model will include treatment, baseline TETRAS Performance Subscale Item 4 upper limb tremor 
score, assessment timepoint, timepoint-by-baseline TETRAS Performance Subscale Item 4 upper 
limb tremor score and timepoint-by-treatment as explanatory variables. All explanatory variables 
will be treated as fixed effects. All postbaseline clinic visits will be included in the model. An 
unstructured covariance structure will be used to model the within-participant errors. If there is a 
convergence issue with the unstructured covariance model, Toeplitz or Autoregressive (1) 
[AR(1)] covariance structure will be used, following this sequence until convergence is achieved. 
If the model still does not converge with AR(1) structure, no results will be reported. When the 
covariance structure is not unstructured, the sandwich estimator for the variance covariance 
matrix will be derived, using the EMPIRICAL option in the PROC MIXED statement in SAS. 
After the MMRM analysis by PROC MIXED, the estimated mean and covariance matrix will be 
passed to the Multiple Comparisons and Modeling (MCP-Mod) analysis to test the dose-response 
relationship. In the analysis, multiple dose-response candidate models will be prespecified. The 
actual dose-response relationship will be assessed using the estimated means and covariance 
matrix from MMRM analysis. A critical value will be determined from the joint multivariate 
normal distribution of the contrast test statistics at the overall one-sided alpha level of 0.05. If the 
test statistic exceeds this critical value, a nonflat dose-response relationship will be 
demonstrated. 


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Secondary efficacy endpoints will be analyzed similarly to the primary endpoint.  
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-324 will be evaluated by stratum (monotherapy cohort and 
adjunct therapy cohort) and overall using incidence of TEAEs/SAEs 
 and changes 
from baseline in vital signs, 12-lead ECGs
. 
 Safety data will also be listed by participant using 
the Safety Set. 
13.6.1. 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities Version 23.1 or higher. A 
TEAE is defined as an AE with onset after the first dose of IP. The analysis of AEs will be based 
on the concept of TEAEs. The incidence of TEAEs will be summarized by System Organ Class 
and Preferred Term. In addition, summaries will be provided by intensity (mild, moderate, 
severe) and by causality (related, not related) to IP. 
Any TEAEs leading to discontinuation of treatment or withdrawal from the study and any 
treatment-emergent SAEs will be summarized. 
All AEs and SAEs (including those with onset or worsening before the start of IP) through the 
end of the study will be listed. 
13.6.2. 
Clinical Laboratory Evaluations 
Results of clinical laboratory parameters in each scheduled visit and mean changes from baseline 
will be summarized in standard units. Normal ranges for each parameter will be provided by the 
laboratory; shift from baseline to postbaseline values in abnormality of results will be provided. 
Potentially clinically significant values will be summarized by treatment. Clinical laboratory 
results will be listed by participant and timing of collection. 
13.6.3. 
Physical Examinations 
The occurrence of a physical examination (yes/no) and the date performed will be listed by 
participant. 
13.6.4. 
Vital Signs 
Vital sign results at each visit and mean changes from baseline will be summarized by scheduled 
visit. Potentially clinically significant values will be summarized by treatment. Vital sign results 
will be listed by participant and timing of collection. 
13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for ECGs for each participant: heart rate, PR, QRS, 
QT, and QTcF. ECG data will be summarized by visit. Potentially clinically significant values of 
QTcF will be summarized by treatment. ECG findings will be listed by participant and visit. 




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randomized. Additional participants may be enrolled if the overall nonevaluable rate is higher 
than 20%.  
The sample size for adjunct therapy cohort is not based on statistical significance, but clinical 
considerations. Up to 56 adjunct therapy participants (14 per dose group) are to provide some 
adjunct therapy directional data on both efficacy and safety measures.  
A blinded interim look at the primary and secondary endpoint data may be conducted to evaluate 
the sample size assumptions.  
Additional participants may be randomized if the variances are larger than the assumptions 
above. However, no more than 200 participants, including adjunct therapy participants, will be 
randomized.  
Figure 3: 
Prespecified Dose-response Models 
 
 
13.8.1. 
Interim and Data Monitoring Committee Analyses 
A blinded interim look at the primary and secondary endpoint data may be conducted to evaluate 
the sample size assumptions.  


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Unless otherwise waived or addressed in another forum (eg, investigator meeting), before an 
investigational site can enter a participant into the study, a representative of Sage will visit the 
investigational study site to: 
• Confirm the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, IP management, GCP/ICH GCP compliance, and the 
responsibilities of Sage or its representatives. This will be documented in a Clinical 
Trial Agreement between Sage and the investigator. 
During the study, a monitor from Sage or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that IP accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of the data in the CRF 
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, Good Clinical Practice (GCP)/International 
Council for Harmonisation (ICH) guidelines, and any applicable regulatory requirements. The 
investigator should contact Sage Therapeutics immediately if contacted by a regulatory agency 
or IRB/IEC about an inspection. 


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


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


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be given a written and 
dated approval or favorable opinion by an IRB/IEC, as appropriate. The investigator must obtain 
and document approval before he or she can enroll any participant into the study. The IRB/IEC 
must supply to the sponsor a list of the IRB/IEC membership and a statement to confirm that the 
IRB is organized and operates according to GCP and applicable laws and regulations. 
The principal investigator is responsible for informing the IRB/IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB/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/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/IEC according to local regulations and guidelines. In addition, the principal investigator 
must inform the IRB/IEC and sponsor of any changes significantly affecting the conduct of the 
study and/or increasing the risk to participants (eg, violations to the protocol or urgent safety 
measures taken for participant safety). 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH and GCP guidelines, as well as all 
applicable regional or national regulatory requirements. 
16.3. 
Written Informed Consent 
Prior to enrolling a study participant, the investigator(s) will ensure that the participant is given 
full and adequate oral and written information about the nature, purpose, possible risk, and 
benefit of the study. Participants must also be notified that they are free to discontinue from the 
study at any time. The participant should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
When the participant decides to participate in the study, the participant (or the participant’s 
parent or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source documentation. The investigator must 
maintain the original, signed ICF. A copy of the signed ICF must be given to the participant or to 
the participant’s parent or legally authorized representative. 
The ICF will include a provision stating that the participant may be contacted during or after the 
study with a request to participate in a related, follow-up research study in which they will be 
asked to provide responses to various questions regarding their experience in the Phase 2 study.  


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Throughout the study participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 
documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 
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. Sage is responsible to inform the investigator/institution as to when study documents 
no longer need to be retained. 


Clinical Protocol 
 
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Study 324-ETD-202, version 6.0 
 
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18. 
PUBLICATION POLICY 
All information concerning SAGE-324 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. 


Clinical Protocol 
 
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Study 324-ETD-202, version 6.0 
 
CONFIDENTIAL 
 
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19. 
LIST OF REFERENCES 
 
 
 
 
 
Deuschl G, Raethjen J, Hellriegel H, et al. Treatment of patients with essential tremor. Lancet 
Neurol. 2011;10(2):148-161. 
Elble R, Bain P, Forjaz MJ, et al. Task force report: scales for screening and evaluating tremor: 
critique and recommendations. Mov Disord. 2013;28(13):1793-1800. 
 
 
 
 
Hopfner F, Haubenberger D, Galpern WR, et al. Knowledge gaps and research recommendations 
for essential tremor. Parkinsonism Relat Disord. 2016;33:27-35. 
 
 
 
 
Koller WC, Busenbark K, Miner K. The relationship of essential tremor to other movement 
disorders: report on 678 patients. Essential Tremor Study Group. Ann Neurol. 
1994;35(6):717-723. 
Koller WC, Vetere-Overfield B. Acute and chronic effects of propranolol and primidone in 
essential tremor. Neurology. 1989;39(12):1587-1588. 
Louis ED, Ottman R. How many people in the USA have essential tremor? Deriving a 
population estimate based on epidemiological data. Tremor Other Hyperkinet Mov (N Y). 
2014;4:259. 


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NIH. Genetics Home Reference: Essential Tremor. Bethesda, MD: U.S. Department of Health 
and Human Services, National Institutes of Health. Published 15 Oct 2019; accessed 21 Oct 
2019. https://ghr.nlm.nih.gov/condition/essential-tremor; 2019. 
Olanow CW. Hyperkinetic Movement Disorders: Essential Tremor. Harrison's Principles of 
Internal Medicine. 2. 17 ed. New York, NY: McGraw Hill; 2008. p. 2560. 
 
 
Rajput AH, Rajput A. Medical treatment of essential tremor. J Cent Nerv Syst Dis. 
2014;6:29-39. 
 
Wyeth. Inderal (propranolol hydrochloride) [package insert]. Philadelphia, PA; 2010. 
Zappia M, Albanese A, Bruno E, et al. Treatment of essential tremor: a systematic review of 
evidence and recommendations from the Italian Movement Disorders Association. J Neurol. 
2013;260(3):714-740. 


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324-ETD-202 Protocol Summary of Changes 
Sage Therapeutics 
Version 6.0, Amendment 5  
 
 
1 
Protocol 324-ETD-202, Amendment 5 
Summary of Changes 
Date of Amendment: 02 November 2023 
A Phase 2 Double-Blind, Randomized, Placebo-Controlled, Dose-Response Study of 
SAGE-324 for the Treatment of Essential Tremor 
Protocol Amendment 5 reflects the following changes:  
• The Sponsor Contact has changed from: 
 
Phone: 
 
E-mail: 
 
to: 
 
Phone: 
 
Email: 
 
 
• The Sponsor Medical Monitor and Study Physician have changed from:  
MD, MSc 
 
Phone: 
 
E-mail: 
 
to: 
MD 
 
Phone: 
 
Email: 
 
• Section 9.2.2 Prohibited Medications: As per Administrative Letter #7 dated July 17, 
2023, the following was added for clarity: 
− Any estrogen-containing products that are widely absorbed into the systemic 
circulation (eg, oral, transdermal, transvaginal, etc.), used for any indication, are 
prohibited from Day -14 and during the study.   
• Section 2 Synopsis, Section 7.1 Overall Study Design, and Section 9.2.3 Other 
Restrictions: 
− Updated guidance regarding gaining experience with how the study drug may 
affect the participant before engaging in potentially hazardous activities requiring 
mental alertness, such as driving.  
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324-ETD-202 Protocol Summary of Changes 
Sage Therapeutics 
Version 6.0, Amendment 5  
 
 
2 
• Section 12.4 Overdose was changed to Section 12.4 Special Considerations, with new 
language for “abuse” and “misuse” to align with the Regulation (EU) No 536/2014 
Of the European Parliament and Of The Council. 
• Section 13.1 Data Analysis Sets and Section 2.2 Synopsis, the definition of the Full 
Analysis Set was updated to include participants enrolled under Version 1 of the 
protocol (dated 03 September 2021), who previously participated in a SAGE-324 
study. 
• The Sponsor Approval page was deleted to align with current Sage process and 
template. 
• Minor formatting changes 
Page 429 of 435


324-ETD-202 Protocol Summary of Changes 
Sage Therapeutics 
Version 5.0, Amendment 4  
 
 
1 
Protocol 324-ETD-202, Amendment 4 
Date of Amendment: 10 January 2023 
A PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
DOSE-RESPONSE STUDY OF SAGE-324 FOR THE TREATMENT OF ESSENTIAL 
TREMOR 
Rationale for Protocol Amendment 
The purpose for this protocol amendment is to update eligibility criteria and statistical analyses 
to include participants who are receiving propranolol for the treatment of essential tremor (ET).  
Changes to the protocol include: 
• Update objectives and endpoints to include monotherapy cohort (SAGE-324), adjunct 
therapy cohort (SAGE-324 + propranolol), and overall population (Synopsis and 
Section 6) 
• Update sample size, stratification, and other statistical analyses to include 
monotherapy cohort and adjunct therapy cohort (Synopsis, Schedule of Assessments 
footnotes, Section 7.1, Section 7.2, Section 7.3, Section 8.4.4, Section 9.5, Section 
13.4, Section 13.5, Section 13.6, and Section 13.8) 
• Include additional 14 days (total of 42 days) in the Screening Period for sufficient 
time to taper ET medications other than propranolol after approval from the sponsor 
(Synopsis, Figure 1, and Section 7.1) 
• Include information that participants in the adjunct therapy cohort must be on stable 
dose of propranolol (maximum total daily propranolol dose up to 320 mg allowed) for 
the treatment of ET from 3 months prior to screening through Day 90 of the study and 
that no additional propranolol as needed (PRN) is allowed (Inclusion criterion 8 
[Synopsis and Section 8.1] and Section 9.2.2.1) 
• Clarify that, a participant is to be excluded if receiving propranolol treatment for a 
medical condition other than ET (Exclusion criterion 9 [Synopsis and Section 8.2] 
and Section 9.2.2.1) 
• Correction to the volume of distilled spirits (Inclusion criterion 9 [Synopsis and 
Section 8.1] and Section 9.2.3. 
• Prohibit use of Cala Trio bracelet for treatment of ET from 2 weeks prior to Day 1 
through Day 97 (Exclusion criterion 4 [Synopsis and Section 8.2] and Section 9.2.3) 
• Clarify that prohibited use of botulinum toxin is for treatment of ET (Exclusion 
criterion 5 [Synopsis and Section 8.2]) 
• Include statement that there is currently no evidence of drug-drug interactions for 
SAGE-324 except for those outlined in the inclusion/exclusion criteria (Section 5.2) 
• Clarify process for participant enrollment in a SAGE-324 long-term open label study 
(Synopsis, Section 7.1, and Section 9.3) 
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324-ETD-202 Protocol Summary of Changes 
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Version 5.0, Amendment 4  
 
 
2 
• Include nicotine products and alcohol use as part of medical history and monitoring 
during the study (Schedule of Assessments and Section 12.1.1) 
Updates to organization, formatting, terminology, and Sage personnel have also been made. 
Page 431 of 435


324-ETD-202 Protocol Summary of Changes 
Sage Therapeutics 
Version 4.0, Amendment 3  
 
 
1 
Protocol 324-ETD-202, Amendment 3 
Date of Amendment: 04 May 2022 
A PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
DOSE-RESPONSE STUDY OF SAGE-324 FOR THE TREATMENT OF ESSENTIAL 
TREMOR 
Rationale for Protocol Amendment 
The main purpose for this protocol amendment is to update eligibility criteria.  
Changes to the protocol include: 
• Permit alcohol consumption with restrictions on amount and timing with scheduled 
study visits (Inclusion Criterion 9 [Synopsis and Section 8.1] and Section 9.2.3) 
• Permit current use of nicotine products at prestudy levels (new Inclusion Criterion 13 
[Synopsis and Section 8.1] and Section 9.2.3) 
• Exclude participants with nicotine use disorder (Exclusion Criterion 11 [Synopsis and 
Section 8.2] and Section 9.2.3) 
• Remove alcohol and cotinine screening (Table 2 Schedule of Assessments and 
Section 12.1.6.1) 
• Clarify that use of tremorgenic drug is prohibited within 14 days or 5 half-lives 
(whichever is longer) prior to Day 1 and that the use of established treatments with 
tremorgenic drugs is permitted if they do not cause or exacerbate tremors (Exclusion 
Criterion 2 and Section 9.2.2) 
• Include creatine kinase, myoglobin, and HgA1c in clinical laboratory assessments 
(Table 2 and Section 12.1.6) 
• Clarify that participants should not engage in potentially hazardous activities 
requiring mental activities until any sleepiness and sedative effects of IP have 
dissipated (Synopsis and Section 7.1) 
• Prohibit use of estrogen-containing contraceptives that are widely absorbed into the 
circulatory system as an acceptable forms of highly effective contraception methods 
for participants of childbearing potential or for partners of male participants who are 
of childbearing potential (Section 9.2.4) 
• Update safety reporting requirements (Table 1, Section 12.2.4, Section 12.2.6, 
Section 12.3, and Section 12.4) 
Updates to organization, formatting, descriptions of procedures, and Sage personnel have also 
been made. 
Page 432 of 435






324-ETD-202 Protocol Summary of Changes 
Sage Therapeutics 
Version 2.0, Amendment 1  
 
 
2 
A new section (Section 12.2.4) describing reporting procedures for Urgent Safety Measures and 
Unanticipated Problems has been added in response to regulatory feedback. 
Updates and corrections to organization, terminology, punctuation, grammar, abbreviations, and 
formatting have also been made. 
Page 435 of 435

SAP_001.pdf: 
Official Title:  A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Dose-Response
                       Study of SAGE-324 for the Treatment of Essential Tremor 
              NCT ID:   NCT05173012
Document Date:     SAP Version 1.0: 18 June 2024


Clinical Study Report 
 
324-ETD-202 
16.1 Study Information 
 
1 
 
 
  
 
9. 
DOCUMENTATION OF STATISTICAL METHODS 
The following statistical analysis plan is provided: 
SAGE-324-ETD-202 SAP v1.0 – 17 June 2024 
 
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Statistical Analysis Plan Methods Version 1.0 17-Jun-2024 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS................................................................... 6 
2. 
INTRODUCTION .................................................................................... 8 
3. 
STUDY OBJECTIVES ............................................................................ 9 
3.1. 
Primary Objective ..................................................................................... 9 
3.2. 
Secondary Objectives ............................................................................... 9 
 
9 
4. 
STUDY ENDPOINTS ............................................................................ 10 
4.1. 
Efficacy Endpoint ................................................................................... 10 
4.1.1. 
Primary Efficacy Endpoint ..................................................................... 10 
4.1.2. 
Secondary Efficacy Endpoint ................................................................. 10 
4.1.3. 
Primary and Secondary Efficacy Endpoint Estimand ............................ 10 
 
10 
4.2. 
Safety Endpoints ..................................................................................... 11 
 
11 
5. 
STUDY DESIGN ................................................................................... 12 
5.1. 
Overall Design ........................................................................................ 12 
5.2. 
Sample Size and Power .......................................................................... 13 
5.3. 
Randomization ........................................................................................ 14 
5.4. 
Blinding and Unblinding ........................................................................ 14 
6. 
MODIFICATIONS ................................................................................. 16 
6.1. 
Modifications from the Approved Clinical Study Protocol .................... 16 
6.2. 
Modifications from the Approved Statistical Analysis Plan .................. 16 
6.3. 
Modifications from the Approved DMC Charter ................................... 16 
7. 
ANALYSIS SETS .................................................................................. 17 
7.1. 
All Participants Set ................................................................................. 17 
7.2. 
Efficacy Analysis Sets ............................................................................ 17 
7.2.1. 
Full Analysis Set ..................................................................................... 17 
7.2.2. 
Per Protocol Set ...................................................................................... 17 
7.3. 
Safety Analysis Set ................................................................................. 17 
8. 
STATISTICAL ANALYSIS .................................................................. 18 
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8.1. 
General Considerations ........................................................................... 18 
8.2. 
Background Characteristics .................................................................... 18 
8.2.1. 
Participant Disposition ............................................................................ 18 
8.2.2. 
Protocol Deviations ................................................................................ 19 
8.2.3. 
Demographics and Baseline Characteristics ........................................... 19 
8.2.4. 
Medical/Surgical History ........................................................................ 20 
8.2.5. 
Prior and Concomitant Medications ....................................................... 20 
8.2.6. 
Investigational Product Exposure ........................................................... 21 
8.2.7. 
Investigational Product Adherence ......................................................... 22 
8.3. 
Efficacy Analysis .................................................................................... 23 
8.3.1. 
Definition of Efficacy Variable(s) .......................................................... 23 
8.3.1.1. 
Primary Efficacy Assessment ................................................................. 23 
8.3.1.2. 
Secondary Efficacy Assessment ............................................................. 23 
 
 24 
8.3.2. 
Visit Windows for Efficacy Analyses .................................................... 27 
8.3.3. 
Analysis of Primary Efficacy Variable(s) ............................................... 29 
8.3.3.1. 
Primary Analysis .................................................................................... 30 
8.3.3.3. 
Supportive Analysis of Primary Endpoint .............................................. 33 
8.3.3.4. 
Subgroup Analyses of Primary Endpoint ............................................... 33 
8.3.4. 
Analysis of Secondary Efficacy Variables ............................................. 34 
 
34 
8.4. 
Safety Analysis ....................................................................................... 37 
8.4.1. 
Adverse Events ....................................................................................... 38 
8.4.2. 
Clinical Laboratory ................................................................................. 40 
8.4.3. 
Electrocardiogram ................................................................................... 42 
8.4.4. 
Vital Signs .............................................................................................. 43 
8.4.5. 
Physical Examination ............................................................................. 44 
 
44 
 
 45 
 
 45 
8.4.9. 
Other Safety Analysis ............................................................................. 46 
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 46 
 
 46 
 
46 
 
 46 
8.7. 
Other Analysis ........................................................................................ 47 
9. 
SUMMARY OF INTERIM AND DMC ANALYSES .......................... 48 
9.1. 
Interim Analysis ...................................................................................... 48 
9.2. 
DMC Analysis ........................................................................................ 48 
10. 
REFERENCES ....................................................................................... 49 
11. 
LIST OF APPENDICES......................................................................... 50 
APPENDIX A. SCHEDULE OF ASSESSMENTS ............................................... 51 
APPENDIX B. HANDLING OF MISSING DATES ............................................. 56 
APPENDIX C. SAS CODE FOR ANALYSIS OF PRIMARY EFFICACY 
ENDPOINT ............................................................................................ 58 
APPENDIX D. LIST OF DISPLAYS..................................................................... 60 
 
 
 
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1. 
LIST OF ABBREVIATIONS 
The following abbreviations and specialist terms are used in this statistical analysis plan 
(SAP).  
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation Definition 
AE 
adverse event 
ADL 
activities of daily living 
AR(1) 
Autoregressive (1) 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
 
 
 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
End-of-Study 
EOT 
End of Treatment 
 
 
 
ET 
essential tremor 
ETV 
Early Termination Visit 
IP 
investigational product 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Effects Model for Repeated Measures 
 
PCS 
potentially clinically  significant 
PCSC 
potentially clinically significant change 
 
 
 
 
 
 
PT 
Preferred Term 
 
 
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Abbreviation Definition 
QTcF 
QT corrected according to Fridericia’s formula 
 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
TETRAS 
The Essential Tremor Rating Assessment Scale 
WHO-DD 
World Health Organization Drug Dictionary 
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2. 
INTRODUCTION 
This SAP is for the final analysis of clinical study protocol SAGE-324-ETD-202 and is based 
on the approved clinical study protocol, dated on 02 November 2023, Version 6.0. 
This SAP addresses the objectives of the study and describes the planned statistical analyses 
and data presentations. All analyses and data presentations will be generated using SAS® 
Version 9.4 or higher software (SAS Institute, Cary, North Carolina, USA). This SAP will be 
finalized and approved before the clinical database lock. Any changes made to the SAP after 
the clinical database lock has occurred will be documented and discussed in the clinical study 
report for this study. 
 
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5. 
STUDY DESIGN  
5.1. 
Overall Design  
This study is a Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to 
evaluate the efficacy, safety, and tolerability of SAGE-324 in participants with ET. 
Participants, site staff, and sponsor personnel will be blinded to treatment allocations. This 
study includes a Screening Period of up to 28 days, a 90-day double-blind Treatment Period 
(90 days of dosing), and a 14-day Follow-up Period. See the Schedule of Assessments 
(Appendix A) for the full list of study assessments and timings. A schematic of the study is 
presented in Figure 1.  
Participants who have provided informed consent will undergo screening assessments to 
determine eligibility. The Screening Period may be extended for an additional 14 days (to a 
total of 42 days) for subjects requiring additional time to taper ET medication (other than 
propranolol), after approval from the sponsor.  
Following completion of screening and Day 1 eligibility assessments, participants will be 
randomly assigned to 1 of 4 treatment groups (placebo or SAGE-324: 15 mg, 30 mg, or 60 
mg, oral daily) in a 1:1:1:1 ratio, stratified by baseline propranolol use (adjunct therapy). 
The 15-mg dose group will receive 15 mg of SAGE-324 from Day 1 to Day 90. 
The 30-mg dose group will receive 30 mg of SAGE-324 from Day 1 to Day 90. 
The 60-mg dose group will receive 15 mg of SAGE-324 from Day 1 to Day 14, then 30 mg 
from Day 15 to Day 28, then 45 mg from Day 29 to Day 42, and then 60 mg from Day 43 to 
Day 90. 
Starting on Day 1, after randomization, participants will receive a single dose of IP once 
daily for 90 days on an outpatient basis, to be taken before bed, with a snack if bedtime is not 
within 2 hours of the evening meal. During the Treatment Period, participants will return to 
the study center for efficacy and safety assessments as specified in Appendix A.  
Follow-up visits will be conducted on an outpatient basis on Days 97 and 104. Participants 
will continue to complete questionnaires as indicated in Appendix A and will return to the 
clinic approximately 6 days after the last dose of IP (ie, Day 97) for efficacy and safety 
monitoring. Participants will return to the study center for an End of Study (EOS) visit 
approximately 13 days following the last dose of IP (ie, Day 104); the EOS visit will be 
conducted at the time of discontinuation if this occurs any time before Day 104. 
No dose reductions of SAGE-324 will be permitted. 
 
 
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Figure 1: Study Design 
 
 
Abbreviation: R = TETRAS = The Essential Tremor Rating Assessment Scale  
Note: The Screening Period may be extended for an additional 14 days (total of 42 days) for subjects requiring 
additional time to taper ET medication (other than propranolol), after approval from the sponsor. 
 
5.2. 
Sample Size and Power 
The planned sample size is 160 participants, randomized in a 1:1:1:1 ratio to each of the dose 
groups (placebo and SAGE-324: 15 mg, 30 mg, and 60 mg), stratified by baseline 
propranolol use, with at least 104 (65%, 26 participants per dose group) monotherapy 
participants and up to 56 (35%, 14 participants per dose group) adjunct therapy participants. 
The sample size of 104 participants for the monotherapy cohort assumes a change from 
baseline at Day 91 in TETRAS upper limb Item 4 score for the placebo group of -1.2 points, 
a maximum decrease of -3.2 points from Baseline for a dose response in the 15-60mg dose 
groups with a standard deviation of 2.5.  
Under these assumptions with a few prespecified candidate dose-response models, including 
linear, loglinear, quadratic, exponential, logistic, Emax, sigEmax, and beta as shown in 
Figure 2 (see Section 8.3.3.1 of this analysis plan for underlying parameters associated with 
each model), a sample size of 22 evaluable participants per group would provide 80% power 
for demonstrating a nonflat dose-response relationship by Multiple Comparisons Procedure - 
Modeling (MCP-Mod) approach, using a 1-sided type I error rate of 0.05.  
Assuming a nonevaluable rate of 15% across all treatment groups, approximately 
104 participants (26 per treatment group) will be randomized. Additional participants may be 
enrolled if the overall nonevaluable rate is higher than 20%.  
The sample size for the adjunct therapy cohort is not based on statistical significance, but 
clinical considerations. Up to 56 adjunct therapy participants (14 per dose group) are to 
provide some adjunct therapy directional data on both efficacy and safety measures. 
A blinded interim look of the primary and secondary endpoint data may be conducted to 
evaluate the sample size assumptions. Additional participants may be randomized if the 
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variances are larger than the assumptions above. However, no more than 200 participants, 
including adjunct therapy participants, will be randomized.  
 
Figure 2: Prespecified Dose Response Models  
 
5.3. 
Randomization 
This is a randomized, double-blind, placebo-controlled study. Participants will be 
randomized in a 1:1:1:1 ratio to treatment groups (15 mg, 30 mg, 60 mg SAGE-324, or 
placebo), stratified by baseline propranolol use. Randomization schedules will be generated 
by an independent statistician, and randomization to treatment group according to the 
randomization schedule will be performed centrally via an interactive response technology 
system. 
5.4. 
Blinding and Unblinding 
This is a randomized, double-blind, placebo-controlled study. Participants, site staff, and the 
study team will be blinded to treatment allocation during the study. The randomization 
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schedules will be kept strictly confidential, accessible only to authorized personnel until the 
time of unblinding. The blinding of the study will be broken after the database has been 
locked. 
During the study, the blind is to be broken 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 diligent attempts to contact Sage prior to 
unblinding the study treatment administered to a participant. If the unblinding occurs without 
Sage’s knowledge, the investigator must notify Sage within 24 hours of breaking the blind.  
 
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and in 
the IRT. At the time of withdrawal from the study/stopping participation, if possible, an EOT 
and/or ETV should be conducted. 
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7. 
ANALYSIS SETS 
7.1. 
All Participants Set 
The All Participants Set will include all participants who have given written informed 
consent and participated in the screening process. This analysis set will be used for all 
listings and disposition. 
7.2. 
Efficacy Analysis Sets 
7.2.1. 
Full Analysis Set 
The Full Analysis Set will include all randomized participants who received any amount of 
IP and have a baseline and at least one post-baseline TETRAS Performance Subscale Item 4 
(upper limb tremor) total score. 
7.2.2. 
Per Protocol Set 
The Per Protocol Set will include all participants in the Full Analysis Set without any major 
protocol deviations that could affect efficacy. The review of major protocol deviations will 
be completed and the decision on whether the deviation affects efficacy and results in 
removal of a participant from the Per Protocol Set will be documented before database 
unblinding. The Per Protocol Set will exclude full analysis set participants satisfying any of 
the following conditions: 
x Study Drug Adherence (defined in Section 8.2.7) < 75% 
x Inappropriate drug consumption (typically due to incorrect kit dispensation): if the 
participant consumed at any time during the study any study drug that the 
participant is not randomized to 
x Day 91 efficacy assessment done 3 days or more after the last dose 
x Essential tremor duration of less than 3 years 
x Prohibited essential tremor medication during the treatment phase of the study 
(after completing the treatment is fine) 
x Any other major protocol deviations that the protocol deviation review committee 
(PDRC) documents as impacting the primary efficacy analysis prior to the 
database lock. 
7.3. 
Safety Analysis Set 
The Safety Analysis Set is defined as all participants administered IP. The Safety Analysis 
Set will be used for safety analysis.  
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8. 
STATISTICAL ANALYSIS 
8.1. 
General Considerations 
All participant data, including those that are derived, that support the tables and figures will 
be presented in the participant data listings. Some data may be presented only in participant 
data listings, some may be presented with a corresponding table or figure; these will be 
indicated in relevant sections below. All summaries will be provided by treatment group. 
For all safety and efficacy analyses where applicable, baseline is defined as the last non-
missing measurement prior to the first dose of IP. A baseline composite endpoint will be 
calculated based on baseline individual endpoints.  
Continuous endpoints will be summarized with n, mean, standard deviation (SD), median, 
first and third quartiles (Q1, Q3), minimum (min), and maximum (max). The minimum and 
maximum will be reported with the same number of decimal places as the source (raw) data. 
In general, mean and median will be reported to 1 decimal place more than the source (raw) 
data and standard deviation will be reported to 2 decimal places more than the source (raw) 
data; source data reported to several decimal places will be reported to an appropriate number 
of decimals places as determined by the study team. Any values that require transformation 
to standard units (metric or SI) will be converted with the appropriate corresponding 
precision. In addition, change from baseline values will be calculated at each time point and 
summarized descriptively. 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place unless otherwise specified.   
Participants will be summarized according to randomized treatment for all analyses except 
for safety analyses. For safety analyses, participants will be summarized according to 
treatment received.  
P-values will be reported to four decimal places, with p-values less than 0.0001 reported as 
“<0.0001”. P-values larger than 0.9999 will be reported as “>0.9999”.  
8.2. 
Background Characteristics  
8.2.1. 
Participant Disposition 
The summaries of disposition will include number of participants who were screened (All 
Participants Set), who were randomized, who received study drug, the number and 
percentage of participants who completed the study and who prematurely withdrew from the 
study, primary reasons for not completing the study, who completed treatment, who 
discontinued treatment prematurely, and primary reasons for discontinuing treatment.  
Study completion summary and treatment completion summary will be based on participants 
who received study drug (Safety Analysis Set). Percentages will be calculated based on the 
participants randomized and dosed. These data will be provided by randomized treatment 
groups, by stratum (monotherapy cohort and adjunct therapy cohort) and overall.  
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If a participant is rescreened because he/she has been a screen failure the first time, the status 
of the participant will be determined from the second screening. In the count of screened 
participants, this participant will be counted only once.   
The number of participants in each of the analysis sets will also be summarized and 
presented by treatment arm, by stratum (monotherapy cohort and adjunct therapy cohort) and 
overall. Randomization data (date and time of randomization, randomization number, and 
randomized treatment) and participants excluded from each analysis set will be listed but not 
summarized.  
A completer for the study is defined as one who completed all study phases, including the 
final follow-up visit (Day 104 visit) and is derived from the Study Disposition CRF page 
with completion question answered Yes. A participant is defined as prematurely 
discontinuing treatment if treatment ends before the final dose of study drug taken on Day 
90, and is derived from the Study Treatment Completion/Discontinuation CRF page with 
completion question answered No. The primary reason for study discontinuation or treatment 
discontinuation of a participant is provided in the respective CRF page. 
8.2.2. 
Protocol Deviations 
Protocol deviations will be captured on the eCRF and categorized by the study team as major 
and minor deviations without any unblinding information. The major deviations will be 
summarized by type and by randomized treatment using the Full Analysis Set. The minor 
deviations will be included in the listing. The COVID-19 related protocol deviations will also 
be summarized.  Summarization will be done by stratum (monotherapy cohort and adjunct 
therapy cohort) and overall. 
Inclusion/exclusion violations will be listed but not summarized. 
8.2.3. 
Demographics and Baseline Characteristics   
Demographic data (age, sex, race, and ethnicity) and baseline characteristics (height, weight, 
BMI, dominant upper limb) will be summarized with descriptive statistics by treatment group 
using the Safety Analysis Set. This summarization will be done by stratum (monotherapy 
cohort and adjunct therapy cohort) and overall. 
Baseline subgroups will be summarized for the following categories:  
x  Race (Black or African American, White, Asian, Other) 
x  Sex (Female, Male) 
x  Age (<65, 65 to 80 years) 
x  BMI (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2) 
Listings will be provided for demographics, other baseline characteristics, and informed 
consent data. 
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8.2.4. 
Medical/Surgical History  
Summarization of medical and surgical history data will be done by stratum (monotherapy 
cohort and adjunct therapy cohort) and overall. 
Medical/surgical history will be coded to Medical Dictionary for Regulatory Activities 
(MedDRA) terms, using Version 24.1, or higher. The MedDRA version will be included in 
the footnotes of related outputs. Medical/surgical history will be summarized using discrete 
summary statistics for each MedDRA System Organ Class (SOC) and Preferred Term (PT) 
by treatment group for the Safety Analysis Set.  
Medical history related to ET including age at diagnosis, age at onset of ET, tremor 
responsiveness to alcohol, past treatments for ET, response to therapy, and reason for 
discontinuation will be listed. Age at diagnosis, age at onset of ET, past treatment for ET 
(yes/no), and whether alcohol helps participant tremor will also be summarized. 
The disease subgroups will be summarized for the following categories: 
x Age at ET diagnosis (<40 years, 40 to 60 years, >60 years) 
x Age participant thinks ET started (<20 years, 20 to <40 years, 40 to 60 years, >60 
years) 
x Years with ET diagnosis (<3 years, 3 to <6 years, 6 to 10 years, >10 years) 
x  Years since participant thinks ET started (<3 years, 3 to <6 years, 6 to 10 years, 
>10 years) 
x Alcohol helps tremor: Yes (Intermediate, Worked Well), No (No, a little), NA 
x Past treatment for ET (Yes, No) 
x Response to past treatment for ET: Yes (Intermediate, Worked Well), No (No, a 
little), NA 
x Reason for discontinuation of past treatment for ET (drug interactions, lack of 
efficacy, physician decision, side effects, other) 
8.2.5. 
Prior and Concomitant Medications  
Medications will be recorded at each study visit and coded into drug class (anatomical 
therapeutic chemical [ATC] Level 2) and PT using World Health Organization-Drug 
dictionary (WHO-DD) Global B3 September 2021, or later.  
All medications taken within 30 days prior to signing the informed consent through the 
duration of the study (including start and end dates, route, dose/units, frequency, and 
indication) will be recorded on the electronic case report form (eCRF); all psychotropic 
medications taken in the 30 days prior to screening and all medications taken at any time prior 
to signing the informed consent through the duration of the study for ET will also be recorded.  
Those medications taken prior and having use ending prior to the initiation of the start of IP 
will be denoted “Prior”. Those medications taken prior to the initiation of the IP and 
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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 flagged in the listing according to whether they are “Prior” or 
“Concomitant” as defined above. In the event of a missing start or stop date associated with a 
medication, only the classification (prior and/or concomitant) will be imputed using the 
algorithm described in Appendix B. Dates will not be imputed. 
Prior and concomitant medications will be summarized separately for the Safety Analysis Set 
as the number and percentage of participants with each medication at both the ATC and PT 
levels; these summarizations will be done by stratum (monotherapy cohort and adjunct 
therapy cohort) and overall. Details of prior and concomitant medications will be listed by 
participant, start date, and verbatim term.  
8.2.6. 
Investigational Product Exposure  
Total drug exposure (in mg) is defined as the total IP in mg for SAGE-324 that was taken 
during the study. Total drug exposure for participants randomized to placebo is zero unless 
the participant has taken SAGE-324 by mistake, in which case the total drug exposure comes 
from SAGE-324 exposure. If a participant skips a dose on any of the days, the dose taken is 
0 mg.   
Total exposure duration to IP (in days) is defined as (date of last dose – date of first dose + 
1). Note that this does not exclude days when the dose has been missed. 
For participants that have been dispensed with SAGE-324 15mg, 30mg, and 45mg pre-
packed kit, but do not take the full 4 tablets, from a safety perspective, the general rule is that 
the tablets taken are assumed to be the active tablet(s) in the dispensed kit before counting 
any placebo tablets.  For example, for a 15mg pre-packed kit, if the patient takes only one 
tablet, the tablet would be the 15mg tablet. If the patient takes 2 tablets, it would be assumed 
that they took the one 15mg tablet and one placebo tablet. 
Planned exposure for the participants who complete the treatment period is defined as 
follows:  
1. For participants randomized to the SAGE-324 15 mg group, 90 days of treatment 
times 15 mg 
2. For participants randomized to the SAGE-324 30 mg group, 90 days of treatment 
times 30 mg 
3. For participants randomized to the SAGE-324 60 mg group, the sum of 14 days of 
treatment times 15 mg, 14 days of treatment times 30 mg, 14 days of treatment times 
45 mg, and 48 days of treatment times 60 mg   
Planned exposure for the participants who discontinue the treatment period early is defined 
as follows: 
1. For participants randomized to the SAGE-324 15 mg group, total exposure duration 
times 15 mg 
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2. For participants randomized to the SAGE-324 30 mg group, total exposure duration 
times 30 mg 
3. For participants randomized to the SAGE-324 60 mg treatment group 
x If 1 ≤ total exposure duration ≤ 14, then planned exposure = total exposure 
duration times 15 mg 
x If 15 ≤ total exposure duration ≤ 28, then planned exposure = 14 days times 
15 mg + (total exposure duration - 14) times 30 mg 
x If 29≤ total exposure duration ≤ 42, then planned exposure = 14 days times 15 mg 
+ 14 days times 30 mg + (total exposure duration - 28) times 45 mg 
x If 43 ≤ total exposure duration ≤ 90, then planned exposure = 14 days times 
15 mg + 14 days times 30 mg + 14 days times 45 mg + (total exposure duration - 
42) times 60 mg 
For participants randomized to placebo, planned exposure is not applicable.  
Percent of the planned exposure received is defined as the total drug exposure, divided by 
planned exposure, times 100. 
Total drug exposure, total exposure duration, and percent of planned exposure received will 
be summarized using the Safety Analysis Set by randomized treatment group. Also, the 
number and percentage of participants with percent of planned exposure <80%, 80% to 
<100%, and ≥100% will be summarized. Summarization will be provided by stratum 
(monotherapy cohort and adjunct therapy cohort) and overall. 
8.2.7. 
Investigational Product Adherence  
IP adherence (%) is defined as the number of tablets taken, divided by the number of tablets 
planned to be taken, times 100.  
The schedule of IP administration is that all participants will take 4 tablets per day in a mix 
of active and placebo tablets to achieve a dose of 15 mg (1 SAGE-324 tablet and 3 placebo 
tablets per dose), 30 mg (2 SAGE-324 tablets and 2 placebo tablets per dose) or 60 mg (4 
SAGE-324 tablets). The number of tablets planned to be taken is defined as 4 times 90 for 
the participants who complete the treatment period. For participants who discontinue 
treatment early, the number of tablets planned to be taken is defined as 4 times total exposure 
duration (see Section 8.2.6).   
IP adherence will be summarized using Safety Analysis Set and randomized treatment group. 
Number and percentage of participants with IP adherence in categories <75%, 75 to 100%, 
>100% will be provided. Summarization will be provided by stratum (monotherapy cohort 
and adjunct therapy cohort) and overall. 
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8.3. 
Efficacy Analysis  
8.3.1. 
Definition of Efficacy Variable(s) 
8.3.1.1. 
Primary Efficacy Assessment 
For the TETRAS Performance Subscale Item 4 (upper limb), three maneuvers/assessments 
will be completed for both arms, first for the right arm and then for the left, specifically Item 
4a, limbs extended forward maneuver (postural tremor), Item 4b, wing-beating [elbows 
flexed] maneuver (postural tremor), and Item 4c finger-nose-finger maneuver (kinetic 
tremor). Each assessment is rated on a 0 to 4 scale of severity in 0.5-point increments, with 
higher scores indicating more severe tremor. The Performance Subscale Item 4 (upper limb) 
total score range for a given side (left or right) is 0 to 12, and for both sides combined is 0 to 
24; if any component of a total score for a side or both sides is missing, the total score is not 
computed. Assessment of the TETRAS Performance Subscale Item 4 (upper limb) occurs at 
Screening and Days 1, 8, 15, 29, 43, 57, 71, 91/EOT, and 97. 
The primary efficacy endpoint is the change from baseline in TETRAS Performance 
Subscale Item 4 (upper limb) total score at Day 91 in the monotherapy cohort for the Full 
Analysis Set. 
8.3.1.2. 
Secondary Efficacy Assessment 
The TETRAS ADL Subscale assesses how ET affects typical activities of daily living (ie, 
speech, eating, drinking, dressing, personal hygiene, writing, occupational impairment, social 
impact, and activities affected by upper limb tremor). It consists of 12 items that are each 
rated on a scale from 0 (normal activity) to 4 (severe abnormality), and the overall ADL 
score range is 0 to 48; if any component of overall ADL score is missing, the overall ADL 
score is not computed. Responses of 0 and 1 in TETRAS ADL Subscale Items 1 to 11 will be 
collapsed and analyzed as a single response of 0 = normal/slightly abnormal such that the 
scale becomes:  
0 = Normal/slightly abnormal 
1 = Mildly abnormal 
2 = Moderately abnormal 
3 = Severely abnormal 
TETRAS Performance Subscale Item 6 (Archimedes Spiral) is assessed for both the right and 
left sides.  Each assessment is rated on a 0 to 4 scale of severity, with higher scores indicating 
more severe tremor.  Since Item 6 may be assessed on a scale with 0.5 point increments, the 
responses of Item 6 will be rescaled as: 
0 = Normal/slightly abnormal (original score of 0, 0.5, 1) 
1 = Mildly abnormal (original score of 1.5, 2) 
2 = Moderately abnormal (original score of 2.5, 3) 
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8.3.3. 
Analysis of Primary Efficacy Variable(s) 
The efficacy analysis uses the Full Analysis Set and presents data by randomized treatment, 
unless specified otherwise.  Summarization and analysis of the primary efficacy variable will 
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be performed for the monotherapy cohort (primary cohort), adjunct therapy cohort (for 
directional investigation, excluding MCP-Mod analysis), and overall. 
8.3.3.1. 
Primary Analysis  
The estimand for the primary efficacy endpoint is defined as follows: 
x There are 4 treatment groups for the monotherapy participants to be evaluated: 
SAGE-324 (15 mg, 30 mg, 60 mg) and placebo. 
x The target population consists of the monotherapy participants aged 18 to 80 years 
and have a diagnosis of ET with combined total upper limb TETRAS Performance 
Subscale Item 4 of at least 12 with the dominant upper limb score of at least 6 and 
baseline TETRAS ADL score of at least 20. 
x The outcome for the primary efficacy endpoint is the change from baseline in 
TETRAS Performance Subscale Item 4 score on Day 91 in the monotherapy cohort. 
x The population-level summary measure is the dose-response of different doses of 
SAGE-324 and placebo for the monotherapy cohort. 
x The treatment/hypothetical policy strategy will be adopted for the primary endpoint. 
For data collected after the intercurrent events, such as rescue medication, the 
treatment policy strategy will be used. For data not available after the intercurrent 
events, like premature discontinuation of study treatment, the hypothetical policy 
strategy will be adopted. This means that the dose-responses of different dose groups 
will be analyzed using all observed on-study data, using appropriate visit mapping 
specified in Table 2, regardless of the occurrence of the intercurrent event, including 
use of additional medication, premature discontinuation of treatment for any reason, 
or other protocol violations.   
The observed value, change from baseline, and percent change from baseline of the TETRAS 
Performance Subscale Item 4 (upper limb tremor) scores (individual and total score by side 
and combined) will be summarized descriptively by randomized treatment at each scheduled 
time point. 
The primary endpoint will be analyzed using a mixed effects model for repeated measures 
(MMRM); the model will include treatment, baseline TETRAS Performance Subscale Item 4 
(upper limb tremor) total score, assessment timepoint, and timepoint-by-treatment as 
explanatory variables. All explanatory variables will be treated as fixed effects. All 
postbaseline clinic visits will be included in the model. An unstructured covariance structure 
will be used to model the within-participant errors. The Kenward-Roger approximation will 
be used to estimate denominator degrees of freedom. If there is a convergence issue with the 
unstructured covariance model, Toeplitz or Autoregressive (1) [AR(1)] covariance structure 
will be used, following this sequence until convergence is achieved. When the covariance 
structure is not unstructured, the sandwich estimator for the variance covariance matrix will 
be derived, using the EMPIRICAL option in the PROC MIXED statement in SAS. A 
pairwise comparison of change from baseline in TETRAS Performance Subscale Item 4 
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(upper limb tremor) for each SAGE-324 treatment group versus placebo will be provided.  
The p-values are not adjusted for multiplicity, so should be interpreted as nominal. 
After the MMRM analysis by PROC MIXED, the estimated mean and covariance matrix at 
Day 91 will be passed to the MCP-Mod analysis (Bretz F, Pinheiro JC, Branson M, 2005) to 
test the dose-response relationship. A critical value will be determined from the joint 
multivariate normal distribution of the contrast test statistics at the overall one-sided alpha 
level of 0.05. If the test statistic exceeds this critical value, a nonflat dose-response 
relationship will be demonstrated. 
In the analysis, multiple dose-response candidate models will be considered, including linear, 
loglinear, quadratic, exponential, logistic, Emax, sigEmax, and beta. In the trial design stage, 
these pre-specified candidate models based on available information were included in the 
MCP-Mod procedure. The parameters used to determine the contrast for testing assumes a 
change from baseline in TETRAS Item 4 upper limb total score in the placebo group 
of -1.2 points, a maximum decrease of -3.2 points from baseline for a dose response in the 15 
to 60-mg dose groups. These can be done using the DoseFinding Package in R. 
 
doses <- c(0, 15, 30, 60) 
 
pboeff  <- -1.2 
acteff  <- -2 
quad    <- guesst (d=45, p=1, 'quadratic') 
exp     <- guesst (d=45, p=0.5, 'exponential', Maxd=60) 
emax    <- guesst(d=30, p=0.8, 'emax') 
sigemax <- guesst (d=c(15, 30), p=c (0.6, 0.8), 'sigEmax') 
logis   <- guesst (d=c(10, 45), p=c( 0.2, 0.8), model='logistic') 
beta<- guesst(d=30, p=0.8, model='betaMod', dMax=45, scal=65, Maxd=60) 
 
my.model <-Mods(linear=NULL,  
                linlog=NULL,  
                quadratic=quad,  
                exponential=exp,  
                emax=emax,  
                sigEmax=sigemax,  
                logistic=logis,  
                betaMod=beta, 
                doses=doses,  
                placEff=pboeff,  
                maxEff=acteff) 
plot(my.model) 
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The optimal contrast coefficients are used to identify the best matching model, which can be 
computed with “optContr” function. It requires input of matrix. In this example it uses the 
covariance matrix exported from SAS, using repeated measurement analysis (MMRM) by 
PROC MIXED. 
ContMatnew <- optContr(my.model, S=cov) 
Model-specific contrast tests with null hypotheses of a flat dose-response curve are 
performed by “MCTtest” function. Any model that has t-statistics > critical value is 
statistically significant.  
my.test <- MCTtest (dose=dose, resp=estimate, data=xxx, my.mode, S=cov, 
                    type=’general’, 
                    placAdj=FALSE, df=Inf, 
                    critV=TRUE, pVal=TRUE, alpha=0.05, 
                    alternative =c (‘one.sided’), na.action=na.fail, 
                    mvtcontrol=mvtnorm.control(), contMat=contMatnew) 
After the MCT test, if any model is significantly different from a flat dose-response curve, 
the best fit model could be selected.   
 
fit.xxx<-fitMod (dose=dose, resp=estimate, data=xxx, my.mode, S=cov, 
                    model=xxx, type=’general’) 
 
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plot(fit.xxx, CI=TRUE, plotData=’meanCI’, level=0.95) 
The main comparison will be between SAGE-324 and placebo at Day 91, if a non-flat dose-
response relationship is established. Model-based point estimates (ie, least squares mean, 
95% confidence intervals, and p-values) will be reported where applicable. Line plots of 
model-based LS Means and standard errors (SE) over time will be prepared for the primary 
endpoint. 
8.3.3.2. 
Sensitivity Analysis of Primary Endpoint 
Sensitivity analysis of the primary endpoint will be performed to assess the robustness of the 
primary analysis results in the presence of missing data. For participants who terminate from 
treatment prior to the end of the analysis period due to adverse event, noncompliance with 
study procedures, death, physician decision, or use of a prohibited medication, missing 
measurements will be considered missing not at random (MNAR); for all other participants 
having missing measurements, missing values will be considered missing completely at 
random (MCAR).  
For FAS monotherapy subjects having missing TETRAS Performance Subscale Item 4 
(upper limb tremor) total score data at any visit, and, separately, for FAS subjects overall, all 
missing data (MCAR or MNAR) will be imputed via multiple imputation (50-100 iterations, 
depending on system run time) using treatment based regression methodology which 
includes baseline TETRAS Performance Subscale Item 4 (upper limb tremor) total score in 
the model, with minimum and maximum possible integer values of 0 to 24, respectively 
(example SAS code is found in Appendix C). The MMRM model, including the selected 
covariance structure, used for the main analysis of the primary efficacy endpoint will be 
repeated for each imputation, and the results combined and reported. The covariance matrices 
resulting from the MMRM run on each imputation will be combined into an overall 
covariance matrix via either the COVB or TCOV options of Proc MIANALYZE in SAS; the 
resulting overall covariance matrix will be passed to the MCP-Mod analysis to perform 
sensitivity analysis of the dose-response relationship. SAS code associated with this 
sensitivity analysis is noted in Appendix C. 
If the sensitivity analysis yields a result/conclusion that is different from the result of the 
primary analysis, the nature of the discrepancy will be examined in order to clearly explain 
the discrepancy based on statistical principles, and the discrepancy will be discussed in the 
clinical study report. 
8.3.3.3. 
Supportive Analysis of Primary Endpoint 
Summarization and analysis of the primary endpoint will be repeated based on the Per 
Protocol Set as a supportive analysis.   
8.3.3.4. 
Subgroup Analyses of Primary Endpoint 
The descriptive summarization and MMRM analysis of the primary endpoint will also be 
presented by the following subgroups: 
x Age group: <65 years, 65 to 80 years 
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emergence will be imputed using the algorithm described in Appendix B. Dates will not be 
imputed.  
A TEAE is defined as an AE with onset at or after the start of IP, or any worsening of a 
preexisting medical condition/AE with onset at or after the start of IP and throughout the 
study. A non-TEAE is any adverse event that starts prior to IP. The term IP includes both 
SAGE-324 and placebo.  
An overall adverse event summary table will be presented for TEAEs and will include the 
number and percent of participants experiencing at least one:  
x TEAE 
x Maximum severity of TEAE (mild TEAE, moderate TEAE, severe TEAE) 
x TEAE leading to study treatment discontinuation 
x TEAE leading to study discontinuation 
x Serious TEAE 
x Serious TEAE leading to study treatment discontinuation 
x Serious TEAE leading to study discontinuation 
x TEAE resulting in death 
The incidence of TEAEs will be summarized by System Organ Class (SOC) and Preferred 
Term (PT). In addition, summaries will be provided by maximum severity (mild, moderate, 
severe) and by maximum relationship (related, not related) to IP. Any TEAEs leading to 
discontinuation of treatment or withdrawal from the study and any treatment-emergent SAEs 
will also be summarized, sorted by descending frequency in SOC and PT within the SAGE-
324 group.  
The incidence of non-TEAEs will be be summarized by SOC and PT. 
Participants will be counted only once within each SOC and PT at the maximum severity in 
the following order: severe, moderate, and mild. Participants will be counted only once 
within each SOC and PT at the strongest relationship to study drug in the following order: 
related, not related to study drug. An AE with missing severity will be considered as ‘severe’, 
and with missing relationship to study treatment will be considered as ‘related’ for the 
purposes of summarizing these data. 
The incidence of TEAEs and treatment-emergent SAEs will also be presented in order of 
decreasing frequency by PT. 
All AEs (including those with onset or worsening before the start of IP) through the end of 
the study will be listed. In addition, separate listings containing individual participant AE 
data for all deaths, SAEs, AEs leading to treatment discontinuation, and AEs leading to study 
discontinuation will be provided. 
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8.4.2. 
Clinical Laboratory 
All statistical analyses of laboratory values will be performed using SI units.  
Some numeric lab values may be reported as ‘<n.n’ or ‘>n.n’; these will be analyzed in the 
summary statistics as n.n/2 and n.n respectively. For example, triglycerides recorded as 
<0.50 mmol/L would be summarized as 0.25 mmol/L and potassium recorded as 
>6.0 mmol/L would be summarized as 6.0 mmol/L. 
Continuous hematology (including coagulation), chemistry, and urinalysis results (raw and 
change from baseline) will be summarized by actual treatment group at each scheduled time 
point. Categorical urinalysis results will be summarized by frequencies and percentages at 
each scheduled timepoint. The number and percentage of participants with shift changes 
from baseline based on the laboratory normal ranges provided by the laboratory will be 
tabulated at each scheduled visit. 
The number and percentage of participants with potentially clinically significant (PCS) 
values at any time after study drug administration (including unscheduled visits) will be 
summarized by treatment group for the hematology, chemistry and coagulation parameters 
defined in  Table 9, Table 10, and Table 11, respectively. 
Liver function tests will be monitored closely for potentially clinically significant values 
(Table 12) and will be summarized for occurrence any time post-baseline for these PCS 
thresholds (for conditions involving more than one parameter, the results need to be from the 
same timepoint). 
Chemistry, hematology (including coagulation), and urinalysis data will be listed with the 
values outside the normal ranges flagged. Blood cell morphology and microscopy test results 
will be listed when available but not summarized. Pregnancy tests, and urine drugs of abuse 
data will be listed but not summarized. 
 
Table 9: Potentially Clinically Significant Values for Hematology 
Laboratory Parameter 
Sex 
Units 
Criteria for PCS Values (Observed values) 
 
 
 
High  
Low  
Hemoglobin                     Male 
g/L  
>185  
<115 
 
Female 
g/L  
>170 
<100 
Hematocrit    
Male 
Fraction of 1 
>0.55  
<0.385  
 
Female 
Fraction of 1 
>0.49 
<0.345 
Platelet count  
 
10^9/L  
>600 
<125 
White blood cell 
 
10^9/L  
>15  
<2.5  
Basophils  
 
10^9/L  
>0.5 
NA 
Eosinophils 
 
10^9/L  
>1.5 
NA 
Neutrophils  
 
10^9/L  
NA  
<1.5  
Lymphocytes  
 
10^9/L  
>6.0  
<0.5  
Monocytes  
 
10^9/L  
>1.4 
NA 
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Table 10: Potentially Clinically Significant Values for Chemistry 
Laboratory Parameter 
Units 
Criteria for PCS Values (Observed values) 
 
 
High  
Low  
Albumin  
g/L  
>70  
<28  
Blood urea nitrogen  
mmol/L 
>10.71 
NA 
Calcium 
mmol/L 
>2.75 
<2.0 
Chloride 
mmol/L 
>120 
<90 
Creatinine 
mmol/L 
>3xULN or >3x Baseline 
 
Gamma Glutamyl Transferase  
 
>3xULN 
 
Glucose 
mmol/L 
>13.9 
<2.8 
HbA1c 
% 
≥6.5% for nondiabetic 
patients and >8% for 
patients with diabetes (at 
screening) 
≥0.25% change from 
baseline 
NA 
Sodium  
mmol/L  
>150 
<132  
Potassium  
mmol/L  
>5.4  
<3.3  
Protein  
g/L 
 
<45 
Bicarbonate  
mmol/L  
>34  
<18  
Chloride  
mmol/L  
>120  
<90  
Phosphorus  
mmol/L 
>1.94 
<0.61 
Creatine phosphokinase 
U/L 
>2xULN 
NA 
Lactate dehydrogenase 
U/L 
>2xULN 
NA 
Liver Function Tests (LFT) 
 
 
 
Bilirubin  
μmol/L  
>2xULN  
NA 
Aspartate Aminotransferase  
U/L  
>3xULN  
NA 
Alanine Aminotransferase  
U/L  
>3xULN  
NA 
Alkaline Phosphatase  
U/L  
>1.5xULN  
NA 
 
Table 11: Potentially Clinically Significant Values for Coagulation 
Parameter  
Potentially Clinically Significant Values  
Prothrombin time (PT)  
>=1.11 x ULN 
Activated partial thromboplastin time (aPTT) 
>1.5 x ULN 
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Table 12: Potentially Clinically Significant Values for Liver Function Tests 
Parameter  
Potentially Clinically Significant Values  
Alanine Aminotransferase   
>3xULN, >5xULN, >10xULN  
Aspartate Aminotransferase  
>3xULN, >5xULN, >10xULN  
Alanine Aminotransferase OR  
Aspartate Aminotransferase  
>3xULN, >5xULN, >10xULN  
Alkaline Phosphatase  
>1.5xULN, >2xULN 
Total Bilirubin 
>1.5xULN, >2xULN 
Total Bilirubin > 2xULN AND (Alanine Aminotransferase OR Aspartate Aminotransferase 
>3xULN) 
Total Bilirubin >2xULN AND Alkaline Phosphatase >2xULN AND (Alanine Aminotransferase OR 
Aspartate Aminotransferase >3xULN)  
Total Bilirubin >2xULN AND Alkaline Phosphatase <2xULN AND [(Alanine Aminotransferase 
OR Aspartate Aminotransferase >3xULN) AND Alkaline Phosphatase <2xULN] 
8.4.3. 
Electrocardiogram 
The average of multiple values collected at one visit will be used for summarization, 
including baseline ECG values.  For each ECG measurement (heart rate and PR, QRS, QT, 
and QTcF intervals), the observed value at each scheduled visit and change from baseline at 
each scheduled visit will be provided by treatment group. This summary will also include last 
values on treatment and on study. Last value on treatment is defined as the last post-baseline 
value between first dose of IP (exclusive) and up to last dose of IP + 1 days (inclusive).  Last 
value on study is defined as the last post-baseline value after the first dose of IP. 
In addition, the number and percentage of participants with PCS and potentially clinically 
significant change (PCSC) values will be summarized by visit/timepoint and for any time 
post-baseline. Potentially clinically significant values will be identified for ECG parameters 
as outlined in Table 13.  
A shift table of overall ECG interpretation from baseline to scheduled post-baseline visits 
will be presented for the following categories: ‘Normal’, ‘Abnormal, Not Clinically 
Significant’, and ‘Abnormal, Clinically Significant’. The shift table will be presented by visit 
and treatment group.  
Clinically significant abnormal findings will be reported as adverse events. The average of 
the multiple values collected at one visit of each parameter will be listed by participant.  
Table 13: Potentially Clinically Significant Values for QTcF 
 
Units 
Criteria for PCS Values 
(Observed Values) 
Criteria for PCSC Values 
(Change from Baseline) 
 
High 
Low 
Increase 
Decrease 
msec 
>450 msec and ≤480msec 
>480 msec and ≤500msec 
>500 msec 
NA 
>30 msec and ≤60 msec 
>60 msec 
NA 
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8.4.4. 
Vital Signs 
Vital sign results (systolic and diastolic blood pressure [mmHg], pulse pressure (mmHg), 
body temperature [qC], heart rate [beats per minute or bpm], and respiratory rate [breaths per 
minute]) and changes from baseline will be summarized by scheduled visit and treatment 
group. Pulse pressure is defined as [systolic blood pressure - diastolic blood pressure].  
The average of multiple values collected at one visit will be used for summarization, 
including the Day 1 triplicates assessments of supine and standing blood pressure and heart 
rate.  
Potentially clinically significant values will be identified for vital sign parameters as outlined 
in Table 14. For any post-baseline visit, potentially clinically significant values will be 
summarized by treatment group and visit. 
The number and percentage of participants with orthostatic hypotension, defined as either a 
decrease in systolic blood pressure of ≥20 mmHg or a decrease in diastolic blood pressure of 
≥10 mmHg from supine to standing position, will be summarized by treatment group at each 
visit.  The PCS and orthostatic hypotension at baseline will be evaluated using the average of 
3 triplicates. 
Vital sign results will be listed by participant and timing of collection. 
Any vital sign results considered clinically significant by the investigator will be captured as 
adverse events. 
Table 14: Potentially Clinically Significant Values for Vital Sign Parameters 
Vital Sign 
Units 
Criteria for PCS Values 
(Observed values) 
Criteria for PCSC 
values (Change from 
Baseline values) 
 
 
High  
Low  
Increase  Decrease  
Heart rate 
(supine and standing) 
Beats/min  
>120  
<40  
 
 
Systolic Blood Pressure 
(supine and standing)  
mmHg  
>180 
<90  
≥30 
≥30 
Diastolic Blood pressure 
(supine and standing)  
mmHg  
>110 
<50  
≥20 
≥20  
Supine - Standing 
Systolic Blood Pressure 
mmHg 
≥20 
 
 
 
Supine – Standing 
Diastolic Blood Pressure 
mmHg 
≥10 
 
 
 
Orthostatic hypotension: 
supine – standing SBP and 
DBP 
mmHg 
SBP ≥20 and 
DBP ≥10 
 
 
 
SBP ≥20 or DBP 
≥10 
 
 
 
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8.7. 
Other Analysis 
Not applicable. 
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9. 
SUMMARY OF INTERIM AND DMC ANALYSES 
9.1. 
Interim Analysis 
Throughout the enrollment period, a blinded interim look at the primary and secondary 
endpoint data may be conducted to evaluate the sample size assumptions. If such an interim 
assessment is scheduled, additional information will be provided in this section. Otherwise, 
no further details will be included. 
9.2. 
DMC Analysis 
Not applicable.  
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11. 
LIST OF APPENDICES 
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APPENDIX A. SCHEDULE OF ASSESSMENTS 
 
 
 
 
 
 
 
 
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APPENDIX B. HANDLING OF MISSING DATES 
Partial dates will adhere to the following conventions in order to classify TEAEs and to 
classify prior and concomitant medications.  
In general, listings will present the actual partial or missing values rather than the imputed 
values that may be used in derivation.  
Adverse Events 
In the event of a missing/incomplete start or stop date associated with an adverse event, only 
the treatment-emergence will be imputed using the algorithm below. Dates will not be 
imputed.  
In general, if the missing/incomplete start date is not clearly prior to initiation of treatment, 
then the AE will be considered a TEAE.   
If the AE end date is prior to the initiation of treatment, the AE will not be considered a 
TEAE. 
If the AE end date is on or after the initiation of treatment: 
x If the AE start date is completely missing or if the year is missing, then the AE will 
be considered a TEAE 
x For partial AE start dates: 
o Known year, unknown month and day (or known year and day, unknown 
month) 
 If the year is the same as or later than the year of the first dose, the AE 
will be considered a TEAE 
 Otherwise, the AE will not be considered a TEAE 
o Known year and month, unknown day 
 If the month and year are the same as or later than the month and year 
of the first dose, the AE will be considered a TEAE 
 Otherwise, the AE will not be considerd a TEAE 
Prior and Concomitant Medications 
No imputation process will be used to estimate missing data, except for the purposes of 
classifying medications as prior and/or concomitant. The following algorithms will be used 
for partially missing dates. 
For start dates of medication uses: 
x The day and month are missing: if the participant started receiving the study dosing in 
the reported year, the first dosing date will be used as the start date; otherwise 
’01 January’ will be used as the start date. 
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x The day is missing: if the participant started receiving the study dosing in the reported 
month and year, the first dosing date will be used as the start date; otherwise, the first 
day of the reported month and year will be used as the start date. 
x If the medication start date is completely missing, do not impute a date, but consider 
it as a concomitant medication, unless the medication end date is before the initiation 
of treatment, in which case the medication will be considered prior. 
For stop dates of events or medication uses: 
x The day and month are missing: if the study end date is in the reported year, the study 
end date will be used as the stop date; otherwise, ‘31 December’ will be used as the 
stop date. 
x The day is missing: if the study end date is in the reported month and year, the study 
end date will be used as the stop date; otherwise, the end of the reported month and 
year will be used as the stop date. 
x If a medication has the stop date completely missing or missing the year, this 
medication will be considered as ongoing and concomitant.  If a participant is missing 
a treatment start date, medication will not be classified as either prior or concomitant. 
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APPENDIX C. SAS CODE FOR ANALYSIS OF PRIMARY EFFICACY 
ENDPOINT 
 
Example code for MMRM: 
The ODS statement is used to create output datasets, particularly COVB, for subsequent 
MCP Mod analysis. 
Proc mixed data=[input dataset name]  
           method=reml covtest alpha=0.05; 
   Where CHG ne .; 
   Class SUBJID TRTP(ref='Placebo') AVISITN; 
   Model CHG = BASE TRTP AVISITN TRTP*AVISITN /  
         htype=3  
         ddfm=KENWARDROGER  
         residual solution covb; 
   Repeated AVISITN / sub=SUBJID type=[desired covariance structure]; 
   Lsmeans AVISITN * TRTP / cov pdiff cl alpha=0.05; 
   ODS output  
       solutionf=[output dataset name]  
       covb=[output dataset name]; 
Run; 
 
Example code for imputation of monotone missing data: 
Proc mi data = [input dataset name] 
        out  = monotone(rename=(_imputation_=impn))  
        nimpute=20  
        seed=XXXXXXX  
        min   = . . 0 0 0 0 0 0 0 0 
        max   = . . 24 24 24 24 24 24 24 24 
        round = . . 1 1 1 1 1 1 1 1;  
   Var trtpn base  
       avisitn8 avisitn15 avisitn29 avisitn43  
       avisitn57 avisitn71 avisitn91 avisitn97;  
   MCMC impute=monotone chain=multiple; 
   EM maxiter=500 converge=0.00001;  
Run; 
 
Example code for treatment-based imputation of non-monotone missing data: 
Proc mi data=monotone  
        out=imputed seed=XXXXXXX nimpute=1 
        min   = . . 0 0 0 0 0 0 0 0 
        max   = . . 24 24 24 24 24 24 24 24 
        round = . . 1 1 1 1 1 1 1 1; 
   By impn; 
   Class trtpn; 
   Var trtpn base  
       avisitn8 avisitn15 avisitn29 avisitn43  
       avisitn57 avisitn71 avisitn91 avisitn97; 
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   Monotone regression(/details); 
Run; 
 
 
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APPENDIX D. LIST OF DISPLAYS 
Tables 
14.1.1 
Disposition of Participants (All Participants) 
14.1.2 
Analysis Sets (All Participants) 
14.1.3.1 
Major Protocol Deviations (Full Analysis Set) 
14.1.3.2 
Protocol Deviations Related to COVID-19 (Full Analysis Set) 
14.1.4 
Demographics and Baseline Characteristics (Safety Analysis Set) 
14.1.5 
Summary of Disease History (Safety Analysis Set) 
14.1.6 
Medical/Surgical History (Safety Analysis Set) 
14.1.7.1 
Prior Medications (Safety Analysis Set) 
14.1.7.2 
Concomitant Medications (Safety Analysis Set) 
14.1.8.1 
Study Drug Exposure (Safety Analysis Set) 
14.1.8.2 
Study Drug Adherence (Safety Analysis Set) 
14.2.1.1 
Summary of Essential Tremor Rating Assessment Scale (TETRAS) 
Performance Subscale Item 4 (Upper Limb) Score (Full Analysis Set) 
14.2.1.2 
Change from Baseline in the Essential Tremor Rating Assessment Scale 
(TETRAS) Performance Subscale Item 4 (Upper Limb) Score – Mixed Effect 
Model for Repeated Measures (MMRM) (Full Analysis Set) 
14.2.1.3 
Change from Baseline in the Essential Tremor Rating Assessment Scale 
(TETRAS) Performance Subscale Item 4 (Upper Limb) Score – Sensitivity 
Analysis – Missing Data Imputation (Full Analysis Set) 
14.2.1.4 
MCP-Mod for Change from Baseline in the Essential Tremor Rating 
Assessment Scale (TETRAS) Performance Subscale Item 4 (Upper Limb) 
Total Score, Both (Full Analysis Set) 
14.2.1.5 
Summary of Essential Tremor Rating Assessment Scale (TETRAS) 
Performance Subscale Item 4 (Upper Limb) Score (Per Protocol Set) 
14.2.1.6 
Change from Baseline in the Essential Tremor Rating Assessment Scale 
(TETRAS) Performance Subscale Item 4 (Upper Limb) Score – Mixed Effect 
Model for Repeated Measures (MMRM) (Per Protocol Set) 
14.2.1.7 
MCP-Mod for Change from Baseline in the Essential Tremor Rating 
Assessment Scale (TETRAS) Performance Subscale Item 4 (Upper Limb) 
Total Score, Both (Per Protocol Set) 
14.2.1.8 
Summary of Essential Tremor Rating Assessment Scale (TETRAS) 
Performance Subscale Item 4 (Upper Limb) Total Score by Subgroup (Full 
Analysis Set) 
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14.2.1.9 
Change from Baseline in the Essential Tremor Rating Assessment Scale 
(TETRAS) Performance Subscale Item 4 (Upper Limb) Total Score by 
Subgroup - Mixed Effect Model for Repeated Measures (MMRM) (Full 
Analysis Set) 
14.2.2.1 
Summary of Essential Tremor Rating Assessment Scale (TETRAS) ADL 
Composite Score (Full Analysis Set) 
14.2.2.2 
Change from Baseline in the Essential Tremor Rating Assessment Scale 
(TETRAS) ADL Composite Score - Mixed Effect Model for Repeated 
Measures (MMRM) (Full Analysis Set) 
14.2.2.3 
Change from Baseline in the Essential Tremor Rating Assessment Scale 
(TETRAS) ADL Composite Score – Sensitivity Analysis – Missing Data 
Imputation (Full Analysis Set) 
14.2.2.4 
MCP-Mod for Change from Baseline in the Essential Tremor Rating 
Assessment Scale (TETRAS) ADL Composite Score (Full Analysis Set) 
14.2.2.5 
Summary of Essential Tremor Rating Assessment Scale (TETRAS) ADL 
Composite Score (Per Protocol Set) 
14.2.2.6 
Change from Baseline in the Essential Tremor Rating Assessment Scale 
(TETRAS) ADL Composite Score – Mixed Effect Model for Repeated 
Measures (MMRM) (Per Protocol Set) 
14.2.2.7 
MCP-Mod for Change from Baseline in the Essential Tremor Rating 
Assessment Scale (TETRAS) ADL Composite Score (Per Protocol Set) 
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14.3.1.1 
Summary of Treatment-Emergent Adverse Events (Safety Analysis Set) 
14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term (Safety Analysis Set) 
14.3.1.3 
Treatment-Emergent Adverse Events by Preferred Term (Safety Analysis Set) 
14.3.1.4 
Serious Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Analysis Set) 
14.3.1.5 
Treatment-Emergent Adverse Events Leading to Treatment Discontinuation 
by System Organ Class and Preferred Term (Safety Analysis Set) 
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14.3.1.6 
Treatment-Emergent Adverse Events Leading to Study Discontinuation by 
System Organ Class and Preferred Term (Safety Analysis Set) 
14.3.1.7 
Treatment-Emergent Adverse Events by Maximum Severity (Safety Analysis 
Set) 
14.3.1.8 
Treatment-Emergent Adverse Events by Maximum Relationship to Study 
Treatment (Safety Analysis Set) 
14.3.1.9 
Serious Treatment-Emergent Adverse Events by Preferred Term (Safety 
Analysis Set) 
14.3.1.10 
Non-Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Analysis Set) 
14.3.4.1.1 
Summary of Clinical Chemistry (Safety Analysis Set) 
14.3.4.1.2 
Shift Table of Clinical Chemistry (Safety Analysis Set) 
14.3.4.1.3 
Potentially Clinically Significant (PCS) Values in Clinical Chemistry (Safety 
Analysis Set) 
14.3.4.1.4 
Potentially Clinically Significant (PCS) Values in Liver Function Tests (Safety 
Analysis Set) 
14.3.4.2.1 
Summary of Hematology (Safety Analysis Set) 
14.3.4.2.2 
Shift Table of Hematology (Safety Analysis Set) 
14.3.4.2.3 
Potentially Clinically Significant (PCS) Values in Hematology (Safety 
Analysis Set) 
14.3.4.3.1 
Summary of Coagulation (Safety Analysis Set) 
14.3.4.3.2 
Shift Table of Coagulation (Safety Analysis Set) 
14.3.4.3.3 
Potentially Clinically Significant (PCS) Values in Coagulation (Safety 
Analysis Set) 
14.3.4.4.1.1 
Summary of Urinalysis, Continuous Parameters (Safety Analysis Set) 
14.3.4.4.1.2 
Summary of Urinalysis, Categorical Parameters (Safety Analysis Set) 
14.3.4.4.2 
Shift Table of Urinalysis (Safety Analysis Set) 
14.3.4.5.1 
Summary of 12-Lead Electrocardiogram (Safety Analysis Set) 
14.3.4.5.2 
Shift Table of Overall Electrocardiogram Interpretation (Safety Analysis Set) 
14.3.4.5.3 
Potentially Clinically Significant (PCS) QTcF Values (Safety Analysis Set) 
14.3.4.6.1 
Summary of Vital Signs (Safety Analysis Set) 
14.3.4.6.2 
Potentially Clinically Significant (PCS) Values in Vital Signs (Safety Analysis 
Set) 
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Listings 
16.2.1.1 
Particpant Disposition 
16.2.1.2 
Screen Failures 
16.2.2.1 
Inclusion/Exclusion Criteria Violations 
16.2.2.2.1 
Inappropriate Study Drug Consumption 
16.2.2.2.2 
Protocol Deviations 
16.2.3 
Analysis Sets 
16.2.4.1 
Demographics and Informed Consent 
16.2.4.2.1 
Medical/Surgical History 
16.2.4.2.2 
Essential Tremor Disease History 
16.2.4.3.1 
Prior Medications 
16.2.4.3.2 
Concomitant Medications 
16.2.5.1 
Study Drug Dispensation and Return 
16.2.5.2 
Study Drug Administration 
16.2.5.3 
Study Drug Exposure and Adherence 
16.2.6.1.1 
Essential Tremor Rating Assessment Scale (TETRAS) – Performance Subscale 
Item 4 (Upper Limb) 
16.2.6.1.2 
Essential Tremor Rating Assessment Scale (TETRAS) – Performance 
Subscales 
16.2.6.1.3 
Essential Tremor Rating Assessment Scale (TETRAS) – Activities of Daily 
Living 
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16.2.7.1 
Adverse Events 
16.2.7.2 
Serious Adverse Events (Safety Set) 
16.2.7.3 
Listing of Deaths (Safety Set) 
16.2.7.4 
Adverse Events Leading to Treatment Discontinuation (Safety Set) 
16.2.7.5 
Adverse Events Leading to Study Discontinuation (Safety Set) 
16.2.8.1.1 
Clinical Chemistry 
16.2.8.1.2 
Clinical Hematology 
16.2.8.1.3 
Clinical Coagulation 
16.2.8.1.4 
Urinalysis 
16.2.8.2.1 
Pregnancy Test 
16.2.8.2.2 
FSH Testing 
16.2.8.2.3 
Drug Screen 
16.2.8.2.4 
Alcohol and Cotinine Screen 
16.2.8.3 
12-Lead Electrocardiogram (ECG) 
16.2.8.4 
Vital Signs 
16.2.8.5 
Physical Examinations 
16.2.8.6 
Mental Status Examination 
16.2.8.7 
Abbreviated Neurological Examination 
16.2.8.9 
Phone Call During Treatment and Follow-up Period 
 
Figures 
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14.2.1.1.1 
Least Squares Mean Change from Baseline in TETRAS Performance Subscale 
Item 4 (Upper Limb Tremor) Score by Time Point (Full Analysis Set) 
14.2.1.1.2 
Forest Plot of Change from Baseline in TETRAS Performance Subscale Item 
4 (Upper Limb Tremor) Score at Day 91, Total Score (Full Analysis Set) 
14.2.1.1.3 
Dose Response for TETRAS Performance Subscale Item 4 (Upper Limb 
Tremor) Score at Day 91, Total Score (Full Analysis Set) 
14.2.1.2.1 
Least Squares Mean Change from Baseline in TETRAS Performance Subscale 
Item 4 (Upper Limb Tremor) Score by Time Point (Per Protocol Set) 
14.2.1.2.2 
Dose Response for TETRAS Performance Subscale Item 4 (Upper Limb 
Tremor) Score at Day 91, Total Score (Per Protocol Set) 
14.2.2.1.1 
Least Squares Mean Change from Baseline in TETRAS ADL Composite Score 
by Time Point (Full Analysis Set) 
14.2.2.1.2 
Forest Plot of Change from Baseline in TETRAS ADL Composite Score at 
Day 91, Total Score (Full Analysis Set) 
14.2.2.1.3 
Dose Response for TETRAS ADL Composite Score at Day 91, Total Score 
(Full Analysis Set) 
14.2.2.2.1 
Least Squares Mean Change from Baseline in TETRAS ADL Composite Score 
by Time Point (Per Protocol Set) 
14.2.2.2.2 
Dose Response for TETRAS ADL Composite Score at Day 91, Total Score 
(Per Protocol Set) 
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& +&'(&'("


   9 9 2;<;+
-'(8"
* ,(&
*- 

   9 9
2;<;+  +(*'  ,2  
?(>8"


    92;<;+ ,2  
&'>&8'8*
& +&&(


   
 
2;<;+
&'>&8'8*
& +&'(&'("


    	
2;<;+
-'(8"
* ,(&
*- 

    		2;<;+  +(*'  ,2  
?(>8"


    
2;<;+ ,2  
&'>&8'8*
& +&&(


    92;<;+
&'>&8'8*
& +&'(&'("


     2;<;+
-'(8"
* ,(&
*- 

    2;<;+  +(*'  ,2  
?(>8"


   9: 	92;<;+ ,2  
Page 72 of 73


&'>&8'8*
& +&&(


    
 2;<;+
&'>&8'8*
& +&'(&'("


    		2;<;+
-'(8"
* ,(&
*- 

    	 2;<;+  +(*'  ,2  
?(>8"


  	
 		2;<;+ ,2  
&'>&8'8*
& +&&(


  	 	92;<;+
*
(


  	 
2;<;+ ,2  
-'(8"
* ,(&
*- 

  	 

2;<;+  +(*'  ,2  
('(


  	 

2;<;+
&'>&8'8*
& +&'(&'("


  	 

2;<;+
Page 73 of 73