A Phase 2, Double-Blind, Placebo-controlled, Randomized Study Evaluating the Efficacy, Safety, and Tolerability of Sage-324 in the Treatment of Individuals With Essential Tremor
Phase: PHASE2
Conditions: Essential Tremor
Sponsor: Sage Therapeutics

Official Title: A Phase 2, Double-blind, Placebo-controlled, Randomized Study 
Evaluating The Efficacy, Safety, And Tolerability Of SAGE-324 In 
The Treatment Of Individuals With Essential Tremor
NCT Number: NCT04305275 
Document Date: Protocol Version 5.0: 18-December-2020
Protocol Version 4.0: 11-June-2020 
Protocol Version 3.0: 24-February-2020 
Protocol Version 2.0: 20-December-2019 
Protocol Version 1.0: 23-October-2019

Clinical Study Report 
324-ETD-201
16.1 Study Information 
1 
1.
PROTOCOL AND AMENDMENTS
Version Number 
Date 
Title 
1.0 
23 October 2019 
A Phase 2, Double-Blind, Placebo-Controlled, Randomized 
Study Evaluating the Efficacy, Safety, and Tolerability of 
SAGE-324 in the Treatment of Individuals with Essential 
Tremor 
2.0 
20 December 2019 
3.0 
24 February 2020 
4.0 
10 June 2020 
5.0 
17 December 2020 
Administrative Letter dated 16 November 2020 

A PHASE 2, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
RANDOMIZED, DOSE-RANGING STUDY EVALUATING THE 
EFFICACY, SAFETY, AND TOLERABILITY OF SAGE-324 
MONOTHERAPY AND ADJUNCTIVE THERAPY WITH 
PROPRANOLOL IN THE TREATMENT OF INDIVIDUALS 
WITH ESSENTIAL TREMOR  
324-ETD-201
Investigational Product 
Clinical Phase 
Sponsor 
Sponsor Contact 
Sponsor Medical Monitor 
SAGE-324 Oral Tablet 
Phase 2  
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
, MD 
, MD, PhD
23 October 2019
Date of Original Protocol 
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. 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
3 
INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-324. I have read the 324-ETD-
201 protocol and agree to conduct the study as outlined. I agree to maintain the confidentiality of 
all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY) 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201
CONFIDENTIAL 
4 
PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sage Study Physician 
, MD  
 
Phone US: 
 
Sage Medical Monitor and 
24-hour Emergency Contact
, MD, PhD 
Office phone: 
 
Mobile: 
 
E-mail: 
SAE Reporting Information 
IQVIA Lifecycle Safety 
4820 Emperor Boulevard 
Durham, NC 27703  
E-mail: Sage.Safety@iqvia.com
Fax: 1-855-638-1674
SAE Hotline: 1-855-564-2229 
Product Complaints 
Sage Therapeutics, Inc. 
E-mail:
productcomplaints@sagerx.com
Phone: 1-833-554-7243

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
5 
1. 
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, Placebo-controlled, Randomized, Dose-ranging Study Evaluating the 
Efficacy, Safety, and Tolerability of SAGE-324 Monotherapy and Adjunctive Therapy with 
Propranolol in the Treatment of Individuals with Essential Tremor  
Number of Sites and Study Location: This study will take place at approximately 30 sites in the 
United States. 
Phase of Development: Phase 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 72 days. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To assess the effect of SAGE-324 compared 
to placebo on tremor reduction in 
individuals with essential tremor (ET) 
Change from baseline compared to placebo in 
Kinesia ONE™ accelerometer scores after 28 days 
of treatment 
Secondary 
 
• 
To assess the effect of SAGE-324 
compared to placebo on activities of 
daily living (ADLs), total 
performance, and upper extremities 
 
 
 
 
 
 
 
• 
To evaluate the safety and 
tolerability of SAGE-324 
• 
Change from baseline compared to placebo 
in Kinesia ONE accelerometer scores at all 
other timepoints 
• 
Change from baseline compared to placebo 
in the following:  
- 
The Essential Tremor Rating 
Assessment (TETRAS) Scale ADL 
score 
- 
TETRAS total performance score  
- 
TETRAS performance subscale part 4 
upper limb tremor score 
• 
Incidence of treatment-emergent adverse 
events (TEAEs) 
 
 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
6 
 
Study Description: 
This is a randomized, double-blind, placebo-controlled, parallel group dose-ranging study to evaluate 
the efficacy, safety, and tolerability of SAGE-324 as monotherapy and adjunctive therapy with 
propranolol in individuals with ET. Participants, site staff, and sponsor personnel will be masked to 
treatment allocation. 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
7 
This study includes a Screening Period of up to 28 days, a 29-day treatment period (28 days of 
dosing), and a 14-day follow up period. After providing informed consent, participants will undergo 
screening assessments as outlined in Table 2 to determine eligibility.  
Screening Period: The Screening Period begins with the signing of the informed consent form (ICF). 
Following completion of screening, on Day 1, eligible participants will visit the study center and will 
be randomized to 1 of 3 treatment groups (SAGE-324 30 mg daily, SAGE-324 60 mg daily, or 
placebo) in a 1:1:1 ratio. Randomization will be stratified based on the use of propranolol for the 
treatment of ET (Y/N). Participants who are on a propranolol regimen must have been on a stable 
dose for at least 1 month prior to Day 1 and will continue to be on a stable dose during the Treatment 
Period. Participants will complete baseline assessments of safety and efficacy, including the clinician-
rated TETRAS and quantitative Kinesia ONE assessments of tremor, as specified in the Schedule of 
Assessments (Table 2). 
Double-Blind Treatment Period: Starting on Day 1, participants will receive a single dose of 
investigational product (IP) once daily for 28 days on an outpatient basis. Doses occurring on 
scheduled clinic visits will be administered in the clinic, and doses occurring on all other days may be 
self-administered by the participant at home during the 29-day Treatment Period (28 days of dosing). 
During the Treatment Period, participants will return to the study center approximately once per week 
for efficacy and safety assessments as specified in Table 2. Participants will be trained on the use of 
software applications and devices necessary to complete questionnaires or other assessments as 
required. 
Follow Up Period: Follow up visits will be conducted on an outpatient basis. Participants will 
continue to complete questionnaires as indicated in Table 2 and will receive a phone call 
approximately 7 days after the last dose of IP (ie, Day 36) for safety monitoring. Participants will 
return to the study center for an end of study visit approximately 14 days following the last dose of IP 
(ie, Day 42). 
Participants who discontinue IP during the Treatment Period will be asked to return to the clinic as 
soon as possible for an end of treatment (EOT) visit. Follow-up visits should take place as scheduled, 
or relative to the last dose of IP if discontinuing treatment early. If at any time after the EOT visit, a 
participant decides to withdraw from the study, the participant should return for an early termination 
visit (ETV). The EOT and ETV can be on the same day if a participant discontinues IP and withdraws 
from the study on the same day during a clinic visit; in this case, all events scheduled for the EOT 
visit will be conducted. 
During the study, a phone call will be conducted once per week (preferably mid-week) in between 
clinic visits, to review current status of participant. 
Number of Participants (planned): Up to 120 participants, with up to 40 participants per arm.  

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
8 
Eligibility Criteria:  
Inclusion Criteria: 
1. Participant has signed an ICF before any study-specific procedures or washout of drugs is 
performed. 
2. Participant is 18 to 80 years of age, inclusive, at the time informed consent is obtained. 
3. 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) 
d. 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 step-wise deterioration of tremor 
4. Participant has a combined total upper extremity TETRAS score of ≥8 with at least 1 upper 
extremity TETRAS score >4. 
5. Participant is willing to discontinue medications taken for the treatment of ET, with the 
exception of propranolol, within 14 days or 5 half-lives (whichever is longer) prior to 
receiving IP. 
6. Participants taking propranolol for the treatment of ET must be on a stable dose for at least 
1 month prior to Day 1 and must be willing to maintain their stable dose through Day 29. 
7. Participant is willing to discontinue the use of alcohol and drugs of abuse within at least ≥1 
week prior to Day 1 and through Day 29 of the study. 
8. Female participant agrees to use at least one method of highly effective contraception as 
listed in Section 8.2.4 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 
>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).  
9. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 13 weeks after receiving 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 8.2.4.  
10. Male participant is willing to abstain from sperm donation for the duration of the study and 
for 13 weeks after receiving study drug. 
11. Female participant must have a pregnancy test result that is confirmed as negative at 
Screening and Day 1. 
12. At the discretion of the Investigator, participant is medically stable and ambulatory, and has 
been on stable dose(s) of any necessary prescription or over the counter medication(s) for at 
least 30 days prior to Day 1, or changes/discontinues their use prior to Day 1 with the 
appropriate washout, as applicable per investigator judgement.  

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
9 
13. Participant has no clinically significant findings, as determined by the investigator, on 
physical examination including mental state examination (MSE) and neurologic examination, 
12-lead ECG, or clinical laboratory tests.  
Exclusion Criteria: 
1. Participant has presence of known causes of enhanced physiological tremor. 
2. Participant has had recent exposure (14 days prior to Day 1) to tremorgenic drugs or presence 
of a drug or 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. 
5. Participant has historical or clinical evidence of tremor with psychogenic origin (including 
but not limited to eating disorders, major depression, etc.) 
6. Participant has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic 
(hypothyroidism with stable thyroid replacement is acceptable), or oncological disease. 
7. Participant has history, presence, and/or current evidence of serologic positive results for 
hepatitis B surface antigen (HBsAg), hepatitis C antibodies (anti-HCV), or human 
immunodeficiency virus (HIV) 1 or 2 antibodies. 
8. Participant has history of alcohol or drug abuse within 6 months prior to Screening, or a 
positive screen for alcohol on the Day 1 visit, or a positive screen for drugs of abuse at 
Screening or at the Day 1 visit. 
9. Participant has a known allergy to SAGE-324 or any excipient.  
10. Participant has had exposure to another investigational drug or device within 30 days prior to 
the Day 1 visit. 
11. Participant has history or suicidal behavior within 2 years or answers “YES” to questions 3, 
4, or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk or suicide in the opinion 
of the investigator 
12. Participant has donated one 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.  
13. Participant is unable to perform Kinesia ONE assessments or unable to use the device 
required to perform the assessment. 
14. 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. 
15. Participant is unwilling or unable to comply with study procedures and required training. 
16. Participant has used any known moderate or strong cytochrome P450 3A4 or P450 2D6 
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. 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
10 
John’s Wort or products containing these within 30 days prior to Day 1. Use of mild 
cytochrome inhibitors and/or inducers may be permitted.  
17. Participant has concurrent or recent exposure (14 days prior to the Day 1 visit) to 
sedative/hypnotic drugs, stimulants, eg, opioids, highly-caffeinated beverages or dietary 
supplements containing high doses of caffeine, or recent increase above regular daily 
consumption of coffee. 
18. Participant has concurrent or recent exposure (30 days prior to the Day 1 visit) to long-acting 
benzodiazepines. 
19. Participant plans to undergo elective surgery or relocate during participation in the study. 
20. Participant is investigative site personnel or a member of their immediate families (spouse, 
parent, child or sibling whether biological or legally adopted).  
Investigational Product Dosage and Mode of Administration:  
Study drug, SAGE-324 or matched placebo oral tablet(s) will be administered in the clinic or self-
administered once daily, in the morning with food. The following dose levels of SAGE-324 will be 
evaluated: 
• 
30 mg daily in the morning 
• 
60 mg daily in the morning 
Duration of Treatment:  
Each participant will receive a single dose of SAGE-324 oral tablet or matching placebo administered 
once daily for 28 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 clinic-based Kinesia ONE accelerometer 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 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
11 
The sample size of this study is based on the assumption of a 3 points difference in the mean change 
from baseline Kinesia ONE accelerometer scores between SAGE-324 and placebo with a standard 
deviation of 3.5 points and a 1:1:1 randomization schedule. Under these assumptions, a sample size of 
30 evaluable subjects per group would provide 90% power assuming a 2-sided test at α level of 0.05. 
By including 3 treatment groups and using a 1:1:1 randomization ratio, a total of 90 evaluable 
subjects are required. Assuming a nonevaluability rate of 25%, at least 120 subjects will be 
randomized.   
Analysis of Primary Efficacy Endpoint 
The estimand for the primary efficacy analysis is the treatment difference between either dose of 
SAGE-324 and placebo in mean change from baseline in clinic-based Kinesia ONE accelerometer 
scores at Day 29 based on Full Analysis Set. This will be analyzed using a mixed effects model for 
repeated measures (MMRM); the model will include treatment, baseline Kinesia ONE accelerometer 
score, stratification factor, 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. The main comparison will be between SAGE-324 and placebo at the 29-day timepoint. 
Model-based point estimates (ie, least squares means, 95% confidence intervals, and p-values) will be 
reported where applicable. An unstructured covariance structure will be used to model the within-
subject errors. If there is a convergence issue with the unstructured covariance model, Toeplitz 
compound symmetry 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. 
Analysis of Secondary Efficacy Endpoints 
Similar to those methods described above for the primary endpoint, an MMRM will be used to 
analyze of the change from baseline in TETRAS total performance scores, TETRAS Performance 
subscale part 4 upper limb tremor scores and TETRAS ADL scores.  
Safety Analysis 
Safety and tolerability of study drug will be evaluated by incidence of TEAEs/serious adverse events, 
 
  
 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
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12 
Table 2: 
Schedule of Assessments 
Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5  
(±1) 
Phone
Call 
8 
(±1) 
12 
(±1) 
Phone
Call 
15  
(±1) 
19 
(±1) 
Phone
Call 
22  
(±1) 
26 
(±1) 
Phone
Call 
29 
(+1) 
EOT 
32 
(±1) 
Phone
Call 
35  
Safety 
Phone
Call 
38 
(±1) 
Phone
Call 
42 
(±1) 
EOS/ 
ETVa 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis/HIV screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
(all women) 
X  
(serum; all 
women) 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
FSH (postmenopausal 
women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Drug/alcohol screens 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Physical examinationc 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Neurological 
examination including 
MSEc 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Body height  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Body weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Vital signsd 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
12-Lead ECGe 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Chemistry/hematology/
coagulation/urinalysis 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 

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PPD

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
15 
d Vital signs without orthostatic blood pressure and heart rate will be collected predose in the beginning of each visit and again prior to departing the clinic, at 
approximately 5 hours (±30 min). Postdose vital signs to include orthostatic blood pressure and heart rate, measured after the participant has been in the supine 
position for at least 5 minutes and then repeated 1 minute and 3 minutes after standing.  
e ECGs will be collected and read centrally. ECGs will be performed approximately 5 hours (±30 min) postdose. All ECGs must be performed after the 
participant has been in a supine position for at least 5 minutes.  
 
  
g Kinesia ONE will be assessed simultaneous to TETRAS Performance subscale part 4 upper limb tremor. On clinic dosing days, participants will perform 
Kinesia ONE assessments approximately 30 to 60 minutes prior to dosing in the morning. In addition, on Day 15, Kinesia ONE assessments will be performed 
at 5 and 8 hours (±30 min) postdose. 
h Training specific to the Investigational Product Diary will be performed prior to randomization.  
i The TETRAS Performance and TETRAS ADL subscales will be assessed at Screening and predose at each clinic visit postrandomization. The TETRAS 
Performance subscale part 4 upper limb tremor will be assessed simultaneous to Kinesia ONE. In addition, on Day 15, the TETRAS Performance subscale will 
be assessed at 5 and 8 hours (±30 min) postdose. Eligibility is determined based on the combined TETRAS performance subscale part 4 upper limb tremor total 
score ≥8, with at least 1 upper limb score >4 at Screening. 
j Participants will be trained on the use of software applications and devices necessary for the conduct of the study by site personnel. 
k Prior and concomitant medications will be recorded during Screening and will include all medications and supplements taken within the 30 days prior to 
signing the ICF through the first dose of IP. Concomitant medications will be recorded thereafter throughout the duration of the study. At Screening, this will 
include year of diagnosis and history of treatments for ET since year of diagnosis and use of antidepressant medications taken in the prior 12 months.  
 

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Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
21 
Abbreviation 
Definition 
 
 
PV 
pharmacovigilance 
QTcF 
QT corrected according to Fridericia’s formula 
 
 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
t½  
terminal elimination half-life  
TEAE 
treatment-emergent adverse event 
TETRAS 
The Essential Tremor Rating Assessment Scale 
tmax 
time of occurrence of Cmax 
WHO 
World Health Organization 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
22 
4. 
INTRODUCTION 
SAGE-324 is a positive allosteric modulator (PAM) of A-type γ-aminobutyric acid-gated 
chloride channel (GABAA) receptors, the major class of inhibitory neurotransmitter receptors in 
the brain. In addition to being developed as an adjunctive therapy in epilepsy and other seizure 
disorders under IND 139201, SAGE-324 is also being developed for the treatment of Essential 
Tremor (ET). 
Essential tremor is a permanently debilitating, neurologically determined, common movement 
disorder characterized by involuntary rhythmic oscillation of a body part due to intermittent 
muscle contractions typically occurring 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 US, 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 term 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.  
The pharmacological profile of SAGE-324 is theorized to induce therapeutic effect in the 
treatment of ET. Based on preclinical studies of SAGE-324, which features a different 
mechanism of action than that of propranolol, the pharmacokinetic (PK)/ pharmacodynamic (PD) 
profile suggests SAGE-324 may safely ameliorate symptoms in patients suffering from ET, 
regardless of propranolol use. 
There are currently ongoing Phase 1 clinical studies of SAGE-324 in healthy adults and in adults 
with ET. These studies, in addition to preclinical studies of SAGE-324, are detailed in the 
investigator’s brochure. 
With a GABAA receptor-based mechanism of action featuring positive allosteric modulation 
capability, SAGE-324 represents a novel approach to treatment of ET with possible utility as 
monotherapy or adjunctive to propranolol, 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. 
Henceforth, this double-blind, placebo-controlled efficacy and safety study of SAGE-324 will be 
conducted in adults with and without concomitant use of propranolol and is designed to assess 
the effect of SAGE-324 on a variety of outcome measures specific to ET disease characteristics 
and associated quality of life domains. 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
23 
4.1. 
Dose Justification 
Doses of SAGE-324 planned for this study are 30 mg and 60 mg given as oral tablets, to be 
administered once daily in the morning with food. The doses were selected based on preliminary 
data from 3 active studies of SAGE-324, which included: unblinded data from completed cohorts 
in 324-CLP-101 Part A (oral solution SAGE-324 doses of 3 mg, 10 mg, 30 mg, 45 mg, 60 mg); 
Part C (oral solution SAGE-324 doses of 30 mg); Part D (oral suspension SAGE-324 doses of 
30 mg) in healthy subjects; and preliminary data from open-label Part E (oral suspension SAGE-
324 doses of 45 mg and 60 mg) in participants with ET; additional preliminary data from 324-
CLP-102 cohorts 1 through 6 (cohorts 1 to 5 unblinded, cohort 6 blinded), which evaluated oral 
suspension doses ranging from 5 mg to 60 mg; and preliminary unblinded data from 324-CLP-
104, which compared the relative bioavailability of the oral tablet (30 mg) vs oral suspension (30 
mg) formulations of SAGE-324 and separately the effect of food on the PK of the SAGE-324 
oral tablet.  In 324-CLP-101 and 324-CLP-102 studies, doses were administered in a fasted state. 
The preliminary data from all of these active studies collectively informed the route of 
administration (oral) and dose strengths of 30 mg and 60 mg as oral tablets planned for further 
evaluation in this study.  
SAGE-324 was generally well-tolerated in participants with ET and in healthy volunteers, as was 
shown in the preliminary data of 324-CLP-101 Part E at single administration doses of 45 mg 
and 60 mg, and in 324-CLP-102 through once-daily administered doses of up to 60 mg for 
14 days. In addition, tremor reduction was observed at both doses on TETRAS and Kinesia 
accelerometry, with greater improvement seen at 60 mg compared to 45 mg.  
In the clinically complete study 324-CLP-104, preliminary data showed that SAGE-324 oral 
tablets, when coadministered with a meal, resulted in exposures approximately equivalent to that 
of SAGE-324 oral suspension under fasted conditions. Therefore, the SAGE-324 oral tablets are 
recommended to be administered with food. 
4.2. 
Benefit/Risk Assessment 
Based on the mechanism of action of SAGE-324 and the results of completed nonclinical studies 
and preliminary data of currently ongoing clinical studies of SAGE-324, it is theorized that 
participants may have symptomatic amelioration, ie, tremor reduction and possibly improved 
quality of life from potentially stabilizing disease characteristics associated with ET. 
Potential risks anticipated in this study are based on available data from toxicology studies of 
SAGE-324 in addition to preliminary data from 3 ongoing, currently active Phase 1 clinical 
studies of SAGE-324.   
As of 18 October 2019, based on the preliminary clinical data available, there have been no 
deaths, SAEs related to IP, or confirmed clinically significant trends in clinical laboratory 
evaluations, vital signs, or physical examinations. Available preliminary clinical data is 
summarized in the Investigator’s Brochure. 
Based on available preliminary clinical data from SAGE-324 active clinical studies, AEs of 
somnolence and feeling of relaxation are considered adverse drug reactions. In addition to 
scheduled clinic visits, the current status of study participants will be reviewed via weekly phone 
calls, in between clinic visits. 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
24 
5. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• To assess the effect of SAGE-324 
compared to placebo on tremor 
reduction in individuals with 
essential tremor (ET) 
• Change from baseline compared to 
placebo in Kinesia ONE™ accelerometer 
scores after 28 days of treatment 
Secondary 
 
• To assess the effect of SAGE-324 
compared to placebo on activities 
of daily living (ADLs), total 
performance, and upper 
extremities 
 
 
 
 
 
 
• To evaluate the safety and 
tolerability of SAGE-324 
• Change from baseline compared to 
placebo in Kinesia ONE accelerometer 
scores at all other timepoints 
• Change from baseline compared to 
placebo in the following:  
- 
The Essential Tremor Rating 
Assessment (TETRAS) Scale ADL 
score 
- 
TETRAS Total Performance Score  
- 
TETRAS Performance Subscale Part 4 
Upper Limb Tremor 
• Incidence of treatment-emergent adverse 
events (TEAEs) 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
25 
 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201 
CONFIDENTIAL 
26 
6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, parallel group dose-ranging study to 
evaluate the efficacy, safety, and tolerability of SAGE-324 as monotherapy and adjunctive 
therapy with propranolol in individuals with ET. Participants, site staff, and sponsor personnel 
will be masked to treatment allocation (see Section 8.5). 
This study includes a Screening Period of up to 28 days, a 29-day treatment period consisting of 
28 days of dosing with the end of treatment visit intended to be on Day 29 at trough, and a 
14-day follow-up period relative to final dose (Figure 1). After providing informed consent, 
participants will undergo screening assessments as outlined in Table 2 to determine eligibility.  
The Screening Period begins with the signing of the informed consent form (ICF). Following 
completion of screening, on Day 1, eligible participants will visit the study center and will be 
randomized to 1 of 3 treatment groups (SAGE-324 30 mg, SAGE-324 60 mg, or placebo) in a 
1:1:1 ratio. Randomization will be stratified based on the use of propranolol for the treatment of 
ET (Y/N). Participants who are on a propranolol regimen must have been on a stable regimen for 
at least 1 month prior to Day 1 and will continue to be on that stable regimen during the 
Treatment Period. Participants will complete baseline assessments of safety and efficacy, 
including the clinician-rated TETRAS and quantitative Kinesia ONE assessments of tremor, as 
specified in the Schedule of Assessments (Table 2). 
During the double-blind Treatment Period, starting on Day 1, participants will receive a single 
dose of investigational product (IP) once daily for 28 days on an outpatient basis. Doses 
occurring on scheduled clinic visits will be administered in the clinic, and doses occurring on all 
other days will be self-administered by the participant at home as specified in Table 2. During 
the Treatment Period, participants will return to the study center approximately once per week 
for efficacy and safety assessments as specified in Table 2. In addition, a phone call will be 
conducted once per week (preferably mid-week) in between clinic visits, to review current status 
of the participant. 
In addition to Kinesia ONE-specific training, clinical study center staff and study participants 
will be trained on the use of software applications and devices necessary to complete 
questionnaires or other assessments as required. During in-clinic visits, clinical study center staff 
will be available to assist participants as needed, to ensure they can access and use the software 
applications and devices correctly according to the training. 
During the follow-up period, visits will be conducted on an outpatient basis. In addition to the 
phone calls to review current status, participants will receive a phone call approximately 7 days 
after the last dose of IP (ie, Day 35) for safety monitoring. Participants will return to the study 
center for an end of study visit approximately 14 days following the last dose of IP (ie, Day 42). 
Participants who discontinue IP during the Treatment Period will be asked to return to the clinic 
as soon as possible for an end of treatment (EOT) visit. Follow-up visits should take place as 
scheduled, or relative to the last dose of IP if discontinuing treatment early. If at any time after 
the EOT visit, a participant decides to withdraw from the study, the participant should return for 
an early termination visit (ETV). The EOT and ETV can be on the same day if a participant 

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discontinues IP and withdraws from the study on the same day during a clinic visit; in this case, 
all events scheduled for the EOT visit will be conducted.  
Figure 1: Study Design  
 
Abbreviation:  EOT = end of treatment 
6.2. 
Number of Participants 
Up to approximately 120 participants are planned, with up to 40 participants enrolled per arm, to 
produce an estimated 30 participants per arm who will complete the study. Additional 
participants may be randomized if the drop-out rate is higher than anticipated (ie, >25%). 
6.3. 
Treatment Assignment 
Participants will be assigned to 30 mg or 60 mg IP (active or placebo) in accordance with the 
randomization schedule on Day 1. Additional details on randomization and blinding are provided 
in Section 8.5.  
6.4. 
Dose Adjustment Criteria 
Doses will not be adjusted for this study except as clinically necessary, eg, interrupting dose due 
to an AE or serious adverse event (SAE) considered related to IP, or as recommended by the 
medical monitor in consultation with the investigator. 
6.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
participants, or for administrative reasons. In the event of study termination, Sage Therapeutics 
will provide written notification to the investigator. Investigational sites must promptly notify 
their IRB/ethics committee (EC), where required, and initiate withdrawal procedures for 
participating participants.  
 

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7. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
7.1. 
Participant Inclusion Criteria 
Participants must meet all of the following criteria to qualify for participation in this study: 
1. Participant has signed an ICF before any study-specific procedures or washout of drugs is 
performed. 
2. Participant is 18 to 80 years of age, inclusive, at the time informed consent is obtained. 
3. 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) 
d. 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 step-wise deterioration of tremor 
4. Participant has a combined total upper extremity TETRAS score of ≥8 with at least 1 
upper extremity TETRAS score >4. 
5. Participant is willing to discontinue medications taken for the treatment of ET, with the 
exception of propranolol, within 14 days or 5 half-lives (whichever is longer) prior to 
receiving IP. 
6. Participants taking propranolol for the treatment of ET must be on a stable dose for at 
least 1 month prior to Day 1 and must be willing to maintain their stable dose through 
Day 29. 
7. Participant is willing to discontinue the use of alcohol and drugs of abuse within at least 
≥1 week prior to Day 1 and through Day 29 of the study. 
8. Female participant agrees to use at least one method of highly effective contraception as 
listed in Section 8.2.4 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 >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).  
9. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 13 weeks after receiving 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 8.2.4.  
10. Male participant is willing to abstain from sperm donation for the duration of the study 
and for 13 weeks after receiving study drug. 
11. Female participant must have a pregnancy test result that is confirmed as negative at 
Screening and Day 1. 

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12. At the discretion of the investigator, participant is medically stable and ambulatory, and 
is on stable dose(s) of any necessary prescription or over-the-counter medication(s) for at 
least 30 Days prior to Day 1, or changes/discontinues their use prior to Day 1 with the 
appropriate washout, as applicable per investigator judgement.  
13. Participant has no clinically significant findings, as determined by the investigator, on 
physical examination including mental state examination (MSE) and neurologic 
examination, 12-lead ECG, or clinical laboratory tests. 
7.2. 
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 recent exposure (14 days prior to Day 1) to tremorgenic drugs or 
presence of a drug or 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. 
5. Participant has historical or clinical evidence of tremor with psychogenic origin 
(including but not limited to eating disorders, major depression, etc.) 
6. Participant has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic 
(hypothyroidism with stable thyroid replacement is acceptable), or oncological disease. 
7. Participant has history, presence, and/or current evidence of serologic positive results for 
hepatitis B surface antigen (HBsAg), hepatitis C antibodies (anti-HCV), or human 
immunodeficiency virus (HIV) 1 or 2 antibodies. 
8. Participant has history of alcohol or drug abuse within 6 months prior to Screening, or a 
positive screen for alcohol on the Day 1 visit, or a positive screen for drugs of abuse at 
Screening or at the Day 1 visit. 
9. Participant has a known allergy to SAGE-324 or any excipient.  
10. Participant has had exposure to another investigational drug or device within 30 days 
prior to the Day 1 visit. 
11. Participant has history or suicidal behavior within 2 years or answers “YES” to questions 
3, 4, or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk or suicide in the 
opinion of the investigator 
12. Participant has donated one 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.  

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13. Participant is unable to perform Kinesia ONE assessments or unable to use the device 
required to perform the assessment. 
14. 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. 
15. Participant is unwilling or unable to comply with study procedures and required training. 
16. Participant has used any known moderate or strong cytochrome P450 3A4 or P450 2D6 
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. Use of 
mild cytochrome inhibitors and/or inducers may be permitted.  
17. Participant has concurrent or recent exposure (14 days prior to the Day 1 visit) to 
sedative/hypnotic drugs, stimulants, eg, opioids, highly-caffeinated beverages or dietary 
supplements containing high doses of caffeine, or recent increase above regular daily 
consumption of coffee. 
18. Participant has concurrent or recent exposure (30 days prior to the Day 1 visit) to long-
acting benzodiazepines 
19. Participant plans to undergo elective surgery or relocate during participation in the study. 
20. Participant is investigative site personnel or a member of their immediate families 
(spouse, parent, child or sibling whether biological or legally adopted). 
7.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned IP or entered in the study, ie, a participant who does not meet 1 or 
more of the eligibility criteria after providing consent and prior to randomization (Day 1). 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. 
7.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
7.4.1. 
Investigational Product Discontinuation 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, or administrative reasons. Participants who elect to discontinue IP will 
be encouraged by the Investigator to remain on study and complete the 14-day follow-up safety 
assessments. 
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).  

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The investigator must notify the sponsor and/or the medical monitor when a participant stops 
participation in the study for any reason.  
If a participant is persistently noncompliant, the investigator should discuss with the sponsor the 
potential discontinuation of the participant. Any reasons for unwillingness or inability to adhere 
to the protocol must be recorded in the participant’s eCRF, including: 
• missed visits; 
• interruptions in the schedule of study drug administration; 
• nonpermitted medications 
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. 
7.4.2. 
Early Termination from the Study 
At the time of study withdrawal/stopping study participation, if possible within 48 hours of final 
IP dose, an ETV/EOT visit should be conducted as specified in the Schedule of Assessments 
(Table 2). The participant will be permanently discontinued both from the IP and from the study 
at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
7.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been unsuccessful.  
7.4.4. 
Replacement of Participants 
Participants will not be replaced. 

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8. 
TREATMENT OF PARTICIPANTS 
8.1. 
Description of Investigational Product 
SAGE-324 is an orally administered tablet provided in 5 mg tablets totaling 30-mg and 60-mg 
doses, to be administered once daily for 28 days, proceeded by a 14-day follow-up period. IP 
doses are to be administered in the morning with food. 
Participants in all cohorts will receive the appropriate dose of IP (30 mg total dose of SAGE-324 
tablets, 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 9. 
8.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements 
8.2.1. 
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 through the first dose of 
IP will be recorded. Use of antidepressant medications taken in the prior 12 months will be 
recorded at Screening; all other medications taken within the 30 days prior to Screening will be 
recorded. 
All medications and/or supplements taken from the first dose of IP through the Day 42 (±1 days) 
visit (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.  
8.2.2. 
Prohibited Medications 
Use or consumption of the following is prohibited for the timeframes specified:  
• 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 Screening or during 
the study  
• Use of any prescription or over-the-counter medication (except for propranolol use as 
prescribed, and/or up to 3 g/day of acetaminophen), herbal medication, vitamins, or 
mineral supplements within 14 days prior to first IP administration, or during the 
study period  
• Use of tremorgenic drugs or agents known to affect SAGE-324 drug metabolism (any 
known CYP450 3A4 inhibitors and/or inducers) within the 28 days or 5 terminal half-
lives (whichever is longer) prior to first IP administration or during the study period  
8.2.3. 
Other Restrictions 
In addition to alcohol and drugs of abuse, the following are not permitted during the study, or 
within 14 days of the first IP dose:  sedative/hypnotic drugs, stimulants, eg, opioids, 
benzodiazepines, highly-caffeinated beverages or dietary supplements containing caffeine. 

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8.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation  
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal ligation or bilateral tubal occlusion (performed at least 3 months prior 
to Screening) 
• Vasectomized partner (performed at least 3 months prior to Screening) 
• Sexual abstinence (no sexual intercourse) 
Acceptable forms of contraception for male participants include: 
• Sexual abstinence (no sexual intercourse) 
• History of vasectomy (performed at least 3 months prior to Screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
8.3. 
Intervention after the End of the Study 
There is no planned intervention following the end of the study. 
8.4. 
Treatment Adherence 
The first dose of IP will be received and administered by participants in the clinic. Participants 
will be dispensed a 7-day supply of IP to orally self-administer at home with instructions 
specifying to administer in the morning with food. 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 9.6. 
8.5. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Participants will be randomized in 
a stratified manner based on propranolol for the treatment of ET (Y/N); randomization will be 
done within each stratum in a 1:1:1 ratio to treatment groups (SAGE-324 30 mg, 
SAGE-324 60 mg, or placebo). Participants, site staff, and the sponsor will be blinded to 
treatment allocation. 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.  

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8.5.1. 
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 Sage prior to unblinding the study 
treatment administered to a participant. Requests from the investigator about the treatment 
administered to study participants should be discussed with the Sage Medical Monitor. If the 
unblinding occurs without Sage’s knowledge, the investigator must notify Sage within 24 hours 
of breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records.  
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and on the 
eCRF. At the time of withdrawal from the study/stopping participation, if possible, an EOT 
and/or ETV should be conducted.  
If a participant or study personnel become unblinded to treatment, the participant will be 
excluded from the Per Protocol analysis set, as detailed further in the statistical analysis plan. 
 

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9. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
9.1. 
Investigational Product 
Table 3: 
Investigational Product 
 
Investigational Product 
Product Name: 
SAGE-324 
Placebo 
Dosage Form: 
Tablet 
Tablet 
Tablet Strength 
5 mg 
0 mg 
Route of Administration 
Oral 
Oral 
Physical Description 
Immediate release white to off-
white, round, film-coated tablet 
containing 5 mg of SAGE-324 
drug substance, and composed 
of lactose, microcrystalline 
cellulose, croscarmellose 
sodium, sodium stearyl fumarate 
and fumed silica, featuring 
Opadry® II white as the coating 
agent. 
Immediate release 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. 
9.2. 
Investigational Product Packaging and Labeling 
SAGE-324 Oral Tablets and Placebo Tablets will be packaged in blinded, high density 
polyethylene (HDPE) containers. The containers used for SAGE-324 and placebo will be 
identical in appearance. The package labeling conforms to FDA and GMP requirements. 
9.3. 
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, dispensing, 
inventory, and accountability of the IP. An accurate, timely record of the disposition of the IP 
must be maintained.  

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9.4. 
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. 
9.5. 
Investigational Product Administration 
The first dose of IP will be administered in the clinic, and at home thereafter as specified in the 
Schedule of Assessments (Table 2). The IP will be provided as tablets in dosage according to the 
randomized dose cohort (30 mg or 60 mg) and will be orally administered once daily in the 
morning, with food. 
9.6. 
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. 
The designated site staff will dispense the supplied participant-specific kits to participants at the 
planned dispensation visit intervals outlined in the Schedule of Assessments (Table 2). 
Site staff will access the interactive response technology (IRT) at the Screening Visit to obtain a 
participant identification (ID) number for each participant who 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 medication ID number for the IP to be dispensed to that participant. The 
medication ID number must be recorded. 
At the subsequent IP-dispensing visit, the investigator or designee will access the IRT, providing 
the same participant ID number assigned at Screening, to obtain the medication ID number for 
the IP to be dispensed at that visit. The medication ID number, and the number of tablets 
returned by the participant at this visit must be recorded.  
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
sponsor must be notified immediately. 
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 tablets will be returned to Sage Therapeutics for 
destruction or destroyed locally per the site’s procedures; disposition of IP will be documented. 

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9.7. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution.  
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1 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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10. 
EFFICACY ASSESSMENTS AND CLINICAL PHARMACOLOGY 
ASSESSMENTS 
10.1. 
Efficacy Assessments 
10.1.1. 
Kinesia ONE™ Accelerometer Score 
Kinesia ONE™ is an ISO-certified wireless motion sensor worn distally on the index finger, 
which utilizes 3 orthogonal accelerometers and 3 orthogonal gyroscopes to monitor three-
dimensional motion. Data is transmitted wirelessly from the sensor to a Bluetooth technology-
enabled device to use with the Kinesia ONE software (eg, Apple iPad or similar device with 
preinstalled Kinesia ONE software). The device has received FDA clearance. 
Via the Kinesia ONE software application, measures of three-dimensional motion are converted 
to scores ranging from 0 to 4, per assessed maneuver; higher scores indicate greater tremor 
severity. Motion in both arms is captured. 
Participants will complete this assessment at each clinic visit as specified in the Schedule of 
Assessments (Table 2).  
10.1.2. 
The Essential Tremor Rating Assessment Scale 
TETRAS is a validated, comprehensive clinical assessment of essential tremor (Elble 2013).  
Three different components of TETRAS will be assessed in this study. The TETRAS ADL 
subscale, total performance score, and performance subscale part 4 upper limb tremor score, and 
will each be separately assessed at each clinic visit as specified in the Schedule of Assessments 
(Table 2). 
The ADL subscale assesses how ET is impacting 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 in from 
0 (normal activity) to 4 (severe abnormality). The overall ADL score range is 0 to 48. 
The total performance score is based on overall rating of the performance subscale, which 
measures tremor amplitude in the voice, limbs, head, face, trunk, 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 the performance subscale part 4 upper limb tremor score, all 3 maneuvers in the upper limb 
assessments of part 4 (subscale items 4a, 4b, and 4c) will be completed for both arms, first for 
the left arm and then for the right. The part 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. 

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10.3. 
Other Patient-Reported Assessments 
10.3.1. 
Patient Perception of Response Burden 
The Patient Perception of Response Burden Questionnaire is a patient-reported measure that 
assesses the multidimensional construct of response burden (Atkinson 2019). 
Participants respond to 6 items assessing 1) how well the questions related to their actual 
concerns, 2) how comfortable the participants were with answering the questions, 3) how well 
the survey characterized their health and well-being, 4) the length of time to complete the 
questionnaires, 5) whether questions seemed unimportant or repetitive, and 6) what additional 
information should have been gathered. Items 1 to 3 are assessed on a 0 to 10 scale, item 4 is 
assessed on a 1 to 3 scale, and items 5 and 6 are open-ended. Items 1 and 4 are reverse scored. A 
composite score can be calculated to create a weighted representative index of relevance, 
comfort, and well-being relative to time to completion (ie, items 1, 2, and 3 were summed and 
multiplied by item 4) for a range of 0 to 72, with higher scores indicative of elevated endorsed 
response burden. The open-ended items will be summarized thematically. The Patient Perception 
of Response Burden Questionnaire will be performed as specified in the Schedule of 
Assessments (Table 2). 
 

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11. 
SAFETY ASSESSMENTS 
11.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
11.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, ethnicity) and a full medical history will be 
documented. This must also additionally include participant recall of history of ET, disease 
duration, past treatments used, and responsiveness to alcohol and/or other treatments with use 
intended as off-label treatment of ET (eg, primidone or similar therapies). 
11.1.2. 
Weight and Height 
Height and weight will be measured and documented. Body mass index (BMI) will be calculated 
and documented.  
11.1.3. 
Physical Examination 
Whenever possible, the same individual should perform all physical examinations. Physical 
examinations will include assessment of body systems (eg, head, eye, ear, nose and throat; heart; 
lungs; abdomen; and extremities) as well as cognitive and neurological examination and MSE. 
Unscheduled physical examinations may also be conducted per the Investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by an investigator as abnormal, not 
clinically significant (NCS); or abnormal, clinically significant (CS) in source documents.  
11.1.4. 
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. When assessed postdose, orthostatic blood pressure and 
heart rate will also be measured after the participant has been in the supine position for at least 5 
minutes and then repeated approximately 1 and 3 minutes after standing.  
Any abnormality in vital signs will be interpreted by an Investigator as abnormal, NCS; or 
abnormal, CS in source documents. 
11.1.5. 
Electrocardiogram 
A 12-lead ECG will be performed. The standard intervals (heart rate, PR, QRS, QT, and QTcF) 
as well as any rhythm abnormalities will be recorded. 
Electrocardiograms will be performed after the participant has been resting in a supine position 
for at least 5 minutes. When ECG measurements coincide with safety assessments, vital signs 
assessment or blood draws, procedures should be carried out in said order (vital signs, ECG, 
blood draw). 
All abnormal ECGs will be interpreted by an investigator as abnormal, NCS, or abnormal, CS in 
source documents. 

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11.1.6. 
Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected. Analytes to be 
evaluated are summarized in Table 4. 
Table 4: 
Summary of Clinical Laboratory Analytes 
Biochemistry 
Renal Panel: glucose, calcium, phosphorus, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate 
Hepatic Panel: albumin, ALT, AST, total bilirubin, direct bilirubin, indirect 
bilirubin, alkaline phosphatase, total protein, lactate dehydrogenase, gamma 
glutamyl transferase 
Other: triglycerides, cholesterol (low density lipoprotein [LDL], high density 
lipoprotein [HDL]), creatine phosphokinase, thyroid stimulating hormone (TSH) 
Coagulation 
activated partial thromboplastin time, prothrombin time, and international 
normalized ratio 
Hematology 
red blood cell count, hemoglobin, hematocrit, white blood cell count with 
differential, platelet count, and if red blood count indices are abnormal, reflex red 
blood cell morphology as indicated 
Urinalysis 
protein, glucose, pH, blood, leukocytes, leukocyte estrase, urobilinogen, bilirubin, 
ketones, nitrite 
Virus Serology 
(Screening only) 
hepatitis B antigen; hepatitis C antibodies; HIV-1 and -2 antibodies 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, NCS; or abnormal, CS in source documents. 
Follicle stimulating hormone testing will be conducted to confirm whether a participant with 
≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being 
postmenopausal (Section 7.1). 
11.1.6.1. Drugs of Abuse, Alcohol, Cotinine 
Separate urine samples for assessment of selected drugs of abuse (amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, THC, stimulants, and opiates), cotinine, and alcohol 
will be collected.  
11.1.6.2. Pregnancy Screen 
A serum pregnancy test will be conducted for all female participants at Screening; a urine 
pregnancy test will be conducted for all participants of childbearing potential as specified in the 
Schedule of Assessments (Table 2).  

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11.2.2. 
Serious Adverse Event (SAE) Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 
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. 
11.2.3. 
Definition of Adverse Events of Special Interest 
There are no known adverse events of special interest as of the date of signature approval of this 
clinical protocol. 

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11.2.4. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP.  
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
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 
11.2.5. 
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 
hospitalized  
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 11.2.2. An AE of severe intensity 
may not necessarily be considered serious. 

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11.2.6. 
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 or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage or designee.  
Additional follow-up information, if required or available, should all be sent to Sage or designee 
within 24 hours of receipt on a follow-up SAE report form and placed with the original SAE 
information and kept with the appropriate section of the eCRF and/or study file. 
SAEs occurring after the designated follow up time for the study, should be reported to Sage or 
designee according to the timelines noted above only if the Investigator considers the SAE 
related to IP.  
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/EC 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. Each site is responsible for notifying its 
IRB of all SUSARs.  
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. 
11.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 
pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy. The investigator will also attempt to collect pregnancy information on any 
participant’s partner who becomes pregnant after the participant has received the first 
administration of IP. After obtaining the necessary signed informed consent from the pregnant 
partner directly, the investigator will follow the same pregnancy reporting procedures specified 
for pregnant participants.  
The participant or participant’s partner will be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies (eg, spontaneous abortion, elective abortion, normal 
birth) must be followed and documented even if the participant was discontinued from the study. 
The investigator will collect follow-up information on the participant or participant’s partner and 
the neonate, and the information will be forwarded to Sage or designee. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 

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Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, preeclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death,), the investigator should follow the procedures 
for reporting an SAE.  
11.4. 
Overdose 
An overdose is any dose of study treatment given to a participant or taken by a participant that 
exceeds more than one extra tablet within 24 hours as described in protocol. Overdoses are not 
considered AEs and should not be recorded as an AE on the eCRF; however, all overdoses must 
be recorded on an overdose form and sent to Sage or designee within 24 hours of the site 
becoming aware of the overdose. An overdose must be reported to Sage or designee even if the 
overdose does not result in an AE. If an overdose results in an AE, the AE must be recorded.  

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12. 
STATISTICS 
Detailed description of the analyses to be performed in the study will be provided in the 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to database lock. 
Any changes or additions to the SAP following database lock will be described in detail in the 
clinical study report. 
12.1. 
Data Analysis Sets 
The Randomized Set will include all participants who are randomized.  
The Safety Set will include all participants 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 Kinesia ONE accelerometer 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. 
12.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All participants will be used in the analyses, 
as per the analysis populations, using all nonmissing data available. No imputation process will 
be used to estimate missing data.  
12.3. 
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. Participants will be summarized according to treatment received. 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to receipt of IP.  
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. 
12.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized using the Safety Set.  
Pregnancy test results and drug screen results will be listed but not summarized.  
Medical history will be listed by participant.  

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12.5. 
Efficacy Analysis  
The estimand for the primary efficacy analysis is the treatment difference between either dose of 
SAGE-324 and placebo in mean change from baseline in clinic-based Kinesia ONE 
accelerometer scores at Day 29 based on the Full Analysis Set. This will be analyzed using a 
mixed effects model for repeated measures (MMRM); the model will include treatment, baseline 
Kinesia ONE accelerometer score, stratification factor, 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. The main comparison will be between 
SAGE-324 and placebo at the 29-day timepoint. Model-based point estimates (ie, least squares 
means, 5% confidence intervals, and p-values) will be reported where applicable. An 
unstructured covariance structure will be used to model the within-subject errors. If there is a 
convergence issue with the unstructured covariance model, Toeplitz compound symmetry 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 UN, the sandwich estimator for the 
variance covariance matrix will be derived, using the EMPIRICAL option in the PROC MIXED 
statement in SAS. 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in TETRAS total performance scores, TETRAS 
performance subscale part 4 upper limb tremor scores and TETRAS ADL scores.  
Other efficacy analyses will be specified in the SAP. In general, data will be analyzed using 
appropriate descriptive statistics or prespecified statistical methods as applicable; participant 
listings will be provided for all efficacy data. Participants will be analyzed according to 
randomized treatment for the purpose of efficacy unless otherwise specified. 
Sensitivity analyses will be described in the SAP. 
12.6. 
Safety Analyses 
Safety and tolerability of SAGE-324 will be evaluated by AEs, concomitant medication usage, 
 
 Safety data will be listed by participant and 
summarized by treatment group. All safety summaries will be performed on the Safety Set using 
treatment received.  
12.6.1. 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 22.1 
or higher. A treatment-emergent adverse event (TEAE) is defined as an AE with onset after the 
first dose of IP. The analysis of AEs will be based on the concept of TEAEs. The incidence of 
TEAEs will be summarized by System Organ Class (SOC) and preferred term. 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.  

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All AEs and SAEs (including those with onset or worsening before the start of IP) through the 
end of the study will be listed.  
12.6.3. 
Physical Examinations 
The occurrence of a physical examination, including MSE, (yes/no) and the date performed will 
be listed by participant. 
 
 
 
 
 
 
 
 
 
 
12.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
All medications taken within 30 days prior to informed consent through the duration of the study 
will be recorded. In addition, all psychotropic medications taken in the previous 30 days prior to 
screening will be recorded. Those medications taken prior to the initiation of the start of IP will 
be denoted “Prior”. Those medications taken prior to the initiation of the IP and continuing 
beyond the initiation of the IP or those medications started at the same time or after the initiation 
of the IP will be denoted “Concomitant”.  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by participant, start date, and 
verbatim term.  

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12.8. 
Sample Size and Power 
The sample size of this study is based on the assumption of a 3 points difference in the change 
from baseline Kinesia ONE accelerometer between SAGE-324 and placebo with a standard 
deviation of 3.5 points and a 1:1:1 randomization schedule. Under these assumptions, a sample 
size of 30 evaluable participants per group would provide 90% power for detecting a placebo-
adjusted treatment difference of 3 points in Kinesia accelerometer assuming a 2-sided test at 
αlevel of 0.05. By including 3 treatment groups and using a 1:1:1 randomization ratio, a total of 
90 evaluable participants are required. Assuming a nonevaluability rate of 25%, at least 120 
subjects will be randomized.  
12.8.1. 
Interim and Data Monitoring Committee (DMC) Analyses 
Not applicable. 

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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Study Monitoring 
Before an investigational site can enter a participant into the study, a representative of Sage 
Therapeutics will visit the investigational study site per Sage SOPs to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or its representatives. 
This will be documented in a Clinical Trial Agreement between Sage Therapeutics and 
the investigator. 
During the study, a monitor from Sage Therapeutics or representative will have regular contacts 
with the investigational site, for the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that IP accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the participant’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
participant (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage Therapeutics. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Sage Therapeutics and those SAEs that met criteria for 
reporting have been forwarded to the IRB or EC. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
13.2. 
Audits and Inspections 
Sage Therapeutics or authorized representatives of Sage Therapeutics, a regulatory authority, or 
an independent EC or an IRB may visit the site to perform an audit(s) or inspection(s), including 
source data verification. The purpose of a Sage Therapeutics audit or a regulatory authority 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP/ICH GCP guidelines, and any 
applicable regulatory requirements. The Investigator should contact Sage Therapeutics 
immediately if contacted by a regulatory agency or IRB/EC about an inspection. 

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13.3. 
Institutional Review Board or Ethics Committee 
The principal investigator must obtain IRB (or EC) approval for the clinical study prior to 
enrolling a participant. Initial IRB (or EC) approval, and all materials approved by the IRB (or 
EC) 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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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit(s) at the clinical site. Please see 
Section 13.2 for more details regarding the audit process. 
The Investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Significant protocol deviations should be reported to the IRB/EC per the IRB/EC’s 
written procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates trial-related duties and functions conducted at the trial site. When the investigator 
retains the services of any individual or party to perform trial-related duties and functions, the 
Investigator must ensure the individual or party is qualified to perform trial-related duties and 
functions and should implement procedures to ensure the integrity of the trial-related duties and 
functions performed, and any data generated.  
The investigator must maintain adequate and accurate source documents and trial records that 
include all pertinent observations on each of the site’s trial 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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15. 
ETHICS 
15.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be given a written and 
dated approval or favorable opinion by an IRB or EC as appropriate. The Investigator must 
obtain and document approval before he or she can enroll any participant into the study. The IRB 
or EC must supply to the sponsor a list of the IRB/EC membership and a statement to confirm 
that the IRB/EC is organized and operates according to GCP and applicable laws and 
regulations. 
The principal investigator is responsible for informing the IRB or EC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or EC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or EC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or EC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the IP. Sage 
Therapeutics will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or EC according to local regulations and guidelines. In addition, the principal investigator must 
inform the IRB/EC and sponsor of any changes significantly affecting the conduct of the trial 
and/or increasing the risk to participants (eg, violations to the protocol or urgent safety measures 
taken for participant safety). 
15.2. 
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. 
15.3. 
Written Informed Consent 
Prior to enrolling a trial 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 trial, the participant (or the participant’s, parent 
or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source records. The investigator must maintain 
the original, signed ICF. A copy of the signed ICF must be given to the participant or to the 
participant’s parent or legally authorized representative. 
Throughout the trial participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 
documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 

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324-ETD-201 
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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Inspection of Records 
Sage Therapeutics or its representative(s) will be allowed to conduct site visits at the 
investigation facilities for the purpose of monitoring any aspect of the study. The investigator 
agrees to allow the monitor to inspect the facility, drug storage area, drug accountability records, 
participant charts and study source documents, and other records relative to study conduct. 
Inspection of the study by a regulatory authority may occur at any time. The investigator must 
agree to the inspection of study-related records and source documents by the regulatory authority 
representative(s).  
16.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. Sage is responsible to inform the Investigator/institution as to 
when study documents no longer need to be retained.  

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324-ETD-201 
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17. 
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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18. 
LIST OF REFERENCES 
Atkinson TM, Schwartz CE, Goldstein L, et al. Assessments in Oncology. Value in Health. 
2019;22(2):225-230. 
Belelli D, Casula A, Ling A, Lambert JJ. The influence of subunit composition on the interaction 
of neurosteroids with GABA(A) receptors. Neuropharmacology. 2002;43(4):651-61. 
Deuschl G, Raethjen J, Hellriegel H, Elble R. Treatment of patients with essential tremor. Lancet 
Neuro. 2011. 10(2):148. 
Elble R, Bain P, Forjaz MJ, et al. Task force report: scales for screening and evaluating tremor: 
critique and recommendations. Mov Disord. 2013 Nov;28(13):1793-800. 
Genetics Home Reference; Essential Tremor. Lister Hill National Center for Biomedical 
Communications;U.S. National Library of Medicine;National Institutes of Health, Department of 
Health & Human Services. Available from: https://ghr.nlm.nih.gov/condition/essential-tremor. 
Accessed Sept 10, 2019. 
 
 
 
Hopfner F, Haubenberger D, Galpern WR, et al. Knowledge gaps and research recommendations 
for essential tremor. Parkinsonism Relat Disord. 2016;33:27-35. 
Inderal® (propranolol hydrochloride) [package insert]. Philadelphia, PA: Wyeth 
Pharmaceuticals, Inc.; 2010. Accessed 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016418s078lbl.pdf 
Koller W, Vetere-Overfield B. Acute and chronic effects of propranolol and primidone in 
essential tremor. Neurology 1989;39:1587-1588 
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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324-ETD-201 
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Olanow CW. Hyperkinetic Movement Disorders: Essential Tremor. In: Harrison's Principles of 
Internal Medicine. Vol 2. 17th ed. New York, NY: McGraw Hill; 2008:2560. 
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. Epub 2012 
Aug 11. Review. Erratum in: J Neurol. 2013 Mar;260(3):741 
 

 
1. 
TITLE PAGEA PHASE 2, DOUBLE-BLIND, PLACEBO-
CONTROLLED, RANDOMIZED STUDY EVALUATING 
THE EFFICACY, SAFETY, AND TOLERABILITY OF 
SAGE-324 MONOTHERAPY AND ADJUNCTIVE 
THERAPY WITH PROPRANOLOL IN THE 
TREATMENT OF INDIVIDUALS WITH ESSENTIAL 
TREMOR  
324-ETD-201  
 
Investigational Product 
SAGE-324 Oral Tablet  
Clinical Phase 
Phase 2  
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
, MD 
Sponsor Medical Monitor 
, MD, PhD 
Date of Original Protocol 
23 October 2019 
Date of Amendment 1 
20 December 2019 
 
 
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. 
 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 2 
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3 
INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-324. I have read the 324-ETD-
201 protocol and agree to conduct the study as outlined. I agree to maintain the confidentiality of 
all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY) 

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Clinical Protocol 
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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, Placebo-controlled, Randomized Study Evaluating the Efficacy, Safety, and 
Tolerability of SAGE-324 Monotherapy and Adjunctive Therapy with Propranolol in the Treatment 
of Individuals with Essential Tremor  
Number of Sites and Study Location: This study will take place at approximately 30 sites in the 
United States. 
Phase of Development: Phase 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 72 days. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To assess the effect of SAGE-324 compared 
to placebo on tremor reduction in 
individuals with essential tremor (ET) 
Change from baseline compared to placebo in 
Kinesia ONE™ accelerometer scores after 28 days 
of treatment 
Secondary 
 
• 
To assess the effect of SAGE-324 
compared to placebo on activities of 
daily living (ADLs), total 
performance, and upper extremities 
 
 
 
 
 
 
 
 
• 
To evaluate the safety and 
tolerability of SAGE-324 
• 
Change from baseline compared to placebo 
in Kinesia ONE accelerometer scores at all 
other timepoints 
• 
Change from baseline compared to placebo 
in the following:  
- 
The Essential Tremor Rating 
Assessment (TETRAS) Scale ADL 
score 
- 
TETRAS total performance score  
- 
TETRAS performance subscale part 4 
upper limb tremor score 
 
• 
Incidence of treatment-emergent adverse 
events (TEAEs) 
 
 

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Study Description: 
This is a randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy, 
safety, and tolerability of SAGE-324 as monotherapy and adjunctive therapy with propranolol in 
individuals with ET. Participants, site staff, and sponsor personnel will be masked to treatment 
allocation. 

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This study includes a Screening Period of up to 28 days, a 29-day treatment period (28 days of 
dosing), and a 14-day follow up period. After providing informed consent, participants will undergo 
screening assessments as outlined in Table 2 to determine eligibility.  
Screening Period: The Screening Period begins with the signing of the informed consent form (ICF). 
Following completion of screening, on Day 1, eligible participants will visit the study center and will 
be randomized to 1 of 2 treatment groups (SAGE-324 60 mg daily, or placebo) in a 1:1 ratio. 
Randomization will be stratified based on the use of propranolol for the treatment of ET (Y/N). 
Participants who are on a propranolol regimen must have been on a stable dose for at least 1 month 
prior to Day 1 and will continue to be on a stable dose during the Treatment Period. Participants will 
complete baseline assessments of safety and efficacy, including the clinician-rated TETRAS and 
quantitative Kinesia ONE assessments of tremor, as specified in the Schedule of Assessments (Table 
2). 
Double-Blind Treatment Period: Starting on Day 1, participants will receive a single dose of 
investigational product (IP) once daily for 28 days on an outpatient basis. Doses occurring on 
scheduled clinic visits will be administered in the clinic, and doses occurring on all other days may be 
self-administered by the participant at home during the 29-day Treatment Period (28 days of dosing). 
During the Treatment Period, participants will return to the study center approximately once per week 
for efficacy and safety assessments as specified in Table 2. Participants will be trained on the use of 
software applications and devices necessary to complete questionnaires or other assessments as 
required. 
Follow Up Period: Follow up visits will be conducted on an outpatient basis. Participants will 
continue to complete questionnaires as indicated in Table 2 and will receive a phone call 
approximately 7 days after the last dose of IP (ie, Day 35) for safety monitoring. Participants will 
return to the study center for an end of study visit approximately 14 days following the last dose of IP 
(ie, Day 42). 
Participants who discontinue IP during the Treatment Period will be asked to return to the clinic as 
soon as possible for an end of treatment (EOT) visit. Follow-up visits should take place as scheduled, 
or relative to the last dose of IP if discontinuing treatment early. If at any time after the EOT visit, a 
participant decides to withdraw from the study, the participant should return for an early termination 
visit (ETV). The EOT and ETV can be on the same day if a participant discontinues IP and withdraws 
from the study on the same day during a clinic visit; in this case, all events scheduled for the EOT 
visit will be conducted. 
During the study, a phone call will be conducted once per week (preferably mid-week) in between 
clinic visits, to review current status of participant. 
Number of Participants (planned): Approximately 60 participants, with approximately 30 per arm. 

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Eligibility Criteria:  
Inclusion Criteria: 
1. Participant has signed an ICF before any study-specific procedures or washout of drugs is 
performed. 
2. Participant is 18 to 80 years of age, inclusive, at the time informed consent is obtained. 
3. 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) 
d. 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 step-wise deterioration of tremor 
4. Participant has a combined total upper extremity TETRAS score of ≥8 with at least 1 upper 
extremity TETRAS score >4. 
5. Participant is willing to discontinue medications taken for the treatment of ET, with the 
exception of propranolol, within 14 days or 5 half-lives (whichever is longer) prior to 
receiving IP. 
6. Participants taking propranolol for the treatment of ET must be on a stable dose for at least 
1 month prior to Day 1 and must be willing to maintain their stable dose through Day 29. 
7. Participant is willing to discontinue the use of alcohol and drugs of abuse within at least ≥1 
week prior to Day 1 and through Day 29 of the study. 
8. Female participant agrees to use at least one method of highly effective contraception as 
listed in Section 8.2.4 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 
>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).  
9. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 13 weeks after receiving 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 8.2.4.  
10. Male participant is willing to abstain from sperm donation for the duration of the study and 
for 13 weeks after receiving study drug. 
11. Female participant must have a pregnancy test result that is confirmed as negative at 
Screening and Day 1. 
12. At the discretion of the Investigator, participant is medically stable and ambulatory, and has 
been on stable dose(s) of any necessary prescription or over the counter medication(s) for at 
least 30 days prior to Day 1, or changes/discontinues their use prior to Day 1 with the 
appropriate washout, as applicable per investigator judgement.  

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13. Participant has no clinically significant findings, as determined by the investigator, on 
physical examination including mental state examination (MSE) and neurologic examination, 
12-lead ECG, or clinical laboratory tests.  
Exclusion Criteria: 
1. Participant has presence of known causes of enhanced physiological tremor. 
2. Participant has had recent exposure (14 days prior to Day 1) to tremorgenic drugs or presence 
of a drug or 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. 
5. Participant has historical or clinical evidence of tremor with psychogenic origin (including 
but not limited to eating disorders, major depression, etc.) 
6. Participant has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic 
(hypothyroidism with stable thyroid replacement is acceptable), or oncological disease. 
7. Participant has history, presence, and/or current evidence of serologic positive results for 
hepatitis B surface antigen (HBsAg), hepatitis C antibodies (anti-HCV), or human 
immunodeficiency virus (HIV) 1 or 2 antibodies. 
8. Participant has history of alcohol or drug abuse within 6 months prior to Screening, or a 
positive screen for alcohol on the Day 1 visit, or a positive screen for drugs of abuse at 
Screening or at the Day 1 visit. 
9. Participant has a known allergy to SAGE-324 or any excipient.  
10. Participant has had exposure to another investigational drug or device within 30 days prior to 
the Day 1 visit. 
11. Participant has history or suicidal behavior within 2 years or answers “YES” to questions 3, 
4, or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk or suicide in the opinion 
of the investigator 
12. Participant has donated one 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.  
13. Participant is unable to perform Kinesia ONE assessments or unable to use the device 
required to perform the assessment. 
14. 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. 
15. Participant is unwilling or unable to comply with study procedures and required training. 
16. Participant has used any known moderate or strong cytochrome P450 3A4 or P450 2D6 
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. 

Clinical Protocol 
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John’s Wort or products containing these within 30 days prior to Day 1. Use of mild 
cytochrome inhibitors and/or inducers may be permitted.  
17. Participant has concurrent or recent exposure (14 days prior to the Day 1 visit) to 
sedative/hypnotic drugs, stimulants, eg, opioids, highly-caffeinated beverages or dietary 
supplements containing high doses of caffeine, or recent increase above regular daily 
consumption of coffee. 
18. Participant has concurrent or recent exposure (30 days prior to the Day 1 visit) to long-acting 
benzodiazepines. 
19. Participant plans to undergo elective surgery or relocate during participation in the study. 
20. Participant is investigative site personnel or a member of their immediate families (spouse, 
parent, child or sibling whether biological or legally adopted).  
21. Participant has a positive urine cotinine screen at Screening or the Day 1 visit. 
Investigational Product Dosage and Mode of Administration:  
SAGE-324 (60 mg) or matched placebo oral tablets will be administered in the clinic or self-
administered once daily, in the morning with food.  
Duration of Treatment:  
Each participant will receive a single dose of SAGE-324 oral tablets or matching placebo 
administered once daily for 28 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 clinic-based Kinesia ONE accelerometer 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 sample size of this study is based on the assumption of a 3 points difference in the change from 
baseline Kinesia ONE accelerometer scores between SAGE-324 and placebo with a standard 
deviation of 3.5 points. Under these assumptions, a sample size of 25 evaluable participants per group 

Clinical Protocol 
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324-ETD-201, Version 2 
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would provide 85% power for detecting a placebo-adjusted treatment difference of 3 points in Kinesia 
accelerometer assuming a 2-sided test at an alpha level of 0.05. By including 2 treatment groups and 
using a 1:1 randomization, a total of 50 evaluable participants are required. Assuming a 
nonevaluability rate of 15%, approximately 60 participants will be randomized. Additional 
participants may be enrolled if the drop-out rate is higher than 15%. 
Analysis of Primary Efficacy Endpoint 
The estimand for the primary efficacy analysis is the treatment difference between SAGE-324 and 
placebo in mean change from baseline in clinic-based Kinesia ONE accelerometer scores at Day 29 
based on Full Analysis Set. This will be analyzed using a mixed effects model for repeated measures 
(MMRM); the model will include treatment, baseline Kinesia ONE accelerometer score, stratification 
factor, 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. 
The main comparison will be between SAGE-324 and placebo at the 29-day timepoint. Model-based 
point estimates (ie, least squares means, 95% confidence intervals, and p-values) will be reported 
where applicable. An unstructured covariance structure will be used to model the within-subject 
errors. If there is a convergence issue with the unstructured covariance model, Toeplitz compound 
symmetry 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. 
Analysis of Secondary Efficacy Endpoints 
Similar to those methods described above for the primary endpoint, an MMRM will be used to 
analyze of the change from baseline in TETRAS total performance scores, TETRAS Performance 
subscale part 4 upper limb tremor scores and TETRAS ADL scores.  
Safety Analysis 
Safety and tolerability of study drug will be evaluated by incidence of TEAEs/serious adverse events, 
 
  
 
 
 
Interim Analysis 
The sponsor may conduct an interim analysis. Detailed descriptions of planned data analyses will be 
provided in a separate interim statistical analysis plan (SAP), if applicable.  
 

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Table 2: 
Schedule of Assessments 
Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5  
(±1) 
Phone
Call 
8 
(±1) 
12 
(±1) 
Phone
Call 
15  
(±1) 
19 
(±1) 
Phone
Call 
22  
(±1) 
26 
(±1) 
Phone
Call 
29 
(+1) 
EOT 
32 
(±1) 
Phone
Call 
35  
Safety 
Phone
Call 
38 
(±1) 
Phone
Call 
42 
(±1) 
EOS/ 
ETVa 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis/HIV screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
(all women) 
X  
(serum; all 
women) 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
FSH (postmenopausal 
women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Drug/alcohol screens 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Physical examinationc 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Neurological 
examination including 
MSEc 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Body height  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Body weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Vital signsd 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
12-Lead ECGe 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Chemistry/hematology/
coagulation/urinalysis 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 

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Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5  
(±1) 
Phone
Call 
8 
(±1) 
12 
(±1) 
Phone
Call 
15  
(±1) 
19 
(±1) 
Phone
Call 
22  
(±1) 
26 
(±1) 
Phone
Call 
29 
(+1) 
EOT 
32 
(±1) 
Phone
Call 
35  
Safety 
Phone
Call 
38 
(±1) 
Phone
Call 
42 
(±1) 
EOS/ 
ETVa 
Kinesiag 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Investigational Product 
Diary trainingh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
TETRASi 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 

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324-ETD-201, Version 2 
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Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5  
(±1) 
Phone
Call 
8 
(±1) 
12 
(±1) 
Phone
Call 
15  
(±1) 
19 
(±1) 
Phone
Call 
22  
(±1) 
26 
(±1) 
Phone
Call 
29 
(+1) 
EOT 
32 
(±1) 
Phone
Call 
35  
Safety 
Phone
Call 
38 
(±1) 
Phone
Call 
42 
(±1) 
EOS/ 
ETVa 
Patient Perception of 
Response Burden 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Participant trainingj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
X  
 
X 
 
X 
 
X 
 
 
 
 
 
 
IP administration 
 
Administered once daily for 28 days 
Not applicable 
AEs/SAEs 
X 
Prior and concomitant 
medication and historyk 
X 
Abbreviations: ADL = activities of daily living; AE = adverse event;
; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; 
 
; ETV = early termination visit; FSH = follicle stimulating hormone; HIV = human immunodeficiency 
virus; ICF = informed consent form; min = minutes; IP = investigational product; MSE = mental state examination; 
 
; 
; 
 
; SAE = serious adverse event; TETRAS = The Essential Tremor Rating Assessment Scale; WOCBP = women of childbearing potential 
 
Note:  
• 
IP doses will be administered in the clinic on Days 1 and 15. On all other days, IP doses may be administered at home. 
• 
A phone call will be performed once, mid-week between clinic visits during the Treatment Period, and once per week during the Follow-Up Period. 
During the phone call, the current status of the participant will be reviewed, including but not limited to, AE reporting and characterization, IP 
compliance review, and assessment of general well-being. Days 1, 8, 15, 22, and 29 are clinic visits.  
• 
The suggested order of assessments during clinic visits is: vital signs, Kinesia, TETRAS, ECG, blood sample collection for 
 and clinical laboratory 
assessments, and questionnaires. 
• 
All Day 1 assessments will be performed predose. 
 
a Participants who discontinue IP during the treatment period should return to the site for an EOT visit as soon as possible. Participants who discontinue IP will 
be encouraged to continue on study and complete safety assessments and follow-up visits. Follow-up visits should take place as scheduled relative to the last 
dose of IP. If at any time after the EOT visit, a participant decides to withdraw from the study, the participant should return for an ETV. The EOT and ETVs 

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can be on the same day if a participant discontinues IP and withdraws from the study on the same day during a clinic visit. In such case, all procedures 
scheduled for EOT and ETV will be conducted. 
b Randomization will occur on Day 1 only. In addition to meeting all other eligibility criteria, eligibility is determined based on the total upper extremity 
TETRAS score of ≥8 with at least 1 upper extremity TETRAS score >4 at Screening. 
c Complete physical examinations (including MSE and neurologic examination as parts of physical examination) should be performed as specified and as 
clinically necessary (see Section 11.1.3).  
d Vital signs without orthostatic blood pressure and heart rate will be collected predose in the beginning of each visit and again prior to departing the clinic, at 
approximately 5 hours (±30 min). Postdose vital signs to include orthostatic blood pressure and heart rate, measured after the participant has been in the supine 
position for at least 5 minutes and then repeated 1 minute and 3 minutes after standing.  
e ECGs will be collected and read centrally. ECGs will be performed approximately 5 hours (±30 min) postdose. All ECGs must be performed after the 
participant has been in a supine position for at least 5 minutes.  
 
 
  
g Kinesia ONE will be assessed simultaneous to TETRAS Performance subscale part 4 upper limb tremor. On clinic dosing days, participants will perform 
Kinesia ONE assessments approximately 30 to 60 minutes prior to dosing in the morning. In addition, on Day 15, Kinesia ONE assessments will be performed 
at 5 and 8 hours (±30 min) postdose. 
h Training specific to the Investigational Product Diary will be performed prior to randomization.  
i The TETRAS Performance and TETRAS ADL subscales will be assessed at Screening and predose at each clinic visit postrandomization. The TETRAS 
Performance subscale part 4 upper limb tremor will be assessed simultaneous to Kinesia ONE. In addition, on Day 15, the TETRAS Performance subscale will 
be assessed at 5 and 8 hours (±30 min) postdose. Eligibility is determined based on the combined TETRAS performance subscale part 4 upper limb tremor total 
score ≥8, with at least 1 upper limb score >4 at Screening. 
j Participants will be trained on the use of software applications and devices necessary for the conduct of the study by site personnel. 
k Prior and concomitant medications will be recorded during Screening and will include all medications and supplements taken within the 30 days prior to 
signing the ICF through the first dose of IP. Concomitant medications will be recorded thereafter throughout the duration of the study. At Screening, this will 
include year of diagnosis and history of treatments for ET since year of diagnosis and use of antidepressant medications taken in the prior 12 months.  
 

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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS ...........................................................................................16 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................20 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Dose Justification ........................................................................................................23 
5.2. 
Benefit/Risk Assessment ............................................................................................23 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................24 
7. 
INVESTIGATIONAL PLAN .....................................................................................26 
7.1. 
Overall Study Design ..................................................................................................26 
7.2. 
Number of Participants ...............................................................................................27 
7.3. 
Treatment Assignment ................................................................................................27 
7.4. 
Dose Adjustment Criteria ...........................................................................................27 
7.5. 
Criteria for Study Termination ...................................................................................27 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .....................................28 
8.1. 
Participant Inclusion Criteria ......................................................................................28 
8.2. 
Participant Exclusion Criteria .....................................................................................29 
8.3. 
Screen Failures ............................................................................................................30 
8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................30 
8.4.1. 
Investigational Product Discontinuation .....................................................................30 
8.4.2. 
Early Termination from the Study ..............................................................................31 
8.4.3. 
Loss to Follow-up .......................................................................................................31 
8.4.4. 
Replacement of Participants .......................................................................................31 
9. 
TREATMENT OF PARTICIPANTS .........................................................................32 
9.1. 
Description of Investigational Product .......................................................................32 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................32 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................32 
9.2.2. 
Prohibited Medications ...............................................................................................32 
9.2.3. 
Other Restrictions .......................................................................................................32 

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9.2.4. 
Acceptable Forms of Contraception ...........................................................................32 
9.3. 
Intervention after the End of the Study .......................................................................33 
9.4. 
Treatment Adherence ..................................................................................................33 
9.5. 
Randomization and Blinding ......................................................................................33 
9.5.1. 
Emergency Unblinding ...............................................................................................33 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............35 
10.1. 
Investigational Product ...............................................................................................35 
10.2. 
Investigational Product Packaging and Labeling .......................................................35 
10.3. 
Investigational Product Storage ..................................................................................35 
10.4. 
Investigational Product Preparation ............................................................................36 
10.5. 
Investigational Product Administration ......................................................................36 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................36 
10.7. 
Product Complaints ....................................................................................................36 
11. 
EFFICACY ASSESSMENTS AND CLINICAL PHARMACOLOGY 
ASSESSMENTS .........................................................................................................38 
11.1. 
Efficacy Assessments .................................................................................................38 
11.1.1. 
Kinesia ONE™ Accelerometer Score ..........................................................................38 
11.1.2. 
The Essential Tremor Rating Assessment Scale ........................................................38 
 
38 
 
39 
 
39 
 
39 
 
40 
 
40 
 
40 
 
40 
 
41 
 
41 
 
41 
 
41 
 
41 
11.3. 
Other Patient-Reported Assessments ..........................................................................42 
11.3.1. 
Patient Perception of Response Burden ......................................................................42 

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12. 
SAFETY ASSESSMENTS ........................................................................................43 
12.1. 
Safety Parameters .......................................................................................................43 
12.1.1. 
Demography and Medical History ..............................................................................43 
12.1.2. 
Weight and Height ......................................................................................................43 
12.1.3. 
Physical Examination .................................................................................................43 
12.1.4. 
Vital Signs ..................................................................................................................43 
12.1.5. 
Electrocardiogram .......................................................................................................43 
12.1.6. 
Laboratory Assessments .............................................................................................44 
12.1.6.1. 
Drugs of Abuse, Alcohol, Cotinine ............................................................................44 
12.1.6.2. 
Pregnancy Screen ........................................................................................................44 
 
44 
12.1.8. 
Safety Phone Call .......................................................................................................45 
12.2. 
Adverse Events and Serious Adverse Events .............................................................45 
12.2.1. 
Adverse Event Definition ...........................................................................................45 
12.2.2. 
Serious Adverse Event (SAE) Definition ...................................................................46 
12.2.3. 
Definition of Adverse Events of Special Interest .......................................................46 
12.2.4. 
Relationship to Investigational Product ......................................................................47 
12.2.5. 
Recording Adverse Events .........................................................................................47 
12.2.6. 
Reporting Serious Adverse Events .............................................................................48 
12.3. 
Pregnancy ...................................................................................................................48 
12.4. 
Overdose .....................................................................................................................49 
13. 
STATISTICS ..............................................................................................................50 
13.1. 
Data Analysis Sets ......................................................................................................50 
13.2. 
Handling of Missing Data ...........................................................................................50 
13.3. 
General Considerations ...............................................................................................50 
13.4. 
Demographics and Baseline Characteristics ...............................................................50 
13.5. 
Efficacy Analysis ........................................................................................................51 
13.6. 
Safety Analyses ..........................................................................................................51 
13.6.1. 
Adverse Events ...........................................................................................................51 
 
52 
13.6.3. 
Physical Examinations ................................................................................................52 
 
52 
 
52 

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13.6.6. 
Prior and Concomitant Medications ...........................................................................52 
 
52 
 
53 
13.8. 
Sample Size and Power ..............................................................................................53 
13.8.1. 
Interim and Data Monitoring Committee (DMC) Analyses .......................................53 
13.8.1.1. 
Interim Analysis ..........................................................................................................53 
13.8.1.2. 
DMC Analysis ............................................................................................................53 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................54 
14.1. 
Study Monitoring ........................................................................................................54 
14.2. 
Audits and Inspections ................................................................................................54 
14.3. 
Institutional Review Board or Ethics Committee .......................................................55 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
16. 
ETHICS ......................................................................................................................57 
16.1. 
Ethics Review .............................................................................................................57 
16.2. 
Ethical Conduct of the Study ......................................................................................57 
16.3. 
Written Informed Consent ..........................................................................................57 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................58 
17.1. 
Inspection of Records .................................................................................................58 
17.2. 
Retention of Records ..................................................................................................58 
18. 
PUBLICATION POLICY ..........................................................................................59 
19. 
LIST OF REFERENCES ............................................................................................60 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................12 
Table 3: 
Investigational Product ...............................................................................................35 
Table 4: 
Summary of Clinical Laboratory Analytes .................................................................44 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................27 
 

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Abbreviation 
Definition 
 
 
PV 
pharmacovigilance 
QTcF 
QT corrected according to Fridericia’s formula 
 
 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
t½  
terminal elimination half-life  
TEAE 
treatment-emergent adverse event 
TETRAS 
The Essential Tremor Rating Assessment Scale 
tmax 
time of occurrence of Cmax 
WHO 
World Health Organization 

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5. 
INTRODUCTION 
SAGE-324 is a positive allosteric modulator (PAM) of A-type γ-aminobutyric acid-gated 
chloride channel (GABAA) receptors, the major class of inhibitory neurotransmitter receptors in 
the brain. In addition to being developed as an adjunctive therapy in epilepsy and other seizure 
disorders under IND 139201, SAGE-324 is also being developed for the treatment of Essential 
Tremor (ET). 
Essential tremor is a permanently debilitating, neurologically determined, common movement 
disorder characterized by involuntary rhythmic oscillation of a body part due to intermittent 
muscle contractions typically occurring 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 US, 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 term 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.  
The pharmacological profile of SAGE-324 is theorized to induce therapeutic effect in the 
treatment of ET. Based on preclinical studies of SAGE-324, which features a different 
mechanism of action than that of propranolol, the pharmacokinetic (PK)/ pharmacodynamic (PD) 
profile suggests SAGE-324 may safely ameliorate symptoms in patients suffering from ET, 
regardless of propranolol use. 
There are currently ongoing Phase 1 clinical studies of SAGE-324 in healthy adults and in adults 
with ET. These studies, in addition to preclinical studies of SAGE-324, are detailed in the 
investigator’s brochure. 
With a GABAA receptor-based mechanism of action featuring positive allosteric modulation 
capability, SAGE-324 represents a novel approach to treatment of ET with possible utility as 
monotherapy or adjunctive to propranolol, 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. 
Henceforth, this double-blind, placebo-controlled efficacy and safety study of SAGE-324 will be 
conducted in adults with and without concomitant use of propranolol and is designed to assess 
the effect of SAGE-324 on a variety of outcome measures specific to ET disease characteristics 
and associated quality of life domains. 

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5.1. 
Dose Justification 
The dose of SAGE-324 planned for this study is 60 mg given as oral tablets, to be administered 
once daily in the morning with food. The dose was selected based on preliminary data from 
3 active studies of SAGE-324, which included: unblinded data from completed cohorts in 
324-CLP-101 Part A (oral solution SAGE-324 doses of 3 mg, 10 mg, 30 mg, 45 mg, 60 mg); 
Part C (oral solution SAGE-324 doses of 30 mg); Part D (oral suspension SAGE-324 doses of 
30 mg) in healthy subjects; and preliminary data from open-label Part E (oral suspension SAGE-
324 doses of 45 mg and 60 mg) in participants with ET; additional preliminary data from 
324-CLP-102 cohorts 1 through 6 (cohorts 1 to 5 unblinded, cohort 6 blinded), which evaluated 
oral suspension doses ranging from 5 mg to 60 mg; and preliminary unblinded data from 
324-CLP-104, which compared the relative bioavailability of the oral tablet (30 mg) vs oral 
suspension (30 mg) formulations of SAGE-324 and separately the effect of food on the PK of the 
SAGE-324 oral tablet. In 324-CLP-101 and 324-CLP-102 studies, doses were administered in a 
fasted state. The preliminary data from all of these active studies collectively informed the route 
of administration (oral) and dose strength of 60 mg as oral tablets planned for further evaluation 
in this study.  
SAGE-324 was generally well-tolerated in participants with ET and in healthy volunteers, as was 
shown in the preliminary data of 324-CLP-101 Part E at single administration doses of 45 mg 
and 60 mg, and in 324-CLP-102 through once-daily administered doses of up to 60 mg for 
14 days. In addition, tremor reduction was observed at both doses on TETRAS and Kinesia 
accelerometry, with greater improvement seen at 60 mg compared to 45 mg.  
In the clinically complete study 324-CLP-104, preliminary data showed that SAGE-324 oral 
tablets, when coadministered with a meal, resulted in exposures approximately equivalent to that 
of SAGE-324 oral suspension under fasted conditions. Therefore, the SAGE-324 oral tablets are 
recommended to be administered with food. 
5.2. 
Benefit/Risk Assessment 
Based on the mechanism of action of SAGE-324 and the results of completed nonclinical studies 
and preliminary data of currently ongoing clinical studies of SAGE-324, it is theorized that 
participants may have symptomatic amelioration, ie, tremor reduction and possibly improved 
quality of life from potentially stabilizing disease characteristics associated with ET. 
Potential risks anticipated in this study are based on available data from toxicology studies of 
SAGE-324 in addition to preliminary data from 3 ongoing, currently active Phase 1 clinical 
studies of SAGE-324.  
As of 20 December 2019, there have been no deaths or SAEs related to IP, and as of 18 October 
2019, based on the preliminary clinical data available, there have been no confirmed clinically 
significant trends in clinical laboratory evaluations, vital signs, or physical examinations. 
Available preliminary clinical data is summarized in the Investigator’s Brochure. 
Based on available preliminary clinical data from SAGE-324 active clinical studies, AEs of 
somnolence and feeling of relaxation are considered adverse drug reactions. In addition to 
scheduled clinic visits, the current status of study participants will be reviewed via weekly phone 
calls, in between clinic visits. 

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6. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• To assess the effect of SAGE-324 
compared to placebo on tremor 
reduction in individuals with 
essential tremor (ET) 
• Change from baseline compared to 
placebo in Kinesia ONE™ accelerometer 
scores after 28 days of treatment 
Secondary 
 
• To assess the effect of SAGE-324 
compared to placebo on activities 
of daily living (ADLs), total 
performance, and upper 
extremities 
 
 
 
 
 
 
• To evaluate the safety and 
tolerability of SAGE-324 
• Change from baseline compared to 
placebo in Kinesia ONE accelerometer 
scores at all other timepoints 
• Change from baseline compared to 
placebo in the following:  
- 
The Essential Tremor Rating 
Assessment (TETRAS) Scale ADL 
score 
- 
TETRAS Total Performance Score  
- 
TETRAS Performance Subscale Part 4 
Upper Limb Tremor 
• Incidence of treatment-emergent adverse 
events (TEAEs) 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, parallel group study to evaluate the 
efficacy, safety, and tolerability of SAGE-324 as monotherapy and adjunctive therapy with 
propranolol in individuals with ET. Participants, site staff, and sponsor personnel will be masked 
to treatment allocation (see Section 8.5). 
This study includes a Screening Period of up to 28 days, a 29-day treatment period consisting of 
28 days of dosing with the end of treatment visit intended to be on Day 29 at trough, and a 
14-day follow-up period relative to final dose (Figure 1). After providing informed consent, 
participants will undergo screening assessments as outlined in Table 2 to determine eligibility.  
The Screening Period begins with the signing of the informed consent form (ICF). Following 
completion of screening, on Day 1, eligible participants will visit the study center and will be 
randomized to 1 of 2 treatment groups (SAGE-324 60 mg or placebo) in a 1:1 ratio. 
Randomization will be stratified based on the use of propranolol for the treatment of ET (Y/N). 
Participants who are on a propranolol regimen must have been on a stable regimen for at least 1 
month prior to Day 1 and will continue to be on that stable regimen during the Treatment Period. 
Participants will complete baseline assessments of safety and efficacy, including the clinician-
rated TETRAS and quantitative Kinesia ONE assessments of tremor, as specified in the Schedule 
of Assessments (Table 2). 
During the double-blind Treatment Period, starting on Day 1, participants will receive a single 
dose of investigational product (IP) once daily for 28 days on an outpatient basis. Doses 
occurring on scheduled clinic visits will be administered in the clinic, and doses occurring on all 
other days will be self-administered by the participant at home as specified in Table 2. During 
the Treatment Period, participants will return to the study center approximately once per week 
for efficacy and safety assessments as specified in Table 2. In addition, a phone call will be 
conducted once per week (preferably mid-week) in between clinic visits, to review current status 
of the participant. 
In addition to Kinesia ONE-specific training, clinical study center staff and study participants 
will be trained on the use of software applications and devices necessary to complete 
questionnaires or other assessments as required. During in-clinic visits, clinical study center staff 
will be available to assist participants as needed, to ensure they can access and use the software 
applications and devices correctly according to the training. 
During the follow-up period, visits will be conducted on an outpatient basis. In addition to the 
phone calls to review current status, participants will receive a phone call approximately 7 days 
after the last dose of IP (ie, Day 35) for safety monitoring. Participants will return to the study 
center for an end of study visit approximately 14 days following the last dose of IP (ie, Day 42). 
Participants who discontinue IP during the Treatment Period will be asked to return to the clinic 
as soon as possible for an end of treatment (EOT) visit. Follow-up visits should take place as 
scheduled, or relative to the last dose of IP if discontinuing treatment early. If at any time after 
the EOT visit, a participant decides to withdraw from the study, the participant should return for 
an early termination visit (ETV). The EOT and ETV can be on the same day if a participant 

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discontinues IP and withdraws from the study on the same day during a clinic visit; in this case, 
all events scheduled for the EOT visit will be conducted.  
Figure 1: Study Design  
 
Abbreviation:  EOT = end of treatment 
7.2. 
Number of Participants 
Approximately 60 participants are planned, with approximately 30 participants enrolled per arm, 
to produce 25 evaluable participants per arm for primary efficacy analysis. Additional 
participants may be randomized if the drop-out rate is higher than anticipated (ie, >15%). 
7.3. 
Treatment Assignment 
Participants will be assigned to IP (active or placebo) in accordance with the randomization 
schedule on Day 1. Additional details on randomization and blinding are provided in Section 8.5.  
7.4. 
Dose Adjustment Criteria  
If participants report adverse events that are considered by the investigator to be related to the IP 
and not tolerable, the investigator may reduce the dose of IP from 60 mg in 15 mg increments 
until tolerability is established. The reduced dose of IP will continue to be administered once 
daily at the same schedule as specified in the Schedule of Assessments (Table 2). The dose of IP 
may not be increased for the remainder of the study. The dose may not be reduced below 30 mg: 
if intolerable adverse events persist at the 30 mg dose, the IP should be permanently stopped. 
Otherwise, IP doses will not be further adjusted for this study except as clinically necessary, eg, 
interrupting dose due to an AE or serious adverse event (SAE) considered related to IP. 
7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
participants, or for administrative reasons. In the event of study termination, Sage Therapeutics 
will provide written notification to the investigator. Investigational sites must promptly notify 
their IRB/ethics committee (EC), where required, and initiate withdrawal procedures for 
participating participants.  
 

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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 ICF before any study-specific procedures or washout of drugs is 
performed. 
2. Participant is 18 to 80 years of age, inclusive, at the time informed consent is obtained. 
3. 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) 
d. 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 step-wise deterioration of tremor 
4. Participant has a combined total upper extremity TETRAS score of ≥8 with at least 1 
upper extremity TETRAS score >4. 
5. Participant is willing to discontinue medications taken for the treatment of ET, with the 
exception of propranolol, within 14 days or 5 half-lives (whichever is longer) prior to 
receiving IP. 
6. Participants taking propranolol for the treatment of ET must be on a stable dose for at 
least 1 month prior to Day 1 and must be willing to maintain their stable dose through 
Day 29. 
7. Participant is willing to discontinue the use of alcohol and drugs of abuse within at least 
≥1 week prior to Day 1 and through Day 29 of the study. 
8. Female participant agrees to use at least one method of highly effective contraception as 
listed in Section 8.2.4 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 >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).  
9. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 13 weeks after receiving 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 8.2.4.  
10. Male participant is willing to abstain from sperm donation for the duration of the study 
and for 13 weeks after receiving study drug. 
11. Female participant must have a pregnancy test result that is confirmed as negative at 
Screening and Day 1. 

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12. At the discretion of the investigator, participant is medically stable and ambulatory, and 
is on stable dose(s) of any necessary prescription or over-the-counter medication(s) for at 
least 30 Days prior to Day 1, or changes/discontinues their use prior to Day 1 with the 
appropriate washout, as applicable per investigator judgement.  
13. Participant has no clinically significant findings, as determined by the investigator, on 
physical examination including mental state examination (MSE) and neurologic 
examination, 12-lead ECG, or clinical laboratory tests. 
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 recent exposure (14 days prior to Day 1) to tremorgenic drugs or 
presence of a drug or 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. 
5. Participant has historical or clinical evidence of tremor with psychogenic origin 
(including but not limited to eating disorders, major depression, etc.) 
6. Participant has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic 
(hypothyroidism with stable thyroid replacement is acceptable), or oncological disease. 
7. Participant has history, presence, and/or current evidence of serologic positive results for 
hepatitis B surface antigen (HBsAg), hepatitis C antibodies (anti-HCV), or human 
immunodeficiency virus (HIV) 1 or 2 antibodies. 
8. Participant has history of alcohol or drug abuse within 6 months prior to Screening, or a 
positive screen for alcohol on the Day 1 visit, or a positive screen for drugs of abuse at 
Screening or at the Day 1 visit. 
9. Participant has a known allergy to SAGE-324 or any excipient.  
10. Participant has had exposure to another investigational drug or device within 30 days 
prior to the Day 1 visit. 
11. Participant has history or suicidal behavior within 2 years or answers “YES” to questions 
3, 4, or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk or suicide in the 
opinion of the investigator 
12. Participant has donated one 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.  

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13. Participant is unable to perform Kinesia ONE assessments or unable to use the device 
required to perform the assessment. 
14. 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. 
15. Participant is unwilling or unable to comply with study procedures and required training. 
16. Participant has used any known moderate or strong cytochrome P450 3A4 or P450 2D6 
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. Use of 
mild cytochrome inhibitors and/or inducers may be permitted.  
17. Participant has concurrent or recent exposure (14 days prior to the Day 1 visit) to 
sedative/hypnotic drugs, stimulants, eg, opioids, highly-caffeinated beverages or dietary 
supplements containing high doses of caffeine, or recent increase above regular daily 
consumption of coffee. 
18. Participant has concurrent or recent exposure (30 days prior to the Day 1 visit) to long-
acting benzodiazepines 
19. Participant plans to undergo elective surgery or relocate during participation in the study. 
20. Participant is investigative site personnel or a member of their immediate families 
(spouse, parent, child or sibling whether biological or legally adopted). 
21. Participant has a positive urine cotinine screen at Screening or the Day 1 visit. 
8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned IP or entered in the study, ie, a participant who does not meet 1 or 
more of the eligibility criteria after providing consent and prior to randomization (Day 1). 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. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
8.4.1. 
Investigational Product Discontinuation 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, or administrative reasons. Participants who elect to discontinue IP will 
be encouraged by the Investigator to remain on study and complete the follow-up safety 
assessments 14 days after the last dose of study drug, in addition to the EOT visit conducted as 
specified in the Schedule of Assessments (Table 2).  

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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.  
If a participant is persistently noncompliant, the investigator should discuss with the sponsor the 
potential discontinuation of the participant. Any reasons for unwillingness or inability to adhere 
to the protocol must be recorded in the participant’s eCRF, including: 
• missed visits; 
• interruptions in the schedule of study drug administration; 
• non-permitted medications 
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/stopping study participation, if possible within 48 hours of final 
IP dose, an EOS/ETV visit should be conducted as specified in the Schedule of Assessments 
(Table 2). The participant will be permanently discontinued both from the IP and from the study 
at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been unsuccessful.  
8.4.4. 
Replacement of Participants 
Participants will not be replaced. 

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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Product 
SAGE-324 is an orally administered tablet provided in 5 mg or 15 mg (when available) dose 
strengths. Participants will receive IP (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 9. 
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 through the first dose of 
IP will be recorded. Use of all medications taken within the 30 days prior to Screening will be 
recorded. 
All medications and/or supplements taken from the first dose of IP through the Day 42 (±1 days) 
visit (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:  
• 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 Screening or during 
the study  
• Use of any prescription or over-the-counter medication (except for propranolol use as 
prescribed, and/or up to 3 g/day of acetaminophen), herbal medication, vitamins, or 
mineral supplements within 14 days prior to first IP administration, or during the 
study period  
• Use of tremorgenic drugs or agents known to affect SAGE-324 drug metabolism (any 
known CYP450 3A4 inhibitors and/or inducers) within the 28 days or 5 terminal half-
lives (whichever is longer) prior to first IP administration or during the study period  
9.2.3. 
Other Restrictions 
In addition to alcohol and drugs of abuse, the following are not permitted during the study, or 
within 14 days of the first IP dose:  sedative/hypnotic drugs, stimulants, eg, opioids, 
benzodiazepines, highly-caffeinated beverages or dietary supplements containing caffeine. 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 

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• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation  
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal ligation or bilateral tubal occlusion (performed at least 3 months prior 
to Screening) 
• Vasectomized partner (performed at least 3 months prior to Screening) 
• Sexual abstinence (no sexual intercourse) 
Acceptable forms of contraception for male participants include: 
• Sexual abstinence (no sexual intercourse) 
• History of vasectomy (performed at least 3 months prior to Screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
9.3. 
Intervention after the End of the Study 
There is no planned intervention following the end of the study. 
9.4. 
Treatment Adherence 
The first dose of IP will be received and administered by participants in the clinic. Participants 
will be dispensed a 7-day supply of IP to orally self-administer at home with instructions 
specifying to administer in the morning with food. 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 9.6. 
9.5. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Participants will be randomized in 
a stratified manner based on propranolol for the treatment of ET (Y/N); randomization will be 
done within each stratum in a 1:1 ratio to treatment groups (SAGE-324, 60 mg or placebo). 
Participants, site staff, and the sponsor will be blinded to treatment allocation. 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 

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risk, the Investigator should make diligent attempts to contact Sage prior to unblinding the study 
treatment administered to a participant. Requests from the investigator about the treatment 
administered to study participants should be discussed with the Sage Medical Monitor. If the 
unblinding occurs without Sage’s knowledge, the investigator must notify Sage within 24 hours 
of breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records.  
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and on the 
eCRF. At the time of withdrawal from the study/stopping participation, if possible, an EOT 
and/or ETV should be conducted.  
If a participant or study personnel become unblinded to treatment, the participant will be 
excluded from the Per Protocol analysis set, as detailed further in the statistical analysis plan. 
 

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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
Table 3: 
Investigational Product 
 
Investigational Product 
Product Name: 
SAGE-324 
Placebo 
Dosage Form: 
Tablet 
Tablet 
Tablet Strength 
5 mg, 15 mg 
0 mg, appearance-matched to 
5 mg, and 15 mg, respectively 
Route of Administration 
Oral 
Oral 
Physical Description 
Immediate release white to off-
white, round, film-coated tablet 
containing 5 mg or 15 mg of 
SAGE-324 drug substance, and 
composed of 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 
SAGE-324 Oral Tablets and Placebo Tablets will be packaged in blinded, high density 
polyethylene (HDPE) containers. The containers used for SAGE-324 and placebo will be 
identical in appearance. The package labeling conforms to FDA and GMP 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. Any 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, 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 in the clinic or at home as specified in the Schedule of Assessments 
(Table 2). The IP will be provided as tablets, sufficient in number to achieve a dose of 60 mg. IP 
will be orally administered once daily in the morning, with food. 
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. 
The designated site staff will dispense the supplied participant-specific kits to participants at the 
planned dispensation visit intervals outlined in the Schedule of Assessments (Table 2). 
An interactive response technology (IRT) will be used to capture participant-identifying 
information. The IRT will be used to randomize the eligible participant into the study and 
provides the kit number of the IP to be dispensed to that participant.  
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 tablets will be returned to Sage Therapeutics for 
destruction or destroyed locally per the site’s procedures; disposition of IP will be documented. 
IP may not be destroyed until accountability and reconciliation procedures have been completed 
and monitored. 
10.7. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution.  
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1 and in 
the Pharmacy Manual. Where possible, personnel should segregate and retain any product, 

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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 ASSESSMENTS AND CLINICAL PHARMACOLOGY 
ASSESSMENTS 
11.1. 
Efficacy Assessments 
11.1.1. 
Kinesia ONE™ Accelerometer Score 
Kinesia ONE™ is an ISO-certified wireless motion sensor worn distally on the index finger, 
which utilizes 3 orthogonal accelerometers and 3 orthogonal gyroscopes to monitor three-
dimensional motion. Data is transmitted wirelessly from the sensor to a Bluetooth technology-
enabled device to use with the Kinesia ONE software (eg, Apple iPad or similar device with 
preinstalled Kinesia ONE software). The device has received FDA clearance. 
Via the Kinesia ONE software application, measures of three-dimensional motion are converted 
to scores ranging from 0 to 4, per assessed maneuver; higher scores indicate greater tremor 
severity. Motion in both arms is captured. 
Participants will complete this assessment at each clinic visit as specified in the Schedule of 
Assessments (Table 2).  
11.1.2. 
The Essential Tremor Rating Assessment Scale 
TETRAS is a validated, comprehensive clinical assessment of essential tremor (Elble 2013).  
Three different components of TETRAS will be assessed in this study. The TETRAS ADL 
subscale, total performance score, and performance subscale part 4 upper limb tremor score, and 
will each be separately assessed at each clinic visit as specified in the Schedule of Assessments 
(Table 2). 
The ADL subscale assesses how ET is impacting 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 in from 
0 (normal activity) to 4 (severe abnormality). The overall ADL score range is 0 to 48. 
The total performance score is based on overall rating of the performance subscale, which 
measures tremor amplitude in the voice, limbs, head, face, trunk, 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 the performance subscale part 4 upper limb tremor score, all 3 maneuvers in the upper limb 
assessments of part 4 (subscale items 4a, 4b, and 4c) will be completed for both arms, first for 
the left arm and then for the right. The part 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. 

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11.3. 
Other Patient-Reported Assessments 
11.3.1. 
Patient Perception of Response Burden 
The Patient Perception of Response Burden Questionnaire is a patient-reported measure that 
assesses the multidimensional construct of response burden (Atkinson 2019). 
Participants respond to 6 items assessing 1) how well the questions related to their actual 
concerns, 2) how comfortable the participants were with answering the questions, 3) how well 
the survey characterized their health and well-being, 4) the length of time to complete the 
questionnaires, 5) whether questions seemed unimportant or repetitive, and 6) what additional 
information should have been gathered. Items 1 to 3 are assessed on a 0 to 10 scale, item 4 is 
assessed on a 1 to 3 scale, and items 5 and 6 are open-ended. Items 1 and 4 are reverse scored. A 
composite score can be calculated to create a weighted representative index of relevance, 
comfort, and well-being relative to time to completion (ie, items 1, 2, and 3 were summed and 
multiplied by item 4) for a range of 0 to 72, with higher scores indicative of elevated endorsed 
response burden. The open-ended items will be summarized thematically. The Patient Perception 
of Response Burden Questionnaire will be performed as specified in the Schedule of 
Assessments (Table 2). 
 

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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, ethnicity) and a full medical history will be 
documented. This must also additionally include participant recall of history of ET, disease 
duration, past treatments used, and responsiveness to alcohol and/or other treatments with use 
intended as off-label treatment of ET (eg, primidone or similar therapies). 
12.1.2. 
Weight and Height 
Height and weight will be measured and documented. Body mass index (BMI) will be calculated 
and documented.  
12.1.3. 
Physical Examination 
Whenever possible, the same individual should perform all physical examinations. Physical 
examinations will include assessment of body systems (eg, head, eye, ear, nose and throat; heart; 
lungs; abdomen; and extremities) as well as cognitive and neurological examination and MSE. 
Unscheduled physical examinations may also be conducted per the Investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by an investigator as abnormal, not 
clinically significant (NCS); or abnormal, clinically significant (CS) in source documents.  
12.1.4. 
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. When assessed postdose, orthostatic blood pressure and 
heart rate will also be measured after the participant has been in the supine position for at least 
5 minutes and then repeated approximately 1 and 3 minutes after standing.  
Any abnormality in vital signs will be interpreted by an Investigator as abnormal, NCS; or 
abnormal, CS in source documents. 
12.1.5. 
Electrocardiogram 
A 12-lead ECG will be performed. The standard intervals (heart rate, PR, QRS, QT, and QTcF) 
as well as any rhythm abnormalities will be recorded. 
Electrocardiograms will be performed after the participant has been resting in a supine position 
for at least 5 minutes. When ECG measurements coincide with safety assessments, vital signs 
assessment or blood draws, procedures should be carried out in said order (vital signs, ECG, 
blood draw). 
All abnormal ECGs will be interpreted by an investigator as abnormal, NCS, or abnormal, CS in 
source documents. 

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12.2.2. 
Serious Adverse Event (SAE) Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
Investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Definition of Adverse Events of Special Interest 
There are no known adverse events of special interest as of the date of signature approval of this 
clinical protocol. 

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12.2.4. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP.  
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
alternative explanation for the AE 
Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE 
12.2.5. 
Recording Adverse Events 
AEs spontaneously reported by the participant and/or in response to an open question from the 
study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the Investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome and seriousness (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s)  
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized  
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 11.2.2. An AE of severe intensity 
may not necessarily be considered serious. 

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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 or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage or designee.  
Additional follow-up information, if required or available, should all be sent to Sage or designee 
within 24 hours of receipt on a follow-up SAE report form and placed with the original SAE 
information and kept with the appropriate section of the eCRF and/or study file. 
SAEs occurring after the designated follow up time for the study, should be reported to Sage or 
designee according to the timelines noted above only if the Investigator considers the SAE 
related to IP.  
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/EC 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. Each site is responsible for notifying its 
IRB of all SUSARs.  
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARs to investigators in a blinded fashion. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 
pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy. The investigator will also attempt to collect pregnancy information on any 
participant’s partner who becomes pregnant after the participant has received the first 
administration of IP. After obtaining the necessary signed informed consent from the pregnant 
partner directly, the investigator will follow the same pregnancy reporting procedures specified 
for pregnant participants.  
The participant or participant’s partner will be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies (eg, spontaneous abortion, elective abortion, normal 
birth) must be followed and documented even if the participant was discontinued from the study. 
The investigator will collect follow-up information on the participant or participant’s partner and 
the neonate, and the information will be forwarded to Sage or designee. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 

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Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, preeclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death), the investigator should follow the procedures 
for reporting an SAE.  
12.4. 
Overdose 
An overdose is any dose of study treatment given to a participant or taken by a participant that 
exceeds more than one extra tablet within 24 hours as described in protocol. Overdoses are not 
considered AEs and should not be recorded as an AE on the eCRF; however, all overdoses must 
be recorded on an overdose form and sent to Sage or designee within 24 hours of the site 
becoming aware of the overdose. An overdose must be reported to Sage or designee even if the 
overdose does not result in an AE. If an overdose results in an AE, the AE must be recorded.  

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13. 
STATISTICS 
Detailed description of the analyses to be performed in the study will be provided in the 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to database lock. 
Any changes or 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 will include all participants who are randomized.  
The Safety Set will include all participants 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 Kinesia ONE accelerometer 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. No imputation process will 
be used to estimate missing data.  
13.3. 
General Considerations 
All participant data, including those that are derived, that support the tables and figures will be 
presented in 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. Participants will be summarized according to treatment received. 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to receipt of IP.  
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. 
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 using the Safety Set.  
Pregnancy test results and drug screen results will be listed but not summarized.  
Medical history will be listed by participant.  

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13.5. 
Efficacy Analysis  
The estimand for the primary efficacy analysis is the treatment difference between SAGE-324 
and placebo in mean change from baseline in clinic-based Kinesia ONE accelerometer scores at 
Day 29 based on the Full Analysis Set. This will be analyzed using a mixed effects model for 
repeated measures (MMRM); the model will include treatment, baseline Kinesia ONE 
accelerometer score, stratification factor, 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. The main comparison will be between SAGE-324 and 
placebo at the 29-day timepoint. Model-based point estimates (ie, least squares means, 5% 
confidence intervals, and p-values) will be reported where applicable. An unstructured 
covariance structure will be used to model the within-subject errors. If there is a convergence 
issue with the unstructured covariance model, Toeplitz compound symmetry 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 UN, the sandwich estimator for the variance covariance 
matrix will be derived, using the EMPIRICAL option in the PROC MIXED statement in SAS. 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in TETRAS total performance scores, TETRAS 
performance subscale part 4 upper limb tremor scores and TETRAS ADL scores.  
Other efficacy analyses will be specified in the SAP. In general, data will be analyzed using 
appropriate descriptive statistics or prespecified statistical methods as applicable; participant 
listings will be provided for all efficacy data. Participants will be analyzed according to 
randomized treatment for the purpose of efficacy unless otherwise specified. 
Sensitivity analyses will be described in the SAP. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-324 will be evaluated by AEs, concomitant medication usage, 
 
 Safety data will be listed by participant and 
summarized by treatment group. All safety summaries will be performed on the Safety Set using 
treatment received.  
13.6.1. 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 22.1 
or higher. A treatment-emergent adverse event (TEAE) is defined as an AE with onset after the 
first dose of IP. The analysis of AEs will be based on the concept of TEAEs. The incidence of 
TEAEs will be summarized by System Organ Class (SOC) and preferred term. In addition, 
summaries will be provided by intensity (mild, moderate, severe) and by causality (related, not 
related) to IP.  
Any TEAEs leading to discontinuation of treatment or withdrawal from the study and any 
treatment-emergent SAEs will be summarized.  
All AEs and SAEs (including those with onset or worsening before the start of IP) through the 
end of the study will be listed.  

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13.6.3. 
Physical Examinations 
The occurrence of a physical examination, including MSE, (yes/no) and the date performed will 
be listed by participant. 
 
 
 
 
 
 
 
 
 
 
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
All medications taken within 30 days prior to informed consent through the duration of the study 
will be recorded. In addition, all psychotropic medications taken in the previous 30 days prior to 
screening will be recorded. Those medications taken prior to the initiation of the start of IP will 
be denoted “Prior”. Those medications taken prior to the initiation of the IP and continuing 
beyond the initiation of the IP or those medications started at the same time or after the initiation 
of the IP will be denoted “Concomitant”.  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by participant, start date, and 
verbatim term.  

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13.8. 
Sample Size and Power 
The sample size of this study is based on the assumption of a 3 points difference in the change 
from baseline Kinesia ONE accelerometer between SAGE-324 and placebo with a standard 
deviation of 3.5 points. Under these assumptions, a sample size of 25 evaluable participants per 
group would provide 85% power for detecting a placebo-adjusted treatment difference of 3 
points in Kinesia accelerometer assuming a 2-sided test at an alpha level of 0.05. By including 
2 treatment groups and using a 1:1 randomization, a total of 50 evaluable participants are 
required. Assuming a nonevaluability rate of 15%, approximately 60 participants will be 
randomized. Additional participants may be enrolled if the dropout rate is greater than 15%. 
13.8.1. 
Interim and Data Monitoring Committee (DMC) Analyses 
13.8.1.1. Interim Analysis 
The sponsor may conduct an interim analysis. Detailed descriptions of planned data analyses will 
be provided in a separate interim statistical analysis plan (SAP), if applicable. 
13.8.1.2. DMC Analysis 
Not applicable 

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

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

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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit(s) at the clinical site. Please see 
Section 13.2 for more details regarding the audit process. 
The Investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Significant protocol deviations should be reported to the IRB/EC per the IRB/EC’s 
written procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates trial-related duties and functions conducted at the trial site. When the investigator 
retains the services of any individual or party to perform trial-related duties and functions, the 
Investigator must ensure the individual or party is qualified to perform trial-related duties and 
functions and should implement procedures to ensure the integrity of the trial-related duties and 
functions performed, and any data generated.  
The investigator must maintain adequate and accurate source documents and trial records that 
include all pertinent observations on each of the site’s trial participants. Source data must be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained, if necessary, 
to provide clarification. 
 

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be given a written and 
dated approval or favorable opinion by an IRB or EC as appropriate. The Investigator must 
obtain and document approval before he or she can enroll any participant into the study. The IRB 
or EC must supply to the sponsor a list of the IRB/EC membership and a statement to confirm 
that the IRB/EC is organized and operates according to GCP and applicable laws and 
regulations. 
The principal investigator is responsible for informing the IRB or EC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or EC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or EC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or EC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the IP. Sage 
Therapeutics will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or EC according to local regulations and guidelines. In addition, the principal investigator must 
inform the IRB/EC and sponsor of any changes significantly affecting the conduct of the trial 
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 trial 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 trial, the participant (or the participant’s, parent 
or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source records. The investigator must maintain 
the original, signed ICF. A copy of the signed ICF must be given to the participant or to the 
participant’s parent or legally authorized representative. 
Throughout the trial participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 
documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 

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

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18. 
PUBLICATION POLICY 
All information concerning SAGE-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. 

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19. 
LIST OF REFERENCES 
Atkinson TM, Schwartz CE, Goldstein L, et al. Assessments in Oncology. Value in Health. 
2019;22(2):225-230. 
Belelli D, Casula A, Ling A, Lambert JJ. The influence of subunit composition on the interaction 
of neurosteroids with GABA(A) receptors. Neuropharmacology. 2002;43(4):651-61. 
Deuschl G, Raethjen J, Hellriegel H, Elble R. Treatment of patients with essential tremor. Lancet 
Neuro. 2011. 10(2):148. 
Elble R, Bain P, Forjaz MJ, et al. Task force report: scales for screening and evaluating tremor: 
critique and recommendations. Mov Disord. 2013 Nov;28(13):1793-800. 
Genetics Home Reference; Essential Tremor. Lister Hill National Center for Biomedical 
Communications;U.S. National Library of Medicine;National Institutes of Health, Department of 
Health & Human Services. Available from: https://ghr.nlm.nih.gov/condition/essential-tremor. 
Accessed Sept 10, 2019. 
Hopfner F, Haubenberger D, Galpern WR, et al. Knowledge gaps and research recommendations 
for essential tremor. Parkinsonism Relat Disord. 2016;33:27-35. 
Inderal® (propranolol hydrochloride) [package insert]. Philadelphia, PA: Wyeth 
Pharmaceuticals, Inc.; 2010. Accessed 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016418s078lbl.pdf 
Koller W, Vetere-Overfield B. Acute and chronic effects of propranolol and primidone in 
essential tremor. Neurology 1989;39:1587-1588 
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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Olanow CW. Hyperkinetic Movement Disorders: Essential Tremor. In: Harrison's Principles of 
Internal Medicine. Vol 2. 17th ed. New York, NY: McGraw Hill; 2008:2560. 
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. Epub 2012 
Aug 11. Review. Erratum in: J Neurol. 2013 Mar;260(3):741 
 

 
1. 
TITLE PAGEA PHASE 2, DOUBLE-BLIND, PLACEBO-
CONTROLLED, RANDOMIZED STUDY EVALUATING 
THE EFFICACY, SAFETY, AND TOLERABILITY OF 
SAGE-324 IN THE TREATMENT OF INDIVIDUALS 
WITH ESSENTIAL TREMOR  
324-ETD-201  
 
Investigational Product 
SAGE-324 Oral Tablet  
Clinical Phase 
Phase 2  
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
, MD 
Sponsor Medical Monitor 
, MD, PhD 
Date of Original Protocol 
23 October 2019 
Date of Amendment 1 
20 December 2019 
Date of Amendment 2 
24 February 2020 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee. 
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from Sage Therapeutics, Inc. 
 

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

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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sage Study Physician 
, MD 
Phone 
 
Sage Medical Monitor and 
24-hour Emergency Contact 
, MD, PhD 
Mobile: 
1 
Office phone: 
 
E-mail: 
 
SAE Reporting Information 
IQVIA Lifecycle Safety  
4820 Emperor Boulevard  
Durham, NC 27703  
E-mail: Sage.Safety@iqvia.com  
Fax: +1-855-638-1674  
SAE Hotline: +1-855-564-2229  
Product Complaints 
Sage Therapeutics, Inc. 
E-mail: 
productcomplaints@sagerx.com 
Phone: +1-833-554-7243 
 

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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, Placebo-controlled, Randomized Study Evaluating the Efficacy, Safety, and 
Tolerability of SAGE-324 in the Treatment of Individuals with Essential Tremor  
Number of Sites and Study Location: This study will take place at approximately 30 sites in the 
United States. 
Phase of Development: Phase 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 71 days. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To assess the effect of SAGE-324 compared to 
placebo on upper limb tremor reduction in 
individuals with essential tremor (ET) after 
28 days of treatment 
Change from baseline compared to placebo in 
The Essential Tremor Rating Assessment 
(TETRAS) performance subscale part 4 upper 
limb tremor score on Day 29 
Secondary 
 
To assess the effect of SAGE-324 compared to 
placebo on overall upper limb tremor reduction 
• Change from baseline compared to placebo in 
TETRAS performance subscale part 4 upper 
limb tremor score at all other timepoints 
• Change from baseline compared to placebo in 
Kinesia ONE accelerometer scores 
To assess the effect of SAGE-324 compared to 
placebo on activities of daily living (ADLs) 
• 
Change from baseline compared to placebo in 
TETRAS Scale ADL score 
To assess the effect of SAGE-324 compared to 
placebo on overall tremor 
• 
Change from baseline compared to placebo in 
TETRAS total performance score 
To evaluate the safety and tolerability of 
SAGE-324 
• 
Incidence of treatment-emergent adverse 
events (TEAEs) 
 
 

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Study Description: 
This is a randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy, 
safety, and tolerability of SAGE-324 in individuals with ET. Participants, site staff, and sponsor 
personnel will be masked to treatment allocation. 
This study includes a Screening Period of up to 28 days, a 29-day treatment period (28 days of dosing), 
and a 14-day follow up period. After providing informed consent, participants will undergo screening 
assessments as outlined in Table 2 to determine eligibility.  
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). Following completion of screening 

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and Day 1 eligibility checks, participants will be randomized to 1 of 2 treatment groups (SAGE-324 60 
mg daily, or placebo) in a 1:1 ratio.   
Double-Blind Treatment Period: Starting on Day 1, participants will receive a single dose of 
investigational product (IP) once daily for 28 days on an outpatient basis, to be taken in the morning 
with food that comprises a minimum of 400 calories. Doses occurring on scheduled clinic visits will be 
administered in the clinic, and doses occurring on all other days will be self-administered by the 
participant at home. During the Treatment Period, participants will return to the study center 
approximately once per week for efficacy and safety assessments as specified in Table 2. Participants 
will be trained on the use of software applications and devices necessary to complete questionnaires or 
other assessments. During the study, a phone call will be conducted once per week, preferably midway 
between clinic visits, to review current status of participant. 
Follow-Up Period: Follow-up visits will be conducted on an outpatient basis. Participants will continue 
to complete questionnaires as indicated in Table 2 and will receive a phone call approximately 7 days 
after the last dose of IP (ie, Day 35) for safety monitoring. Participants will return to the study center for 
an end of study visit approximately 14 days following the last dose of IP (ie, Day 42). 
Number of Participants (planned): Approximately 60 participants, with approximately 30 per arm. 

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Eligibility Criteria:  
Inclusion Criteria: 
1. Participant has signed an ICF before any study-specific procedures or washout of drugs is 
performed. 
2. Participant is ambulatory and is 18 to 80 years of age, inclusive, at the time informed consent is 
obtained. 
3. 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) 
d. 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 
4. Participant scores at least 1.5 for each of the six items that comprise the combined total upper 
limb TETRAS (total performance subscale part 4) with the total score for the dominant upper 
limb (the sum of the 3 items for either the right or left upper limb, whichever is dominant) 
being at least 5.5, at both Screening and predose on Day 1. 
5. Participant is willing to discontinue medications taken for the treatment of ET within 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 29. 
6. Participant is willing to discontinue the use of alcohol and products that contain nicotine within 
at least 1 week prior to Day 1 and through Day 29 of the study. 
7. 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 
>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).  
8. Male participant agrees to use an acceptable method of effective contraception for the duration 
of the study and for 13 weeks after receiving 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.  
9. Male participant is willing to abstain from sperm donation for the duration of the study and for 
13 weeks after receiving study drug. 
10. Participant has no clinically significant findings, as determined by the investigator, on 
Screening and predose Day 1 physical examination including mental state examination (MSE) 
and neurologic examination, 12-lead ECG, or screening clinical laboratory tests.  
Exclusion Criteria: 
1. Participant has presence of known causes of enhanced physiological tremor. 

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2. Participant has had recent exposure (14 days prior to Day 1) to tremorgenic drugs 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. 
5. Participant has historical or clinical evidence of tremor with psychogenic origin (including but 
not limited to eating disorders, major depression, etc.) 
6. Participant has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic (hypothyroidism with 
stable thyroid replacement is acceptable), or oncological disease. 
7. Participant has history of substance abuse prior to Screening, has a positive screen for drugs of 
abuse at Screening or predose on Day 1, or has a positive screen for alcohol predose on Day 1. 
8. Participant has a known allergy to SAGE-324 or any excipient.  
9. Participant has had exposure to another investigational drug or device within 30 days or 5 half-
lives (if known) of the investigational drug, whichever is longer, prior to the Day 1 visit. 
10. Participant has history of suicidal behavior within 2 years or answers “YES” to questions 3, 4, 
or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk of suicide in the opinion of 
the investigator 
11. Participant has donated one 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.  
12. 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. 
13. Participant is unwilling or unable to comply with study procedures and required training. 
14. 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. Use of mild cytochrome inhibitors 
and/or inducers may be permitted.  
15. 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. 
16. Participant plans to undergo elective surgery or relocate during participation in the study. 
17. Participant is investigative site personnel or a member of their immediate families (spouse, 
parent, child or sibling whether biological or legally adopted).  

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18. Participant currently uses or has used within 14 days or 5 half-lives (whichever is 
longer) prior to Day 1, any prescription or over-the-counter medication that is a substrate of 
the OATP1B1 transporter. 
19. Female participant has a positive pregnancy test or confirmed pregnancy. 
Investigational Product Dosage and Mode of Administration:  
SAGE-324 (60 mg) or matched placebo oral tablets will be administered in the clinic or self-
administered once daily, in the morning with food that comprises a minimum of 400 calories.  
Duration of Treatment:  
Each participant will receive a single dose of SAGE-324 oral tablets or matching placebo administered 
once daily for 28 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 TETRAS performance subscale part 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 sample size of this study is based on the assumption of a 3-point difference in the change from 
baseline TETRAS performance subscale part 4 upper limb tremor scores between SAGE-324 and 
placebo with a standard deviation of 3.5 points. Under these assumptions, a sample size of 25 evaluable 
participants per group would provide 85% power for detecting a placebo-adjusted treatment difference 
of 3 points in TETRAS performance subscale part 4 upper limb tremor score, assuming a 2-sided test at 
an alpha level of 0.05. By including 2 treatment groups and using a 1:1 randomization, a total of 
50 evaluable participants are required. Assuming a nonevaluability rate of 15%, approximately 
60 participants will be randomized. Additional participants may be enrolled if the drop-out rate is higher 
than 15%. 
Analysis of Primary Efficacy Endpoint 
The estimand for the primary efficacy analysis is the treatment difference between SAGE-324 and 
placebo in mean change from baseline in clinic-based TETRAS performance subscale part 4 upper limb 
tremor score at Day 29 based on the Full Analysis Set. This will be analyzed using a mixed-effects 

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model for repeated measures (MMRM); the model will include treatment, baseline TETRAS 
performance subscale part 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. The main comparison will be between SAGE-324 and 
placebo at the 29-day timepoint. Model-based point estimates (ie, least squares means, 95% confidence 
intervals, and p-values) will be reported where applicable. An unstructured covariance structure will be 
used to model the within-subject errors. If there is a convergence issue with the unstructured covariance 
model, Toeplitz compound symmetry 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. 
Analysis of Secondary Efficacy Endpoints 
Similar to those methods described above for the primary endpoint, an MMRM will be used to analyze 
of the change from baseline in TETRAS total performance scores, Kinesia ONE accelerometer scores 
and TETRAS ADL scores. Individual items of the TETRAS subscales will be summarized. 
Safety Analysis 
Safety and tolerability of study drug will be evaluated by incidence of TEAEs/serious adverse events, 
Interim Analysis 
The sponsor may conduct an interim analysis. Detailed descriptions of planned data analyses will be 
provided in a separate interim statistical analysis plan (SAP), if applicable.  

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Table 2: 
Schedule of Assessments 
Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5 (±1) 
Phone 
Call 
8 (±1) 
12 (±1) 
Phone 
Call 
15(±1) 
19 (±1) 
Phone 
Call 
22 (±1) 
26 (±1) 
Phone 
Call 
29 (+1) 
EOT 
 
35 (±1) 
Safety 
Phone Call 
42 (±1) 
EOS/ETV 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testl 
X  
(serum; all 
women) 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
 
X  
(urine; 
WOCBP only) 
FSH (postmenopausal 
women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomizationa 
 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol/cotinine screens 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Neurological examination 
including MSEb 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Body height  
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signsc 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
12-Lead ECGd 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Chemistry/hematology/ 
coagulation/urinalysis 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 

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Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5 (±1) 
Phone 
Call 
8 (±1) 
12 (±1) 
Phone 
Call 
15(±1) 
19 (±1) 
Phone 
Call 
22 (±1) 
26 (±1) 
Phone 
Call 
29 (+1) 
EOT 
 
35 (±1) 
Safety 
Phone Call 
42 (±1) 
EOS/ETV 
Kinesiaf 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
TETRASg 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 

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Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5 (±1) 
Phone 
Call 
8 (±1) 
12 (±1) 
Phone 
Call 
15(±1) 
19 (±1) 
Phone 
Call 
22 (±1) 
26 (±1) 
Phone 
Call 
29 (+1) 
EOT 
 
35 (±1) 
Safety 
Phone Call 
42 (±1) 
EOS/ETV 
Patient Perception of 
Response Burden 
 
 
 
 
 
 
 
 
 
X 
 
X 
Participant trainingh 
X 
X 
 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
X  
 
X 
 
X 
 
X 
 
 
 
 
IP administration 
 
Administered once daily for 28 days 
Not applicable 
AEs/SAEs 
X 
Prior and concomitant 
medication and historyi 
X 
Abbreviations: ADL = activities of daily living; AE = adverse event; 
 
; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; 
; 
; ETV = early termination visit; FSH = follicle stimulating hormone; HIV = human immunodeficiency 
virus; ICF = informed consent form; min = minutes; IP = investigational product; MSE = mental state examination; 
 
 
; SAE = serious adverse event; TETRAS = The Essential Tremor Rating Assessment 
Scale; WOCBP = women of childbearing potential 
Notes:  
• 
The suggested order of assessments during clinic visits is: vital signs, TETRAS, Kinesia, ECG, blood sample collection for 
 and clinical laboratory 
assessments, and questionnaires. 
• 
All assessments will be performed predose unless specified in a footnote. 
 
a Randomization will occur on Day 1 after meeting all eligibility criteria. 
b Complete physical examinations (including MSE and neurologic examination as parts of physical examination) should be performed as specified and as 
clinically necessary (see Section 12.1.3).  
c Predose on Day 1, supine and standing blood pressure and heart rate will be collected in triplicate at least 15 minutes apart, measured after the participant has 
been in the supine position for at least 5 minutes and then repeated 1 minute and 3 minutes after standing. Respiratory rate and temperature are collected once 
predose on Day 1. Vital signs will be collected once predose at all other visits. All postdose vital signs will be collected once at approximately 3 hours (±60 
min) after dosing. 
d ECGs will be collected and read centrally. ECGs will be performed predose and approximately 3 hours (±60 min) postdose. All ECGs must be performed after 
the participant has been in a supine position for at least 5 minutes.  

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f Kinesia ONE will be assessed simultaneously to TETRAS Performance subscale part 4 upper limb tremor.  
g The TETRAS Performance and TETRAS ADL subscales will be assessed at Screening and predose at each clinic visit. The TETRAS Performance subscale 
part 4 upper limb tremor will be assessed simultaneously to Kinesia ONE. In addition, on Day 15, the TETRAS Performance subscale will be assessed at 5 and 
8 hours (±30 min) postdose. A videographer will record each TETRAS administration. 
h Participants will be trained by study personnel on the use of software applications, Investigational Product Diary, and devices necessary for the conduct of the 
study. 
i Prior medications will be recorded during Screening and will include 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. Concomitant medications will be recorded thereafter 
throughout the duration of the study.  
   

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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS ...........................................................................................16 
LIST OF TABLES .........................................................................................................................20 
LIST OF FIGURES .......................................................................................................................20 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................21 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Dose Justification ........................................................................................................23 
5.2. 
Benefit/Risk Assessment ............................................................................................24 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................25 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Number of Participants ...............................................................................................28 
7.3. 
Treatment Assignment ................................................................................................28 
7.4. 
Dose Adjustment Criteria ...........................................................................................28 
7.5. 
Criteria for Study Termination ...................................................................................28 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.....................................29 
8.1. 
Participant Inclusion Criteria ......................................................................................29 
8.2. 
Participant Exclusion Criteria .....................................................................................30 
8.3. 
Screen Failures ............................................................................................................31 
8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................31 
8.4.1. 
Investigational Product Discontinuation .....................................................................31 
8.4.2. 
Early Termination from the Study ..............................................................................32 
8.4.3. 
Loss to Follow-up .......................................................................................................32 
8.4.4. 
Replacement of Participants .......................................................................................32 
9. 
TREATMENT OF PARTICIPANTS .........................................................................33 
9.1. 
Description of Investigational Product .......................................................................33 

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9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................33 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................33 
9.2.2. 
Prohibited Medications ...............................................................................................33 
9.2.3. 
Other Restrictions .......................................................................................................33 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................34 
9.3. 
Intervention after the End of the Study .......................................................................34 
9.4. 
Treatment Adherence ..................................................................................................35 
9.5. 
Randomization and Blinding ......................................................................................35 
9.5.1. 
Emergency Unblinding ...............................................................................................35 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............36 
10.1. 
Investigational Product ...............................................................................................36 
10.2. 
Investigational Product Packaging and Labeling .......................................................36 
10.3. 
Investigational Product Storage ..................................................................................36 
10.4. 
Investigational Product Preparation ............................................................................37 
10.5. 
Investigational Product Administration ......................................................................37 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................37 
10.7. 
Product Complaints ....................................................................................................37 
11. 
EFFICACY ASSESSMENTS AND CLINICAL PHARMACOLOGY 
ASSESSMENTS.........................................................................................................39 
11.1. 
Efficacy Assessments .................................................................................................39 
11.1.1. 
The Essential Tremor Rating Assessment Scale ........................................................39 
11.1.2. 
Kinesia ONE™ Accelerometer Score ..........................................................................39 
 
40 
 
40 
 
40 
 
40 
 
41 
 
41 
 
41 
 
42 
 
42 
 
42 

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42 
 
42 
 
42 
11.3. 
Other Patient-Reported Assessments ..........................................................................43 
11.3.1. 
Patient Perception of Response Burden ......................................................................43 
12. 
SAFETY ASSESSMENTS ........................................................................................44 
12.1. 
Safety Parameters .......................................................................................................44 
12.1.1. 
Demography and Medical History ..............................................................................44 
12.1.2. 
Weight and Height ......................................................................................................44 
12.1.3. 
Physical Examination .................................................................................................44 
12.1.4. 
Vital Signs ..................................................................................................................44 
12.1.5. 
Electrocardiogram .......................................................................................................44 
12.1.6. 
Laboratory Assessments .............................................................................................45 
12.1.6.1. 
Drugs of Abuse, Alcohol, Nicotine (Cotinine) ...........................................................45 
12.1.6.2. 
Pregnancy Screen ........................................................................................................45 
 
46 
 
46 
12.1.9. 
Safety Phone Call .......................................................................................................46 
12.2. 
Adverse Events and Serious Adverse Events .............................................................46 
12.2.1. 
Adverse Event Definition ...........................................................................................46 
12.2.2. 
Serious Adverse Event (SAE) Definition ...................................................................47 
12.2.3. 
Definition of Adverse Events of Special Interest .......................................................48 
12.2.4. 
Relationship to Investigational Product ......................................................................48 
12.2.5. 
Recording Adverse Events .........................................................................................48 
12.2.6. 
Reporting Serious Adverse Events .............................................................................49 
12.3. 
Pregnancy ...................................................................................................................49 
12.4. 
Overdose .....................................................................................................................50 
13. 
STATISTICS ..............................................................................................................51 
13.1. 
Data Analysis Sets ......................................................................................................51 
13.2. 
Handling of Missing Data ...........................................................................................51 
13.3. 
General Considerations ...............................................................................................51 
13.4. 
Demographics and Baseline Characteristics ...............................................................51 
13.5. 
Efficacy Analysis ........................................................................................................52 

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13.6. 
Safety Analyses ..........................................................................................................52 
13.6.1. 
Adverse Events ...........................................................................................................52 
 
53 
13.6.3. 
Physical Examinations ................................................................................................53 
 
53 
 
53 
13.6.6. 
Prior and Concomitant Medications ...........................................................................53 
 
54 
 
54 
 
54 
13.8. 
Sample Size and Power ..............................................................................................54 
13.8.1. 
Interim and Data Monitoring Committee (DMC) Analyses .......................................54 
13.8.1.1. 
Interim Analysis ..........................................................................................................54 
13.8.1.2. 
DMC Analysis ............................................................................................................55 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................56 
14.1. 
Study Monitoring ........................................................................................................56 
14.2. 
Audits and Inspections ................................................................................................56 
14.3. 
Institutional Review Board or Ethics Committee .......................................................57 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................58 
16. 
ETHICS ......................................................................................................................59 
16.1. 
Ethics Review .............................................................................................................59 
16.2. 
Ethical Conduct of the Study ......................................................................................59 
16.3. 
Written Informed Consent ..........................................................................................59 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................60 
17.1. 
Inspection of Records .................................................................................................60 
17.2. 
Retention of Records ..................................................................................................60 
18. 
PUBLICATION POLICY ..........................................................................................61 
19. 
LIST OF REFERENCES ............................................................................................62 
 
 
 

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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................12 
Table 3: 
Investigational Product ...............................................................................................36 
Table 4: 
Summary of Clinical Laboratory Analytes .................................................................45 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................27 
 

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Abbreviation 
Definition 
PV 
Pharmacovigilance 
QTcF 
QT corrected according to Fridericia’s formula 
 
 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
t½  
terminal elimination half-life  
TEAE 
treatment-emergent adverse event 
TETRAS 
The Essential Tremor Rating Assessment Scale 
tmax 
time of occurrence of Cmax 
WHO 
World Health Organization 

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5. 
INTRODUCTION 
SAGE-324 is a positive allosteric modulator (PAM) of A-type γ-aminobutyric acid-gated 
chloride channel (GABAA) receptors, the major class of inhibitory neurotransmitter receptors in 
the brain. In addition to being developed as an adjunctive therapy in epilepsy and other seizure 
disorders under IND 139201, SAGE-324 is also being developed for the treatment of Essential 
Tremor (ET). 
Essential tremor is a permanently debilitating, neurologically determined, common movement 
disorder characterized by involuntary rhythmic oscillation of a body part due to intermittent 
muscle contractions typically occurring 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 US, 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 term 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.  
The pharmacological profile of SAGE-324 is theorized to induce therapeutic effect in the 
treatment of ET. Based on preclinical studies of SAGE-324, which features a different 
mechanism of action than that of propranolol, the pharmacokinetic (PK)/ pharmacodynamic (PD) 
profile suggests SAGE-324 may safely ameliorate symptoms in patients suffering from ET, 
regardless of propranolol use. 
There are currently ongoing Phase 1 clinical studies of SAGE-324 in healthy adults and in adults 
with ET. These studies, in addition to preclinical studies of SAGE-324, are detailed in the 
investigator’s brochure. 
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. 
Henceforth, 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 SAGE-324 on a variety of outcome 
measures specific to ET disease characteristics and associated quality of life domains. 
5.1. 
Dose Justification 
The dose of SAGE-324 planned for this study is 60 mg given as oral tablets, to be administered 
once daily in the morning with food. The dose was selected based on preliminary data from 
3 active studies of SAGE-324, which included: unblinded data from completed cohorts in 

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324-CLP-101 Part A (oral solution SAGE-324 doses of 3 mg, 10 mg, 30 mg, 45 mg, 60 mg); 
Part C (oral solution SAGE-324 doses of 30 mg); Part D (oral suspension SAGE-324 doses of 
30 mg) in healthy subjects; and preliminary data from open-label Part E (oral suspension 
SAGE-324 doses of 45 mg and 60 mg) in participants with ET; additional preliminary data from 
324-CLP-102 cohorts 1 through 6 (cohorts 1 to 5 unblinded, cohort 6 blinded), which evaluated 
oral suspension doses ranging from 5 mg to 60 mg; and preliminary unblinded data from 
324-CLP-104, which compared the relative bioavailability of the oral tablet (30 mg) vs oral 
suspension (30 mg) formulations of SAGE-324 and separately the effect of food on the PK of the 
SAGE-324 oral tablet. In 324-CLP-101 and 324-CLP-102 studies, doses were administered in a 
fasted state. The preliminary data from all of these active studies collectively informed the route 
of administration (oral) and dose strength of 60 mg as oral tablets planned for further evaluation 
in this study.  
SAGE-324 was generally well-tolerated in participants with ET and in healthy volunteers, as was 
shown in the preliminary data of 324-CLP-101 Part E at single administration doses of 45 mg 
and 60 mg, and in 324-CLP-102 through once-daily administered doses of up to 60 mg for 
14 days. In addition, tremor reduction was observed at both doses on TETRAS and Kinesia 
accelerometry, with greater improvement seen at 60 mg compared to 45 mg.  
In the clinically complete study 324-CLP-104, preliminary data showed that SAGE-324 oral 
tablets, when coadministered with a meal, resulted in exposures approximately equivalent to that 
of SAGE-324 oral suspension under fasted conditions. Therefore, the SAGE-324 oral tablets are 
recommended to be administered with food. 
5.2. 
Benefit/Risk Assessment 
Based on the mechanism of action of SAGE-324 and the results of completed nonclinical studies 
and preliminary data of currently ongoing clinical studies of SAGE-324, it is theorized that 
participants may have symptomatic amelioration, ie, tremor reduction and possibly improved 
quality of life from potentially stabilizing disease characteristics associated with ET. 
Potential risks anticipated in this study are based on available data from toxicology studies of 
SAGE-324 in addition to preliminary data from 3 ongoing, currently active Phase 1 clinical 
studies of SAGE-324.  
Available preliminary clinical data are summarized in the SAGE-324 Investigator’s Brochure. 
There have been no deaths or SAEs related to IP, and based on the preliminary clinical data 
available, there have been no confirmed clinically significant trends in clinical laboratory 
evaluations, vital signs, or physical examinations.  
Based on available preliminary clinical data from SAGE-324 active clinical studies, AEs of 
somnolence and feeling of relaxation are considered adverse drug reactions. In addition to 
scheduled clinic visits, the current status of study participants will be reviewed via weekly phone 
calls, in between clinic visits. 

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6. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
To assess the effect of SAGE-324 compared 
to placebo on upper limb tremor reduction in 
individuals with essential tremor (ET) after 
28 days of treatment 
Change from baseline compared to placebo in 
The Essential Tremor Rating Assessment 
(TETRAS) performance subscale part 4 upper 
limb tremor score on Day 29 
Secondary 
 
To assess the effect of SAGE-324 compared 
to placebo on overall upper limb tremor 
reduction 
• Change from baseline compared to placebo 
in TETRAS performance subscale part 4 
upper limb tremor score at all other 
timepoints 
• Change from baseline compared to placebo 
in Kinesia ONE accelerometer scores 
To assess the effect of SAGE-324 compared 
to placebo on activities of daily living (ADLs) 
• Change from baseline compared to 
placebo in TETRAS Scale ADL score 
To assess the effect of SAGE-324 compared 
to placebo on overall tremor 
• Change from baseline compared to 
placebo in TETRAS total performance 
score 
To evaluate the safety and tolerability of 
SAGE-324 
• Incidence of treatment-emergent adverse 
events (TEAEs) 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, parallel group study to evaluate the 
efficacy, safety, and tolerability of SAGE-324 in individuals with ET. Participants, site staff, and 
sponsor personnel will be masked to treatment allocation (see Section 9.5). 
This study includes a Screening Period of up to 28 days, a 29-day treatment period consisting of 
28 days of dosing with the end of treatment visit intended to be on Day 29 at trough, and a 
14-day follow-up period relative to final dose (Figure 1). After providing informed consent, 
participants will undergo screening assessments as outlined in Table 2 to determine eligibility.  
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 assessments 
of safety and efficacy, as specified in the Schedule of Assessments (Table 2). Following 
completion of screening and Day 1 eligibility checks, participants will be randomized to 1 of 2 
treatment groups (SAGE-324 60 mg daily, or placebo) in a 1:1 ratio.   
During the double-blind Treatment Period, starting on Day 1, participants will receive a single 
dose of investigational product (IP) once daily in the morning with food for 28 days on an 
outpatient basis. Doses occurring on scheduled clinic visits will be administered in the clinic, and 
doses occurring on all other days will be self-administered by the participant at home as 
specified in Table 2. During the Treatment Period, participants will return to the study center 
approximately once per week for efficacy and safety assessments as specified in Table 2. In 
addition, a phone call will be conducted once per week, preferably mid-way between clinic 
visits, to review current status of the participant. 
In addition to Kinesia ONE-specific training, clinical study center staff and study participants 
will be trained on the use of software applications and devices necessary to complete 
questionnaires or other assessments as required. During in-clinic visits, clinical study center staff 
will be available to assist participants as needed, to ensure they can access and use the software 
applications and devices correctly according to the training. 
During the follow-up period, visits will be conducted on an outpatient basis. In addition to the 
phone calls to review current status, participants will receive a phone call approximately 7 days 
after the last dose of IP (ie, Day 35) for safety monitoring. Participants will return to the study 
center for an end of study visit approximately 14 days following the last dose of IP (ie, Day 42). 
Figure 1: Study Design  
 
Abbreviation:  EOT = end of treatment 

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7.2. 
Number of Participants 
Approximately 60 participants are planned, with approximately 30 participants enrolled per arm, 
to produce 25 evaluable participants per arm for primary efficacy analysis. Additional 
participants may be randomized if the drop-out rate is higher than anticipated (ie, >15%). 
7.3. 
Treatment Assignment 
Participants will be assigned to IP (active or placebo) in accordance with the randomization 
schedule on Day 1. Additional details on randomization and blinding are provided in Section 9.5.  
7.4. 
Dose Adjustment Criteria  
If participants report adverse events that are considered by the investigator to be related to the IP 
and not tolerable, the investigator may reduce the dose of IP from 60 mg in 15 mg decrements 
(ie, 60, to 45, to 30 mg), as medically appropriate. The dose may not be reduced below 30 mg: if 
intolerable adverse events persist at the 30 mg dose, the IP should be permanently stopped. The 
reduced dose of IP will continue to be administered once daily at the same schedule as specified 
in the Schedule of Assessments (Table 2). The dose of IP may not be increased for the remainder 
of the study.  
Otherwise, IP doses will not be further adjusted for this study except as clinically necessary, eg, 
interrupting dose due to an AE or serious adverse event (SAE) considered related to IP. 
7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
participants, or for administrative reasons. In the event of study termination, Sage Therapeutics 
will provide written notification to the investigator. Investigational sites must promptly notify 
their IRB, where required, and initiate withdrawal procedures for participating participants.  

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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 ICF before any study-specific procedures or washout of drugs is 
performed. 
2. Participant is ambulatory and is 18 to 80 years of age, inclusive, at the time informed 
consent is obtained. 
3. 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) 
d. 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 
4. Participant scores at least 1.5 for each of the six items that comprise the combined total 
upper limb TETRAS (total performance subscale part 4) with the total score for the 
dominant upper limb (the sum of the three items for either the right or left upper limb, 
whichever is dominant) being at least 5.5, at both Screening and predose on Day 1. 
5. Participant is willing to discontinue medications taken for the treatment of ET within 
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 29. 
6. Participant is willing to discontinue the use of alcohol and products that contain nicotine 
within at least 1 week prior to Day 1 and through Day 29 of the study. 
7. 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 >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).  
8. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 13 weeks after receiving 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.  
9. Male participant is willing to abstain from sperm donation for the duration of the study 
and for 13 weeks after receiving study drug. 
10. Participant has no clinically significant findings, as determined by the investigator, on 
Screening and predose Day 1 physical examination including mental state examination 
(MSE) and neurologic examination, 12-lead ECG, or screening clinical laboratory tests.  

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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 recent exposure (14 days prior to Day 1) to tremorgenic drugs 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. 
5. Participant has historical or clinical evidence of tremor with psychogenic origin 
(including but not limited to eating disorders, major depression, etc.) 
6. Participant has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic 
(hypothyroidism with stable thyroid replacement is acceptable), or oncological disease. 
7. Participant has history of substance abuse prior to Screening or has a positive screen for 
drugs of abuse at Screening or predose on Day 1 or has a positive screen for alcohol 
predose on Day 1. 
8. Participant has a known allergy to SAGE-324 or any excipient.  
9. Participant has had exposure to another investigational drug or device within 30 days or 5 
half-lives (if known) of the investigational drug, whichever is longer, prior to the Day 1 
visit. 
10. Participant has history or suicidal behavior within 2 years or answers “YES” to questions 
3, 4, or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk or suicide in the 
opinion of the investigator 
11. Participant has donated one 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.  
12. 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. 
13. Participant is unwilling or unable to comply with study procedures and required training. 
14. 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. Use of mild 
cytochrome inhibitors and/or inducers may be permitted.  
15. Participant has concurrent or recent exposure (14 days or 5 half-lives, whichever is 
longer, prior to the Day 1 visit) to sedative/hypnotic drugs, stimulants, highly caffeinated 

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beverages or dietary supplements containing high doses of caffeine, or recent increase 
above regular daily consumption of caffeine. 
16. Participant plans to undergo elective surgery or relocate during participation in the study. 
17. Participant is investigative site personnel or a member of their immediate families 
(spouse, parent, child or sibling whether biological or legally adopted).  
18. Participant currently uses or has used within 14 days or 5 half-lives (whichever is longer) 
prior to Day 1, any prescription or over-the-counter medication that is a substrate of the 
OATP1B1 transporter. 
19. Female participant has a positive pregnancy test or confirmed pregnancy. 
8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned IP or entered in the study, ie, a participant who does not meet 1 or 
more of the eligibility criteria after providing consent and prior to randomization (Day 1). 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. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
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 EOT visit, the safety phone call 7 days later, and then, after a 
further 7 days, the End of Study/Early Termination visit (EOS/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 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 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. 

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8.4.2. 
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 for safety, behavioral, compliance, 
or administrative reasons.  
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.  
If a participant is persistently noncompliant, the investigator should discuss with the sponsor the 
potential discontinuation of the participant. Any reasons for unwillingness or inability to adhere 
to the protocol must be recorded in the participant’s eCRF, including: 
• missed visits; 
• interruptions in the schedule of study drug administration; 
• non-permitted medications 
If the participant withdraws from the study after completing 28 days of dosing with IP, they will 
be encouraged to attend follow-up visits for safety assessments at Day 35 and Day 42, as 
specified in the Schedule of Assessments (Table 2). If the participant withdraws their consent to 
collect protected health information, the EOS/ETV visit will be conducted and the participant 
will be permanently discontinued from the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been unsuccessful.  
8.4.4. 
Replacement of Participants 
Participants will not be replaced. 

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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Product 
SAGE-324 is an orally administered tablet provided in 5 mg or 15 mg (when available) dose 
strengths. Participants will receive IP (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 through the first dose of 
IP will be recorded.  
All medications and/or supplements taken from the first dose of IP through the Day 42 (±1 days) 
visit (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:  
• 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.  
• Use of tremorgenic drugs within the 14 days or 5 half-lives (whichever is longer) of 
Day 1 or during the study. 
• Use of agents known to affect SAGE-324 drug metabolism (any known cytochrome 
P450 3A4 inhibitors and/or inducers) within the 14 days or 5 half-lives (whichever is 
longer) of Day 1 and through Day 29 of the study period. Use of mild cytochrome P 
inhibitors and/or inducers may be permitted. 
• Concomitant use of any prescription or over-the-counter medication that is a substrate 
of the OATP1B1 transporter for 14 days or 5 half-lives prior to Day 1 and during the 
28-day dosing period. 
• Concomitant use of sedative/hypnotic drugs for 14 days or 5 half-lives prior to Day 1 
and during the 28-day dosing period. 
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. 

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• Use of alcohol within 1 week prior to Day 1 and through Day 29 of the study period 
is prohibited. If the alcohol test is positive on Days 1, 8, 15, 22, or 29, the participant 
will not be administered further IP and will be withdrawn from the study; no further 
efficacy assessments such as TETRAS will be undertaken. 
• Use of products that contain nicotine within 1 week prior to Day 1 and through 
Day 29 of the study period is prohibited. Positive cotinine testing on Days 1, 8, 15, 
22, or 29 would be considered a major protocol deviation and the participant will be 
excluded from the Per Protocol Analysis Set. 
• 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 29 of the study period is prohibited.  
• Use of stimulants, highly caffeinated beverages or dietary supplements containing 
high doses of caffeine within 14 days prior to the Day 1 visit and through Day 29 of 
the study period is prohibited. Note: participants should not increase their regular 
daily consumption of caffeine during the study period. 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation  
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal ligation or bilateral tubal occlusion (performed at least 3 months prior 
to Screening) 
• Vasectomized partner (performed at least 3 months prior to Screening) 
• Sexual abstinence (no sexual intercourse) 
Acceptable forms of contraception for male participants include: 
• Sexual abstinence (no sexual intercourse) 
• History of vasectomy (performed at least 3 months prior to Screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
9.3. 
Intervention after the End of the Study 
There is no planned intervention following the end of the study. 

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9.4. 
Treatment Adherence 
The first dose of IP will be received and administered by participants in the clinic. Participants 
will be dispensed a 7-day supply of IP to orally self-administer at home with instructions 
specifying to administer in the morning with food. 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 10.6. 
Patients will be asked to record the dates and times of their IP dose administrations at home in a 
diary. They will also record details around how well they complied with the study instructions 
for self-administering IP at home. 
9.5. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Participants will be randomized in 
a 1:1 ratio to treatment groups (SAGE-324, 60 mg or placebo). Participants, site staff, and the 
sponsor will be blinded to treatment allocation. 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 Sage prior to unblinding the study 
treatment administered to a participant. Requests from the investigator about the treatment 
administered to study participants should be discussed with the Sage Medical Monitor. If the 
unblinding occurs without Sage’s knowledge, the investigator must notify Sage within 24 hours 
of breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records.  
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and on the 
eCRF.  
If a participant or any study personnel become unblinded to treatment, the participant will be 
excluded from the Per Protocol analysis set, as detailed further in the statistical analysis plan. 

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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
Table 3: 
Investigational Product 
 
Investigational Product 
Product Name: 
SAGE-324 
Placebo 
Dosage Form: 
Tablet 
Tablet 
Tablet Strength 
5 mg, 15 mg 
0 mg, appearance-matched to 
5 mg, and 15 mg, respectively 
Route of Administration 
Oral 
Oral 
Physical Description 
Immediate release white to off-
white, round, film-coated tablet 
containing 5 mg or 15 mg of 
SAGE-324 drug substance, and 
composed of 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 
SAGE-324 Oral Tablets and Placebo Tablets will be packaged in blinded, high density 
polyethylene (HDPE) containers. The containers used for SAGE-324 and placebo will be 
identical in appearance. The package labeling conforms to FDA and GMP 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. Any 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, 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 in the clinic or at home as specified in the Schedule of Assessments 
(Table 2). The IP will be provided as tablets, sufficient in number to achieve a dose of 60 mg. IP 
will be orally administered once daily in the morning, with food. Patients will be instructed to 
take the IP with food that comprises a minimum of 400 calories. 
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. 
The designated site staff will dispense the supplied participant-specific kits to participants at the 
planned dispensation visit intervals outlined in the Schedule of Assessments (Table 2). 
An interactive response technology (IRT) will be used to capture participant-identifying 
information. The IRT will be used to randomize the eligible participant into the study and 
provides the kit number of the IP to be dispensed to that participant.  
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 tablets will be returned to Sage Therapeutics for 
destruction or destroyed locally per the site’s procedures; disposition of IP will be documented. 
IP may not be destroyed until accountability and reconciliation procedures have been completed 
and monitored. 
10.7. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution.  
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1 and in 

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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 ASSESSMENTS AND CLINICAL PHARMACOLOGY 
ASSESSMENTS 
11.1. 
Efficacy Assessments 
11.1.1. 
The Essential Tremor Rating Assessment Scale 
TETRAS is a validated, comprehensive clinical assessment of essential tremor (Elble 2013).  
Three different components of TETRAS will be assessed in this study. The TETRAS ADL 
subscale, total performance score, and performance subscale part 4 upper limb tremor score will 
each be separately assessed at each clinic visit as specified in the Schedule of Assessments 
(Table 2). 
The ADL subscale assesses how ET is impacting 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). The overall ADL score range is 0 to 48. 
The total performance score is based on overall rating of tremor amplitude in the voice, limbs, 
head, face, trunk, while performing pre-specified 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 the performance subscale part 4 upper limb tremor score, all 3 maneuvers in the upper limb 
assessments of part 4 (subscale items 4a, 4b, and 4c) will be completed for both arms, first for 
the left arm and then for the right. The part 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. 
In this study, a videographer will videotape each TETRAS administration. 
11.1.2. 
Kinesia ONE™ Accelerometer Score 
Kinesia ONE™ is an ISO-certified wireless motion sensor worn distally on the index finger, 
which utilizes 3 orthogonal accelerometers and 3 orthogonal gyroscopes to monitor 
3-dimensional motion. Data is transmitted wirelessly from the sensor to a Bluetooth technology-
enabled device to use with the Kinesia ONE software (eg, Apple iPad or similar device with 
preinstalled Kinesia ONE software). The device has received FDA clearance. 
Via the Kinesia ONE software application, measures of 3-dimensional motion are converted to 
scores ranging from 0 to 4, per assessed maneuver; higher scores indicate greater tremor severity. 
Motion in both arms is captured. 
Participants will complete this assessment at each clinic visit as specified in the Schedule of 
Assessments (Table 2).  

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11.3. 
Other Patient-Reported Assessments 
11.3.1. 
Patient Perception of Response Burden 
The Patient Perception of Response Burden Questionnaire is a patient-reported measure that 
assesses the multidimensional construct of response burden (Atkinson 2019). 
Participants respond to 6 items assessing 1) how well the questions related to their actual 
concerns, 2) how comfortable the participants were with answering the questions, 3) how well 
the survey characterized their health and well-being, 4) the length of time to complete the 
questionnaires, 5) whether questions seemed unimportant or repetitive, and 6) what additional 
information should have been gathered. Items 1 to 3 are assessed on a 0 to 10 scale, item 4 is 
assessed on a 1 to 3 scale, and items 5 and 6 are open-ended. Items 1 and 4 are reverse scored. A 
composite score can be calculated to create a weighted representative index of relevance, 
comfort, and well-being relative to time to completion (ie, items 1, 2, and 3 were summed and 
multiplied by item 4) for a range of 0 to 72, with higher scores indicative of elevated endorsed 
response burden. The open-ended items will be summarized thematically. The Patient Perception 
of Response Burden Questionnaire will be performed as specified in the Schedule of 
Assessments (Table 2). 
 

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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, ethnicity) and a full medical history will be 
documented. Whether the participant is left-handed or right-handed will be recorded. This must 
also additionally include participant recall of history of ET, disease duration, past treatments 
used, and responsiveness to alcohol and/or other treatments with use intended as off-label 
treatment of ET (eg, primidone or similar therapies). 
12.1.2. 
Weight and Height 
Height and weight will be measured and documented. Body mass index (BMI) will be calculated 
and documented.  
12.1.3. 
Physical Examination 
Whenever possible, the same individual should perform all physical examinations. Physical 
examinations will include assessment of body systems (eg, head, eye, ear, nose and throat; heart; 
lungs; abdomen; and extremities) as well as cognitive and neurological examination and MSE. 
Unscheduled physical examinations may also be conducted per the Investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by an investigator as abnormal, not 
clinically significant (NCS); or abnormal, clinically significant (CS) in source documents.  
12.1.4. 
Vital Signs 
Vital signs comprise blood pressure and heart rate (supine and standing), respiratory rate, and 
temperature. Systolic and diastolic blood pressure and heart rate are to be measured after the 
participant has been supine for at least 5 minutes and then repeated 1 minute and 3 minutes after 
standing.  
Vital signs are measured once at each timepoint with the exception of predose on Day 1, when 
blood pressure and heart rate are measured supine and standing in triplicate at least 15 minutes 
apart. 
Any abnormality in vital signs will be interpreted by an Investigator as abnormal, NCS; or 
abnormal, CS in source documents. 
12.1.5. 
Electrocardiogram 
A 12-lead ECG will be performed. The standard intervals (heart rate, PR, QRS, QT, and QTcF) 
as well as any rhythm abnormalities will be recorded. 
Electrocardiograms will be performed after the participant has been resting in a supine position 
for at least 5 minutes. When ECG measurements coincide with safety assessments, vital signs 
assessment or blood draws, procedures should be carried out in said order (vital signs, ECG, 
blood draw). 

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All abnormal ECGs will be interpreted by an investigator as abnormal, NCS, or abnormal, CS in 
source documents. 
12.1.6. 
Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected. Analytes to be 
evaluated are summarized in Table 4. 
Table 4: 
Summary of Clinical Laboratory Analytes 
Biochemistry 
Renal Panel: glucose, calcium, phosphorus, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate 
Hepatic Panel: albumin, ALT, AST, total bilirubin, direct bilirubin, indirect 
bilirubin, alkaline phosphatase, total protein, lactate dehydrogenase, gamma 
glutamyl transferase 
Other: triglycerides, cholesterol (low density lipoprotein [LDL], high density 
lipoprotein [HDL]), creatine phosphokinase, thyroid stimulating hormone (TSH) 
Coagulation 
activated partial thromboplastin time, prothrombin time, and international 
normalized ratio 
Hematology 
red blood cell count, hemoglobin, hematocrit, white blood cell count with 
differential, platelet count, and if red blood count indices are abnormal, reflex red 
blood cell morphology as indicated 
Urinalysis 
protein, glucose, pH, blood, leukocyte esterase, urobilinogen, bilirubin, ketones, 
nitrite 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, NCS; or abnormal, CS in source documents. 
Follicle stimulating hormone testing will be conducted to confirm whether a participant with 
≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being 
postmenopausal (Section 8.1). 
12.1.6.1. Drugs of Abuse, Alcohol, Nicotine (Cotinine) 
A urine sample will be collected for assessment of the following selected drugs of abuse per the 
Schedule of Assessments (Table 2): amphetamines, barbiturates, benzodiazepines, 
cannabinoids/THC, cocaine, methadone, MDMA, methamphetamines, opiates, oxycodone, 
tricyclic antidepressants, and PCP. 
Urine samples will be collected and tested for cotinine. Either urine dipstick or breathalyzer will 
be used for alcohol testing. 
12.1.6.2. Pregnancy Screen 
A serum pregnancy test will be conducted for all female participants at Screening; subsequently, 
a urine pregnancy test will be conducted for all participants of childbearing potential as specified 
in the Schedule of Assessments (Table 2).  

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• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
Investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Definition of Adverse Events of Special Interest 
There are no known adverse events of special interest as of the date of signature approval of this 
clinical protocol. 
12.2.4. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP.  
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
alternative explanation for the AE 
Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE 
12.2.5. 
Recording Adverse Events 
AEs spontaneously reported by the participant and/or in response to an open question from the 
study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
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)  

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• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized  
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.6. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage or designee.  
Additional follow-up information, if required or available, should all be sent to Sage or designee 
within 24 hours of receipt on a follow-up SAE report form and placed with the original SAE 
information and kept with the appropriate section of the eCRF and/or study file. 
SAEs occurring after the designated follow up time for the study, should be reported to Sage or 
designee according to the timelines noted above only if the investigator considers the SAE 
related to IP.  
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/EC 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. Each site is responsible for notifying its 
IRB of all SUSARs.  
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARs to investigators in a blinded fashion. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 
pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy. The investigator will also attempt to collect pregnancy information on any 
participant’s partner who becomes pregnant after the participant has received the first 

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administration of IP. After obtaining the necessary signed informed consent from the pregnant 
partner directly, the investigator will follow the same pregnancy reporting procedures specified 
for pregnant participants.  
The participant or participant’s partner will be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies (eg, spontaneous abortion, elective abortion, normal 
birth) must be followed and documented even if the participant was discontinued from the study. 
The investigator will collect follow-up information on the participant or participant’s partner and 
the neonate, and the information will be forwarded to Sage or designee. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, preeclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death), the investigator should follow the procedures 
for reporting an SAE.  
12.4. 
Overdose 
An overdose is any dose of study treatment given to a participant or taken by a participant that 
exceeds more than one extra tablet within 24 hours as described in protocol. Overdoses are not 
considered AEs and should not be recorded as an AE on the eCRF; however, all overdoses must 
be recorded on an overdose form and sent to Sage or designee within 24 hours of the site 
becoming aware of the overdose. An overdose must be reported to Sage or designee even if the 
overdose does not result in an AE. If an overdose results in an AE, the AE must be recorded.  

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13. 
STATISTICS 
Detailed description of the analyses to be performed in the study will be provided in the 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to database lock. 
Any changes or 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 will include all participants who are randomized.  
The Safety Set will include all participants 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 TETRAS performance subscale part 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. Note that a positive cotinine test on Days 1, 8, 15, 22 or 29 constitutes a 
major protocol deviation. 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All participants will be used in the analyses, 
as per the analysis populations, using all nonmissing data available. No imputation process will 
be used to estimate missing data.  
13.3. 
General Considerations 
All participant data, including those that are derived, that support the tables and figures will be 
presented in 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. Participants will be summarized according to treatment received. 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to receipt of IP.  
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. 
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 using the Safety Set.  

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Pregnancy test results and drug screen results will be listed but not summarized.  
Medical history will be listed by participant.  
13.5. 
Efficacy Analysis  
The estimand for the primary efficacy analysis is the treatment difference between SAGE-324 
and placebo in mean change from baseline in clinic-based TETRAS performance subscale part 4 
upper limb tremor  scores at Day 29 based on the Full Analysis Set. This will be analyzed using a 
mixed effects model for repeated measures (MMRM); the model will include treatment, baseline 
TETRAS performance subscale part 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. The main comparison 
will be between SAGE-324 and placebo at the 29-day timepoint. Model-based point estimates 
(ie, least squares means, 5% confidence intervals, and p-values) will be reported where 
applicable. An unstructured covariance structure will be used to model the within-subject errors. 
If there is a convergence issue with the unstructured covariance model, Toeplitz compound 
symmetry 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 UN, the sandwich 
estimator for the variance covariance matrix will be derived, using the EMPIRICAL option in 
the PROC MIXED statement in SAS. 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in TETRAS total performance scores, Kinesia ONE 
accelerometer scores and TETRAS ADL scores.  
Other efficacy analyses will be specified in the SAP. In general, data will be analyzed using 
appropriate descriptive statistics or prespecified statistical methods as applicable; participant 
listings will be provided for all efficacy data. Participants will be analyzed according to 
randomized treatment for the purpose of efficacy unless otherwise specified. 
Sensitivity analyses will be described in the SAP. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-324 will be evaluated by AEs, concomitant medication usage, 
 
 
 Safety data will be listed by participant and summarized by treatment group. All 
safety summaries will be performed on the Safety Set using treatment received.  
13.6.1. 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 22.1 
or higher. A treatment-emergent adverse event (TEAE) is defined as an AE with onset after the 
first dose of IP. The analysis of AEs will be based on the concept of TEAEs. The incidence of 
TEAEs will be summarized by System Organ Class (SOC) and preferred term. In addition, 
summaries will be provided by intensity (mild, moderate, severe) and by causality (related, not 
related) to IP.  

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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.  
13.6.3. 
Physical Examinations 
The occurrence of a physical examination, including MSE, (yes/no) and the date performed will 
be listed by participant. 
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
All medications taken within 30 days prior to informed consent through the duration of the study 
will be recorded. In addition, all psychotropic medications taken in the previous 30 days prior to 
screening will be recorded. Those medications taken prior to the initiation of the start of IP will 
be denoted “Prior”. Those medications taken prior to the initiation of the IP and continuing 
beyond the initiation of the IP or those medications started at the same time or after the initiation 
of the IP will be denoted “Concomitant”.  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by participant, start date, and 
verbatim term.  

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13.8. 
Sample Size and Power 
The sample size of this study is based on the assumption of a 3 points difference in the change 
from baseline TETRAS performance subscale part 4 upper limb tremor score between 
SAGE-324 and placebo with a standard deviation of 3.5 points. Under these assumptions, a 
sample size of 25 evaluable participants per group would provide 85% power for detecting a 
placebo-adjusted treatment difference of 3 points in TETRAS performance subscale part 4 upper 
limb tremor score assuming a 2-sided test at an alpha level of 0.05. By including 2 treatment 
groups and using a 1:1 randomization, a total of 50 evaluable participants are required. Assuming 
a nonevaluability rate of 15%, approximately 60 participants will be randomized. Additional 
participants may be enrolled if the dropout rate is greater than 15%. 
13.8.1. 
Interim and Data Monitoring Committee (DMC) Analyses 
13.8.1.1. Interim Analysis 
The sponsor may conduct an interim analysis. Detailed descriptions of planned data analyses will 
be provided in a separate interim statistical analysis plan (SAP), if applicable. 

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13.8.1.2. DMC Analysis 
Not applicable 

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

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

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

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be given a written and 
dated approval or favorable opinion by an IRB or EC as appropriate. The investigator must 
obtain and document approval before he or she can enroll any participant into the study. The IRB 
or EC must supply to the sponsor a list of the IRB/EC membership and a statement to confirm 
that the IRB/EC is organized and operates according to GCP and applicable laws and 
regulations. 
The principal investigator is responsible for informing the IRB or EC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or EC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or EC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or EC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the IP. Sage 
Therapeutics will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or EC according to local regulations and guidelines. In addition, the principal investigator must 
inform the IRB/EC and sponsor of any changes significantly affecting the conduct of the trial 
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 trial 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 trial, the participant (or the participant’s, parent 
or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source records. The investigator must maintain 
the original, signed ICF. A copy of the signed ICF must be given to the participant or to the 
participant’s parent or legally authorized representative. 
Throughout the trial participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 
documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 

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

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18. 
PUBLICATION POLICY 
All information concerning SAGE-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. 

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Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 3 
CONFIDENTIAL 
63 
Olanow CW. Hyperkinetic Movement Disorders: Essential Tremor. In: Harrison's Principles of 
Internal Medicine. Vol 2. 17th ed. New York, NY: McGraw Hill; 2008:2560. 
 
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. Epub 2012 
Aug 11. Review. Erratum in: J Neurol. 2013 Mar;260(3):741. 

 
1. 
TITLE PAGEA PHASE 2, DOUBLE-BLIND, PLACEBO-
CONTROLLED, RANDOMIZED STUDY EVALUATING 
THE EFFICACY, SAFETY, AND TOLERABILITY OF 
SAGE-324 IN THE TREATMENT OF INDIVIDUALS 
WITH ESSENTIAL TREMOR  
324-ETD-201  
 
Investigational Product 
SAGE-324 Oral Tablet  
Clinical Phase 
Phase 2  
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
, MD 
Sponsor Medical Monitor 
, MD, PhD 
Date of Original Protocol 
23 October 2019 
Date of Amendment 1 
20 December 2019 
Date of Amendment 2 
24 February 2020 
Date of Amendment 3 
10 June 2020 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee. 
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from Sage Therapeutics, Inc. 
 

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Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
3 
INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-324. I have read the 324-ETD-
201 protocol and agree to conduct the study as outlined. I agree to maintain the confidentiality of 
all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY) 

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Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
5 
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, Placebo-controlled, Randomized Study Evaluating the Efficacy, Safety, and 
Tolerability of SAGE-324 in the Treatment of Individuals with Essential Tremor  
Number of Sites and Study Location: This study will take place at approximately 30 sites in the 
United States. 
Phase of Development: Phase 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 71 days. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To assess the effect of SAGE-324 compared to 
placebo on upper limb tremor reduction in 
individuals with essential tremor (ET) after 
28 days of treatment 
Change from baseline compared to placebo in 
The Essential Tremor Rating Assessment 
(TETRAS) performance subscale part 4 upper 
limb tremor score on Day 29 
Secondary 
 
To assess the effect of SAGE-324 compared to 
placebo on overall upper limb tremor reduction 
• Change from baseline compared to placebo in 
TETRAS performance subscale part 4 upper 
limb tremor score at all other timepoints 
• Change from baseline compared to placebo in 
Kinesia ONE accelerometer scores 
To assess the effect of SAGE-324 compared to 
placebo on activities of daily living (ADLs) 
• 
Change from baseline compared to placebo in 
TETRAS Scale ADL score 
To assess the effect of SAGE-324 compared to 
placebo on overall tremor 
• 
Change from baseline compared to placebo in 
TETRAS total performance score 
To evaluate the safety and tolerability of 
SAGE-324 
• 
Incidence of treatment-emergent adverse 
events (TEAEs) 
 
 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
6 
Study Description: 
This is a randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy, 
safety, and tolerability of SAGE-324 in individuals with ET. Participants, site staff, and sponsor 
personnel will be masked to treatment allocation. 
This study includes a Screening Period of up to 28 days, a 29-day treatment period (28 days of dosing), 
and a 14-day follow up period. After providing informed consent, participants will undergo screening 
assessments as outlined in Table 2 to determine eligibility.  
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). Following completion of screening 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
7 
and Day 1 eligibility checks, participants will be randomized to 1 of 2 treatment groups (SAGE-324 60 
mg daily, or placebo) in a 1:1 ratio.   
Double-Blind Treatment Period: Starting on Day 1, participants will receive a single dose of 
investigational product (IP) once daily for 28 days on an outpatient basis, to be taken in the morning 
with food that comprises a minimum of 400 calories. Doses occurring on scheduled clinic visits will be 
administered in the clinic, and doses occurring on all other days will be self-administered by the 
participant at home. During the Treatment Period, participants will return to the study center 
approximately once per week for efficacy and safety assessments as specified in Table 2. Participants 
will be trained on the use of software applications and devices necessary to complete questionnaires or 
other assessments. During the study, a phone call will be conducted once per week, preferably midway 
between clinic visits, to review current status of participant. 
Follow-Up Period: Follow-up visits will be conducted on an outpatient basis. Participants will continue 
to complete questionnaires as indicated in Table 2 and will receive a phone call approximately 7 days 
after the last dose of IP (ie, Day 35) for safety monitoring. Participants will return to the study center for 
an end of study visit approximately 14 days following the last dose of IP (ie, Day 42). 
Number of Participants (planned): Approximately 60 participants, with approximately 30 per arm. 
Eligibility Criteria:  
Inclusion Criteria: 
1. Participant has signed an ICF before any study-specific procedures or washout of drugs is 
performed. 
2. Participant is ambulatory and is 18 to 80 years of age, inclusive, at the time informed consent is 
obtained. 
3. 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) 
d. 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 
4. Participant scores at least 1.5 for each of the six items that comprise the combined total upper 
limb TETRAS (total performance subscale part 4) with the total score for the dominant upper 
limb (the sum of the 3 items for either the right or left upper limb, whichever is dominant) 
being at least 5.5, at both Screening and predose on Day 1. 
5. Participant is willing to discontinue medications taken for the treatment of ET within 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 29. 
6. Participant is willing to discontinue the use of alcohol and products that contain nicotine within 
at least 1 week prior to Day 1 and through Day 29 of the study. 
7. 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 
>40 mIU/mL), and/or surgically sterile (bilateral oophorectomy, hysterectomy, and/or bilateral 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
8 
salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy (does 
include abstinence).  
8. Male participant agrees to use an acceptable method of effective contraception for the duration 
of the study and for 13 weeks after receiving 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.  
9. Male participant is willing to abstain from sperm donation for the duration of the study and for 
13 weeks after receiving study drug. 
10. Participant has no clinically significant findings, as determined by the investigator, on 
Screening and predose Day 1 physical examination including mental state examination (MSE) 
and neurologic examination, 12-lead ECG, or screening clinical laboratory tests.  
Exclusion Criteria: 
1. Participant has presence of known causes of enhanced physiological tremor. 
2. Participant has had recent exposure (14 days prior to Day 1) to tremorgenic drugs 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. 
5. Participant has historical or clinical evidence of tremor with psychogenic origin (including but 
not limited to eating disorders, major depression, etc.) 
6. Participant has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic (hypothyroidism with 
stable thyroid replacement is acceptable), or oncological disease. 
7. Participant has history of substance abuse prior to Screening, has a positive screen for drugs of 
abuse at Screening or predose on Day 1, or has a positive screen for alcohol predose on Day 1. 
8. Participant has a known allergy to SAGE-324 or any excipient.  
9. Participant has had exposure to another investigational drug or device within 30 days or 5 half-
lives (if known) of the investigational drug, whichever is longer, prior to the Day 1 visit. 
10. Participant has history of suicidal behavior within 2 years or answers “YES” to questions 3, 4, 
or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk of suicide in the opinion of 
the investigator. 
11. Participant has donated one 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.  
12. 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. 
13. Participant is unwilling or unable to comply with study procedures and required training. 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
9 
14. 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. Use of mild cytochrome inhibitors 
and/or inducers may be permitted.  
15. 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. 
16. Participant plans to undergo elective surgery or relocate during participation in the study. 
17. Participant is investigative site personnel or a member of their immediate families (spouse, 
parent, child or sibling whether biological or legally adopted).  
18. [Removed] 
19. Female participant has a positive pregnancy test or confirmed pregnancy. 
Investigational Product Dosage and Mode of Administration:  
SAGE-324 (60 mg) or matched placebo oral tablets will be administered in the clinic or self-
administered once daily, in the morning, at approximately the same time each day, with food that 
comprises a minimum of 400 calories.  
Duration of Treatment:  
Each participant will receive a single dose of SAGE-324 oral tablets or matching placebo administered 
once daily for 28 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 TETRAS performance subscale part 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. 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
10 
Determination of Sample Size 
The sample size of this study is based on the assumption of a 3-point difference in the change from 
baseline TETRAS performance subscale part 4 upper limb tremor scores between SAGE-324 and 
placebo with a standard deviation of 3.5 points. Under these assumptions, a sample size of 25 evaluable 
participants per group would provide 85% power for detecting a placebo-adjusted treatment difference 
of 3 points in TETRAS performance subscale part 4 upper limb tremor score, assuming a 2-sided test at 
an alpha level of 0.05. By including 2 treatment groups and using a 1:1 randomization, a total of 
50 evaluable participants are required. Assuming a nonevaluability rate of 15%, approximately 
60 participants will be randomized. Additional participants may be enrolled if the drop-out rate is higher 
than 15%. 
Analysis of Primary Efficacy Endpoint 
The estimand for the primary efficacy analysis is the treatment difference between SAGE-324 and 
placebo in mean change from baseline in clinic-based TETRAS performance subscale part 4 upper limb 
tremor score at Day 29 based on the Full Analysis Set. This will be analyzed using a mixed-effects 
model for repeated measures (MMRM); the model will include treatment, baseline TETRAS 
performance subscale part 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. The main comparison will be between SAGE-324 and 
placebo at the 29-day timepoint. Model-based point estimates (ie, least squares means, 95% confidence 
intervals, and p-values) will be reported where applicable. An unstructured covariance structure will be 
used to model the within-subject errors. If there is a convergence issue with the unstructured covariance 
model, Toeplitz compound symmetry 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. 
Analysis of Secondary Efficacy Endpoints 
Similar to those methods described above for the primary endpoint, an MMRM will be used to analyze 
of the change from baseline in TETRAS total performance scores, Kinesia ONE accelerometer scores 
and TETRAS ADL scores. Individual items of the TETRAS subscales will be summarized. 
Safety Analysis 
Safety and tolerability of study drug will be evaluated by incidence of TEAEs/serious adverse events, 
 
 
 
 
 
 
Interim Analysis 
The sponsor may conduct an interim analysis. Detailed descriptions of planned data analyses will be 
provided in a separate interim statistical analysis plan (SAP), if applicable.  

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
11 
Table 2: 
Schedule of Assessments 
Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5 (±1) 
Phone 
Call 
8 (±1) 
12 (±1) 
Phone 
Call 
15(±1) 
19 (±1) 
Phone 
Call 
22 (±1) 
26 (±1) 
Phone 
Call 
29 (+1) 
EOT 
 
35 (±1) 
Safety 
Phone Call 
42 (±1) 
EOS/ETV 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X  
(serum; all 
women) 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
 
X  
(urine; 
WOCBP only) 
FSH (postmenopausal 
women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomizationa 
 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol/cotinine screens 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Neurological examination 
including MSEb 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Body height  
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signsc 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
12-Lead ECGd 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Chemistry/hematology/ 
coagulation/urinalysis 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
12 
Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5 (±1) 
Phone 
Call 
8 (±1) 
12 (±1) 
Phone 
Call 
15(±1) 
19 (±1) 
Phone 
Call 
22 (±1) 
26 (±1) 
Phone 
Call 
29 (+1) 
EOT 
 
35 (±1) 
Safety 
Phone Call 
42 (±1) 
EOS/ETV 
Kinesia ONEf 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
TETRASg 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
13 
Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5 (±1) 
Phone 
Call 
8 (±1) 
12 (±1) 
Phone 
Call 
15(±1) 
19 (±1) 
Phone 
Call 
22 (±1) 
26 (±1) 
Phone 
Call 
29 (+1) 
EOT 
 
35 (±1) 
Safety 
Phone Call 
42 (±1) 
EOS/ETV 
Patient Perception of 
Response Burden 
 
 
 
 
 
 
 
 
 
X 
 
X 
Participant trainingh 
X 
X 
 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
X  
 
X 
 
X 
 
X 
 
 
 
 
IP administration 
 
Administered once daily for 28 days 
Not applicable 
AEs/SAEs 
X 
Prior and concomitant 
medication and historyi 
X 
Abbreviations: ADL = activities of daily living; AE = adverse event; 
; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; 
 
; ETV = early termination visit; FSH = follicle stimulating hormone; HIV = human immunodeficiency 
virus; ICF = informed consent form; min = minutes; IP = investigational product; MSE = mental state examination; 
; 
; 
; 
; SAE = serious adverse event; TETRAS = The Essential Tremor Rating Assessment 
Scale; WOCBP = women of childbearing potential 
Notes:  
• 
The suggested order of assessments during clinic visits is: vital signs, TETRAS, Kinesia ONE, ECG, blood sample collection for 
 and clinical 
laboratory assessments, and questionnaires. 
• 
All assessments will be performed predose unless specified in a footnote. 
 
a Randomization will occur on Day 1 after meeting all eligibility criteria. 
b Complete physical examinations (including MSE and comprehensive neurologic examination) should be performed as specified and additionally as clinically 
necessary (see Section 12.1.3).  
c Predose on Day 1, supine and standing blood pressure and heart rate will be collected in triplicate at least 15 minutes apart, measured after the participant has 
been in the supine position for at least 5 minutes and then repeated 1 minute and 3 minutes after standing. Respiratory rate and temperature are collected once 
predose on Day 1. Vital signs will be collected once predose at all other visits. All postdose vital signs will be collected once at approximately 3 hours (±60 
min) after dosing. 
d ECGs will be collected and read centrally. ECGs will be performed predose and approximately 3 hours (±60 min) postdose. All ECGs must be performed after 
the participant has been in a supine position for at least 5 minutes.  

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
14 
e 
 
f Kinesia ONE will be assessed subsequently to TETRAS Performance subscale part 4 upper limb tremor.  
g The TETRAS Performance and TETRAS ADL subscales will be assessed at Screening and predose at each clinic visit. The TETRAS Performance subscale 
part 4 upper limb tremor will be assessed before Kinesia ONE. In addition, on Day 15, the TETRAS Performance subscale will be assessed at 5 and 8 hours 
(±30 min) postdose. A videographer will record each TETRAS administration. 
h Participants will be trained by study personnel on the use of software applications, Investigational Product Diary, and devices necessary for the conduct of the 
study. 
i Prior medications will be recorded during Screening and will include 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. Concomitant medications will be recorded thereafter 
throughout the duration of the study.  
   

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Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
21 
Abbreviation 
Definition 
PV 
Pharmacovigilance 
QTcF 
QT corrected according to Fridericia’s formula 
 
 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
t½  
terminal elimination half-life  
TEAE 
treatment-emergent adverse event 
TETRAS 
The Essential Tremor Rating Assessment Scale 
tmax 
time of occurrence of Cmax 
WHO 
World Health Organization 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4
CONFIDENTIAL 
22 
5.
INTRODUCTION
SAGE-324 is a positive allosteric modulator (PAM) of A-type γ-aminobutyric acid-gated 
chloride channel (GABAA) receptors, the major class of inhibitory neurotransmitter receptors in 
the brain. In addition to being developed as an adjunctive therapy in epilepsy and other seizure 
disorders under IND 139201, SAGE-324 is also being developed for the treatment of Essential 
Tremor (ET). 
Essential tremor is a permanently debilitating, neurologically determined, common movement 
disorder characterized by involuntary rhythmic oscillation of a body part due to intermittent 
muscle contractions typically occurring 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 US, 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 term 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.  
The pharmacological profile of SAGE-324 is theorized to induce therapeutic effect in the 
treatment of ET. Based on preclinical studies of SAGE-324, which features a different 
mechanism of action than that of propranolol, the pharmacokinetic (PK)/ pharmacodynamic (PD) 
profile suggests SAGE-324 may safely ameliorate symptoms in patients suffering from ET, 
regardless of propranolol use. 
There are currently ongoing Phase 1 clinical studies of SAGE-324 in healthy adults and in adults 
with ET. These studies, in addition to preclinical studies of SAGE-324, are detailed in the 
investigator’s brochure. 
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. 
Henceforth, 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 SAGE-324 on a variety of outcome 
measures specific to ET disease characteristics and associated quality of life domains. 
5.1. 
Dose Justification 
The dose of SAGE-324 planned for this study is 60 mg given as oral tablets, to be administered 
once daily in the morning with food. The dose was selected based on preliminary data from 
3 active studies of SAGE-324, which included: unblinded data from completed cohorts in 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
23 
324-CLP-101 Part A (oral solution SAGE-324 doses of 3 mg, 10 mg, 30 mg, 45 mg, 60 mg); 
Part C (oral solution SAGE-324 doses of 30 mg); Part D (oral suspension SAGE-324 doses of 
30 mg) in healthy subjects; and preliminary data from open-label Part E (oral suspension 
SAGE-324 doses of 45 mg and 60 mg) in participants with ET; additional preliminary data from 
324-CLP-102 cohorts 1 through 6 (cohorts 1 to 5 unblinded, cohort 6 blinded), which evaluated 
oral suspension doses ranging from 5 mg to 60 mg; and preliminary unblinded data from 
324-CLP-104, which compared the relative bioavailability of the oral tablet (30 mg) vs oral 
suspension (30 mg) formulations of SAGE-324 and separately the effect of food on the PK of the 
SAGE-324 oral tablet. In 324-CLP-101 and 324-CLP-102 studies, doses were administered in a 
fasted state. The preliminary data from all of these active studies collectively informed the route 
of administration (oral) and dose strength of 60 mg as oral tablets planned for further evaluation 
in this study.  
SAGE-324 was generally well-tolerated in participants with ET and in healthy volunteers, as was 
shown in the preliminary data of 324-CLP-101 Part E at single administration doses of 45 mg 
and 60 mg, and in 324-CLP-102 through once-daily administered doses of up to 60 mg for 
14 days. In addition, tremor reduction was observed at both doses on TETRAS and Kinesia ONE 
accelerometry, with greater improvement seen at 60 mg compared to 45 mg.  
In the clinically complete study 324-CLP-104, preliminary data showed that SAGE-324 oral 
tablets, when coadministered with a meal, resulted in exposures approximately equivalent to that 
of SAGE-324 oral suspension under fasted conditions. Therefore, the SAGE-324 oral tablets are 
recommended to be administered with food. 
5.2. 
Benefit/Risk Assessment 
Based on the mechanism of action of SAGE-324 and the results of completed nonclinical studies 
and preliminary data of currently ongoing clinical studies of SAGE-324, it is theorized that 
participants may have symptomatic amelioration, ie, tremor reduction and possibly improved 
quality of life from potentially stabilizing disease characteristics associated with ET. 
Potential risks anticipated in this study are based on available data from toxicology studies of 
SAGE-324 in addition to preliminary data from 3 ongoing, currently active Phase 1 clinical 
studies of SAGE-324.  
Available preliminary clinical data are summarized in the SAGE-324 Investigator’s Brochure. 
There have been no deaths or SAEs related to IP, and based on the preliminary clinical data 
available, there have been no confirmed clinically significant trends in clinical laboratory 
evaluations, vital signs, or physical examinations.  
Based on available preliminary clinical data from SAGE-324 active clinical studies, AEs of 
somnolence and feeling of relaxation are considered adverse drug reactions. In addition to 
scheduled clinic visits, the current status of study participants will be reviewed via weekly phone 
calls, in between clinic visits. 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
24 
6. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
To assess the effect of SAGE-324 compared 
to placebo on upper limb tremor reduction in 
individuals with essential tremor (ET) after 
28 days of treatment 
Change from baseline compared to placebo in 
The Essential Tremor Rating Assessment 
(TETRAS) performance subscale part 4 upper 
limb tremor score on Day 29 
Secondary 
 
To assess the effect of SAGE-324 compared 
to placebo on overall upper limb tremor 
reduction 
• Change from baseline compared to placebo 
in TETRAS performance subscale part 4 
upper limb tremor score at all other 
timepoints 
• Change from baseline compared to placebo 
in Kinesia ONE accelerometer scores 
To assess the effect of SAGE-324 compared 
to placebo on activities of daily living (ADLs) 
• Change from baseline compared to 
placebo in TETRAS Scale ADL score 
To assess the effect of SAGE-324 compared 
to placebo on overall tremor 
• Change from baseline compared to 
placebo in TETRAS total performance 
score 
To evaluate the safety and tolerability of 
SAGE-324 
• Incidence of treatment-emergent adverse 
events (TEAEs) 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4 
CONFIDENTIAL 
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Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 4
CONFIDENTIAL 
26 
7.
INVESTIGATIONAL PLAN
7.1. 
Overall Study Design
This is a randomized, double-blind, placebo-controlled, parallel group study to evaluate the 
efficacy, safety, and tolerability of SAGE-324 in individuals with ET. Participants, site staff, and 
sponsor personnel will be masked to treatment allocation (see Section 9.5). 
This study includes a Screening Period of up to 28 days, a 29-day treatment period consisting of 
28 days of dosing with the end of treatment visit intended to be on Day 29 at trough, and a 
14-day follow-up period relative to final dose (Figure 1). After providing informed consent,
participants will undergo screening assessments as outlined in Table 2 to determine eligibility.
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 assessments 
of safety and efficacy, as specified in the Schedule of Assessments (Table 2). Following 
completion of screening and Day 1 eligibility checks, participants will be randomized to 1 of 2 
treatment groups (SAGE-324 60 mg daily, or placebo) in a 1:1 ratio.   
During the double-blind Treatment Period, starting on Day 1, participants will receive a single 
dose of investigational product (IP) once daily in the morning with food for 28 days on an 
outpatient basis (see Section 10.5). Doses occurring on scheduled clinic visits will be 
administered in the clinic, and doses occurring on all other days will be self-administered by the 
participant at home as specified in Table 2. During the Treatment Period, participants will return 
to the study center approximately once per week for efficacy and safety assessments as specified 
in Table 2. In addition, a phone call will be conducted once per week, preferably mid-way 
between clinic visits, to review current status of the participant. 
In addition to Kinesia ONE-specific training, clinical study center staff and study participants 
will be trained on the use of software applications and devices necessary to complete 
questionnaires or other assessments as required. During in-clinic visits, clinical study center staff 
will be available to assist participants as needed, to ensure they can access and use the software 
applications and devices correctly according to the training. 
During the follow-up period, visits will be conducted on an outpatient basis. In addition to the 
phone calls to review current status, participants will receive a phone call approximately 7 days 
after the last dose of IP (ie, Day 35) for safety monitoring. Participants will return to the study 
center for an end of study visit approximately 14 days following the last dose of IP (ie, Day 42). 
Figure 1: Study Design 
Abbreviation:  EOT = end of treatment 

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7.2. 
Number of Participants 
Approximately 60 participants are planned, with approximately 30 participants enrolled per arm, 
to produce 25 evaluable participants per arm for primary efficacy analysis. Additional 
participants may be randomized if the drop-out rate is higher than anticipated (ie, >15%). 
7.3. 
Treatment Assignment 
Participants will be assigned to IP (active or placebo) in accordance with the randomization 
schedule on Day 1. Additional details on randomization and blinding are provided in Section 9.5.  
7.4. 
Dose Adjustment Criteria  
If participants report adverse events that are considered by the investigator to be related to the IP 
and not tolerable, the investigator may reduce the dose of IP from 60 mg in 15 mg decrements 
(ie, 60, to 45, to 30 mg), as medically appropriate. The dose may not be reduced below 30 mg: if 
intolerable adverse events persist at the 30 mg dose, the IP should be permanently stopped. The 
reduced dose of IP will continue to be administered once daily at the same schedule as specified 
in the Schedule of Assessments (Table 2). The dose of IP may not be increased for the remainder 
of the study.  
Otherwise, IP doses will not be further adjusted for this study except as clinically necessary, eg, 
interrupting dose due to an AE or serious adverse event (SAE) considered related to IP. 
7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
participants, or for administrative reasons. In the event of study termination, Sage Therapeutics 
will provide written notification to the investigator. Investigational sites must promptly notify 
their IRB, where required, and initiate withdrawal procedures for participating participants.  

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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 ICF before any study-specific procedures or washout of drugs is 
performed. 
2. Participant is ambulatory and is 18 to 80 years of age, inclusive, at the time informed 
consent is obtained. 
3. 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) 
d. 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 
4. Participant scores at least 1.5 for each of the six items that comprise the combined total 
upper limb TETRAS (total performance subscale part 4) with the total score for the 
dominant upper limb (the sum of the three items for either the right or left upper limb, 
whichever is dominant) being at least 5.5, at both Screening and predose on Day 1. 
5. Participant is willing to discontinue medications taken for the treatment of ET within 
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 29. 
6. Participant is willing to discontinue the use of alcohol and products that contain nicotine 
within at least 1 week prior to Day 1 and through Day 29 of the study. 
7. 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 >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).  
8. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 13 weeks after receiving 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.  
9. Male participant is willing to abstain from sperm donation for the duration of the study 
and for 13 weeks after receiving study drug. 
10. Participant has no clinically significant findings, as determined by the investigator, on 
Screening and predose Day 1 physical examination including mental state examination 
(MSE) and neurologic examination, 12-lead ECG, or screening clinical laboratory tests.  

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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 recent exposure (14 days prior to Day 1) to tremorgenic drugs 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. 
5. Participant has historical or clinical evidence of tremor with psychogenic origin 
(including but not limited to eating disorders, major depression, etc.) 
6. Participant has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic 
(hypothyroidism with stable thyroid replacement is acceptable), or oncological disease. 
7. Participant has history of substance abuse prior to Screening or has a positive screen for 
drugs of abuse at Screening or predose on Day 1 or has a positive screen for alcohol 
predose on Day 1. 
8. Participant has a known allergy to SAGE-324 or any excipient.  
9. Participant has had exposure to another investigational drug or device within 30 days or 5 
half-lives (if known) of the investigational drug, whichever is longer, prior to the Day 1 
visit. 
10. Participant has history or suicidal behavior within 2 years or answers “YES” to questions 
3, 4, or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk of suicide in the 
opinion of the investigator. 
11. Participant has donated one 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.  
12. 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. 
13. Participant is unwilling or unable to comply with study procedures and required training. 
14. 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. Use of mild 
cytochrome inhibitors and/or inducers may be permitted.  
15. Participant has concurrent or recent exposure (14 days or 5 half-lives, whichever is 
longer, prior to the Day 1 visit) to sedative/hypnotic drugs, stimulants, highly caffeinated 

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beverages or dietary supplements containing high doses of caffeine, or recent increase 
above regular daily consumption of caffeine. 
16. Participant plans to undergo elective surgery or relocate during participation in the study. 
17. Participant is investigative site personnel or a member of their immediate families 
(spouse, parent, child or sibling whether biological or legally adopted).  
18. [Removed] 
19. Female participant has a positive pregnancy test or confirmed pregnancy. 
8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned IP or entered in the study, ie, a participant who does not meet 1 or 
more of the eligibility criteria after providing consent and prior to randomization (Day 1). 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. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
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 EOT visit, the safety phone call 7 days later, and then, after a 
further 7 days, the End of Study/Early Termination visit (EOS/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 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 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 
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 for safety, behavioral, compliance, 
or administrative reasons.  

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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.  
If a participant is persistently noncompliant, the investigator should discuss with the sponsor the 
potential discontinuation of the participant. Any reasons for unwillingness or inability to adhere 
to the protocol must be recorded in the participant’s eCRF, including: 
• missed visits; 
• interruptions in the schedule of study drug administration; 
• non-permitted medications 
If the participant withdraws from the study after completing 28 days of dosing with IP, they will 
be encouraged to attend follow-up visits for safety assessments at Day 35 and Day 42, as 
specified in the Schedule of Assessments (Table 2). If the participant withdraws their consent to 
collect protected health information, the EOS/ETV visit will be conducted and the participant 
will be permanently discontinued from the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been unsuccessful.  
8.4.4. 
Replacement of Participants 
Participants will not be replaced. 

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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Product 
SAGE-324 is an orally administered tablet provided in 5 mg or 15 mg (when available) dose 
strengths. Participants will receive IP (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 through the first dose of 
IP will be recorded.  
All medications and/or supplements taken from the first dose of IP through the Day 42 (±1 days) 
visit (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:  
• 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.  
• Use of tremorgenic drugs within the 14 days or 5 half-lives (whichever is longer) of 
Day 1 or during the study. 
• Use of agents known to affect SAGE-324 drug metabolism (any known cytochrome 
P450 3A4 inhibitors and/or inducers) within the 14 days or 5 half-lives (whichever is 
longer) of Day 1 and through Day 29 of the study period. Use of mild cytochrome P 
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 28-day dosing period. 
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 within 1 week prior to Day 1 and through Day 29 of the study period 
is prohibited. If the alcohol test is positive on Days 1, 8, 15, 22, or 29, the participant 
will not be administered further IP and will be withdrawn from the study; no further 
efficacy assessments such as TETRAS will be undertaken. 

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• Use of products that contain nicotine within 1 week prior to Day 1 and through 
Day 29 of the study period is prohibited. Positive cotinine testing on Days 1, 8, 15, 
22, or 29 would be considered a major protocol deviation and the participant will be 
excluded from the Per Protocol Analysis Set. 
• 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 29 of the study period is prohibited.  
• Use of stimulants, highly caffeinated beverages or dietary supplements containing 
high doses of caffeine within 14 days prior to the Day 1 visit and through Day 29 of 
the study period is prohibited. Note: participants should not increase their regular 
daily consumption of caffeine during the study period. 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation  
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal ligation or bilateral tubal occlusion (performed at least 3 months prior 
to Screening) 
• Vasectomized partner (performed at least 3 months prior to Screening) 
• Sexual abstinence (no sexual intercourse) 
Acceptable forms of contraception for male participants include: 
• Sexual abstinence (no sexual intercourse) 
• History of vasectomy (performed at least 3 months prior to Screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
9.3. 
Intervention after the End of the Study 
There is no planned intervention following the end of the study. 
9.4. 
Treatment Adherence 
The first dose of IP will be received and administered by participants in the clinic. Participants 
will be dispensed a 7-day supply of IP to orally self-administer at home with instructions 

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specifying to administer in the morning with food. 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 10.6. 
Patients will be asked to record the dates and times of their IP dose administrations at home in a 
diary. They will also record details around how well they complied with the study instructions 
for self-administering IP at home. 
9.5. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Participants will be randomized in 
a 1:1 ratio to treatment groups (SAGE-324, 60 mg or placebo). Participants, site staff, and the 
sponsor will be blinded to treatment allocation. 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 Sage prior to unblinding the study 
treatment administered to a participant. Requests from the investigator about the treatment 
administered to study participants should be discussed with the Sage Medical Monitor. If the 
unblinding occurs without Sage’s knowledge, the investigator must notify Sage within 24 hours 
of breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records.  
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and on the 
eCRF.  
If a participant or any study personnel become unblinded to treatment, the participant will be 
excluded from the Per Protocol analysis set, as detailed further in the statistical analysis plan. 

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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
Table 3: 
Investigational Product 
 
Investigational Product 
Product Name: 
SAGE-324 
Placebo 
Dosage Form: 
Tablet 
Tablet 
Tablet Strength 
5 mg, 15 mg 
0 mg, appearance-matched to 
5 mg, and 15 mg, respectively 
Route of Administration 
Oral 
Oral 
Physical Description 
Immediate release white to off-
white, round, film-coated tablet 
containing 5 mg or 15 mg of 
SAGE-324 drug substance, and 
composed of 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 
SAGE-324 Oral Tablets and Placebo Tablets will be packaged in blinded, high density 
polyethylene (HDPE) containers. The containers used for SAGE-324 and placebo will be 
identical in appearance. The package labeling conforms to FDA and GMP 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. Any 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, 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 in the clinic or at home as specified in the Schedule of Assessments 
(Table 2). The IP will be provided as tablets, sufficient in number to achieve a dose of 60 mg. IP 
will be orally administered once daily in the morning, with food. Participants will be instructed 
to take the IP with food that comprises a minimum of 400 calories, and to take the IP at 
approximately the same time each morning.  
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. 
The designated site staff will dispense the supplied participant-specific kits to participants at the 
planned dispensation visit intervals outlined in the Schedule of Assessments (Table 2). 
An interactive response technology (IRT) will be used to capture participant-identifying 
information. The IRT will be used to randomize the eligible participant into the study and 
provides the kit number of the IP to be dispensed to that participant.  
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 tablets will be returned to Sage Therapeutics for 
destruction or destroyed locally per the site’s procedures; disposition of IP will be documented. 
IP may not be destroyed until accountability and reconciliation procedures have been completed 
and monitored. 
10.7. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution.  
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 

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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 ASSESSMENTS AND CLINICAL PHARMACOLOGY 
ASSESSMENTS 
11.1. 
Efficacy Assessments 
11.1.1. 
The Essential Tremor Rating Assessment Scale 
TETRAS is a validated, comprehensive clinical assessment of essential tremor (Elble 2013).  
Three different components of TETRAS will be assessed in this study. The TETRAS ADL 
subscale, total performance score, and performance subscale part 4 upper limb tremor score will 
each be separately assessed at each clinic visit as specified in the Schedule of Assessments 
(Table 2). 
The ADL subscale assesses how ET is impacting 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). The overall ADL score range is 0 to 48. 
The total performance score is based on overall rating of tremor amplitude in the voice, limbs, 
head, face, trunk, while performing pre-specified 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 the performance subscale part 4 upper limb tremor score, all 3 maneuvers in the upper limb 
assessments of part 4 (subscale items 4a, 4b, and 4c) will be completed for both arms, first for 
the right arm and then for the left. The part 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. 
In this study, a videographer will videotape each TETRAS administration. 
11.1.2. 
Kinesia ONE™ Accelerometer Score 
Kinesia ONE™ is an ISO-certified wireless motion sensor worn distally on the index finger, 
which utilizes 3 orthogonal accelerometers and 3 orthogonal gyroscopes to monitor 
3-dimensional motion. Data is transmitted wirelessly from the sensor to a Bluetooth technology-
enabled device to use with the Kinesia ONE software (eg, Apple iPad or similar device with 
preinstalled Kinesia ONE software). The device has received FDA clearance. 
Via the Kinesia ONE software application, measures of 3-dimensional motion are converted to 
scores ranging from 0 to 4, per assessed maneuver; higher scores indicate greater tremor severity. 
Motion in both arms is captured. 
Participants will complete this assessment at each clinic visit as specified in the Schedule of 
Assessments (Table 2).  

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11.3. 
Other Patient-Reported Assessments 
11.3.1. 
Patient Perception of Response Burden 
The Patient Perception of Response Burden Questionnaire is a patient-reported measure that 
assesses the multidimensional construct of response burden (Atkinson 2019). 
Participants respond to 6 items assessing 1) how well the questions related to their actual 
concerns, 2) how comfortable the participants were with answering the questions, 3) how well 
the survey characterized their health and well-being, 4) the length of time to complete the 
questionnaires, 5) whether questions seemed unimportant or repetitive, and 6) what additional 
information should have been gathered. Items 1 to 3 are assessed on a 0 to 10 scale, item 4 is 
assessed on a 1 to 3 scale, and items 5 and 6 are open-ended. Items 1 and 4 are reverse scored. A 
composite score can be calculated to create a weighted representative index of relevance, 
comfort, and well-being relative to time to completion (ie, items 1, 2, and 3 were summed and 
multiplied by item 4) for a range of 0 to 72, with higher scores indicative of elevated endorsed 
response burden. The open-ended items will be summarized thematically. The Patient Perception 
of Response Burden Questionnaire will be performed as specified in the Schedule of 
Assessments (Table 2). 
 

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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, ethnicity) and a full medical history will be 
documented. Whether the participant is left-handed or right-handed will be recorded. This must 
also additionally include participant recall of history of ET, disease duration, past treatments 
used, and responsiveness to alcohol and/or other treatments with use intended as off-label 
treatment of ET (eg, primidone or similar therapies). 
12.1.2. 
Weight and Height 
Height and weight will be measured and documented. Body mass index (BMI) will be calculated 
and documented.  
12.1.3. 
Physical Examination 
Whenever possible, the same individual should perform all physical examinations. Physical 
examinations will include review of systems (eg, head, eye, ear, nose and throat; heart; lungs; 
abdomen; and extremities) as well as comprehensive neurological examination and MSE. 
Unscheduled physical examinations may also be conducted per the Investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by an investigator as abnormal, not 
clinically significant (NCS); or abnormal, clinically significant (CS) in source documents.  
12.1.4. 
Vital Signs 
Vital signs comprise blood pressure and heart rate (supine and standing), respiratory rate, and 
temperature. Systolic and diastolic blood pressure and heart rate are to be measured after the 
participant has been supine for at least 5 minutes and then repeated 1 minute and 3 minutes after 
standing.  
Vital signs are measured once at each timepoint with the exception of predose on Day 1, when 
blood pressure and heart rate are measured supine and standing in triplicate at least 15 minutes 
apart. 
Any abnormality in vital signs will be interpreted by an Investigator as abnormal, NCS; or 
abnormal, CS in source documents. 
12.1.5. 
Electrocardiogram 
A 12-lead ECG will be performed. The standard intervals (heart rate, PR, QRS, QT, and QTcF) 
as well as any rhythm abnormalities will be recorded. 
Electrocardiograms will be performed after the participant has been resting in a supine position 
for at least 5 minutes. When ECG measurements coincide with safety assessments, vital signs 
assessment or blood draws, procedures should be carried out in said order (vital signs, ECG, 
blood draw). 

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All abnormal ECGs will be interpreted by an investigator as abnormal, NCS, or abnormal, CS in 
source documents. 
12.1.6. 
Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected. Analytes to be 
evaluated are summarized in Table 4. 
Table 4: 
Summary of Clinical Laboratory Analytes 
Biochemistry 
Renal Panel: glucose, calcium, phosphorus, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate 
Hepatic Panel: albumin, ALT, AST, total bilirubin, direct bilirubin, indirect 
bilirubin, alkaline phosphatase, total protein, lactate dehydrogenase, gamma 
glutamyl transferase 
Other: triglycerides, cholesterol (low density lipoprotein [LDL], high density 
lipoprotein [HDL]), creatine phosphokinase, thyroid stimulating hormone (TSH) 
Coagulation 
activated partial thromboplastin time, prothrombin time, and international 
normalized ratio 
Hematology 
red blood cell count, hemoglobin, hematocrit, white blood cell count with 
differential, platelet count, and if red blood count indices are abnormal, reflex red 
blood cell morphology as indicated 
Urinalysis 
protein, glucose, pH, blood, leukocyte esterase, urobilinogen, bilirubin, ketones, 
nitrite 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, NCS; or abnormal, CS in source documents. 
Follicle stimulating hormone testing will be conducted to confirm whether a participant with 
≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being 
postmenopausal (Section 8.1). 
12.1.6.1. Drugs of Abuse, Alcohol, Nicotine (Cotinine) 
A urine sample will be collected for assessment of the following selected drugs of abuse per the 
Schedule of Assessments (Table 2): amphetamines, barbiturates, benzodiazepines, 
cannabinoids/THC, cocaine, methadone, MDMA, methamphetamines, opiates, oxycodone, 
tricyclic antidepressants, and PCP. 
Urine samples will be collected and tested for cotinine. Either urine dipstick or breathalyzer will 
be used for alcohol testing. 
12.1.6.2. Pregnancy Screen 
A serum pregnancy test will be conducted for all female participants at Screening; subsequently, 
a urine pregnancy test will be conducted for all participants of childbearing potential as specified 
in the Schedule of Assessments (Table 2).  

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• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
Investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Definition of Adverse Events of Special Interest 
There are no known adverse events of special interest as of the date of signature approval of this 
clinical protocol. 
12.2.4. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP.  
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
alternative explanation for the AE 
Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE 
12.2.5. 
Recording Adverse Events 
AEs spontaneously reported by the participant and/or in response to an open question from the 
study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
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)  

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• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized  
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.6. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage or designee.  
Additional follow-up information, if required or available, should all be sent to Sage or designee 
within 24 hours of receipt on a follow-up SAE report form and placed with the original SAE 
information and kept with the appropriate section of the eCRF and/or study file. 
SAEs occurring after the designated follow up time for the study, should be reported to Sage or 
designee according to the timelines noted above only if the investigator considers the SAE 
related to IP.  
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/EC 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. Each site is responsible for notifying its 
IRB of all SUSARs.  
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARs to investigators in a blinded fashion. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 
pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy. The investigator will also attempt to collect pregnancy information on any 
participant’s partner who becomes pregnant after the participant has received the first 

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administration of IP. After obtaining the necessary signed informed consent from the pregnant 
partner directly, the investigator will follow the same pregnancy reporting procedures specified 
for pregnant participants.  
The participant or participant’s partner will be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies (eg, spontaneous abortion, elective abortion, normal 
birth) must be followed and documented even if the participant was discontinued from the study. 
The investigator will collect follow-up information on the participant or participant’s partner and 
the neonate, and the information will be forwarded to Sage or designee. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, preeclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death), the investigator should follow the procedures 
for reporting an SAE.  
12.4. 
Overdose 
An overdose is any dose of 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 eCRF; however, all overdoses must be recorded on an overdose form and sent to 
Sage or designee within 24 hours of the site becoming aware of the overdose. An overdose must 
be reported to Sage or designee even if the overdose does not result in an AE. If an overdose 
results in an AE, the AE must be recorded.  

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13. 
STATISTICS 
Detailed description of the analyses to be performed in the study will be provided in the 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to database lock. 
Any changes or 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 will include all participants who are randomized.  
The Safety Set will include all participants 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 TETRAS performance subscale part 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. Note that a positive cotinine test on Days 1, 8, 15, 22 or 29 constitutes a 
major protocol deviation. 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All participants will be used in the analyses, 
as per the analysis populations, using all nonmissing data available. No imputation process will 
be used to estimate missing data.  
13.3. 
General Considerations 
All participant data, including those that are derived, that support the tables and figures will be 
presented in 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. Participants will be summarized according to treatment received. 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to receipt of IP.  
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. 
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 using the Safety Set.  

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Pregnancy test results and drug screen results will be listed but not summarized.  
Medical history will be listed by participant.  
13.5. 
Efficacy Analysis  
The estimand for the primary efficacy analysis is the treatment difference between SAGE-324 
and placebo in mean change from baseline in clinic-based TETRAS performance subscale part 4 
upper limb tremor  scores at Day 29 based on the Full Analysis Set. This will be analyzed using a 
mixed effects model for repeated measures (MMRM); the model will include treatment, baseline 
TETRAS performance subscale part 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. The main comparison 
will be between SAGE-324 and placebo at the 29-day timepoint. Model-based point estimates 
(ie, least squares means, 5% confidence intervals, and p-values) will be reported where 
applicable. An unstructured covariance structure will be used to model the within-subject errors. 
If there is a convergence issue with the unstructured covariance model, Toeplitz compound 
symmetry 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 UN, the sandwich 
estimator for the variance covariance matrix will be derived, using the EMPIRICAL option in 
the PROC MIXED statement in SAS. 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in TETRAS total performance scores, Kinesia ONE 
accelerometer scores and TETRAS ADL scores.  
Other efficacy analyses will be specified in the SAP. In general, data will be analyzed using 
appropriate descriptive statistics or prespecified statistical methods as applicable; participant 
listings will be provided for all efficacy data. Participants will be analyzed according to 
randomized treatment for the purpose of efficacy unless otherwise specified. 
Sensitivity analyses will be described in the SAP. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-324 will be evaluated by AEs, concomitant medication usage, 
 
Safety data will be listed by participant and summarized by treatment group. All 
safety summaries will be performed on the Safety Set using treatment received.  
13.6.1. 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 22.1 
or higher. A treatment-emergent adverse event (TEAE) is defined as an AE with onset after the 
first dose of IP. The analysis of AEs will be based on the concept of TEAEs. The incidence of 
TEAEs will be summarized by System Organ Class (SOC) and preferred term. In addition, 
summaries will be provided by intensity (mild, moderate, severe) and by causality (related, not 
related) to IP.  

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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.  
 
 
 
 
 
  
13.6.3. 
Physical Examinations 
The occurrence of a physical examination, including MSE, (yes/no) and the date performed will 
be listed by participant. 
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
All medications taken within 30 days prior to informed consent through the duration of the study 
will be recorded. In addition, all psychotropic medications taken in the previous 30 days prior to 
screening will be recorded. Those medications taken prior to the initiation of the start of IP will 
be denoted “Prior”. Those medications taken prior to the initiation of the IP and continuing 
beyond the initiation of the IP or those medications started at the same time or after the initiation 
of the IP will be denoted “Concomitant”.  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by participant, start date, and 
verbatim term.  

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13.8. 
Sample Size and Power 
The sample size of this study is based on the assumption of a 3 points difference in the change 
from baseline TETRAS performance subscale part 4 upper limb tremor score between 
SAGE-324 and placebo with a standard deviation of 3.5 points. Under these assumptions, a 
sample size of 25 evaluable participants per group would provide 85% power for detecting a 
placebo-adjusted treatment difference of 3 points in TETRAS performance subscale part 4 upper 
limb tremor score assuming a 2-sided test at an alpha level of 0.05. By including 2 treatment 
groups and using a 1:1 randomization, a total of 50 evaluable participants are required. Assuming 
a nonevaluability rate of 15%, approximately 60 participants will be randomized. Additional 
participants may be enrolled if the dropout rate is greater than 15%. 
13.8.1. 
Interim and Data Monitoring Committee (DMC) Analyses 
13.8.1.1. Interim Analysis 
The sponsor may conduct an interim analysis. Detailed descriptions of planned data analyses will 
be provided in a separate interim statistical analysis plan (SAP), if applicable. 

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13.8.1.2. DMC Analysis 
Not applicable 

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

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

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

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be given a written and 
dated approval or favorable opinion by an IRB or EC as appropriate. The investigator must 
obtain and document approval before he or she can enroll any participant into the study. The IRB 
or EC must supply to the sponsor a list of the IRB/EC membership and a statement to confirm 
that the IRB/EC is organized and operates according to GCP and applicable laws and 
regulations. 
The principal investigator is responsible for informing the IRB or EC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or EC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or EC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or EC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the IP. Sage 
Therapeutics will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or EC according to local regulations and guidelines. In addition, the principal investigator must 
inform the IRB/EC and sponsor of any changes significantly affecting the conduct of the trial 
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 trial 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 trial, the participant (or the participant’s, parent 
or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source records. The investigator must maintain 
the original, signed ICF. A copy of the signed ICF must be given to the participant or to the 
participant’s parent or legally authorized representative. 
Throughout the trial participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 
documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 

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

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18. 
PUBLICATION POLICY 
All information concerning SAGE-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. 

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Olanow CW. Hyperkinetic Movement Disorders: Essential Tremor. In: Harrison's Principles of 
Internal Medicine. Vol 2. 17th ed. New York, NY: McGraw Hill; 2008:2560. 
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. Epub 2012 
Aug 11. Review. Erratum in: J Neurol. 2013 Mar;260(3):741. 

 
1. 
TITLE PAGEA PHASE 2, DOUBLE-BLIND, PLACEBO-
CONTROLLED, RANDOMIZED STUDY EVALUATING 
THE EFFICACY, SAFETY, AND TOLERABILITY OF 
SAGE-324 IN THE TREATMENT OF INDIVIDUALS 
WITH ESSENTIAL TREMOR  
324-ETD-201  
 
Investigational Product 
SAGE-324 Oral Tablet  
Clinical Phase 
Phase 2  
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
  
Phone: 
e-mail: 
 
Sponsor Medical Monitor 
, MD, PhD 
Date of Original Protocol 
23 October 2019 
Date of Amendment 1 
20 December 2019 
Date of Amendment 2 
24 February 2020 
Date of Amendment 3 
10 June 2020 
Date of Amendment 4 
17 December 2020 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee. 
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from Sage Therapeutics, Inc. 
 

Clinical Protocol 
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324-ETD-201, Version 5 
CONFIDENTIAL 
2 
SPONSOR APPROVAL 
 
 
Protocol Number: 
324-ETD-201 
Study Title: 
A Phase 2, Double-Blind, Placebo-Controlled, 
Randomized Study Evaluating the Efficacy, 
Safety, and Tolerability of SAGE-324 in the 
Treatment of Individuals with Essential Tremor 
Protocol Version and Date: 
Version 5, 17 December 2020  
 
 
 
 
 
_______________________________________________ ___________________________ 
Date 
 
 
 
 
 
_______________________________________________ ___________________________ 
, MD 
Date  
  
 
 
 
 
 
_______________________________________________ ___________________________ 
 MD 
Date  
 
 
 
DocuSign Envelope ID: F888EA4C-1D59-4EE2-89C0-33D8C6E572C6
18-Dec-2020 | 09:49 EST
18-Dec-2020 | 13:32 EST
17-Dec-2020 | 14:43 EST

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_______________________________________________ ___________________________ 
Date  
 
 
 
 
 
_______________________________________________ ___________________________ 
, PhD 
Date  
 
 
 
 
 
 
______________________________________________ ___________________________ 
, PhD 
Date  
 
 
 
 
 
 
______________________________________________ ___________________________ 
 
Date 
 
DocuSign Envelope ID: F888EA4C-1D59-4EE2-89C0-33D8C6E572C6
17-Dec-2020 | 14:19 EST
17-Dec-2020 | 15:19 EST
18-Dec-2020 | 12:07 EST
17-Dec-2020 | 14:16 EST

C ertifi c at e Of C o m pl eti o n
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( R e q uir e d)
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Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 1 7- D e c- 2 0 2 0 | 1 4: 0 8
R e s e nt: 1 8- D e c- 2 0 2 0 | 1 2: 0 4
Vi e w e d: 1 8- D e c- 2 0 2 0 | 1 2: 0 7 
Si g n e d: 1 8- D e c- 2 0 2 0 | 1 2: 0 7

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CONTACT INFORMATION 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sage Study Physician 
, MD 
Phone 
 
Sage Medical Monitor  
, MD, PhD 
Mobile: 
 
Office phone: 
 
E-mail:
 
CRO Medical Monitor and 
24-Hour Emergency Contact 
, MD, 
MPH 
Phone: 
 
E-mail: 
 
SAE Reporting Information 
IQVIA Lifecycle Safety  
4820 Emperor Boulevard  
Durham, NC 27703  
E-mail: Sage.Safety@iqvia.com  
Fax: +1-855-638-1674  
SAE Hotline: +1-855-564-2229  
Product Complaints 
Sage Therapeutics, Inc. 
E-mail: productcomplaints@sagerx.com 
Phone: +1-833-554-7243 
 

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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, Placebo-controlled, Randomized Study Evaluating the Efficacy, Safety, and 
Tolerability of SAGE-324 in the Treatment of Individuals with Essential Tremor  
Number of Sites and Study Location: This study will take place at approximately 30 sites in the 
United States. 
Phase of Development: Phase 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 71 days. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To assess the effect of SAGE-324 compared to 
placebo on upper limb tremor reduction in 
individuals with essential tremor (ET) after 
28 days of treatment 
• Change from baseline compared to placebo in 
The Essential Tremor Rating Assessment 
(TETRAS) performance subscale part 4 upper 
limb tremor score on Day 29 
Secondary 
 
To assess the effect of SAGE-324 compared to 
placebo on overall upper limb tremor reduction 
• Change from baseline compared to placebo in 
TETRAS performance subscale part 4 upper 
limb tremor score at all other timepoints 
• Change from baseline compared to placebo in 
Kinesia ONE accelerometer scores 
To assess the effect of SAGE-324 compared to 
placebo on activities of daily living (ADLs) 
• Change from baseline compared to placebo in 
TETRAS Scale ADL score 
To assess the effect of SAGE-324 compared to 
placebo on overall tremor 
• Change from baseline compared to placebo in 
TETRAS total performance score 
To evaluate the safety and tolerability of 
SAGE-324 
• Incidence of treatment-emergent adverse events 
(TEAEs) 

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Study Description: 
This is a randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy, 
safety, and tolerability of SAGE-324 in individuals with ET. Participants, site staff, and sponsor 
personnel will be masked to treatment allocation. 
This study includes a Screening Period of up to 28 days, a 29-day treatment period (28 days of dosing), 
and a 14-day follow up period. After providing informed consent, participants will undergo screening 
assessments as outlined in Table 2 to determine eligibility.  
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). Following completion of screening 
and Day 1 eligibility checks, participants will be randomized to 1 of 2 treatment groups (SAGE-324 60 
mg daily, or placebo) in a 1:1 ratio.   
Double-Blind Treatment Period: Starting on Day 1, participants will receive a single dose of 
investigational product (IP) once daily for 28 days on an outpatient basis, to be taken in the morning 
with food that comprises a minimum of 400 calories. Doses occurring on scheduled clinic visits will be 
administered in the clinic, and doses occurring on all other days will be self-administered by the 
participant at home. During the Treatment Period, participants will return to the study center 
approximately once per week for efficacy and safety assessments as specified in Table 2. Participants 

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will be trained on the use of software applications and devices necessary to complete questionnaires or 
other assessments. If on Day 1 or at any point during the treatment period participants experience 
moderate or severe AEs of somnolence, drowsiness, dizziness or similar, or have these events at any 
severity with associated symptoms such as confusion or balance impairment, they must have a dose 
interruption (drug holiday) of at least 1 day (missing at least 1 dose). Following a drug holiday, the dose 
of study drug must then be reduced by 15 mg decrements to tolerability (ie, from 60 mg to 45 mg to 
30 mg). The dose of IP may not be increased for the remainder of the study. At the investigator’s 
discretion, participants unable to tolerate the 30 mg dose may be discontinued from study drug. During 
the study, a phone call will be conducted at least once per week, preferably midway between clinic 
visits, or as deemed appropriate by the investigator, to review the current status of the participant.   
Follow-Up Period: Follow-up visits will be conducted on an outpatient basis. Participants will continue 
to complete questionnaires as indicated in Table 2 and will receive a phone call approximately 7 days 
after the last dose of IP (ie, Day 35) for safety monitoring. Participants will return to the study center for 
an end of study (EOS) visit approximately 14 days following the last dose of IP (ie, Day 42). 
Number of Participants (planned): Approximately 60 participants, with approximately 30 per arm. 
Eligibility Criteria:  
Inclusion Criteria: 
1. Participant has signed an ICF before any study-specific procedures or washout of drugs is 
performed. 
2. Participant is ambulatory and is 18 to 80 years of age, inclusive, at the time informed consent is 
obtained. 
3. 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) 
d. 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 
4. Participant scores at least 1.5 for each of the six items that comprise the combined total upper 
limb TETRAS (total performance subscale part 4) with the total score for the dominant upper 
limb (the sum of the 3 items for either the right or left upper limb, whichever is dominant) 
being at least 5.5, at both Screening and predose on Day 1. 
5. Participant is willing to completely downtitrate and discontinue from medications taken for the 
treatment of ET 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 29.  
6. Participant is willing to discontinue the use of alcohol and products that contain nicotine within 
at least 1 week prior to Day 1 and through Day 29 of the study.  
7. 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 
>40 mIU/mL), and/or surgically sterile (bilateral oophorectomy, hysterectomy, and/or bilateral 

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salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy (does 
include abstinence).  
8. Male participant agrees to use an acceptable method of effective contraception for the duration 
of the study and for 13 weeks after receiving 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.  
9. Male participant is willing to abstain from sperm donation for the duration of the study and for 
13 weeks after receiving study drug. 
10. Participant has no clinically significant findings, as determined by the investigator, on 
Screening and predose Day 1 physical examination including mental state examination (MSE) 
and neurologic examination, 12-lead ECG, or screening clinical laboratory tests.  
Exclusion Criteria: 
1. Participant has presence of known causes of enhanced physiological tremor. 
2. Participant has had recent exposure (14 days prior to Day 1) to tremorgenic drugs 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. 
5. Participant has historical or clinical evidence of tremor with psychogenic origin (including but 
not limited to eating disorders, major depression, etc.) 
6. Participant has currently active, medically significant hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic (hypothyroidism with 
stable thyroid replacement is acceptable), or oncological disease. 
7. Participant has history of substance abuse prior to Screening, has a positive screen for drugs of 
abuse at Screening or predose on Day 1, or has a positive screen for alcohol or cotinine predose 
on Day 1. 
8. Participant has a known allergy to SAGE-324 or any excipient.  
9. Participant has had exposure to another investigational drug or device within 30 days or 5 half-
lives (if known) of the investigational drug, whichever is longer, prior to the Day 1 visit. 
10. Participant has history of suicidal behavior within 2 years or answers “YES” to questions 3, 4, 
or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk of suicide in the opinion of 
the investigator. 
11. Participant has donated one 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.  
12. 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. 
13. Participant is unwilling or unable to comply with study procedures and required training. 

Clinical Protocol 
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324-ETD-201, Version 5 
CONFIDENTIAL 
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14. 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. Use of mild cytochrome inhibitors 
and/or inducers may be permitted.  
15. 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. 
16. Participant plans to undergo elective surgery or relocate during participation in the study. 
17. Participant is investigative site personnel or a member of their immediate families (spouse, 
parent, child or sibling whether biological or legally adopted).  
18. [Removed] 
19. Female participant has a positive pregnancy test or confirmed pregnancy. 
Investigational Product Dosage and Mode of Administration:  
SAGE-324 (60 mg) or matched placebo oral tablets will be administered in the clinic or self-
administered once daily, in the morning, at approximately the same time each day, with food that 
comprises a minimum of 400 calories.  
Duration of Treatment:  
Each participant will receive a single dose of SAGE-324 oral tablets or matching placebo administered 
once daily for 28 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 TETRAS performance subscale part 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. 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 5 
CONFIDENTIAL 
11 
Determination of Sample Size 
The sample size of this study is based on the assumption of a 3-point difference in the change from 
baseline TETRAS performance subscale part 4 upper limb tremor scores between SAGE-324 and 
placebo with a standard deviation of 3.5 points. Under these assumptions, a sample size of 25 evaluable 
participants per group would provide 85% power for detecting a placebo-adjusted treatment difference 
of 3 points in TETRAS performance subscale part 4 upper limb tremor score, assuming a 2-sided test at 
an alpha level of 0.05. By including 2 treatment groups and using a 1:1 randomization, a total of 
50 evaluable participants are required. Assuming a nonevaluability rate of 15%, approximately 
60 participants will be randomized. Additional participants may be enrolled if the drop-out rate is higher 
than 15%. 
Analysis of Primary Efficacy Endpoint 
The estimand for the primary efficacy analysis is the treatment difference between SAGE-324 and 
placebo in mean change from baseline in clinic-based TETRAS performance subscale part 4 upper limb 
tremor score at Day 29 based on the Full Analysis Set. This will be analyzed using a mixed-effects 
model for repeated measures (MMRM); the model will include treatment, baseline TETRAS 
performance subscale part 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. The main comparison will be between SAGE-324 and 
placebo at the 29-day timepoint. Model-based point estimates (ie, least squares means, 95% confidence 
intervals, and p-values) will be reported where applicable. An unstructured covariance structure will be 
used to model the within-subject errors. If there is a convergence issue with the unstructured covariance 
model, Toeplitz compound symmetry 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. 
Analysis of Secondary Efficacy Endpoints 
Similar to those methods described above for the primary endpoint, an MMRM will be used to analyze 
of the change from baseline in TETRAS total performance scores, Kinesia ONE accelerometer scores 
and TETRAS ADL scores. Individual items of the TETRAS subscales will be summarized. 
Safety Analysis 
Safety and tolerability of study drug will be evaluated by incidence of TEAEs/serious adverse events, 
 
 
 
 
 
 
Interim Analysis 
The sponsor may conduct an interim analysis. Detailed descriptions of planned data analyses will be 
provided in a separate interim statistical analysis plan (SAP), if applicable.  

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 5 
CONFIDENTIAL 
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Table 2: 
Schedule of Assessments 
Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5 (±1) 
Phone 
Call 
8 (±1) 
12 (±1) 
Phone 
Call 
15(±1) 
19 (±1) 
Phone 
Call 
22 (±1) 
26 (±1) 
Phone 
Call 
29 (+1) 
EOT 
 
35 (±1) 
Safety 
Phone Call 
42 (±1) 
EOS/ETV 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X  
(serum; all 
women) 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
 
 
 
X  
(urine; 
WOCBP 
only) 
 
X  
(urine; 
WOCBP only) 
FSH (postmenopausal 
women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomizationa 
 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol/cotinine screens 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Neurological examination 
including MSEb 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Body height  
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signsc 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
12-Lead ECGd 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Chemistry/hematology/ 
coagulation/urinalysis 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 5 
CONFIDENTIAL 
13 
Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5 (±1) 
Phone 
Call 
8 (±1) 
12 (±1) 
Phone 
Call 
15(±1) 
19 (±1) 
Phone 
Call 
22 (±1) 
26 (±1) 
Phone 
Call 
29 (+1) 
EOT 
 
35 (±1) 
Safety 
Phone Call 
42 (±1) 
EOS/ETV 
Kinesia ONEf 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
TETRASg 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 5 
CONFIDENTIAL 
14 
Assessment 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
-28 to -1 
1 
5 (±1) 
Phone 
Call 
8 (±1) 
12 (±1) 
Phone 
Call 
15(±1) 
19 (±1) 
Phone 
Call 
22 (±1) 
26 (±1) 
Phone 
Call 
29 (+1) 
EOT 
 
35 (±1) 
Safety 
Phone Call 
42 (±1) 
EOS/ETV 
Patient Perception of 
Response Burden 
 
 
 
 
 
 
 
 
 
X 
 
X 
Participant trainingh 
X 
X 
 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
X  
 
X 
 
X 
 
X 
 
 
 
 
IP administration i 
 
Administered once daily for 28 days 
Not applicable 
AEs/SAEs 
X 
Prior and concomitant 
medication and historyj 
X 
Abbreviations: ADL = activities of daily living; AE = adverse event;
; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; 
; 
; ETV = early termination visit; FSH = follicle stimulating hormone; HIV = human immunodeficiency 
virus; ICF = informed consent form; min = minutes; IP = investigational product; MSE = mental state examination;
; 
; 
; 
; SAE = serious adverse event; TETRAS = The Essential Tremor Rating Assessment 
Scale; WOCBP = women of childbearing potential 
Notes:  
• 
The suggested order of assessments during clinic visits is: vital signs, TETRAS, Kinesia ONE, ECG, blood sample collection for 
 and clinical 
laboratory assessments, and questionnaires. 
• 
All assessments will be performed predose unless specified in a footnote. 
 
a Randomization will occur on Day 1 after meeting all eligibility criteria. 
b Complete physical examinations (including MSE and comprehensive neurologic examination) should be performed as specified and additionally as clinically 
necessary (see Section 12.1.3).  
c Predose on Day 1, supine and standing blood pressure and heart rate will be collected in triplicate at least 15 minutes apart, measured after the participant has 
been in the supine position for at least 5 minutes and then repeated 1 minute and 3 minutes after standing. Respiratory rate and temperature are collected once 
predose on Day 1. Vital signs will be collected once predose at all other visits. All postdose vital signs will be collected once at approximately 3 hours (±60 
min) after dosing. 
d ECGs will be collected and read centrally. ECGs will be performed predose and approximately 3 hours (±60 min) postdose. All ECGs must be performed after 
the participant has been in a supine position for at least 5 minutes.  

Clinical Protocol 
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324-ETD-201, Version 5 
CONFIDENTIAL 
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f Kinesia ONE will be assessed subsequently to TETRAS Performance subscale part 4 upper limb tremor.  
g The TETRAS Performance and TETRAS ADL subscales will be assessed at Screening and predose at each clinic visit. The TETRAS Performance subscale 
part 4 upper limb tremor will be assessed before Kinesia ONE. In addition, on Day 15, the TETRAS Performance subscale will be assessed at 5 and 8 hours 
(±30 min) postdose. A videographer will record each TETRAS administration. 
h Participants will be trained by study personnel on the use of software applications, Investigational Product Diary, and devices necessary for the conduct of the 
study. 
i On Day 1, participants will receive the first dose of IP at the research site and will be observed for AEs before leaving the site. 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.  
j Prior medications will be recorded during Screening and will include 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. Concomitant medications will be recorded thereafter 
throughout the duration of the study.  
   

Clinical Protocol 
Sage Therapeutics, Inc. 
324-ETD-201, Version 5 
CONFIDENTIAL 
16 
3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................4 
CONTACT INFORMATION ..........................................................................................................5 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS ...........................................................................................16 
LIST OF TABLES .........................................................................................................................20 
LIST OF FIGURES .......................................................................................................................20 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................21 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Dose Justification ........................................................................................................23 
5.2. 
Benefit/Risk Assessment ............................................................................................24 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................25 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Number of Participants ...............................................................................................28 
7.3. 
Treatment Assignment ................................................................................................28 
7.4. 
Dose Adjustment Criteria ...........................................................................................28 
7.5. 
Criteria for Study Termination ...................................................................................29 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .....................................30 
8.1. 
Participant Inclusion Criteria ......................................................................................30 
8.2. 
Participant Exclusion Criteria .....................................................................................31 
8.3. 
Screen Failures ............................................................................................................32 
8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................32 
8.4.1. 
Investigational Product Discontinuation .....................................................................32 
8.4.2. 
Early Termination from the Study ..............................................................................32 
8.4.3. 
Loss to Follow-up .......................................................................................................33 
8.4.4. 
Replacement of Participants .......................................................................................33 
9. 
TREATMENT OF PARTICIPANTS .........................................................................34 
9.1. 
Description of Investigational Product .......................................................................34 

Clinical Protocol 
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324-ETD-201, Version 5 
CONFIDENTIAL 
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9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................34 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................34 
9.2.2. 
Prohibited Medications ...............................................................................................34 
9.2.3. 
Other Restrictions .......................................................................................................35 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................35 
9.3. 
Intervention after the End of the Study .......................................................................36 
9.4. 
Treatment Adherence ..................................................................................................36 
9.5. 
Randomization and Blinding ......................................................................................36 
9.5.1. 
Emergency Unblinding ...............................................................................................36 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............37 
10.1. 
Investigational Product ...............................................................................................37 
10.2. 
Investigational Product Packaging and Labeling .......................................................37 
10.3. 
Investigational Product Storage ..................................................................................37 
10.4. 
Investigational Product Preparation ............................................................................38 
10.5. 
Investigational Product Administration ......................................................................38 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................38 
10.7. 
Product Complaints ....................................................................................................39 
11. 
EFFICACY ASSESSMENTS AND CLINICAL PHARMACOLOGY 
ASSESSMENTS .........................................................................................................40 
11.1. 
Efficacy Assessments .................................................................................................40 
11.1.1. 
The Essential Tremor Rating Assessment Scale ........................................................40 
11.1.2. 
Kinesia ONE™ Accelerometer Score ..........................................................................40 
 
41 
 
41 
 
41 
 
41 
 
42 
 
42 
 
42 
 
43 
 
43 
 
43 

Clinical Protocol 
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324-ETD-201, Version 5 
CONFIDENTIAL 
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43 
 
43 
 
43 
11.3. 
Other Patient-Reported Assessments ..........................................................................44 
11.3.1. 
Patient Perception of Response Burden ......................................................................44 
12. 
SAFETY ASSESSMENTS ........................................................................................45 
12.1. 
Safety Parameters .......................................................................................................45 
12.1.1. 
Demography and Medical History ..............................................................................45 
12.1.2. 
Weight and Height ......................................................................................................45 
12.1.3. 
Physical Examination .................................................................................................45 
12.1.4. 
Vital Signs ..................................................................................................................45 
12.1.5. 
Electrocardiogram .......................................................................................................45 
12.1.6. 
Laboratory Assessments .............................................................................................46 
12.1.6.1. 
Drugs of Abuse, Alcohol, Nicotine (Cotinine) ...........................................................46 
12.1.6.2. 
Pregnancy Screen ........................................................................................................46 
 
47 
 
47 
12.1.9. 
Safety Phone Call .......................................................................................................47 
12.2. 
Adverse Events and Serious Adverse Events .............................................................47 
12.2.1. 
Adverse Event Definition ...........................................................................................47 
12.2.2. 
Serious Adverse Event (SAE) Definition ...................................................................48 
12.2.3. 
Definition of Adverse Events of Special Interest .......................................................49 
12.2.4. 
Relationship to Investigational Product ......................................................................49 
12.2.5. 
Recording Adverse Events .........................................................................................49 
12.2.6. 
Reporting Serious Adverse Events .............................................................................50 
12.3. 
Pregnancy ...................................................................................................................50 
12.4. 
Overdose .....................................................................................................................51 
13. 
STATISTICS ..............................................................................................................52 
13.1. 
Data Analysis Sets ......................................................................................................52 
13.2. 
Handling of Missing Data ...........................................................................................52 
13.3. 
General Considerations ...............................................................................................52 
13.4. 
Demographics and Baseline Characteristics ...............................................................52 
13.5. 
Efficacy Analysis ........................................................................................................53 

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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................5 
Table 2: 
Schedule of Assessments ............................................................................................12 
Table 3: 
Investigational Product ...............................................................................................37 
Table 4: 
Summary of Clinical Laboratory Analytes .................................................................46 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................28 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
AE 
adverse event 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
AUCinf 
area under the curve from 0 to infinity 
AUC0-tau 
area under the concentration-time curve from 0 to end of the dosing period 
BMI 
body mass index 
 
 
Cmax 
maximum observed concentration 
CRO 
contract research organization 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
End-of-Study 
 
 
 
 
ET 
essential tremor 
 
 
ETV 
early termination visit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IP 
investigational product 
IRB 
institutional review board 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
PD 
pharmacodynamic 
 
 
PI 
principal investigator 

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Abbreviation 
Definition 
PK 
pharmacokinetic 
PV 
Pharmacovigilance 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
t½  
terminal elimination half-life  
TEAE 
treatment-emergent adverse event 
TETRAS 
The Essential Tremor Rating Assessment Scale 
tmax 
time of occurrence of Cmax 
WHO 
World Health Organization 

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5. 
INTRODUCTION 
SAGE-324 is a positive allosteric modulator (PAM) of A-type γ-aminobutyric acid-gated 
chloride channel (GABAA) receptors, the major class of inhibitory neurotransmitter receptors in 
the brain. In addition to being developed as an adjunctive therapy in epilepsy and other seizure 
disorders under IND 139201, SAGE-324 is also being developed for the treatment of Essential 
Tremor (ET). 
Essential tremor is a permanently debilitating, neurologically determined, common movement 
disorder characterized by involuntary rhythmic oscillation of a body part due to intermittent 
muscle contractions typically occurring 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 US, 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 term 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.  
The pharmacological profile of SAGE-324 is theorized to induce therapeutic effect in the 
treatment of ET. Based on preclinical studies of SAGE-324, which features a different 
mechanism of action than that of propranolol, the pharmacokinetic (PK)/ pharmacodynamic (PD) 
profile suggests SAGE-324 may safely ameliorate symptoms in patients suffering from ET, 
regardless of propranolol use. 
There are currently ongoing Phase 1 clinical studies of SAGE-324 in healthy adults and in adults 
with ET. These studies, in addition to preclinical studies of SAGE-324, are detailed in the 
investigator’s brochure. 
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. 
Henceforth, 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 SAGE-324 on a variety of outcome 
measures specific to ET disease characteristics and associated quality of life domains. 
5.1. 
Dose Justification 
The dose of SAGE-324 planned for this study is 60 mg given as oral tablets, to be administered 
once daily in the morning with food. The dose was selected based on preliminary data from 
3 active studies of SAGE-324, which included: unblinded data from completed cohorts in 

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324-CLP-101 Part A (oral solution SAGE-324 doses of 3 mg, 10 mg, 30 mg, 45 mg, 60 mg); 
Part C (oral solution SAGE-324 doses of 30 mg); Part D (oral suspension SAGE-324 doses of 
30 mg) in healthy subjects; and preliminary data from open-label Part E (oral suspension 
SAGE-324 doses of 45 mg and 60 mg) in participants with ET; additional preliminary data from 
324-CLP-102 cohorts 1 through 6 (cohorts 1 to 5 unblinded, cohort 6 blinded), which evaluated 
oral suspension doses ranging from 5 mg to 60 mg; and preliminary unblinded data from 
324-CLP-104, which compared the relative bioavailability of the oral tablet (30 mg) vs oral 
suspension (30 mg) formulations of SAGE-324 and separately the effect of food on the PK of the 
SAGE-324 oral tablet. In 324-CLP-101 and 324-CLP-102 studies, doses were administered in a 
fasted state. The preliminary data from all of these active studies collectively informed the route 
of administration (oral) and dose strength of 60 mg as oral tablets planned for further evaluation 
in this study.  
SAGE-324 was generally well-tolerated in participants with ET and in healthy volunteers, as was 
shown in the preliminary data of 324-CLP-101 Part E at single administration doses of 45 mg 
and 60 mg, and in 324-CLP-102 through once-daily administered doses of up to 60 mg for 
14 days. In addition, tremor reduction was observed at both doses on TETRAS and Kinesia ONE 
accelerometry, with greater improvement seen at 60 mg compared to 45 mg.  
In the clinically complete study 324-CLP-104, preliminary data showed that SAGE-324 oral 
tablets, when coadministered with a meal, resulted in exposures approximately equivalent to that 
of SAGE-324 oral suspension under fasted conditions. Therefore, the SAGE-324 oral tablets are 
recommended to be administered with food. 
5.2. 
Benefit/Risk Assessment 
Based on the mechanism of action of SAGE-324 and the results of completed nonclinical studies 
and preliminary data of currently ongoing clinical studies of SAGE-324, it is theorized that 
participants may have symptomatic amelioration, ie, tremor reduction and possibly improved 
quality of life from potentially stabilizing disease characteristics associated with ET. 
Potential risks anticipated in this study are based on available data from toxicology studies of 
SAGE-324 in addition to preliminary data from 3 ongoing, currently active Phase 1 clinical 
studies of SAGE-324.  
Available preliminary clinical data are summarized in the SAGE-324 Investigator’s Brochure. 
There have been no deaths or SAEs related to IP, and based on the preliminary clinical data 
available, there have been no confirmed clinically significant trends in clinical laboratory 
evaluations, vital signs, or physical examinations.  
Based on available preliminary clinical data from SAGE-324 active clinical studies, AEs of 
somnolence and feeling of relaxation are considered adverse drug reactions (ADRs). In addition 
to scheduled clinic visits, the current status of study participants will be reviewed via phone calls 
in between clinic visits, or more frequently for AE monitoring. 

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6. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
To assess the effect of SAGE-324 compared to 
placebo on upper limb tremor reduction in 
individuals with essential tremor (ET) after 
28 days of treatment 
• 
Change from baseline compared to placebo in 
The Essential Tremor Rating Assessment 
(TETRAS) performance subscale part 4 upper 
limb tremor score on Day 29 
Secondary 
 
To assess the effect of SAGE-324 compared to 
placebo on overall upper limb tremor reduction 
• 
Change from baseline compared to placebo in 
TETRAS performance subscale part 4 upper 
limb tremor score at all other timepoints 
• 
Change from baseline compared to placebo in 
Kinesia ONE accelerometer scores 
To assess the effect of SAGE-324 compared to 
placebo on activities of daily living (ADLs) 
• 
Change from baseline compared to placebo in 
TETRAS Scale ADL score 
To assess the effect of SAGE-324 compared to 
placebo on overall tremor 
• 
Change from baseline compared to placebo in 
TETRAS total performance score 
To evaluate the safety and tolerability of 
SAGE-324 
• 
Incidence of treatment-emergent adverse 
events (TEAEs) 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, parallel group study to evaluate the 
efficacy, safety, and tolerability of SAGE-324 in individuals with ET. Participants, site staff, and 
sponsor personnel will be masked to treatment allocation (see Section 9.5). 
This study includes a Screening Period of up to 28 days, a 29-day treatment period consisting of 
28 days of dosing with the end of treatment visit intended to be on Day 29 at trough, and a 
14-day follow-up period relative to final dose (Figure 1). After providing informed consent, 
participants will undergo screening assessments as outlined in Table 2 to determine eligibility.  
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 assessments 
of safety and efficacy, as specified in the Schedule of Assessments (Table 2). Following 
completion of screening and Day 1 eligibility checks, participants will be randomized to 1 of 
2 treatment groups (SAGE-324 60 mg daily, or placebo) in a 1:1 ratio.   
During the double-blind Treatment Period, starting on Day 1, participants will receive a single 
dose of investigational product (IP) once daily in the morning with food for 28 days on an 
outpatient basis (see Section 10.5). Doses occurring on scheduled clinic visits will be 
administered in the clinic, and doses occurring on all other days will be self-administered by the 
participant at home as specified in Table 2. During the Treatment Period, participants will return 
to the study center approximately once per week for efficacy and safety assessments as specified 
in Table 2. If on Day 1 or at any point during the treatment period, participants experience 
moderate or severe AEs of somnolence, drowsiness, dizziness or similar, or experience these 
events at any severity with associated symptoms such as confusion or balance impairment, they 
must have a dose interruption (drug holiday) of at least 1 day (missing at least 1 dose). Following 
a drug holiday, the dose of study drug must then be reduced by 15 mg decrements to tolerability 
(ie, from 60 mg to 45 mg to 30 mg). The dose of IP may not be increased for the remainder of 
the study. At the investigator’s discretion, participants unable to tolerate the 30-mg dose will be 
discontinued from IP. During the study, a phone call will be conducted once per week, preferably 
midway between clinic visits, or more frequently if deemed appropriate by the investigator, to 
review the current status of the participant.  Details regarding dose adjustment criteria and 
procedures are provided in Section 7.4. 
In addition to Kinesia ONE-specific training, clinical study center staff and study participants 
will be trained on the use of software applications and devices necessary to complete 
questionnaires or other assessments as required. During in-clinic visits, clinical study center staff 
will be available to assist participants as needed, to ensure they can access and use the software 
applications and devices correctly according to the training. 
During the follow-up period, visits will be conducted on an outpatient basis. In addition to the 
phone calls to review current status, participants will receive a phone call approximately 7 days 
after the last dose of IP (ie, Day 35) for safety monitoring. Participants will return to the study 
center for an end of study visit approximately 14 days following the last dose of IP (ie, Day 42). 

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Figure 1: Study Design
Abbreviation:  EOT = end of treatment 
7.2. 
Number of Participants 
Approximately 60 participants are planned, with approximately 30 participants enrolled per arm, 
to produce 25 evaluable participants per arm for primary efficacy analysis. Additional 
participants may be randomized if the drop-out rate is higher than anticipated (ie, >15%). 
7.3. 
Treatment Assignment 
Participants will be assigned to IP (active or placebo) in accordance with the randomization 
schedule on Day 1. Additional details on randomization and blinding are provided in Section 9.5. 
7.4. 
Dose Adjustment Criteria 
If a participant reports moderate or severe adverse events (as defined in Section 12.2.5) of 
somnolence, drowsiness, dizziness, or similar events or experiences these events at any severity 
with associated symptoms such as confusion or balance impairment on Day 1 or at any point 
during the treatment period, the participant must have a drug holiday (dose interruption) of at 
least 1 day (missing at least 1 dose) (Table 2). The drug holiday must be followed by reducing 
the dose of IP from 60 mg to 45 mg (ie, from 4 tablets of 15 mg to 3 tablets of 15 mg).   
If the events persist and continue to be moderate or severe, despite the drug holiday and dose 
reduction, or the participant experiences a new moderate or severe AE of somnolence, 
drowsiness, dizziness or similar, the participant must have a further drug holiday of at least 1 
day and a further dose reduction from 45 mg to 30 mg (from 3 tablets to 2 tablets).  
The participant’s condition must be closely monitored via phone calls or in-person visits to 
assess the impact of any drug holiday and dose reduction. 
The reduced dose of IP will continue to be administered once daily at the same schedule as 
specified in the Schedule of Assessments (Table 2). The dose of IP may not be increased for the 
remainder of the study.  
Following a second drug holiday and dose reduction to 30 mg, if the events persist or recur and 
are moderate or severe, the investigator must discontinue the participant from the IP. The dose 
may not be reduced below 30 mg. 

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The investigator will continue to institute drug holidays, dose reductions, or IP discontinuation 
over and above this minimum as clinically appropriate.  
7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
participants, or for administrative reasons. In the event of study termination, Sage Therapeutics 
will provide written notification to the investigator. Investigational sites must promptly notify 
their IRB, where required, and initiate withdrawal procedures for participating participants.  

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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 ICF before any study-specific procedures or washout of drugs is 
performed. 
2. Participant is ambulatory and is 18 to 80 years of age, inclusive, at the time informed 
consent is obtained. 
3. 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) 
d. 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 
4. Participant scores at least 1.5 for each of the six items that comprise the combined total 
upper limb TETRAS (total performance subscale part 4) with the total score for the 
dominant upper limb (the sum of the three items for either the right or left upper limb, 
whichever is dominant) being at least 5.5, at both Screening and predose on Day 1. 
5. Participant is willing to completely downtitrate and discontinue from medications taken 
for the treatment of ET 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 29. 
6. Participant is willing to discontinue the use of alcohol and products that contain nicotine 
within at least 1 week prior to Day 1 and through Day 29 of the study. 
7. 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 >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).  
8. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 13 weeks after receiving 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.  
9. Male participant is willing to abstain from sperm donation for the duration of the study 
and for 13 weeks after receiving study drug. 
10. Participant has no clinically significant findings, as determined by the investigator, on 
Screening and predose Day 1 physical examination including mental state examination 
(MSE) and neurologic examination, 12-lead ECG, or screening clinical laboratory tests.  

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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 recent exposure (14 days prior to Day 1) to tremorgenic drugs 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. 
5. Participant has historical or clinical evidence of tremor with psychogenic origin 
(including but not limited to eating disorders, major depression, etc.) 
6. Participant has currently active, medically significant hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic 
(hypothyroidism with stable thyroid replacement is acceptable), or oncological disease. 
7. Participant has history of substance abuse prior to Screening or has a positive screen for 
drugs of abuse at Screening or predose on Day 1 or has a positive screen for alcohol or 
cotinine predose on Day 1. 
8. Participant has a known allergy to SAGE-324 or any excipient.  
9. Participant has had exposure to another investigational drug or device within 30 days or 5 
half-lives (if known) of the investigational drug, whichever is longer, prior to the Day 1 
visit. 
10. Participant has history or suicidal behavior within 2 years or answers “YES” to questions 
3, 4, or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk of suicide in the 
opinion of the investigator. 
11. Participant has donated one 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.  
12. 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. 
13. Participant is unwilling or unable to comply with study procedures and required training. 
14. 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. Use of mild 
cytochrome inhibitors and/or inducers may be permitted.  
15. Participant has concurrent or recent exposure (14 days or 5 half-lives, whichever is 
longer, prior to the Day 1 visit) to sedative/hypnotic drugs, stimulants, highly caffeinated 

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beverages or dietary supplements containing high doses of caffeine, or recent increase 
above regular daily consumption of caffeine. 
16. Participant plans to undergo elective surgery or relocate during participation in the study. 
17. Participant is investigative site personnel or a member of their immediate families 
(spouse, parent, child or sibling whether biological or legally adopted).  
18. [Removed] 
19. Female participant has a positive pregnancy test or confirmed pregnancy. 
8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned IP or entered in the study, ie, a participant who does not meet 1 or 
more of the eligibility criteria after providing consent and prior to randomization (Day 1). 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. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
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 EOT visit, the safety phone call 7 days later, and then, after a 
further 7 days, the End of Study/Early Termination visit (EOS/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 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 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 
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 for safety, behavioral, compliance, 
or administrative reasons.  

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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.  
If a participant is persistently noncompliant, the investigator should discuss with the sponsor the 
potential discontinuation of the participant. Any reasons for unwillingness or inability to adhere 
to the protocol must be recorded in the participant’s eCRF, including: 
• missed visits; 
• interruptions in the schedule of study drug administration; 
• non-permitted medications 
If the participant withdraws from the study after completing 28 days of dosing with IP, they will 
be encouraged to attend follow-up visits for safety assessments at Day 35 and Day 42, as 
specified in the Schedule of Assessments (Table 2). If the participant withdraws their consent to 
collect protected health information, the EOS/ETV visit will be conducted and the participant 
will be permanently discontinued from the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been unsuccessful.  
8.4.4. 
Replacement of Participants 
Participants will not be replaced. However, additional participants may be enrolled if the drop-
out rate is higher than 15%. 

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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 (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 through the first dose of 
IP will be recorded.  
All medications and/or supplements taken from the first dose of IP through the Day 42 (±1 days) 
visit (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:  
• 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.  
• Use of tremorgenic drugs within the 14 days or 5 half-lives (whichever is longer) of 
Day 1 or during the study. 
• Use of agents known to affect SAGE-324 drug metabolism (any known cytochrome 
P450 3A4 inhibitors and/or inducers) within the 14 days or 5 half-lives (whichever is 
longer) of Day 1 and through Day 29 of the study period. Use of mild cytochrome P 
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 28-day dosing period.  
• Any prior ET medications must be discontinued prior to the Screening TETRAS: 
− There must be 14 days or 5 half-lives (whichever is longer) washout period prior 
to the Day 1 (baseline) visit.    
− For drugs requiring downtitration, there must be the required number of days for 
downtitration plus 14 days or 5 half-lives (whichever is longer) prior to the Day 1 
(baseline) visit.  

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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 within 1 week prior to Day 1 and through Day 29 of the study period 
is prohibited. If the alcohol test is positive on Days 1, 8, 15, 22, or 29, the participant 
will not be administered further IP and will be withdrawn from the study; no further 
efficacy assessments such as TETRAS will be undertaken. 
• Use of products that contain nicotine within 1 week prior to Day 1 and through 
Day 29 of the study period is prohibited. Positive cotinine testing on Days 8, 15, 22, 
or 29 would be considered a major protocol deviation and the participant will be 
excluded from the Per Protocol Analysis Set. Positive cotinine testing on Day 1 is 
exclusionary. 
• 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 29 of the study period is prohibited.  
• Use of stimulants, highly caffeinated beverages or dietary supplements containing 
high doses of caffeine within 14 days prior to the Day 1 visit and through Day 29 of 
the study period is prohibited. Note: participants should not increase their regular 
daily consumption of caffeine during the study period. 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation  
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal ligation or bilateral tubal occlusion (performed at least 3 months prior 
to Screening) 
• Vasectomized partner (performed at least 3 months prior to Screening) 
• Sexual abstinence (no sexual intercourse) 
Acceptable forms of contraception for male participants include: 
• Sexual abstinence (no sexual intercourse) 
• History of vasectomy (performed at least 3 months prior to Screening) 

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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) 
9.3. 
Intervention after the End of the Study 
There is no planned intervention following the end of the study. 
9.4. 
Treatment Adherence 
The first dose of IP will be received and administered by participants in the clinic. Participants 
will be dispensed a 7-day supply of IP to orally self-administer at home with instructions 
specifying to administer in the morning with food. 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 10.6. 
Patients will be asked to record the dates and times of their IP dose administrations at home in a 
diary. They will also record details around how well they complied with the study instructions 
for self-administering IP at home. 
9.5. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Participants will be randomized in 
a 1:1 ratio to treatment groups (SAGE-324, 60 mg or placebo). Participants, site staff, and the 
sponsor will be blinded to treatment allocation. 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 Sage prior to unblinding the study 
treatment administered to a participant. Requests from the investigator about the treatment 
administered to study participants should be discussed with the Sage Medical Monitor. If the 
unblinding occurs without Sage’s knowledge, the investigator must notify Sage within 24 hours 
of breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records.  
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and on the 
eCRF.  
If a participant or any study personnel become unblinded to treatment, the participant will be 
excluded from the Per Protocol analysis set, as detailed further in the statistical analysis plan. 

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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
Table 3: 
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 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 
SAGE-324 Oral Tablets and Placebo Tablets will be packaged in blinded, high density 
polyethylene (HDPE) containers. The containers used for SAGE-324 and placebo will be 
identical in appearance. The package labeling conforms to FDA and GMP 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. Any 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, 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 in the clinic or at home as specified in the Schedule of Assessments 
(Table 2). The IP will be provided as tablets, sufficient in number to achieve a dose of 60 mg. IP 
will be orally administered once daily in the morning, with food. Participants will be instructed 
to take the IP with food that comprises a minimum of 400 calories, and to take the IP at 
approximately the same time each morning.  
If a participant reports moderate or severe adverse events (as defined in Section 12.2.5) of 
somnolence, drowsiness, dizziness, or similar events, or experiences these events at any severity 
with associated symptoms such as confusion or balance impairment on Day 1 or at any point 
during the treatment period, the dose must be adjusted per the criteria in Section 7.4. 
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. 
The designated site staff will dispense the supplied participant-specific kits to participants at the 
planned dispensation visit intervals outlined in the Schedule of Assessments (Table 2). 
An interactive response technology (IRT) will be used to capture participant-identifying 
information. The IRT will be used to randomize the eligible participant into the study and 
provides the kit number of the IP to be dispensed to that participant.  
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 tablets will be returned to Sage Therapeutics for 
destruction or destroyed locally per the site’s procedures; disposition of IP will be documented. 
IP may not be destroyed until accountability and reconciliation procedures have been completed 
and monitored. 

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10.7. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution.  
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the 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 ASSESSMENTS AND CLINICAL PHARMACOLOGY 
ASSESSMENTS 
11.1. 
Efficacy Assessments 
11.1.1. 
The Essential Tremor Rating Assessment Scale 
TETRAS is a validated, comprehensive clinical assessment of essential tremor (Elble 2013).  
Three different components of TETRAS will be assessed in this study. The TETRAS ADL 
subscale, total performance score, and performance subscale part 4 upper limb tremor score will 
each be separately assessed at each clinic visit as specified in the Schedule of Assessments 
(Table 2). 
The ADL subscale assesses how ET is impacting 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). The overall ADL score range is 0 to 48. 
The total performance score is based on overall rating of tremor amplitude in the voice, limbs, 
head, face, trunk, while performing pre-specified 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 the performance subscale part 4 upper limb tremor score, all 3 maneuvers in the upper limb 
assessments of part 4 (subscale items 4a, 4b, and 4c) will be completed for both arms, first for 
the right arm and then for the left. The part 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. 
In this study, a videographer will videotape each TETRAS administration. 
Prior medications for ET must be discontinued prior to Screening TETRAS ratings (see 
Section 9.2.2 for washout periods). 
11.1.2. 
Kinesia ONE™ Accelerometer Score 
Kinesia ONE™ is an ISO-certified wireless motion sensor worn distally on the index finger, 
which utilizes 3 orthogonal accelerometers and 3 orthogonal gyroscopes to monitor 
3-dimensional motion. Data is transmitted wirelessly from the sensor to a Bluetooth technology-
enabled device to use with the Kinesia ONE software (eg, Apple iPad or similar device with 
preinstalled Kinesia ONE software). The device has received FDA clearance. 
Via the Kinesia ONE software application, measures of 3-dimensional motion are converted to 
scores ranging from 0 to 4, per assessed maneuver; higher scores indicate greater tremor severity. 
Motion in both arms is captured. 
Participants will complete this assessment at each clinic visit as specified in the Schedule of 
Assessments (Table 2).  

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11.3. 
Other Patient-Reported Assessments 
11.3.1. 
Patient Perception of Response Burden 
The Patient Perception of Response Burden Questionnaire is a patient-reported measure that 
assesses the multidimensional construct of response burden (Atkinson 2019). 
Participants respond to 6 items assessing 1) how well the questions related to their actual 
concerns, 2) how comfortable the participants were with answering the questions, 3) how well 
the survey characterized their health and well-being, 4) the length of time to complete the 
questionnaires, 5) whether questions seemed unimportant or repetitive, and 6) what additional 
information should have been gathered. Items 1 to 3 are assessed on a 0 to 10 scale, item 4 is 
assessed on a 1 to 3 scale, and items 5 and 6 are open-ended. Items 1 and 4 are reverse scored. A 
composite score can be calculated to create a weighted representative index of relevance, 
comfort, and well-being relative to time to completion (ie, items 1, 2, and 3 were summed and 
multiplied by item 4) for a range of 0 to 72, with higher scores indicative of elevated endorsed 
response burden. The open-ended items will be summarized thematically. The Patient Perception 
of Response Burden Questionnaire will be performed as specified in the Schedule of 
Assessments (Table 2). 
 

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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, ethnicity) and a full medical history will be 
documented. Whether the participant is left-handed or right-handed will be recorded. This must 
also additionally include participant recall of history of ET, disease duration, past treatments 
used, and responsiveness to alcohol and/or other treatments with use intended as off-label 
treatment of ET (eg, primidone or similar therapies). 
12.1.2. 
Weight and Height 
Height and weight will be measured and documented. Body mass index (BMI) will be calculated 
and documented.  
12.1.3. 
Physical Examination 
Whenever possible, the same individual should perform all physical examinations. Physical 
examinations will include review of systems (eg, head, eye, ear, nose and throat; heart; lungs; 
abdomen; and extremities) as well as comprehensive neurological examination and MSE. 
Unscheduled physical examinations may also be conducted per the Investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by an investigator as abnormal, not 
clinically significant (NCS); or abnormal, clinically significant (CS) in source documents.  
12.1.4. 
Vital Signs 
Vital signs comprise blood pressure and heart rate (supine and standing), respiratory rate, and 
temperature. Systolic and diastolic blood pressure and heart rate are to be measured after the 
participant has been supine for at least 5 minutes and then repeated 1 minute and 3 minutes after 
standing.  
Vital signs are measured once at each timepoint with the exception of predose on Day 1, when 
blood pressure and heart rate are measured supine and standing in triplicate at least 15 minutes 
apart. 
Any abnormality in vital signs will be interpreted by an Investigator as abnormal, NCS; or 
abnormal, CS in source documents. 
12.1.5. 
Electrocardiogram 
A 12-lead ECG will be performed. The standard intervals (heart rate, PR, QRS, QT, and QTcF) 
as well as any rhythm abnormalities will be recorded. 
Electrocardiograms will be performed after the participant has been resting in a supine position 
for at least 5 minutes. When ECG measurements coincide with safety assessments, vital signs 
assessment or blood draws, procedures should be carried out in said order (vital signs, ECG, 
blood draw). 

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All abnormal ECGs will be interpreted by an investigator as abnormal, NCS, or abnormal, CS in 
source documents. 
12.1.6. 
Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected. Analytes to be 
evaluated are summarized in Table 4. 
Table 4: 
Summary of Clinical Laboratory Analytes 
Biochemistry 
Renal Panel: glucose, calcium, phosphorus, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate 
Hepatic Panel: albumin, ALT, AST, total bilirubin, direct bilirubin, indirect 
bilirubin, alkaline phosphatase, total protein, lactate dehydrogenase, gamma 
glutamyl transferase 
Other: triglycerides, cholesterol (low density lipoprotein [LDL], high density 
lipoprotein [HDL]), creatine phosphokinase, thyroid stimulating hormone (TSH) 
Coagulation 
activated partial thromboplastin time, prothrombin time, and international 
normalized ratio 
Hematology 
red blood cell count, hemoglobin, hematocrit, white blood cell count with 
differential, platelet count, and if red blood count indices are abnormal, reflex red 
blood cell morphology as indicated 
Urinalysis 
protein, glucose, pH, blood, leukocyte esterase, urobilinogen, bilirubin, ketones, 
nitrite 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, NCS; or abnormal, CS in source documents. 
Follicle stimulating hormone testing will be conducted to confirm whether a participant with 
≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being 
postmenopausal (Section 8.1). 
12.1.6.1. Drugs of Abuse, Alcohol, Nicotine (Cotinine) 
A urine sample will be collected for assessment of the following selected drugs of abuse per the 
Schedule of Assessments (Table 2): amphetamines, barbiturates, benzodiazepines, 
cannabinoids/THC, cocaine, methadone, MDMA, methamphetamines, opiates, oxycodone, 
tricyclic antidepressants, and PCP. 
Urine samples will be collected and tested for cotinine. Either urine dipstick or breathalyzer will 
be used for alcohol testing. 
12.1.6.2. Pregnancy Screen 
A serum pregnancy test will be conducted for all female participants at Screening; subsequently, 
a urine pregnancy test will be conducted for all participants of childbearing potential as specified 
in the Schedule of Assessments (Table 2).  

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12.1.9. 
Safety Phone Call 
A phone call will be conducted once per week, preferably mid-week in between clinic visits (as 
specified in Table 2), and again at Day 35, to collect information about current health status, 
general well-being, IP compliance, or to gather other pertinent health-related information as per 
investigator judgement. 
If a dose interruption (drug holiday) followed by a dose reduction is required, the investigator 
will speak with the participant to provide instructions via the phone or the participant will have 
an in-person visit. 
12.2. 
Adverse Events and Serious Adverse Events 
12.2.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is defined as an AE with onset after the start of IP, or any worsening of a preexisting 
medical condition/AE with onset after the start of IP and throughout the study. The term IP 
includes any Sage IP, a comparator, or a placebo administered in a clinical trial.  

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• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
Investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Definition of Adverse Events of Special Interest 
There are no known adverse events of special interest as of the date of signature approval of this 
clinical protocol. 
12.2.4. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP.  
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
alternative explanation for the AE 
Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE 
12.2.5. 
Recording Adverse Events 
AEs spontaneously reported by the participant and/or in response to an open question from the 
study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
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: 

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• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s)  
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized  
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.6. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage or designee.  
Additional follow-up information, if required or available, should all be sent to Sage or designee 
within 24 hours of receipt on a follow-up SAE report form and placed with the original SAE 
information and kept with the appropriate section of the eCRF and/or study file. 
SAEs occurring after the designated follow up time for the study, should be reported to Sage or 
designee according to the timelines noted above only if the investigator considers the SAE 
related to IP.  
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/EC 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. Each site is responsible for notifying its 
IRB of all SUSARs.  
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARs to investigators in a blinded fashion. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 

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pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy. The investigator will also attempt to collect pregnancy information on any 
participant’s partner who becomes pregnant after the participant has received the first 
administration of IP. After obtaining the necessary signed informed consent from the pregnant 
partner directly, the investigator will follow the same pregnancy reporting procedures specified 
for pregnant participants.  
The participant or participant’s partner will be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies (eg, spontaneous abortion, elective abortion, normal 
birth) must be followed and documented even if the participant was discontinued from the study. 
The investigator will collect follow-up information on the participant or participant’s partner and 
the neonate, and the information will be forwarded to Sage or designee. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, preeclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death), the investigator should follow the procedures 
for reporting an SAE.  
12.4. 
Overdose 
An overdose is any dose of 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 eCRF; however, all overdoses must be recorded on an overdose form and sent to 
Sage or designee within 24 hours of the site becoming aware of the overdose. An overdose must 
be reported to Sage or designee even if the overdose does not result in an AE. If an overdose 
results in an AE, the AE must be recorded.  

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13. 
STATISTICS 
Detailed description of the analyses to be performed in the study will be provided in the 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to database lock. 
Any changes or 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 will include all participants who are randomized.  
The Safety Set will include all participants 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 TETRAS performance subscale part 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. Note that a positive cotinine test on Days 1, 8, 15, 22 or 29 constitutes a 
major protocol deviation. 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All participants will be used in the analyses, 
as per the analysis populations, using all nonmissing data available. No imputation process will 
be used to estimate missing data.  
13.3. 
General Considerations 
All participant data, including those that are derived, that support the tables and figures will be 
presented in 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. Participants will be summarized according to treatment received. 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to receipt of IP.  
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. 
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 using the Safety Set.  

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Pregnancy test results and drug screen results will be listed but not summarized.  
Medical history will be listed by participant.  
13.5. 
Efficacy Analysis  
The estimand for the primary efficacy analysis is the treatment difference between SAGE-324 
and placebo in mean change from baseline in clinic-based TETRAS performance subscale part 4 
upper limb tremor scores at Day 29 based on the Full Analysis Set. This will be analyzed using a 
mixed effects model for repeated measures (MMRM); the model will include treatment, baseline 
TETRAS performance subscale part 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. The main comparison 
will be between SAGE-324 and placebo at the 29-day timepoint. Model-based point estimates 
(ie, least squares means, 5% confidence intervals, and p-values) will be reported where 
applicable. An unstructured covariance structure will be used to model the within-subject errors. 
If there is a convergence issue with the unstructured covariance model, Toeplitz compound 
symmetry 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 UN, the sandwich 
estimator for the variance covariance matrix will be derived, using the EMPIRICAL option in 
the PROC MIXED statement in SAS. 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in TETRAS total performance scores, Kinesia ONE 
accelerometer scores and TETRAS ADL scores.  
Other efficacy analyses will be specified in the SAP. In general, data will be analyzed using 
appropriate descriptive statistics or prespecified statistical methods as applicable; participant 
listings will be provided for all efficacy data. Participants will be analyzed according to 
randomized treatment for the purpose of efficacy unless otherwise specified. 
Sensitivity analyses will be described in the SAP. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-324 will be evaluated by AEs, concomitant medication usage, 
 
 Safety data will be listed by participant and summarized by treatment group. All 
safety summaries will be performed on the Safety Set using treatment received.  
13.6.1. 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 22.1 
or higher. A treatment-emergent adverse event (TEAE) is defined as an AE with onset after the 
first dose of IP. The analysis of AEs will be based on the concept of TEAEs. The incidence of 
TEAEs will be summarized by System Organ Class (SOC) and preferred term. In addition, 
summaries will be provided by intensity (mild, moderate, severe) and by causality (related, not 
related) to IP.  

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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.  
13.6.3. 
Physical Examinations 
The occurrence of a physical examination, including MSE, (yes/no) and the date performed will 
be listed by participant. 
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
All medications taken within 30 days prior to informed consent through the duration of the study 
will be recorded. In addition, all psychotropic medications taken in the previous 30 days prior to 
screening will be recorded. Those medications taken prior to the initiation of the start of IP will 
be denoted “Prior”. Those medications taken prior to the initiation of the IP and continuing 
beyond the initiation of the IP or those medications started at the same time or after the initiation 
of the IP will be denoted “Concomitant”.  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by participant, start date, and 
verbatim term.  

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13.8. 
Sample Size and Power 
The sample size of this study is based on the assumption of a 3 points difference in the change 
from baseline TETRAS performance subscale part 4 upper limb tremor score between 
SAGE-324 and placebo with a standard deviation of 3.5 points. Under these assumptions, a 
sample size of 25 evaluable participants per group would provide 85% power for detecting a 
placebo-adjusted treatment difference of 3 points in TETRAS performance subscale part 4 upper 
limb tremor score assuming a 2-sided test at an alpha level of 0.05. By including 2 treatment 
groups and using a 1:1 randomization, a total of 50 evaluable participants are required. Assuming 
a nonevaluability rate of 15%, approximately 60 participants will be randomized. Additional 
participants may be enrolled if the dropout rate is greater than 15%. 
13.8.1. 
Interim and Data Monitoring Committee (DMC) Analyses 
13.8.1.1. Interim Analysis 
The sponsor may conduct an interim analysis. Detailed descriptions of planned data analyses will 
be provided in a separate interim statistical analysis plan (SAP), if applicable. 

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13.8.1.2. DMC Analysis 
Not applicable 

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

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

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

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be given a written and 
dated approval or favorable opinion by an IRB or EC as appropriate. The investigator must 
obtain and document approval before he or she can enroll any participant into the study. The IRB 
or EC must supply to the sponsor a list of the IRB/EC membership and a statement to confirm 
that the IRB/EC is organized and operates according to GCP and applicable laws and 
regulations. 
The principal investigator is responsible for informing the IRB or EC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or EC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or EC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or EC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the IP. Sage 
Therapeutics will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or EC according to local regulations and guidelines. In addition, the principal investigator must 
inform the IRB/EC and sponsor of any changes significantly affecting the conduct of the trial 
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 trial 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 trial, the participant (or the participant’s, parent 
or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source records. The investigator must maintain 
the original, signed ICF. A copy of the signed ICF must be given to the participant or to the 
participant’s parent or legally authorized representative. 
Throughout the trial participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 
documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 

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

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18. 
PUBLICATION POLICY 
All information concerning SAGE-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. 

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Olanow CW. Hyperkinetic Movement Disorders: Essential Tremor. In: Harrison's Principles of 
Internal Medicine. Vol 2. 17th ed. New York, NY: McGraw Hill; 2008:2560. 
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. Epub 2012 
Aug 11. Review. Erratum in: J Neurol. 2013 Mar;260(3):741. 

 
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324-ETD-201_Protocol Administrative Letter #1_16Nov2020 
   Page 1 of 3 
 
 
324-ETD-201 Protocol Administrative Letter #1 
 
The purpose of this letter is to notify Investigators of an upcoming protocol amendment on the 
management of participants experiencing adverse events of somnolence or similar events.  
 
This letter should be submitted to the local Independent Review Board (IRB) and filed within 
the Investigator Site File. 
 
The following represents the minimum action an investigator must take in response to an 
experience of somnolence or similar adverse events experienced by a participant.  The 
investigator should, as always, continue to use their clinical judgement and institute drug 
holidays, dose reductions and IP discontinuations over and above these instructions to ensure 
the safety and well-being of all participants. 
 
If a participant experiences moderate or severe adverse events of somnolence, drowsiness, 
dizziness or similar on Day 1 or at any point during the treatment period: 
 The Investigator must carefully assess the participant before they leave the clinic 
 The Investigator must instruct the participant prior to resuming study drug dosing via 
phone call or in person to ensure that: 
o The participant has a drug holiday of at least one day (they must miss at least 
one dose) 
o The participant’s daily dose of study drug must then be reduced from 60 mg to 
45 mg when study drug dosing resumes 
 The Investigator must closely monitor the participant’s condition via phone call or in 
person visit to assess the effectiveness of the drug holiday and dose reduction. 
 
Following the first drug holiday and dose reduction, if the events persist and continue to be 
moderate or severe, or the participant experiences a new moderate or severe AE of 
somnolence, drowsiness, dizziness or similar:  
 The Investigator must instruct the participant prior to resuming study drug dosing via 
phone call or in person to ensure that: 
o The participant has another drug holiday of at least one day (they must miss at 
least one dose) 
o The participant’s daily dose of study drug must then be further reduced from 45 
mg to 30 mg when study drug dosing resumes 
 The Investigator must closely monitor the participant’s condition via phone call or in 
person visit to assess the effectiveness of the drug holiday and dose reduction 
 
DocuSign Envelope ID: 32AFE171-CE9C-45E4-B67E-71C2F2C1BDDD

 
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324-ETD-201_Protocol Administrative Letter #1_16Nov2020 
   Page 2 of 3 
 
Following the second drug holiday and dose reduction to 30 mg, if the events persist or recur 
and are moderate or severe: 
 The investigator must discontinue the participant from the Investigational Product (See 
Section 8.4.1 of Protocol: Investigational Product Discontinuation) 
  
If at any time somnolence, drowsiness, dizziness or similar events of any severity are also 
associated with symptoms such as confusion or balance impairment: 
 The Investigator must follow the instructions as above on drug holidays, dose reductions 
and IP discontinuation.  
 
 
 
 
 
 
 
 
 
____________________________________________                _________________________ 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________                _________________________ 
 
 
 
 
 
 
 
 
 
Date 
, MD  
    
 
 
 
 
DocuSign Envelope ID: 32AFE171-CE9C-45E4-B67E-71C2F2C1BDDD
16-Nov-2020 | 21:03 EST
16-Nov-2020 | 14:09 EST

 
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324-ETD-201_Protocol Administrative Letter #1_16Nov2020 
   Page 3 of 3 
 
 
 
 
 
_____________________________________              
   _________________________ 
 
 
 
 
 
 
 
 
 
Date 
  
  
 
 
  
 
 
 
 
____________________________________________                _________________________ 
 
 
 
 
 
 
 
 
 
Date 
, MD, 
   
DocuSign Envelope ID: 32AFE171-CE9C-45E4-B67E-71C2F2C1BDDD
16-Nov-2020 | 13:14 EST
16-Nov-2020 | 14:54 EST

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S a g e T h er a p e uti c s - P art 1 1
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I h a v e r e vi e w e d t hi s d o c u m e nt
S e nt: 1 6- N o v- 2 0 2 0 | 1 3: 0 4
R e s e nt: 1 6- N o v- 2 0 2 0 | 1 6: 1 9
Vi e w e d: 1 6- N o v- 2 0 2 0 | 2 0: 5 2 
Si g n e d: 1 6- N o v- 2 0 2 0 | 2 1: 0 3
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
S a g e T h er a p e uti c s - P art 1 1
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 1 6- N o v- 2 0 2 0 | 1 3: 0 4
Vi e w e d: 1 6- N o v- 2 0 2 0 | 1 4: 0 9 
Si g n e d: 1 6- N o v- 2 0 2 0 | 1 4: 0 9
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
S a g e T h er a p e uti c s - P art 1 1
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 1 6- N o v- 2 0 2 0 | 1 3: 0 4
Vi e w e d: 1 6- N o v- 2 0 2 0 | 1 3: 1 2 
Si g n e d: 1 6- N o v- 2 0 2 0 | 1 3: 1 4

Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
S a g e T h er a p e uti c s - P art 1 1
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 1 6- N o v- 2 0 2 0 | 1 3: 0 4
Vi e w e d: 1 6- N o v- 2 0 2 0 | 1 4: 5 3 
Si g n e d: 1 6- N o v- 2 0 2 0 | 1 4: 5 4
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p
A g e nt D eli v er y E v e nt s
St at u s
Ti m e st a m p
I nt er m e di ar y D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ertifi e d D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ar b o n C o p y E v e nt s
St at u s
Ti m e st a m p
Wit n e s s E v e nt s
Si g n at ur e
Ti m e st a m p
N ot ar y E v e nt s
Si g n at ur e
Ti m e st a m p
E n v el o p e S u m m ar y E v e nt s
St at u s
Ti m e st a m p s
E n v el o p e S e nt
H a s h e d/ E n cr y pt e d
1 6- N o v- 2 0 2 0 | 1 3: 0 4
C ertifi e d D eli v er e d
S e c urit y C h e c k e d
1 6- N o v- 2 0 2 0 | 1 4: 5 3
Si g ni n g C o m pl et e
S e c urit y C h e c k e d
1 6- N o v- 2 0 2 0 | 1 4: 5 4
C o m pl et e d
S e c urit y C h e c k e d
1 6- N o v- 2 0 2 0 | 2 1: 0 3
P a y m e nt E v e nt s
St at u s
Ti m e st a m p s