Clinical trial NCT02978781
Conditions: Essential Tremor
Keywords: Tremor
Sponsor: Biogen
Start date: 2017-03-24; Completion date: 2017-12-05
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a three-part, multicenter, Phase 2a study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of SAGE-217 in adult participants with essential tremor.

Detailed description:
Part A of the study was an open-label design with morning dosing of SAGE-217 for 7 days and included 16 participants, 8 of whom qualified for, and entered, Part B.

Part B had a double-blind, placebo-controlled, randomized withdrawal design with morning dosing for 7 days.

Part C was an open-label design with morning and evening dosing for 14 days and included a different set of 18 participants.

Parts A and B were stopped early (in advance of the planned sample size).

This study was previously posted by Sage Therapeutics. In November 2023, sponsorship of the trial was transferred to Biogen.

Arms: arm 1: Participants received SAGE-217 10 mg oral solution on Day 1, 20 mg on Day 2 and 30 mg on Days 3 to 7 with food in the morning. arm 2: Participants received SAGE-217 10 mg capsules on Day 1, 20 mg on Day 2 and 30 mg on Days 3 to 7, orally, with food in the morning. arm 3: Participants who received maximum tolerated dose of SAGE-217 in Part A and achieved response on Day 8 were randomized to receive to SAGE-217 matching placebo for 7 days beginning on Day 8 with food in the morning. arm 4: Participants who received maximum tolerated dose of SAGE-217 in Part A and achieved response on Day 8 were randomized to receive to SAGE-217 for 7 days beginning on Day 8 with food in the morning. arm 5: Participants received SAGE-217 10 mg capsules on Day 1, 20 mg on Day 2, 30 mg on Day 3, orally, with food in the evening. Beginning on Day 4 through Day 14, participants received a 40-mg total daily dose (administered as 10 mg with food in the morning and 30 mg with food in the evening).
Interventions: intervention 1: SAGE-217 intervention 2: SAGE-217 intervention 3: Placebo
Intervention descriptions: intervention 1: SAGE-217 Oral Solution intervention 2: SAGE-217 Capsules intervention 3: SAGE-217 matching placebo capsules

Protocol documents:
Prot_002.pdf: 
 
Official Title: 
 
A Phase 2A, Double-blind, Placebo-controlled, Randomized 
Withdrawal Study Evaluating the Efficacy, Safety, Tolerability, and 
Pharmacokinetics of SAGE-217 in the Treatment of Subjects with 
Essential Tremor (ET) 
NCT Number: NCT02978781 
Document Date: Protocol Version 5- 05 September 2017 
 
 
 


Clinical Study Report 
 
217-ETD-201 
16.1 Study Information 
 
1 
 
 
  
 
1. 
PROTOCOL AND AMENDMENTS 
 
Protocols and amendments 
 Protocol V5.0 Amendment #4 dated 05Sep2017 
 Protocol V4.0 Amendment #3 dated 28Apr2017 
 Protocol V3.0 Amendment #2 dated 27Jan2017 
 Protocol V2.0 Amendment #1 dated 28Oct2016 
 Protocol V1.0 dated 19Aug2016 






Protocol 217-ETD-201 
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3 
 
INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-217.  I have read the Clinical 
Protocol 217-ETD-201 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 


Protocol 217-ETD-201 
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CONTACTS IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sponsor Physician 
, M.D., M.P.H. 
 
Sage Therapeutics 
 
215 First Street, Suite 220 
Cambridge, MA 02142 
Cell: 
 
Sponsor Signatory 
, M.D., Ph.D. 
 
  
215 First Street, Suite 220 
Cambridge, MA 02142 
Office:
 
Cell: 
 
 
Medical Monitor 
 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street  
Cambridge, MA  02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
SAGE-217 Capsules 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 2a, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study 
Evaluating the Efficacy, Safety, Tolerability, and Pharmacokinetics of SAGE-217 in the Treatment of 
Subjects with Essential Tremor (ET) 
Study center(s):  Up to 25 centers 
Phase of development: 2a 
Methodology:  
This study will assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of SAGE-217.  
Subjects who consent prior to the approval of Protocol Amendment #3 by the IRB will receive the 
oral solution formulation for the duration of the study.  Subjects who consent after Amendment #3 is 
approved by the IRB will receive the capsule formulation for the duration of the study. 
There are three parts: 
Part A: Open-label with morning dosing (7 days). 
A screening period to determine subject eligibility will occur between Day -28 to Day -1.  All eligible 
subjects will start on a 10-mg dose of study drug administered with food on Day 1.  Subjects will 
receive 20 mg with food on Day 2 and 30 mg with food daily on Days 3 to 7.   
Part B: Double-blind, placebo-controlled, randomized withdrawal with morning dosing (7 days). 
In order to qualify for Part B of the study, a subject must tolerate a dose of at least 10 mg of 
SAGE-217, and the subject must have responded to SAGE-217, defined as a 30% reduction from 
baseline in the TRG Essential Tremor Rating Assessment Scale (TETRAS) kinetic tremor combined 
score (ie, the sum of item 4c scores from both sides of the body) predose on Day 8. 
Eligible subjects will be randomized in a 1:1 fashion to SAGE-217 or placebo and will receive their 
maximum dose as determined in Part A in the morning with food.  Subjects randomized to the 
placebo arm will represent randomized withdrawal (withdrawal from treatment they received in 
Part A). 
Subjects will be exposed to study drug (SAGE-217 or placebo) for up to 14 days and will be followed 
for an additional 14 days after the administration of the last dose.   
Part C: Open-label with evening dosing (14 days).  Subjects in Part C will not have participated in 
Part A or Part B.  
A screening period to determine subject eligibility will occur between Day -28 to Day -1. All eligible 
subjects will start on a 10-mg dose of study drug administered with food in the evening (8:00pm ±30 
min) on Day 1.  Subjects will receive 20 mg with food in the evening on Day 2, and 30 mg with food 
in the evening on Day 3. Beginning on Day 4 and continuing through Day 14, subjects will receive a 
40-mg total daily dose (administered as 10 mg with food in the morning [8:00am ±30 min] and 30 mg 


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with food in the evening [8:00pm ±30 min]). Study drug will be self-administered by subjects on an 
outpatient basis for the entire 14-day Treatment Period. Compliance with study drug administration 
will be monitored via a follow-up call from the site each evening (within approximately 1 hour 
following the scheduled evening dose) on Days 1-14.  
Subjects will be exposed to study drug (SAGE-217) for up to 14 days and will be followed for an 
additional 14 days after the administration of the last dose.   
Dose adjustments will only be allowed during the open-label phases of the study (Parts A and C). See 
Section 9.3  for dose adjustment criteria.   
Assessments will be performed periodically during Parts A, B, and C, as outlined in the Schedule of 
Events (Table 2, Table 3, and Table 4, respectively). 
Objectives and Endpoints: 
Primary Efficacy: 
o
For Parts A and B, the primary efficacy objective is to compare the effect of 7 days
administration of SAGE-217 Capsules to placebo on the change in tremor severity, as measured
by the change from randomization (Day 8) in the accelerometer-based Kinesia™ kinetic tremor
combined score (ie, the sum of Kinesia kinetic tremor scores from both sides of the body) at Day
14.
o
For Part C, the primary efficacy objective is to assess the effect of 14 days administration of
SAGE 217 Capsules on tremor severity, as measured by the change from baseline (Day 1) in the
accelerometer-based Kinesia™ upper limb tremor combined score (ie, the sum of accelerometer-
based Kinesia forward outstretched postural tremor, lateral "wing beating" postural tremor, and
kinetic tremor item scores from both sides of the body) at Day 15.
Secondary Efficacy: 
o
For Parts A and B, the secondary efficacy objectives are to compare the effect of 7 days
administration of SAGE-217 Capsules to placebo (Part A) and to assess the effect of 14 days
administration of SAGE-217 Capsules (Part B) on the following endpoints:
o
Tremor severity, as assessed by the change from randomization (Day 8) in the Kinesia
upper limb total score (ie, the sum of accelerometer-based Kinesia forward outstretched
postural tremor, lateral "wing beating" postural tremor, and kinetic tremor item scores
from both sides of the body) and individual item scores at Day 14.
o
Tremor severity, as measured by the change from randomization (Day 8) in the TETRAS
upper limb total score (ie, the sum of TETRAS Performance Subscale item 4 scores [4a,
4b, and 4c] from both sides of the body) and individual TETRAS Performance Subscale
upper limb item scores at Day 14.
o
Tremor severity, as assessed by the change from randomization (Day 8) in other
TETRAS Performance Subscale scores measured at Day 14.
The above endpoints may also be assessed for SAGE-217 Oral Solution if sufficient data are 
available.  
o
For Part C, the secondary efficacy objectives are to assess the effect of 14 days administration of
SAGE-217 Capsules on the following endpoints:
o
Tremor severity, as assessed by the change from baseline (Day 1) in the Kinesia upper
limb individual item scores at Day 15.
o
Tremor severity, as measured by the change from baseline (Day 1) in the TETRAS upper
limb total score (ie, the sum of TETRAS Performance Subscale item 4 scores [4a, 4b, and
4c] from both sides of the body) and individual TETRAS Performance Subscale upper
limb item scores at Day 15.


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o Tremor severity, as assessed by the change from baseline (Day 1) in the total TETRAS 
Performance subscale score and other TETRAS Performance Subscale scores measured 
at Day 15.   
Safety: 
Safety and tolerability, as assessed by vital signs measurements, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Severity 
Rating Scale (C-SSRS) and adverse event reporting.   
 
Exploratory: 
o For Parts A and B, the exploratory objectives are to compare the effect of 7 days administration 
of SAGE-217 Capsules to placebo on: 
o Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring), as assessed by the 
Empatica E4 Wristband.  Tremor oscillation, as assessed by multi-dimensional 
accelerometer measurements (ie, raw accelerometer values) using the Empatica E4 
Wristband. 
o Quality of life (QOL), as assessed by TETRAS activities of daily living (ADL), Quality 
of Life in Essential Tremor Questionnaire (QUEST), and video recording assessment of 
subjects performing three everyday tasks (drinking a glass of water, fastening a button, 
and one additional task that the subject experiences difficulty with on a daily basis).   
The above exploratory endpoints may also be assessed for SAGE-217 Oral Solution if sufficient 
data are available. 
o For Part C, the exploratory objectives are to assess the effect of 14 days administration of 
SAGE-217 Capsules on: 
o Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring), as assessed by the 
Empatica E4 Wristband.  Tremor oscillation, as assessed by multi-dimensional 
accelerometer measurements (ie, raw accelerometer values) using the Empatica E4 
Wristband. 
o Quality of life (QOL), as assessed by TETRAS activities of daily living (ADL), Quality 
of Life in Essential Tremor Questionnaire (QUEST), and video recording assessment of 
subjects performing three everyday tasks (drinking a glass of water, fastening a button, 
and one additional task that the subject experiences difficulty with on a daily basis).   
In addition, in Parts A, B, and C, plasma concentrations of SAGE-217 and SAGE-217 metabolites 
may be measured.  Pharmacokinetic parameters, such as area under the concentration-time curve from 
time zero to last time point (AUC0-t), area under the concentration-time curve from time zero to 
infinity (AUC0-∞), maximum plasma concentration (Cmax), time to reach maximum concentration 
(tmax), and terminal half-life (t½), will be derived, where appropriate.  PK/pharmacodynamic (PD) 
modelling assessment of the relationship between plasma exposure of SAGE-217 and change from 
baseline in Kinesia scores may be assessed. 
  
Number of subjects (planned):  
Parts A and B are closed to enrollment. For Part C, approximately 15 subjects will be enrolled to 
ensure at least 10 subjects complete the study (through Day 15). 
Diagnosis and main criteria for inclusion:  
Inclusion criteria: 


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1. Subject has signed an informed consent form before any study-specific procedures are performed. 
2. Subject must be between 18 and 80 years of age, inclusive. 
3. Subject must have a diagnosis of ET, defined as bilateral postural tremor and kinetic tremor, 
involving hands and forearms, that is visible and persistent and the duration is >5 years prior to 
screening. 
4. Subject must have bilateral TETRAS scores of at least two on each side (left and right) for kinetic 
tremor and at least two on each side (left and right) for either wing beating or forward 
outstretched postural tremor.   
5. Subject must be willing to discontinue medications taken for the treatment of ET, alcohol, 
nicotine, and caffeine through Day 21 of the study.   
6. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests.   
7. Intentionally blank (criteria removed in Amendment 4, Version 5) 
8. Intentionally blank (criteria removed in Amendment 4, Version 5) 
9. Intentionally blank (criteria removed in Amendment 4, Version 5) 
10. Subject agrees to use one of the following methods of contraception during participation in the 
study and for 30 days following the last dose of study drug, unless they are surgically sterile: 
• 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 
Exclusion criteria: 
1. Subject has presence of abnormal neurological signs other than tremor or Froment’s sign. 
2. Subject has presence of known causes of enhanced physiological tremor. 
3. Subject has concurrent or recent exposure (14 days prior to Day -1 visit) to tremorogenic drugs, as 
defined in Appendix 1, or the presence of a drug withdrawal state. 
4. Subject has had direct or indirect trauma to the nervous system within 3 months before the onset 
of tremor.  
5. Subject has historical or clinical evidence of tremor with psychogenic origin (including but not 
limited to eating disorders, major depression, etc.). 
6. Subject has convincing evidence of sudden tremor onset or evidence of stepwise deterioration of 
tremor. 
7. Subject has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or oncological disease. 
8. Intentionally blank (criteria removed in Amendment 4, Version 5) 


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9. Subject has a history, presence, and/or current evidence of serologic positive results for hepatitis 
B surface antigen, hepatitis C antibodies, or human immunodeficiency virus 1 or 2 antibodies. 
10. Subject has hypothyroidism.  Stable thyroid replacement is acceptable. 
11. Subject has used alcohol, caffeine, or nicotine within 3 days prior to the Day -1 visit. 
12. Subject has a known allergy to SAGE-217, or any capsule excipient. 
13. Subject has exposure to another investigational medication or device within the prior 30 days. 
14. Subject has a history of suicidal behavior within 2 years or answers “YES” to questions 3, 4, or 5 
on the C-SSRS at the Screening visit or on Day -1 or is currently at risk of suicide in the opinion 
of the Investigator. 
15. Subject has donated one or more units (1 unit = 450 mL) of blood or acute loss of an equivalent 
amount of blood within 60 days prior to dosing. 
16. Subject is unwilling or unable to comply with study procedures. 
17. Use of any known strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, as defined 
in Appendix 2, within the 14 days or 5 half-lives (whichever is longer) or consumed grapefruit 
juice, grapefruit, Seville oranges, pomegranates, tangelos, or St. John's Wort or products 
containing these within 30 days prior to receiving the first dose of study drug. 
18. Intentionally blank (criteria removed in Amendment 4, Version 5) 
19. Subject has concurrent or recent exposure (14 days prior to the Day -1 visit) to sedative/hypnotic 
(eg, opioids) drugs.   
20. Intentionally blank (criteria removed in Amendment 4, Version 5)    
Investigational product, dosage and mode of administration:  
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection and administered as an approximate 40 mL solution with a 10 mg, 20 mg, or 
30 mg dose given once daily in the morning with food. 
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white powder.  In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules contain 
croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl fumarate as 
excipients.  Capsules will be available in 5-mg, 10-mg and 20-mg dose strengths.   
See the Pharmacy Manual for information regarding which capsules are to be administered for each 
dose.   
Reference therapy, dosage and mode of administration:  
Placebo is available as a solution of 40% HPβCD and 0.0025% sucralose, which is further diluted 
with Sterile Water for Injection and administered as an approximate 40 mL solution given once daily 
in the morning with food in Part B.  Matched placebo capsules containing only the above-listed 
capsule excipients will be provided.  Subjects randomized to placebo treatment will be administered 
2 placebo capsules per day.   


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Duration of treatment:  
Screening Duration: up to 28 days; Treatment Period: 14 days; Follow-up: 14 days 
Planned Study Duration per Subject: up to 56 days 
Criteria for evaluation: 
Efficacy: 
Tremor severity will be measured by accelerometer-based Kinesia and clinician-rated TETRAS 
Performance Subscale scores.  The following measures will be exploratory measures.  Quality-of-life 
will be evaluated using the TETRAS ADL, QUEST, and video recording of subjects performing three 
everyday tasks.  Physiological activity (ie, sympathetic nervous system tone as measured by 
electrodermal activity, skin temperature monitoring, and heart rate monitoring) and tremor oscillation 
will be assessed by the Empatica E4 Wristband.   
Pharmacokinetics: 
Plasma will be collected to assay for concentrations of SAGE-217 and may be assayed for SAGE-217 
metabolites, if deemed necessary.  The following PK parameters will be derived from the plasma 
concentrations (where evaluable): AUC0-t, AUC0-∞, Cmax, tmax, and t½.   
Safety and Tolerability: 
Safety and tolerability of study drug will be evaluated by vital signs measurements, clinical laboratory 
measures, physical examination, ECGs, concomitant medication usage, C-SSRS, and adverse event 
reporting.  The Bond-Lader Mood Rating Scale and a DEQ-5 will be used to assess mood and 
perception of drug effects, respectively.   
Statistical methods: 
Study Populations 
The safety population is defined as all subjects who are administered at least one dose of study drug.   
The efficacy population will consist of all subjects in the safety population who complete at least one 
dose and have at least one post-dose efficacy evaluation (Kinesia assessment).   
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations.   
Efficacy Analysis 
Analyses will be done separately for each part. 
Efficacy data (including change from randomization or baseline values for accelerometer-derived 
Kinesia and clinician-rated TETRAS scores) will be summarized using appropriate descriptive 
statistics and listed by subject. 
The change from randomization or baseline in the Kinesia kinetic tremor combined score (ie, the sum 
of Kinesia kinetic tremor scores from both sides of the body) at Day 14 or 15 will be summarized by 
treatment.  Additionally, the change from randomization or baseline in the Kinesia upper limb total 
score and individual item scores at Day 14 or 15 will be summarized by treatment.   
The change from randomization or baseline in TETRAS upper limb total score, individual TETRAS 
Performance Subscale upper limb item scores, and other TETRAS Performance Subscale scores at 
Day 14 or 15 will also be summarized by treatment.   
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics and listed by 
subject.  Wherever necessary and appropriate, PK parameters will be dose-adjusted to account for 
individual differences in dose. 


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Safety Analysis 
Adverse events will be coded using Medical Dictionary for Regulatory Activities™.  The overall 
incidence of adverse events will be displayed by System Organ Class, preferred term, and dose group.  
Incidence of adverse events will also be presented by maximum severity and relationship to study 
drug.  Data from vital signs, clinical laboratory measures, ECG, and C-SSRS will be summarized 
using descriptive statistics by dose group, where applicable.  Continuous endpoints will be 
summarized with n, mean, standard deviation, median, minimum, and maximum.  In addition, change 
from baseline values will be calculated at each time point and will be summarized using the same 
summary statistics.  Out-of-range safety endpoints may be categorized as low or high, where 
applicable.  For all categorical endpoints, summaries will include counts and percentages.   
Sample Size 
Parts A and B are closed to enrollment. Approximately 15 subjects will be enrolled in Part C to 
ensure 10 subjects complete the study (through Day 15).  The sample size for Part C was selected 
based on clinical and not statistical considerations. 
 


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Table 2: 
Schedule of Events:  Part A (Open-Label) 
Visit Days 
Screening 
(Day -28 to Day -1) 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Body weight/height 
X 
 
 
 
 
 
 
 
 
Drug/alcohol screena 
X 
X 
 
 
 
 
 
 
 
Complete blood count/ 
serum chemistryb 
X 
X 
X 
X 
 
 
 
 
 
Pregnancy test  
X 
(serum) 
X 
(urine) 
 
 
 
 
 
 
 
Urinalysisb 
X 
X 
X 
X 
 
 
 
 
 
Hepatitis & HIV screen 
X 
 
 
 
 
 
 
 
 
Exploratory biochemistry 
samplec 
O 
 
 
 
O 
 
 
 
O 
Genetic sampled 
O 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetrye 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
 
X 
X 
X 
X 
 
 
X 
C-SSRSg 
X 
X 
X 
 
 
X 
X 
X 
X 
SSSh 
 
 
X 
X 
X 
X 
X 
X 
X 
Bond-Lader-VASi 
 
 
X 
X 
 
 
 
 
X 
DEQ-5j 
 
 
X 
 
 
 
 
 
X 


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Visit Days 
Screening 
(Day -28 to Day -1) 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Kinesia (accelerometer)k 
 
X 
X 
X 
X 
 
 
 
X 
TETRAS upper limb itemsk 
X 
X 
X 
X 
X 
 
 
 
X 
TETRAS (ADL Subscale and 
items 4, 6, 7, and 8 of 
Performance Subscale)l 
 
X 
 
 
 
 
 
 
X 
Empatica E4 Wristband m 
 
X 
X 
X 
X 
 
 
 
X 
QUEST 
 
X 
 
 
 
 
 
 
X 
Plasma PK samplesn 
 
 
X 
X 
X 
X 
X 
X 
X 
Administer study drugo 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
Prior/concomitant medicationsp 
X 
Videosq 
 
X 
 
 
 
 
 
 
X 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram; HIV = 
human immunodeficiency virus; O = optional; PK = pharmacokinetic; QUEST = Quality of Life in Essential Tremor Questionnaire; SSS = Stanford Sleepiness 
Scale; TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue score 
  
a A urine sample for assessment of selected drugs (sedative/hypnotics [eg, opioids], cotinine, and caffeine) and a breath sample for alcohol screen will be 
collected at screening and Day -1. 
b Screening and safety laboratory tests will be performed at screening, Day -1, predose on Day 1, and predose on Day 2. 
c An optional blood sample for exploratory biochemistry, where consent is given. 
d An optional genetic sample for biomarker testing, where consent is given. 
e Vital signs (heart rate, respiratory rate, temperature, and supine [for at least 5 minutes prior to the measurement] and standing [for at least 2 to 3 minutes] 
systolic and diastolic blood pressure) and pulse oximetry will be performed at screening (vital signs only) and Day -1, predose and at 1, 2, 3, 4, 6, and 8 hours 
postdose on Days 1, 2, 3, and 4, and predose on Days 5, 6, and 7.  Vital signs and pulse oximetry assessments will be performed within ±10 minutes of the 
scheduled times. 
f 12-lead ECGs will be performed at screening, predose, and at 1 and 8 hours (±10 minutes) postdose on Days 1, 2, 3, 4, and 7. 
g The C-SSRS will be performed at screening, on Day -1, 8 hours (±1 hour) postdose on Day 1, and predose on Days 4, 5, 6, and 7.  Baseline/Screening version 
of C-SSRS should be used on day of screening and Since Last Visit version should be used on all subsequent time points. 
h The SSS will be performed predose and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 1, 2, 3, and 4, and predose only on Days 5, 6, and 7.  The SSS is to be 
performed within ±10 minutes of the scheduled times. 


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i The Bond-Lader VAS will be performed predose and 2 hours (±10 minutes) postdose on Days 1, 2, and 7. 
j The DEQ-5 will be performed 2 hours (±10 minutes) postdose on Days 1 and 7. 
k Kinesia and TETRAS upper limb items will be performed at screening (TETRAS upper limb items only), on Day -1 (three assessments separated by at least 
30 minutes); single assessments will be performed predose and 2 and 8 hours (±30 minutes) postdose on Days 1, 2, 3, and 7.  In addition, the TETRAS upper 
limb items will be performed, while wearing the Empatica E4 Wristband, on Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3, and 7. All three 
maneuvers in the upper limb assessments (items 4a, 4b, and 4c) will be completed for both arms, first for the RIGHT arm and then for the LEFT. 
l TETRAS (ADL Subscale and items 4, 6, 7, and 8 of Performance Subscale) will be performed on Day -1 and predose (±30 minutes) on Day 7. 
m The Empatica E4 Wristband will be worn during the study visits while in clinic on Days -1, 1, 2, 3, and 7.  With the exception of during the TETRAS upper 
limb assessments, the Empatica E4 Wristband will be worn on the wrist that, of the two arms, exhibits more severe tremor symptoms.  During the TETRAS 
upper limb assessments on Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3, and 7, the Empatica E4 Wristband will be worn on the wrist 
corresponding to the side of the body being assessed. 
n Plasma pharmacokinetic samples will be taken predose (±5 minutes) and 0.25, 0.5, 1, 2, 4, and 8 hours postdose on Days 1 and 7 and predose on Days 2, 3, 4, 
5, and 6. 
o Study drug will be administered in the morning with food. 
p To include those taken within 2 weeks prior to informed consent and throughout the study. 
q Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis) will be taken on Day -1and predose on Day 7. 
 


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Table 3: 
Schedule of Events:  Part B (Randomized Withdrawal) 
Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21±1 
daya(Early 
Termination 
Visit) 
End of Study 
Day 28±1 day 
Randomization 
X 
 
 
 
 
 
 
 
 
Complete blood count/ 
serum chemistryb 
X 
X 
 
 
 
 
 
X 
 
Pregnancy testc 
X 
(urine) 
 
 
 
 
 
 
 
X 
(urine) 
Urinalysisb 
X 
X 
 
 
 
 
 
X 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pulse oximetryd 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGe 
X 
X 
X 
 
 
 
X 
X 
 
C-SSRSf 
X 
 
 
X 
X 
X 
X 
X 
X 
SSSg 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bond-Lader-VASh 
X 
X 
 
 
 
 
X 
X 
 
DEQ-5i 
X 
 
 
 
 
 
X 
 
 
Kinesia (accelerometer)j 
X 
X 
 
 
 
 
X 
X 
 
TETRAS upper limb itemsj 
X 
X 
 
 
 
 
X 
X 
 
TETRAS (ADL Subscale and 
items 4, 6, 7, and 8 of 
Performance Subscale)k 
 
 
 
 
 
 
X 
X 
 
Empatica E4 Wristband l 
X 
X 
 
 
 
 
X 
X 
 
QUEST 
 
 
 
 
 
 
X 
 
 
Plasma PK samplesm 
X 
X 
X 
X 
X 
X 
X 
 
 


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Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21±1 
daya(Early 
Termination 
Visit) 
End of Study 
Day 28±1 day 
Administer study drugn 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events 
X 
Concomitant medicationso 
X 
Videosp 
 
 
 
 
 
 
X 
X 
 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram;  
HIV = human immunodeficiency virus; PK = pharmacokinetic; QUEST = Quality of Life in Essential Tremor Questionnaire; SSS = Stanford Sleepiness Scale; 
TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue score 
a In addition to subjects who complete Part B, subjects who receive at least one dose of study drug and do not complete Part B will have a visit 1 week following 
the last dose of study drug to assess safety measures. 
b Safety laboratory tests will be performed predose on Day 8 and Day 9 and anytime during the visit on Day 21. 
c To be performed predose on Day 8 and anytime during the visit on Day 28. 
d Vital signs (heart rate, respiratory rate, temperature, and supine [for at least 5 minutes prior to the measurement] and standing [for at least 2 to 3 minutes] 
systolic and diastolic blood pressure) and pulse oximetry will be performed predose on Day 8 and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 8, 9, and 10, 
predose on Days 11, 12, 13, and 14, and anytime during the visit on Day 21.  Vital signs and pulse oximetry assessments will be performed within ±10 minutes 
of the scheduled times. 
e 12-lead ECGs will be performed at 1 and 8 hours (±10 minutes) postdose on Days 8, 9, 10, and 14, and anytime during the visit on Day 21. 
f The C-SSRS (Since Last Visit version) will be performed 8 hours (±1 hour) postdose on Days 8, 11, 12, 13 and 14 and anytime during the visits on Days 21 
and 28. 
g The SSS will be performed predose and 1, 2, 4, 6, and 8 hours postdose on Days 8, 9, 10, 11, 12, 13, and 14, and anytime during the visit on Day 21.  The SSS 
is to be performed within ±10 minutes of the scheduled times. 
h The Bond-Lader VAS will be performed predose and 2 hours (±10 minutes) postdose on Days 8, 9, and 14 and anytime during the visit on Day 21. 
i The DEQ-5 will be performed 2 hours (±10 minutes) postdose on Days 8 and 14. 
j Kinesia and TETRAS upper limb items will be performed predose, 2 and 8 hours (±30 minutes) postdose on Days 8, 9, and 14, and anytime during the visit on 
Day 21.  In addition, the TETRAS upper limb items will be performed, while wearing the Empatica E4 Wristband, 3 hours (±30 minutes) postdose on Days 8, 
9, and 14, and anytime during the visit on Day 21.  All three maneuvers in the upper limb assessments (items 4a, 4b, and 4c) will be completed for both arms, 
first for the RIGHT arm and then for the LEFT. 
k TETRAS ADL Subscale and items 4, 6, 7, and 8 of Performance Subscale will be performed predose (±30 minutes) on Day 14 and anytime during the visit on 
Day 21. 
l The Empatica E4 Wristband will be worn during the study visits while in clinic on Days 8, 9, 14, and 21.  With the exception of during the TETRAS upper 
limb assessments, the Empatica E4 Wristband will be worn on the wrist that, of the two arms, exhibits more severe tremor symptoms.  During the TETRAS 


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upper limb assessments 3 hours (±30 minutes) postdose on Days 8, 9, and 14 and anytime during the visit on Day 21, the Empatica E4 Wristband will be worn 
on the wrist corresponding to the side of the body being assessed. 
m Plasma pharmacokinetic samples will be taken predose (±5 minutes) on Days 8, 9, 10, 11, 12, 13, and 14. 
n Study drug will be administered in the morning with food. 
o To include those taken throughout the study. 
p Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis) will be taken predose on Day 14 and anytime during the visit on Day 21. 
 


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Table 4: 
Schedule of Events:  Part C (Open-Label) 
Study Procedure 
Study Period / Visit Day 
Screening 
Treatmenta 
Follow-up 
Day -28 to Day -1 
Day -1 
Day 1 
Day 8 
Day 15 
Day 21±1 dayb 
(Early Termination 
Visit) 
End of Study 
Day 28±1 day 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
X 
X 
X 
Body weight/height 
X 
 
 
 
 
 
 
Drug/alcohol screenc 
X 
X 
 
X 
 
 
 
Complete blood count/ 
serum chemistryd 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test  
X 
(serum) 
X 
(urine) 
 
 
 
X 
(urine) 
X 
(urine) 
Urinalysisd 
X 
X 
X 
X 
X 
X 
X 
Hepatitis & HIV screen 
X 
 
 
 
 
 
 
Exploratory biochemistry samplee 
O 
 
 
O 
O 
O 
 
Genetic samplef 
O 
 
 
 
 
O 
 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGh 
X 
X 
X 
X 
X 
X 
X 
C-SSRSi 
X 
X 
X 
X 
X 
X 
X 
Bond-Lader-VASj 
 
 
X 
X 
X 
X 
 
DEQ-5k 
 
 
 
X 
X 
X 
 


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Study Procedure 
Study Period / Visit Day 
Screening 
Treatmenta 
Follow-up 
Day -28 to Day -1 
Day -1 
Day 1 
Day 8 
Day 15 
Day 21±1 dayb 
(Early Termination 
Visit) 
End of Study 
Day 28±1 day 
Kinesia (accelerometer)l 
 
 
X 
X 
X 
X 
 
TETRAS Performance Subscalel 
X 
X 
X 
X 
X 
X 
 
TETRAS ADL Subscalem 
 
 
X 
X 
X 
X 
 
Empatica E4 Wristbandn 
 
X 
X 
X 
X 
 
 
QUEST 
 
 
X 
X 
X 
X 
 
Plasma PK sampleso 
 
 
X 
X 
X 
 
 
Dispense study drugp 
 
 
X 
X 
 
 
 
Adverse events/Serious adverse 
events 
X 
X 
Prior/concomitant medicationsq 
X 
X 
Videosr 
 
 
X 
X 
X 
X 
 
Treatment compliance calls 
 
 
X 
 
 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram; HIV = 
human immunodeficiency virus; O = optional; PK = pharmacokinetic; QUEST = Quality of Life in Essential Tremor Questionnaire; TETRAS = TRG Essential 
Tremor Rating Assessment Scale; VAS = visual analogue score. 
Note: Pre-dose assessments refer to the evening dose only. 
a An unscheduled visit may be needed if a dose adjustment is deemed necessary by the Investigator at any time during the treatment period in order for the 
adjusted dose to be dispensed. 
b In addition to subjects who complete Part C, subjects who receive at least one dose of study drug and do not complete Part C will have a visit 1 week following 
the last dose of study drug to assess safety measures. 
c A urine sample for assessment of selected drugs (sedative/hypnotics [eg, opioids], cotinine, and caffeine) and a breath sample for alcohol screen will be 
collected at screening, Day -1 and Day 8. 
d Screening and safety laboratory tests will be performed at screening, Day -1, predose on Day 1, predose on Day 8, on Day 15, and follow-up on Day 21 and 
Day 28. 
e An optional blood sample for exploratory biochemistry, where consent is given. 


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f An optional genetic sample for biomarker testing, where consent is given. 
g Vital signs (heart rate, respiratory rate, temperature, and supine [for at least 5 minutes prior to the measurement] and standing [for at least 2 to 3 minutes] 
systolic and diastolic blood pressure) will be performed at screening, Day -1, predose on Day 1 and Day 8, on Day 15, and at follow-up on Day 21 and Day 28.   
h 12-lead ECGs will be performed at screening, on Day -1, predose on Days 1 and 8, on Day 15, and follow-up on Days 21 and 28. 
i The C-SSRS will be performed at screening, on Day -1, predose on Days 1 and 8, on Day 15, and follow-up on Days 21 and 28.  Baseline/Screening version of 
C-SSRS should be used on day of screening and Since Last Visit version should be used on all subsequent time points. 
j The Bond-Lader VAS will be performed predose on Days 1 and 8, on Day 15, and follow-up on Day 21.  
k The DEQ-5 will be performed predose on Day 8, on Day 15, and follow-up on Day 21. 
l Kinesia and TETRAS Performance Subscale will be performed at screening and Day -1 (TETRAS Performance Subscale only), and predose on Days 1 and 8, 
on Day 15, and follow-up on Day 21.  
m TETRAS ADL Subscale will be performed predose on Days 1 and 8, on Day 15, and follow-up on Day 21. 
n The Empatica E4 Wristband will be worn at all times (except while bathing) during three 5-day intervals: at the start of the Day -1 visit until the morning of 
Day 4, at the start of the Day 8 visit until the morning of Day 12, and at the start of the Day 15 visit until the morning of Day 19.  The Empatica E4 Wristband 
will be worn on the wrist that, of the two arms, exhibits more severe tremor symptoms (i.e. tremor-dominant hand), as determined during screening. 
o Plasma pharmacokinetic samples will be taken predose on Days 1 and 8, and on Day 15. 
p Study drug will be dispensed at the scheduled clinic visits during the treatment period for outpatient administration daily with food (in the evening on Days 1-3 
and in the morning and in the evening on Days 4-14). 
q To include those taken within 2 weeks prior to informed consent and throughout the study. 
r Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis) will be taken predose on Day 1 and Day 8, on Day 15, and follow-up on Day 21. 
s A treatment compliance call will be made within approximately 60 minutes after the scheduled evening dose (between approximately 8:00PM and 9:00PM) on 
Days 1-14.   
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............21 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................26 
5. 
INTRODUCTION ......................................................................................................28 
5.1. 
Background of Essential Tremor and Unmet Medical Need ......................................28 
5.2. 
SAGE-217 ...................................................................................................................29 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 ..........................29 
5.3.1. 
Nonclinical Studies with SAGE-217 ..........................................................................29 
5.3.2. 
Clinical Experience .....................................................................................................30 
5.4. 
Potential Risks and Benefits .......................................................................................32 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................34 
6.1. 
Primary Efficacy Objective ........................................................................................34 
6.2. 
Secondary Efficacy Objectives ...................................................................................34 
6.3. 
Safety Objectives ........................................................................................................35 
6.4. 
Exploratory Objectives ...............................................................................................35 
7. 
INVESTIGATIONAL PLAN .....................................................................................37 
7.1. 
Overall Study Design ..................................................................................................37 
7.2. 
Blinding and Randomization ......................................................................................38 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................39 
8.1. 
Subject Inclusion Criteria ...........................................................................................39 
8.2. 
Subject Exclusion Criteria ..........................................................................................39 
8.3. 
Subject Withdrawal Criteria .......................................................................................41 
8.3.1. 
Study Drug Withdrawal ..............................................................................................41 
8.3.2. 
Criteria for Study Termination ...................................................................................41 
9. 
TREATMENT OF SUBJECTS ..................................................................................42 
9.1. 
Number of Subjects ....................................................................................................42 
9.2. 
Treatment Assignment ................................................................................................42 
9.2.1. 
Part A ..........................................................................................................................42 


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9.2.2. 
Part B ..........................................................................................................................42 
9.2.3. 
Part C ..........................................................................................................................42 
9.3. 
Dose Adjustment Criteria ...........................................................................................42 
9.4. 
Prior/Concomitant Medications and Restrictions .......................................................43 
9.4.1. 
Prior/Concomitant Medications ..................................................................................43 
9.4.2. 
Prohibited Medications ...............................................................................................43 
9.5. 
Treatment Compliance ................................................................................................43 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................45 
10.1. 
Study Drug ..................................................................................................................45 
10.1.1. 
SAGE-217 Oral Solution ............................................................................................45 
10.1.1.1. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL ...................................45 
10.1.2. 
SAGE-217 Capsules ...................................................................................................45 
10.2. 
Study Drug Packaging and Labeling ..........................................................................46 
10.3. 
Study Drug Storage .....................................................................................................46 
10.4. 
Administration and Study Drug Accountability .........................................................47 
10.4.1. 
Study Drug Administration.........................................................................................47 
10.4.2. 
Study Drug Accountability .........................................................................................47 
10.5. 
Study Drug Handling and Disposal ............................................................................47 
11. 
ASSESSMENT OF EFFICACY ................................................................................49 
11.1. 
Kinesia ........................................................................................................................49 
11.2. 
TRG Essential Tremor Rating Assessment Scale (TETRAS) Performance 
Scale ............................................................................................................................49 
11.3. 
Empatica E4 Wristband ..............................................................................................49 
11.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST) ....................................50 
11.5. 
Video Recording .........................................................................................................50 
12. 
PHARMACOKINETICS ...........................................................................................51 
12.1. 
Blood Sample Collection ............................................................................................51 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ..................................................51 
12.3. 
Sample Analysis .........................................................................................................51 
13. 
ASSESSMENT OF SAFETY .....................................................................................52 
13.1. 
Safety and Tolerability Parameters .............................................................................52 
13.1.1. 
Demographic/Medical History ...................................................................................52 
13.1.2. 
Vital Signs ..................................................................................................................52 


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13.1.3. 
Weight and Height ......................................................................................................52 
13.1.4. 
Physical Examination .................................................................................................52 
13.1.5. 
Electrocardiogram (ECG) ...........................................................................................52 
13.1.6. 
Laboratory Assessments .............................................................................................52 
13.1.6.1. 
Hematology .................................................................................................................53 
13.1.6.2. 
Blood Chemistry .........................................................................................................53 
13.1.6.3. 
Urinalysis ....................................................................................................................53 
13.1.6.4. 
Drugs Screen and Alcohol Test ..................................................................................53 
13.1.6.5. 
Virus Serology ............................................................................................................53 
13.1.6.6. 
Pregnancy Test ............................................................................................................53 
13.1.6.7. 
Exploratory Biochemistry ...........................................................................................53 
13.1.6.8. 
Genetic Testing ...........................................................................................................54 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................54 
13.1.8. 
Bond-Lader VAS Mood Scale ....................................................................................54 
13.1.9. 
Drug Effects Questionnaire (DEQ-5) .........................................................................54 
13.2. 
Adverse and Serious Adverse Events .........................................................................55 
13.2.1. 
Definition of Adverse Events .....................................................................................55 
13.2.1.1. 
Adverse Event .............................................................................................................55 
13.2.1.2. 
Suspected Adverse Reaction .......................................................................................55 
13.2.1.3. 
Serious Adverse Event ................................................................................................55 
13.2.2. 
Pregnancy ...................................................................................................................56 
13.3. 
Relationship to Study Drug ........................................................................................56 
13.4. 
Recording Adverse Events .........................................................................................56 
13.5. 
Reporting Serious Adverse Events .............................................................................57 
14. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................58 
14.1. 
Data Analysis Sets ......................................................................................................58 
14.2. 
Handling of Missing Data ...........................................................................................58 
14.3. 
Demographics and Baseline Characteristics ...............................................................58 
14.4. 
Primary Efficacy Endpoint .........................................................................................58 
14.5. 
Secondary Efficacy Endpoints ....................................................................................58 
14.6. 
Exploratory Efficacy Endpoints .................................................................................59 
14.7. 
Safety and Tolerability Analyses ................................................................................59 


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14.7.1. 
Adverse Events ...........................................................................................................59 
14.7.2. 
Vital Signs ..................................................................................................................59 
14.7.3. 
Physical Examinations ................................................................................................60 
14.7.4. 
12-Lead ECG ..............................................................................................................60 
14.7.5. 
Clinical Laboratory Evaluations .................................................................................60 
14.7.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................60 
14.7.7. 
Bond-Lader VAS Mood Scale ....................................................................................60 
14.7.8. 
Drug Effects Questionnaire (DEQ-5) .........................................................................60 
14.7.9. 
Prior and Concomitant Medications ...........................................................................60 
14.8. 
Pharmacokinetic Analysis ..........................................................................................61 
14.9. 
Determination of Sample Size ....................................................................................61 
14.10. 
Changes From Protocol Specified Analyses ...............................................................61 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................62 
15.1. 
Study Monitoring ........................................................................................................62 
15.2. 
Audits and Inspections ................................................................................................62 
15.3. 
Institutional Review Board (IRB) ...............................................................................63 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................64 
17. 
ETHICS ......................................................................................................................65 
17.1. 
Ethics Review .............................................................................................................65 
17.2. 
Ethical Conduct of the Study ......................................................................................65 
17.3. 
Written Informed Consent ..........................................................................................65 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................66 
18.1. 
Inspection of Records .................................................................................................66 
18.2. 
Retention of Records ..................................................................................................66 
18.3. 
Confidentiality ............................................................................................................66 
19. 
PUBLICATION POLICY ..........................................................................................68 
20. 
LIST OF REFERENCES ............................................................................................69 
21. 
APPENDICES ............................................................................................................72 
APPENDIX 1. TREMOROGENIC DRUGS ..............................................................................73 
APPENDIX 2. STRONG INHIBITORS AND INDUCERS OF CYP3A4 ................................75 
APPENDIX 3. TRG ESSENTIAL TREMOR RATING ASSESSMENT SCALE 
(TETRAS) ..........................................................................................................76 


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APPENDIX 4. QUALITY OF LIFE IN ESSENTIAL TREMOR QUESTIONNAIRE 
(QUEST).............................................................................................................82 
APPENDIX 5. COLUMBIA – SUICIDE SEVERITY RATING SCALE (C-SSRS) ................84 
APPENDIX 6. BOND-LADER VAS (MOOD RATING SCALE) ...........................................91 
APPENDIX 7. DRUG EFFECTS QUESTIONNAIRE (DEQ-5) ...............................................92 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events:  Part A (Open-Label) .................................................................12 
Table 3: 
Schedule of Events:  Part B (Randomized Withdrawal) ............................................15 
Table 4: 
Schedule of Events:  Part C (Open-Label) .................................................................18 
Table 5: 
Abbreviations and Specialist Terms ...........................................................................26 
Table 6: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL..................45 
 
LIST OF FIGURES 
Figure 1. 
Simulated Concentration-Time Curves for SAGE-217 Capsules with Daily 
and Twice Daily Dosing .............................................................................................32 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 5: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
ADL 
activities of daily living 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-t 
area under the concentration-time curve from time zero to last 
time point 
AUC0-∞  
area under the concentration-time curve from time zero to infinity 
BMI 
body mass index 
Cmax  
maximum plasma concentration 
CNS 
central nervous system 
CRF 
case report form 
CS 
clinically significant  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450  
DEQ-5 
Drug Effects Questionnaire 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
ET 
essential tremor 
GABA 
γ-aminobutyric acid 
GABAA 
γ-aminobutyric acid-ligand gated chloride channel 
GABAB 
γ-aminobutyric acid-G protein-coupled 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg  
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxypropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 


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Abbreviation or Specialist Term 
Explanation 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
NCS 
not clinically significant 
NF  
National Formulary 
PI 
Principal Investigator 
PK 
pharmacokinetic 
QOL 
quality of life 
QTcF 
QT interval calculated using the Fridericia method 
QUEST 
Quality of Life in Essential Tremor Questionnaire 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAEs 
treatment-emergent adverse events 
TETRAS 
TRG Essential Tremor Rating Assessment Scale 
t1/2 
terminal half-life 
tmax  
time to reach maximum concentration 
USP  
United States Pharmacopeia 
VAS 
visual analogue score 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 
WMA 
World Medical Association 
 


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5. 
INTRODUCTION 
5.1. 
Background of Essential Tremor and Unmet Medical Need 
Essential tremor (ET) is among the most common neurological diseases, with an overall 
prevalence of 0.9%.  Prevalence increases with age and is estimated to be 4.6% in people over 
65 years of age (Louis 2010, Deuschl 2011).  Essential tremor is largely a bilateral, symmetrical 
postural or kinetic tremor involving hands and forearms that is visible and persistent.  Additional 
or isolated tremor of the head or lower limbs may occur, but in the absence of abnormal 
posturing (Deuschl 1998, Habib-ur-Rehman 2000).  The onset of tremor has a bimodal 
distribution, with onset between 15 to 20 and 50 to 70 years.  Over time, tremors can become 
more pronounced and may prevent eating, drinking, and writing, as well as executing personal 
hygiene like shaving or applying make-up.  Voice tremors can be severe enough to inhibit 
talking and singing in public.   
Several lines of evidence suggest that cerebellar dysfunction through the 
cerebellothalamocortical pathway plays a key role in ET (McAuley 2000, Pinto 2003, 
Elble 2009, Schnitzler 2009, Deuschl 2009).  Thalamotomy and deep brain stimulation of the 
ventral intermediate nucleus and of the subthalamic nucleus improve ET (Deuschl 2011, 
Zappia 2013, Rajput 2014).  Microscopic cerebellar pathology has been identified, including 
gliosis, Purkinje cell loss, and increased torpedoes (swellings) in the Purkinje cell axons 
(Louis 2007, Axelrad 2008, Shill 2008, Louis 2009).  Activation studies with positron emission 
tomography indicate abnormally increased regional cerebral blood flow in the cerebellum both at 
rest and when tremor is provoked by unilateral arm extension (Boecker 1994, Wills 1996).   
Essential tremor is associated with impaired γ-aminobutyric acid (GABA)ergic function (and 
consequent hyperactivity) in the cerebellum (Málly 1996, Bucher 1997, Louis 2007, Louis 2008, 
Paris-Robidas 2012).  γ-aminobutyric acid, the major inhibitory neurotransmitter in the central 
nervous system (CNS), is released from GABAergic neurons and binds to several types of 
GABA receptors (γ-aminobutyric acid-ligand gated chloride channel [GABAA] and 
γ-aminobutyric acid-G protein-coupled [GABAB]) on target neurons.  γ-aminobutyric acid-gated 
chloride channel receptors, the major class of inhibitory neurotransmitter receptors in the brain, 
are macromolecular proteins that form a chloride ion channel complex and contain specific 
binding sites for GABA and a number of allosteric regulators, including barbiturates, 
benzodiazepines, and some anesthetic agents.   
Drugs acting on GABAA receptors, such as primidone, benzodiazepines, or ethanol decrease 
tremor amplitude, suggesting that altered GABAergic neurotransmission is involved in ET.  
Postmortem analysis revealed a 35% reduction of GABAA receptors and a 22% to 31% reduction 
of GABAB receptors in the dentate nucleus of cerebella of ET subjects (Paris-Robidas 2012).  
Reduced levels of GABA in the cerebrospinal fluid are also reported in ET subjects 
(Málly 1996).  Moreover, toxins such as aflatrem, penitrem A, or harmaline have been proposed 
to induce tremor in rodents by interacting with GABA receptors (Cavanagh 1998, Miwa 2007), 
and targeted deletion of the α1 subunit of GABAA receptor in knockout mice exhibits a 
15 to 19 Hz action tremor, similar to ET in humans (Kralic 2005).   
Consistent with the role of GABA, the majority of therapeutics for ET act by augmenting 
GABAergic transmission (Louis 2012, Benito-Leon 2007, Pahapill 1999).  First-line treatments 


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for ET include the anticonvulsant primidone and the β-adrenergic blocker propranolol 
(Gorman 1986).  Like primidone, gabapentin is an anticonvulsant found to be effective in the 
treatment of ET (O’Brien 1981, Gironell 1999).  The oldest treatment for ET is ethanol, which 
temporarily ameliorates tremor and is frequently used by subjects to self-medicate; however, 
chronic use of ethanol for tremor management carries the known risks of alcohol dependence and 
overuse (Pahwa 2003).   
These treatments are moderately effective, reducing, though not resolving, tremor amplitudes in 
about 50% of the subjects (Schmouth 2014).  In addition, one out of three patients abandon 
treatment because of side effects or poor efficacy (Louis 2010), illustrating that with few feasible 
treatment options and a range of handicaps in daily living makes ET an area of high unmet 
medical need.   
5.2. 
SAGE-217  
SAGE-217 is a positive allosteric modulator of the GABAA receptor and thus is expected to be 
of benefit for the treatment of ET.  Unlike benzodiazepines that are selective for the γ-subunit-
containing subset of GABAA receptors (Pritchett 1989, Esmaeili 2009), SAGE-217 and other 
neuroactive steroids, which bind to the ubiquitous α-subunit, have a wider range of activity 
(Belelli 2002). 
Two dosage forms of SAGE-217 for oral administration will be used in this study (SAGE-217 
Oral Solution and SAGE-217 Capsules). 
SAGE-217 Oral Solution 6 mg/mL (40% w/w aqueous hydroxypropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a nonviscous, clear solution.   
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white 
powder. In addition to SAGE-217 Drug Substance, the active, SAGE-217 capsules contain 
croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl 
fumarate as excipients. 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 
5.3.1. 
Nonclinical Studies with SAGE-217 
In nonclinical studies of SAGE-217, sedative-hypnotic effects were consistently observed at 
higher doses in both in vivo pharmacology studies as well as in toxicology studies.  The 
sedative-hypnotic impairments seen with SAGE-217 were typical for GABAA positive 
modulators, ranging from hyperexcitability and ataxia at the lower doses through deep sedation 
and ultimately anesthesia at higher doses.  Depth and duration of sedation demonstrated a clear 
dose response over the range tested, with evidence of tolerance occurring with continued 
exposure.  Tolerance to the effects of SAGE-217 on motor incoordination was not observed after 
7 days of dosing.   
The compound has been assessed in 14-day rat and dog toxicology studies with daily 
administration of SAGE-217 as a solution in HPβCD in dogs and Labrasol® in rats.  The no 
observed adverse effect level was 3 mg/kg (females) and 22.5 mg/kg (males) in rats and 
2.5 mg/kg in dogs.  There were no adverse effects in dogs or rats in the main toxicology studies.  
A single observation of mortality occurred in one female rat at the high dose in a toxicokinetic 


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study which was suspected to have been related to exaggerated pharmacology.  Additional 
toxicology and pharmacology information is provided in the Investigator’s Brochure.   
5.3.2. 
Clinical Experience 
To date, two clinical studies employing SAGE-217 Oral Solution are clinically complete and 
final clinical study reports are pending.  Discussions of pharmacokinetic (PK) data are limited to 
the single-ascending dose, food, and essential tremor cohorts from Study 217-CLP-101 and the 
multiple-ascending dose and drug-drug interaction (DDI) cohorts from Study 217-CLP-102.  
Discussions of safety data are limited to the single-ascending dose cohorts in Study 217-CLP-
101 and the multiple-ascending dose cohorts in Study 217-CLP-102.  In addition, one clinical 
study of the safety, tolerability, PK, and relative bioavailability SAGE-217 Capsules is clinically 
complete and the final study report is pending.  The results of this study (217-CLP-103) are 
briefly described below. 
Study 217-CLP-101 was a first-in-human, four-part study that assessed the effects of a single 
dose of SAGE-217 Oral Solution.  The study was a double-blind, placebo-controlled, single-
ascending dose design in healthy adult volunteers, with the objective of identifying the maximum 
tolerated dose (MTD) and PK profiles of SAGE-217 Oral Solution.  Subjects in each of the 
single-ascending dose cohorts received a single dose of study drug, either SAGE-217 Oral 
Solution (six subjects) or placebo (two subjects), with SAGE-217 Oral Solution doses of 
0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 mg, 55 mg, and 66 mg.  Escalation to the 
next dose was undertaken only after safety and PK data were reviewed by the Safety Review 
Committee (SRC) and agreement reached that it was safe to increase the dose.  The MTD was 
determined to be 55 mg.  Two cohorts, 6 subjects each received SAGE-217 Oral Solution in an 
open-label manner (one cohort received 50% of the MTD [22 mg] to study the food effects and 
the other cohort received the MTD [55 mg] to study the effects on subjects with essential 
tremor).  SAGE-217 Oral Solution was orally bioavailable, demonstrated dose-linear PK from 
the lowest (0.25 mg) through the highest (66 mg) dose, and supported once daily oral dosing 
with food.   
Study 217-CLP-102 was a two-part study that assessed the effects of multiple-ascending doses of 
SAGE-217 Oral Solution.  The study was a double-blind, placebo-controlled, multiple-ascending 
dose study in healthy adult volunteers.  Subjects in each of the multiple-ascending dose cohorts 
received study drug, either SAGE-217 Oral Solution (nine subjects) or placebo (three subjects), 
once daily for 7 days, with SAGE-217 Oral Solution doses of 15 mg, 30 mg, and 35 mg.  
Escalation to the next dose was undertaken only after safety and PK data were reviewed by the 
SRC and agreement reached that it was safe to increase the dose.  The MTD was determined to 
be 30 mg.  It was observed that subjects receiving the drug in the evening did better in terms of 
tolerability compared to when they received the drug in the morning.  A fourth cohort of 12 
subjects received 30 mg of SAGE-217 Oral Solution in an open-label manner to study drug-drug 
interactions.  SAGE-217 Oral Solution is not likely to induce the metabolism of CYP2B6 or 
CYP3A4 substrates.  SAGE-217 Oral Solution was orally bioavailable and suitable for once 
daily oral dosing at night time with food.   
SAGE-217 Oral Solution was generally well tolerated.  In both Phase 1 studies (217-CLP-101 
and 217-CLP-102), doses were escalated until the stopping criteria were met.  Most adverse 
events were reported as mild or moderate in intensity, and there were no serious adverse events 


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reported in either study.  In addition, none of the observed adverse events resulted in 
discontinuation of the study drug.  At doses planned for further study, the observed sedation was 
mild, transient, and associated with daily peak exposure.  The most common treatment-emergent 
adverse events were sedation, somnolence, dizziness, euphoric mood, fatigue, tremor, and 
muscle twitching, reported most frequently in the highest dose group (66 mg).  Some changes in 
mean blood pressure and heart rate were observed after single doses of 44 mg and greater.  After 
multiple doses of 30 mg (AM or PM) or 35 mg (PM) over 7 days, there was no evidence of 
changes in mean vital sign measures even though Day 7 plasma concentrations approximated 
that of the highest single dose in the single-ascending dose study.  Subjects seemed to tolerate 
SAGE-217 Oral Solution better when given as night time dosing.   
The safety, tolerability, PK, and relative bioavailability of the SAGE-217 Capsules were 
assessed in a Phase 1 randomized, open-label, cross-over study (Study 217-CLP-103). In the 
fasted state, SAGE-217 Capsules demonstrated reduced exposure in terms of maximum (peak) 
plasma concentration (Cmax) and area under the curve from zero to the time of the last 
quantifiable concentration (AUClast) compared to SAGE-217 Oral Solution.  SAGE-217 Capsules 
administered in the fed state (with standard and high-fat meal) showed increased exposure 
compared to the fasted state and approximately equivalent exposure in terms of geometric mean 
AUClast compared to SAGE-217 Oral Solution; however, the Cmax for SAGE-217 Capsules was 
reduced by approximately 50% when compared with SAGE-217 Oral Solution.  Based on these 
study results, exposures with SAGE-217 Capsules are anticipated to be equal to or less than 
exposures observed at the same dose with SAGE-217 Oral Solution.  
The present study is the first study of SAGE-217 in ET.  Preliminary results of the present study 
demonstrated continued improvement in TETRAS Upper Limb Score over the course of the 7-
day treatment with a 30 mg SAGE-217 dose administered each morning.  While general 
improvement was observed, there were two apparent opportunities to optimize the therapeutic 
utility of SAGE-217 in ETD patients. First, sedation events coincided near the time that SAGE-
217 reaches maximal concentrations in plasma.  Accordingly, the dose will be administered in 
the evening in Part C to minimize the impact of sedation.  Second, an apparent diminution of 
TETRAS response was observed at the end of the dosing interval; therefore, in Part C, an 
additional 10 mg dose will be given in the morning with the intention of elevating plasma 
concentrations of SAGE-217 to levels associated with beneficial effects, but where sedation is 
unlikely. 
The divided dose regimen will prolong plasma concentrations of SAGE-217, and will increase 
the Cmax by approximately 11% at steady-state compared to dosing once per day.  Model 
predictions are dose-proportional and, as such, the 24-hour AUC is expected to increase by  
1.33-fold based on the increase in total daily dose from 30 to 40 mg in Part C.  Figure 1 
compares PK profiles of the dose regimen used in Parts A and B and the proposed 30+10mg 
regimen in Part C. 


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Figure 1. 
Simulated Concentration-Time Curves for SAGE-217 Capsules with Daily 
and Twice Daily Dosing 
 
QD = once daily 
NOTE:  Simulations represent the median and 10th to 90th percentiles of the expected plasma concentrations for the 
regimens as indicated on Day 1 and at steady-state. 
5.4. 
Potential Risks and Benefits 
Protocol 217-ETD-201 is the first clinical study of SAGE-217 in ET evaluating the efficacy of 
this product.  Thus, the potential benefits in this population are unknown, although the risks are 


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likely to be similar to those mentioned in the Investigator’s Brochure.  Many compounds that 
target the GABAA receptors exhibit clinical efficacy in ET, validating this receptor as a 
therapeutic target.  Given the promising SAGE-547 clinical data in conjunction with the shared 
broad receptor selectivity profile, oral bioavailability, long half-life, preclinical evidence of 
anxiolytic activity and safety data of SAGE-217, it is possible that patients may have a clinical 
benefit at the exposures selected for this study.  In view of the few risks associated with 
administration of SAGE-217 that have been identified to date, an intra-patient dose-escalation 
design has been chosen to permit titration of treatment effect vs tolerability (adverse events), 
specifically sedation.  Given the high medical need and potential for benefit in ET, there is a 
favorable benefit-risk evaluation to investigate SAGE-217 in ET.   
In the 217-CLP-103 study, SAGE-217 Capsules were found to be generally well-tolerated with 
no serious AEs reported during the treatment and follow-up periods.  The most frequent AE 
observed was sedation that was mild, transient, and occurred within 1 to 4 hours and generally 
dissipated by 8 hours.  The clinical portion of this study has recently completed; the final report 
is in progress. 
In conclusion, selection criteria for the proposed study take into account the potential safety 
risks. Safety monitoring, and the implementation of a formal dose-reduction and study drug 
discontinuation scheme also have the potential to mitigate risk.  From a benefit/risk perspective, 
the appropriate measures are being taken in order to ensure the safety of the subjects who will be 
enrolled.   


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Efficacy Objective 
• For Parts A and B, the primary efficacy objective is to compare the effect of 7 days 
administration of SAGE-217 Capsules to placebo on the change in tremor severity, as 
measured by the change from randomization (Day 8) in the accelerometer-based 
Kinesia™ kinetic tremor combined score (ie, the sum of Kinesia kinetic tremor scores 
from both sides of the body) at Day 14. 
For Part C, the primary efficacy objective is to assess the effect of 14 days 
administration of SAGE 217 Capsules on tremor severity, as measured by the change 
from baseline (Day 1) in the accelerometer-based Kinesia™ upper limb tremor 
combined score (ie, the sum of accelerometer-based Kinesia forward outstretched 
postural tremor, lateral "wing beating" postural tremor, and kinetic tremor item scores 
from both sides of the body) at Day 15.   
6.2. 
Secondary Efficacy Objectives 
• For Parts A and B, the secondary efficacy objectives are to compare the effect of 7 
days administration of SAGE-217 Capsules to placebo on the following endpoints: 
− Tremor severity as assessed by the change from randomization (Day 8) in the 
Kinesia upper limb total score (ie, the sum of accelerometer-based Kinesia 
forward outstretched postural tremor, lateral “wing beating” postural tremor, and 
kinetic tremor item scores from both sides of the body) and individual item scores 
at Day 14. 
− Tremor severity as measured by the change from randomization (Day 8) in TRG 
Essential Tremor Rating Assessment Scale (TETRAS) upper limb total score (ie, 
the sum of TETRAS Performance Subscale item 4 scores [4a, 4b, and 4c] from 
both sides of the body) and individual TETRAS Performance Subscale upper limb 
item scores at Day 14. 
− Tremor severity as assessed by the change from randomization (Day 8) in other 
TETRAS Performance Subscale scores measured at Day 14. 
The above endpoints may also be assessed for SAGE-217 Oral Solution if sufficient data are 
available.  
• For Part C, the secondary objectives are to assess the effect of 14 days administration 
of SAGE-217 Capsules on the following endpoints: 
− Tremor severity, as assessed by the change from baseline (Day 1) in the Kinesia 
upper limb individual item scores at Day 15.   
− Tremor severity, as measured by the change from baseline (Day 1) in the 
TETRAS upper limb total score (ie, the sum of TETRAS Performance Subscale 
item 4 scores [4a, 4b, and 4c] from both sides of the body) and individual 
TETRAS Performance Subscale upper limb item scores at Day 15.   


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− Tremor severity, as assessed by the change from baseline (Day 1) in the total 
TETRAS Performance subscale score and other TETRAS Performance Subscale 
scores measured at Day 15.  
6.3. 
Safety Objectives 
For Parts A, B, and C, safety and tolerability, as assessed by vital signs measurements, clinical 
laboratory data, electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-
Suicide Severity Rating Scale (C-SSRS), and adverse event reporting.   
6.4. 
Exploratory Objectives 
• For Parts A and B, the exploratory objectives are to compare the effect of 7 days 
administration of SAGE-217 Capsules to placebo on: 
− Physiological activity (ie, sympathetic nervous system tone as measured by 
electrodermal activity, skin temperature monitoring, and heart rate monitoring) as 
assessed by the Empatica E4 Wristband.  Tremor oscillation as assessed by 
multidimensional accelerometer measurements (ie, raw accelerometer values) 
using the Empatica E4 Wristband. 
− Quality of life (QOL) as assessed by TETRAS activities of daily living (ADL), 
Quality of Life in Essential Tremor Questionnaire (QUEST), and video recording 
assessment of subjects performing three everyday tasks (drinking a glass of water, 
fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis). 
The above exploratory endpoints may also be assessed for SAGE-217 Oral Solution if sufficient 
data are available.  
• For Part C, the exploratory objectives are to assess the effect of 14 days 
administration of SAGE 217 Capsules on: 
− Physiological activity (ie, sympathetic nervous system tone as measured by 
electrodermal activity, skin temperature monitoring, and heart rate monitoring), as 
assessed by the Empatica E4 Wristband.  Tremor oscillation, as assessed by multi-
dimensional accelerometer measurements (ie, raw accelerometer values) using the 
Empatica E4 Wristband. 
− Quality of life (QOL), as assessed by TETRAS activities of daily living (ADL), 
Quality of Life in Essential Tremor Questionnaire (QUEST), and video recording 
assessment of subjects performing three everyday tasks (drinking a glass of water, 
fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis).   
In addition, in Parts A, B, and C, plasma concentrations of SAGE-217 and SAGE-217 
metabolites may be measured.  Pharmacokinetic parameters, such as area under the 
concentration-time curve from time zero to last time point (AUC0-t), area under the 
concentration-time curve from time zero to infinity (AUC0-∞), maximum plasma concentration 
(Cmax), time to reach maximum concentration (tmax), and terminal half-life (t½), will be derived, 


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where appropriate.  PK and pharmacodynamic modelling assessment of the relationship between 
plasma exposure of SAGE-217 and change from baseline in Kinesia scores may be assessed.   


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study is a three-part, multicenter, Phase 2a study to evaluate the efficacy, safety, 
tolerability, and PK of SAGE-217 in approximately 60 adult subjects with ET.  Subjects who 
consent prior to the approval of Protocol Amendment #3 by the IRB will receive the oral solution 
formulation for the duration of the study.  Subjects who consent after Amendment #3 is approved 
by the IRB will receive the capsule formulation for the duration of the study. 
Part A of the study is an open-label design with morning dosing for 7 days.  Part B of the study is 
a double-blind, placebo-controlled, randomized withdrawal design.  Subjects will be exposed to 
study drug (SAGE-217 or placebo) for up to 14 days.  Part C of the study is an open-label design 
with evening dosing (and morning and evening dosing beginning on Day 4) for up to 14 days.  
All subjects will be followed for an additional 14 days after the administration of the last dose.   
During the Screening Period (Day -28 to Day -1), after signing the informed consent form (ICF), 
subjects will be assessed for study eligibility and the severity of each subject’s ET will be 
evaluated using TETRAS.  Eligible subjects will return to the clinical study unit on Day -1.   
The study will be conducted in three parts: 
• Part A:  Beginning on Day 1, all subjects will receive open-label SAGE-217 in the 
morning with food (as outlined in Section 9.2) for 7 days.  Subjects will receive 
SAGE-217 10 mg on Day 1, SAGE-217 20 mg on Day 2, and SAGE-217 30 mg from 
Day 3 to Day 7, with dose adjustments for severe adverse events judged by the 
Investigator to be related to study drug (Section 9.3). 
• Part B:  In order to qualify for Part B of the study, a subject must tolerate a dose of 
≥10 mg of SAGE-217, and the subject must have responded to SAGE-217, defined as 
a 30% reduction from baseline in TETRAS kinetic tremor (item 4c) combined score 
predose on Day 8.  Eligible subjects will be randomized in a 1:1 fashion to receive 
SAGE-217 or placebo for 7 days beginning on Day 8.  All doses of study drug will be 
administered with food as outlined in Section 9.2.  Subjects randomized to SAGE-217 
or placebo will receive their maximum dose as determined in Part A in the morning 
with food. 
• Part C:  All eligible subjects will start on a 10-mg dose of study drug administered 
with food in the evening on Day 1, 20 mg with food in the evening on Day 2, and 
30 mg with food in the evening on Day 3.  Beginning on Day 4 and continuing 
through Day 14, subjects will receive a 40-mg total daily dose (administered as 10 mg 
with food in the morning and 30 mg with food in the evening).  Study drug will be 
self-administered by subjects on an outpatient basis for the entire 14-day Treatment 
Period. 
Dose adjustments will only be allowed during the open-label phases of the study (Parts A and C, 
see Section 9.3 for Dose Adjustment Criteria).   


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7.2. 
Blinding and Randomization 
The double-blind portion of this study (Part B) is closed to enrollment. Part C is open-label with 
no control group; therefore, there will be no randomization or blinding.   


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
It is anticipated that up to 60 subjects will be enrolled at up to 25 study centers.  The following 
inclusion and exclusion criteria will be applied during screening for Part A of the study.  
8.1. 
Subject Inclusion Criteria 
Subjects must meet the following inclusion criteria for enrollment in the study: 
1. Subject has signed an ICF before any study-specific procedures are performed.   
2. Subject must be between 18 and 80 years of age, inclusive. 
3. Subject must have a diagnosis of ET, defined as bilateral postural tremor and kinetic 
tremor, involving hands and forearms, that is visible and persistent and the duration is 
>5 years prior to screening. 
4. Subject must have bilateral TETRAS scores of at least two on each side (left and right) 
for kinetic tremor and at least two on each side (left and right) for either wing beating or 
forward outstretched postural tremor.   
5. Subject must be willing to discontinue medications taken for the treatment of ET, 
alcohol, nicotine, and caffeine through Day 21 of the study.   
6. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. 
7. Intentionally blank (criteria removed in Amendment 4, Version 5) 
8. Intentionally blank (criteria removed in Amendment 4, Version 5) 
9. Intentionally blank (criteria removed in Amendment 4, Version 5)  
10. Subject agrees to use one of the following methods of contraception during participation 
in the study and for 30 days following the last dose of study drug, unless they are 
surgically sterile: 
• 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 
8.2. 
Subject Exclusion Criteria 
Subjects who met the following exclusion criteria will be excluded from the study: 
1. Subject has presence of abnormal neurological signs other than tremor or Froment’s sign. 
2. Subject has presence of known causes of enhanced physiological tremor. 


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3. Subject has or recent exposure (14 days prior to the Day -1 visit) to tremorogenic drugs, 
as defined in Appendix 1, or the presence of a drug withdrawal state. 
4. Subject has had direct or indirect trauma to the nervous system within 3 months before 
the onset of tremor.   
5. Subject has historical or clinical evidence of tremor with psychogenic origin (including 
but not limited to eating disorders, major depression, etc.).   
6. Subject has convincing evidence of sudden tremor onset or evidence of stepwise 
deterioration of tremor.   
7. Subject has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or 
oncological disease.   
8. Intentionally blank (criteria removed in Amendment 4, Version 5) 
9. Subject has a 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. 
10. Subject has hypothyroidism.  Stable thyroid replacement is acceptable. 
11. Subject has used alcohol, caffeine, or nicotine within 3 days prior to the Day -1 visit. 
12. Subject has a known allergy to SAGE-217, or any capsule excipient.   
13. Subject has exposure to another investigational medication or device within the prior 
30 days. 
14. Subject has a history of suicidal behavior within 2 years or answers “YES” to questions 
3, 4, or 5 on the C-SSRS at the Screening visit or on Day -1 or is currently at risk of 
suicide in the opinion of the Investigator. 
15. Subject has donated one or more units (1 unit = 450 mL) of blood or acute loss of an 
equivalent amount of blood within 60 days prior to dosing. 
16. Subject is unwilling or unable to comply with study procedures. 
17. Use of any known strong inhibitors and/or inducers of CYP3A4, as defined in 
Appendix 2, within the 14 days or 5 half-lives (whichever is longer) or consumed 
grapefruit juice, grapefruit, Seville oranges, pomegranates, tangelos, or St. John's Wort or 
products containing these within 30 days prior to receiving the first dose of study drug.   
18. Intentionally blank (criteria removed in Amendment 4, Version 5)   
19. Subject has concurrent or recent exposure (14 days prior to the Day -1 visit) to 
sedative/hypnotic (eg, opioids) drugs.   
20. Intentionally blank (criteria removed in Amendment 4, Version 5)  


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8.3. 
Subject Withdrawal Criteria 
If there is an adverse event or medical reason for the withdrawal, the subject should be followed 
medically until the condition has either resolved itself or is stable.  Details of the reason for 
withdrawal should be recorded in the subject’s case report form (CRF).   
Subjects who withdraw should, if possible, have a follow-up examination, including a physical 
examination, the appropriate investigations, vital signs, and clinical laboratory tests, as outlined 
for the Day 21 visit (Table 4).  If the subject cannot return on Day 21 (Early Termination visit), 
their visit can be scheduled at an alternative time, at the discretion of the Investigator and 
subject.  All details of this follow-up examination should be recorded in the subject’s medical 
source documents.   
8.3.1. 
Study Drug Withdrawal 
Participation in the study is strictly voluntary.  Subjects are free to discontinue the study at any 
time without giving their reason(s).   
A subject must be withdrawn from the study treatment in the event of any of the following: 
•
Withdrawal of the subject’s consent;
•
New onset of a condition that would have met exclusion criterion, is clinically
relevant and affects the subject’s safety, and discontinuation is considered necessary
by the Investigators and/Sponsor;
•
Occurrence of intolerable adverse events at the lowest dose;
•
Occurrence of pregnancy;
•
Intake of nonpermitted concomitant medication;
•
Subject noncompliance;
•
Significant protocol deviation determined in consultation with the Medical Monitor.
If a subject failed to attend scheduled assessments during the course of the study, the 
Investigators must determine the reasons and the circumstances as completely and accurately as 
possible and document this in the subject’s source documents.   
Subjects who withdraw or are withdrawn from the study will be replaced only if they withdraw 
prior to dosing.  Subjects who are withdrawn from the study, fail to return or are no longer 
qualified will not be replaced.   
8.3.2. 
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 adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons.  In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator. Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
participating subjects.   


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Number of Subjects 
Parts A and B are closed to enrollment.  For Part C, approximately 15 subjects will be enrolled to 
ensure at least 10 subjects complete the study (through Day 15).  
9.2. 
Treatment Assignment 
Study drug will be administered in the morning with food during Part A and Part B and with 
food in the evening on Days 1 through 3 and split into 2 doses (10 mg in the morning and 30 mg 
in the evening) beginning on Day 4 (through Day 14) in Part C. 
9.2.1. 
Part A 
Subjects participating in Part A of the study will take study drug (SAGE-217) in an open-label 
manner.  All subjects will start on a 10-mg dose of study drug administered with food in the 
morning on Day 1.  Subjects will receive 20 mg with food on Day 2 and 30 mg with food daily 
on Days 3 to 7.  Dose adjustments may be allowed per the criteria in Section 9.3.  The dose 
tolerated for Days 5, 6, and 7 of the open-label dosing period will be determined to be the 
maximum dose for that subject.   
9.2.2. 
Part B 
Subjects participating in the double-blind, placebo-controlled, randomized withdrawal portion of 
the study (Part B) will be randomized to SAGE-217 or placebo on Day 8.  Subjects randomized 
to SAGE-217 will receive the maximum dose of SAGE-217 from Part A of the study.  Following 
randomization, subjects will receive 7 days of study drug starting on Day 8.   
9.2.3. 
Part C 
All eligible subjects will start on a 10-mg dose of study drug administered with food in the 
evening (8:00pm ±30 min) on Day 1.  Subjects will receive 20 mg with food in the evening on 
Day 2, and 30 mg with food in the evening on Day 3. Beginning on Day 4 and continuing 
through Day 14, subjects will receive a 40-mg total daily dose (administered as 10 mg with food 
in the morning [8:00am ±30 min] and 30 mg with food in the evening [8:00pm ±30 min]).   
9.3. 
Dose Adjustment Criteria 
Dose adjustments will only be allowed during the open-label phases of the study (Parts A and C).  
If at any time the dose is not tolerated in Part A, assessed by occurrence of a severe adverse 
event judged by the investigator to be related to study drug, the dose on the next day will be 
reduced to the next lowest dose and continued for the remainder of the open-label dosing period 
(ie, subjects who are unable to tolerate the 30-mg dose will receive a lower dose of 20 mg, and 
subjects who are unable to tolerate 20 mg will be given a 10-mg dose).  The dose tolerated for 
Days 5, 6, and 7 of the open-label dosing period will be determined to be the maximum dose for 
that subject.  Subjects who require dose adjustments on Days 5, 6, or 7 of Part A will not 
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If at any time the dose is not tolerated in Part C, assessed by occurrence of a severe AE or a 
moderate AE of special interest (sedation, somnolence, dizziness, euphoric mood, confusion, 
drowsiness, inebriation (feeling drunk), or fatigue) judged by the investigator to be related to 
study drug, the dose on the next day will be reduced to the next lowest dose and continued for 
the remainder of the treatment period.  Subjects who cannot tolerate the 20-mg dose on Day 2 
will be discontinued.  Subjects who do not tolerate 30 mg on Day 3 will receive 20 mg for the 
remainder of the treatment period (10 mg in the morning and 10 mg in the evening).  Subjects 
who do not tolerate 40 mg on Day 4 or any time thereafter will receive 30 mg for the remainder 
of the treatment period (10 mg in the morning and 20 mg in the evening).  If a dose adjustment is 
deemed necessary by the Investigator at any time during the treatment period, the subject will 
return to the site for the adjusted dose to be dispensed. 
9.4. 
Prior/Concomitant Medications and Restrictions 
9.4.1. 
Prior/Concomitant Medications 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 9.4.2.   
Record the name, start date (if known), indication for use and whether ongoing or stopped of 
medications/treatments taken within 2 weeks prior to informed consent and throughout the study.   
The charts of all study participants will be reviewed for new concomitant medications through 
discharge from the unit.  Chart reviews will include examination of nursing and physician 
progress notes, vital signs, and medication records in order to identify adverse events that may be 
associated with new concomitant medications.  New concomitant medications, ongoing 
concomitant medications with a change in dose and medical procedures ordered (eg, laboratory 
assessments, computed tomography or magnetic resonance imaging scans) will be reviewed to 
determine if they are associated with an adverse event not previously identified.   
9.4.2. 
Prohibited Medications 
The drug classes listed in Appendix 1 are not permitted in the 14 days prior to the Day -1 visit 
and for the duration of the study (up to the Day 28 visit).  The list provides non-exhaustive 
examples of each drug class.   
Subjects are not permitted to use alcohol, caffeine, or nicotine within 3 days prior to the Day -1 
visit through the Day 21 visit. 
For subjects who have previously received primidone or topiramate, a 1-week washout period 
(prior to Day -1) will be used for subjects with past exposures of ≤1 year and a 2-week washout 
period (prior to Day -1) will be used for subjects with exposures >1 year.  For subjects who have 
previously received propranolol, a 3-day washout period (prior to Day -1) will be used. 
9.5. 
Treatment Compliance 
Investigational product will be dispensed by the site.  The Investigator(s) or designee will record 
the time and dose of study drug administration in the source documents.  Any reasons for non-
compliance will also be documented, including: 


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• Missed visits;  
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible.   


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
10.1.1. 
SAGE-217 Oral Solution 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose which is further diluted with Sterile 
Water for Injection to achieve the selected dosages.  The 6 mg/mL stock SAGE-217 Oral 
Solution will be compounded from SAGE-217 Drug Substance Powder in the Bottle and 
Excipient (s) in the Bottle (manufactured under clinical Good Manufacturing Practice [GMP] 
conditions at 
) and further admixed at the clinical site in preparation for dosing.  
Placebo oral solution will be matched to SAGE-217 study drug.   
Detailed instructions for study drug preparation will be provided in the Pharmacy Manual.   
10.1.1.1. Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured by 
 and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual.  The batch formula for a 125-mL solution of the 6 mg/mL 
stock solution is shown in Table 6.   
Table 6: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
Ingredient 
Compendia Specification Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD (Kleptose®) 
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.025 
3.124 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations:  EP = European Pharmacopeia; HPβCD = hydroxypropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
10.1.2. 
SAGE-217 Capsules 
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white 
powder.  In addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 
Capsules contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and 
sodium stearyl fumarate as excipients.  Capsules will be available in 5-mg, 10-mg and 20-mg 
dose strengths.  Subjects will be administered one or two capsules per dose.   
Matched placebo capsules containing only the above-listed capsule excipients will be provided.  
Subjects randomized to placebo treatment will be administered 2 placebo capsules per day.   
Detailed instructions for study drug preparation will be provided in the Pharmacy Manual.  


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10.2. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation.  Study drug (oral solution) will be provided to the 
site as powder in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy 
at a volume of 125 mL of a 6 mg/mL stock solution and then further diluted to approximately 
40 mL at the identified doses.  Study drug capsules will be provided to the site in appropriately 
labeled bottles.  Study drug labels with all required information and conforming to all applicable 
Code of Federal Regulations and GMP/GCP guidelines will be prepared by the clinical research 
organization.   
10.3. 
Study Drug Storage 
Upon receipt of study drug (SAGE-217 and placebo), the Investigator or designee will inspect 
the medication and complete and return the acknowledgment of receipt form enclosed with the 
parcel.  A copy of the signed receipt will be kept in the study files.  
The study drug must be carefully stored at the temperature specified in the Pharmacy Manual 
(eg, clinical dosing solutions stored at approximately 2 to 8°C for 10 days or room temperature 
for up to 24 hours after preparation), safely and separately from other drugs.   
SAGE-217 Capsules and matched placebo capsules may be stored at room temperature. 
The study drug may not be used for any purpose other than the present study.  After the study is 
completed, all unused study drug must be retained, returned as directed, or destroyed on site per 
the Sponsor’s instructions.   
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies.  An accurate, timely record of 
the disposition of all clinical supplies must be maintained.  The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed; 
• The date(s) and quantity of the drug dispensed to the subject; and 
• The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
A copy of the inventory record and a record of any clinical supplies that have been destroyed 
must be documented.  This documentation must include at least the information below or as 
agreed with the Sponsor: 
• The number of prepared units; 
• The number of administered units; 
• The number of unused units; 


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• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 
10.4. 
Administration and Study Drug Accountability 
Doses of SAGE-217 Oral Solution will be prepared as an approximate 40 mL oral solution to be 
swallowed all at once, followed by approximately 200 mL of water which has been used to rinse 
the dosing bottle.  The start time of swallowing the approximately 40 mL oral solution is time 
zero for all assessments.  Subjects may have assistance from the clinic staff when taking the 
study drug.   
For the capsule formulation, subjects will swallow two capsules per dose with food. 
10.4.1. 
Study Drug Administration 
Subjects in Part A will receive a 10-mg dose of study drug administered in the morning on 
Day 1, 20 mg on Day 2, and 30 mg on Days 3 to 7.   
Subjects in Part B will receive randomized study drug in the morning on Days 8 to 14. 
In Part C, study drug will be self-administered by subjects on an outpatient basis for the entire 
14-day Treatment Period. Study drug will be dispensed by the clinic on Day 1 and Day 8 (7 days 
of dosing per dispensation). Subjects will administer a 10-mg dose of study drug in the evening 
on Day 1, 20 mg on Day 2, 30 mg on Day 3, and 40 mg (administered as one 10 mg dose in the 
morning and one 30 mg dose in the evening on Days 4 through 14).  
10.4.2. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol.   
In Part C, if a dose adjustment is deemed necessary by the Investigator at any time during the 
treatment period (see Section 9.3 for dose adjustment criteria), the subject will be instructed to 
return to the site to return any remaining current dose and for the adjusted dose to be dispensed. 
The Investigator or designee must maintain a record of all study drug received, used, and 
discarded.  It must be clear from the records which subject received which dose of active or 
placebo treatment.   
The Sponsor will be permitted access to the study supplies at any time within usual business 
hours and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation.  Only unblinded personnel will be able to access the study drug and 
accountability documentation from first dosing through database hard lock.   
10.5. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding (oral solution only), subsequent admixture (oral solution only), administration of 
test article, and for which subject the study drug was intended (ie, record subject initials and birth 
date or other unique identifier).   


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At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions; disposition of study drug will be 
documented.   


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11. 
ASSESSMENT OF EFFICACY 
Efficacy assessments include evaluation of subject symptom response by a measurement of 
Kinesia, TETRAS upper limb items, and TETRAS Performance Subscale (items 4, 6, 7, and 8).  
Quality-of-life assessments include TETRAS ADL, QUEST, and video recording of subjects 
performing three everyday tasks.  Physiological activity (ie, sympathetic nervous system tone as 
measured by electrodermal activity, skin temperature monitoring, and heart rate monitoring) and 
tremor oscillation as assessed by multidimensional accelerometer measurements (ie, raw 
accelerometer values) will be assessed by the Empatica E4 Wristband.  All efficacy assessments 
will be performed at the scheduled time points as outlined in the Schedule of Events (Table 4). 
11.1. 
Kinesia 
In order to measure tremor amplitude, subjects will wear a wireless ring motion sensor 
(Kinesia, Great Lakes Neuro Technologies).  The motion sensor uses three orthogonal 
accelerometers and three orthogonal gyroscopes to monitor three-dimensional motion.  Data are 
then transmitted from the sensor to a computer using Bluetooth technology.  These measures of 
three-dimensional motion for each maneuver are then converted to Kinesia scores, which have 
been shown to correlate with corresponding clinician-rated TETRAS scores (Giovanni 2010).  
Each Kinesia score ranges from 0 to 4; higher scores indicate more severe tremor.  The Kinesia 
assessment is completed in conjunction with the TETRAS Performance Subscale Item 4 
assessment. 
11.2. 
TRG Essential Tremor Rating Assessment Scale (TETRAS) 
Performance Scale 
Item #4 (upper limb tremor) of the TETRAS Performance Subscale will be completed using both 
the Kinesia device and clinician assessment.  Testing should be completed within ±10 minutes of 
the planned questionnaire time points.  All three maneuvers in the upper limb assessments 
(items 4a, 4b, and 4c) will be completed for both arms, first for the RIGHT arm and then for the 
LEFT.  Predose assessments can be done any time within 2 hours prior to the start of 
administration of study drug.  The Day 21 follow-up visit assessments can be done at any time 
during the visit. 
Note that the TETRAS upper limb scores from the test conducted during screening will be used 
to determine eligibility and must be ≥2 on each side (left and right) for kinetic tremor and ≥2 on 
each side (left and right) for either wing beating or forward outstretched postural tremor.  A copy 
of the TETRAS is provided in Appendix 3.   
11.3. 
Empatica E4 Wristband 
Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring) will be assessed by the 
Empatica E4 Wristband.  The Empatica E4 Wristband is a wearable device that captures 
motion-based activity and sympathetic nervous system arousal.  Data from the Empatica E4 
Wristband will not be presented in the study report; instead, they will be part of a separate report.   
In Part C, the Empatica E4 Wristband will be worn at all times (except while bathing) during the 
three 5-day intervals outlined in the Schedule of Events (Table 4).  The Empatica E4 Wristband 


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will be worn on the wrist that, of the two arms, exhibits more severe tremor symptoms (i.e. 
tremor-dominant hand), as determined during screening. 
11.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST) 
The QUEST is a brief, 30-item, ET-specific QOL scale in which subjects rate the extent to which 
tremor impacts a function or state, tremor severity in various body parts, perceived health, and 
overall QOL (Tröster 2005).  A copy of the QUEST is provided in Appendix 4.   
11.5. 
Video Recording 
Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, 
and one additional task that the subject experiences difficulty with on a daily basis) will be taken.   


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
For plasma sample collection, the time of study drug administration is time zero and all post-
dosing sampling times are relative to this time.  Samples are to be collected within ±5 minutes of 
the scheduled sampling time.  The Investigator or designee will arrange to have the plasma 
samples processed, stored, and transported as directed for bioanalysis.   
An additional PK sample may be collected at any time if clinically indicated and at the discretion 
of the Investigator (eg, for unusual or severe adverse events).   
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time.  The date and actual time that the blood sample was taken will be 
recorded on the CRF or electronically with a bar code or other method.   
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70°C to -80°C until analyzed.  At 
sites where a -70°C to -80°C freezer is not available, plasma samples may be stored at -15°C 
to -30°C prior to being transported for bioanalysis.  They should be packed as directed to avoid 
breakage during transit and with sufficient dry ice to prevent thawing for at least 72 hours.  A 
specimen-identification form must be completed and sent to the laboratory with each set of 
samples.  The clinical site will arrange to have the plasma samples transported as directed for 
bioanalysis as detailed in the PK instructions.   
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of SAGE-217 will be performed utilizing a 
validated liquid chromatography-tandem mass spectrometry method at a qualified laboratory.   


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety and Tolerability Parameters 
Safety and tolerability of study drug will be evaluated by vital signs measurements, clinical 
laboratory measures, physical examination, ECGs, concomitant medication usage, C-SSRS, and 
adverse event reporting.  The Bond-Lader Mood Rating Scale and a DEQ-5 will be used to 
assess mood and perception of drug effects, respectively.   
13.1.1. 
Demographic/Medical History 
Age, gender, race, and ethnic origin will be recorded at the Screening visit.  A full medical 
history including medication history will be recorded at the Screening visit.   
13.1.2. 
Vital Signs 
Vital signs comprise heart rate, respiratory rate, temperature, and supine (supine for at least 
5 minutes prior to the measurement) and standing (for at least 2 to 3 minutes) systolic and 
diastolic blood pressure.  Vital sign assessments will be performed within ±10 minutes of the 
scheduled times. 
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visit.   
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening visit.   
13.1.5. 
Electrocardiogram (ECG) 
A supine (supine for at least 5 minutes prior to the measurement) 12-lead ECG will be performed 
at the times specified below and the standard intervals recorded as well as any abnormalities.  All 
ECG results will be interpreted by the Investigator as Normal, Abnormal; not clinically 
significant (NCS), or Abnormal; clinically significant (CS).  
All time points are relative to the time of dosing.  ECGs will be performed within ±10 minutes of 
the predose and 1- and 8-hour time points. 
13.1.6. 
Laboratory Assessments 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS); or abnormal, clinically significant 
(CS).  Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the medical monitor.  Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to 
Section 13.2.1, and recorded in the eCRF.   


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Serum and urine samples for pregnancy tests (females only) will also be collected.  These 
assessments should be performed in accordance with the Schedule of Events (Table 4).   
13.1.6.1. Hematology 
Hematology tests will include complete blood count, including red blood cells, white blood cells 
with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets.  The coagulation panel 
will include activated partial thromboplastin time, prothrombin time, and international 
normalized ratio.   
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes, renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide, liver function tests, including total 
bilirubin, AST, and ALT, total protein, and albumin.   
Thyroid-stimulating hormone, thyroxine (T4), and triiodothyronine (T3) will be performed at 
screening to confirm subject eligibility.   
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity.   
13.1.6.4. Drugs Screen and Alcohol Test 
A urine sample for assessment of selected drugs (sedative/hypnotics [eg, opioids], cotinine, and 
caffeine) and a breath sample for alcohol screen will be collected at screening and on Day -1.  
Results may be obtained through subject history.  Subjects who use concomitant 
sedative/hypnotics will be excluded from the study.  Use of alcohol, caffeine, or cotinine is not 
allowed through Day 21. 
13.1.6.5. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
the study.   
13.1.6.6. Pregnancy Test 
Females of child-bearing potential will be tested for pregnancy by serum or urine pregnancy test 
as outlined in the Schedule of Events (Table 4). 
13.1.6.7. Exploratory Biochemistry 
Optional blood samples will be collected at screening and on Days 3 and 7 and may be analyzed 
for exploratory biochemistry, where consent is given.  Future research may suggest other 
biochemical markers as candidates for influencing not only response to SAGE-217 but also 
susceptibility to disorders for which SAGE-217 may be evaluated.  Thus, the biochemical 
research may involve study of additional unnamed biochemical biomarkers, but only as related to 
disease susceptibility and drug action.   


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13.1.6.8. Genetic Testing 
Where consent is given, an optional genetic sample for biomarker testing will be collected at the 
Screening visit.   
The objective of this research is to collect and store blood samples for possible DNA extraction 
and exploratory research into how genes or specific genetic variation may influence response 
(ie, distribution, safety, tolerability, and efficacy) to SAGE-217.  Specific genetic variations of 
interest include but are not limited to: classes of metabolizing enzymes (eg, cytochrome P450 
supra-family genes), genes encoding enzymes involved in the production and metabolism of 
SAGE-217 (eg, AKR1C4 [3α-hydroxysteroid dehydrogenase]), genes associated with the 
γ-aminobutyric acid (GABA) receptor (eg, GABRA1-A6, GABRB1-B3, GABRD, GABRE, 
GABRG1-3), and genes associated with the production and degradation of GABA.   
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to SAGE-217 but also susceptibility to disorders for which SAGE-217 may be 
evaluated.  Thus, the genetic research may involve study of additional unnamed genes or gene 
categories, but only as related to disease susceptibility and drug action.   
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011).  This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit.  The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).   
If in the opinion of the Investigator, the subject is showing any suicidal tendency, no further 
study drug will be administered and the subject will be referred to a psychologist or psychiatrist 
for further evaluation.  This information will be tracked.   
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months) and the “Since Last Visit” version should be used on all subsequent time points.  The 
C-SSRS is provided in Appendix 5.   
13.1.8. 
Bond-Lader VAS Mood Scale 
Mood will be assessed using the Bond-Lader Mood Rating Scale (Bond 1974).  This is a 16-part 
self-administered questionnaire that employs a 100-mm VAS to explore different aspects of self-
reported mood.  The Bond-Lader Mood Rating Scale is provided in Appendix 6.   
13.1.9. 
Drug Effects Questionnaire (DEQ-5) 
A DEQ-5 (Morean 2013) will be administered as follows: 
1. Do you FEEL a drug effect right now? 
2. Are you HIGH right now? 
3. Do you DISLIKE any of the effects that you are feeling right now? 
4. Do you LIKE any of the effects that you are feeling right now? 


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5. Would you like MORE of the drug you took, right now? 
The answers are recorded on a 100-mm VAS, with the answer for each being “Not at all” and 
“Extremely” at the extremes.  There will be options to record “Not applicable” for 
questions 3 and 4 if no drug effects are felt and for question 5 prior to administration of study 
medication.  The DEQ-5 is provided in Appendix 7. 
13.2. 
Adverse and Serious Adverse Events 
Adverse events will be collected after the ICF has been signed.  Medical conditions that occur 
after the ICF has been signed will be captured on the adverse event eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (version 18.1 or higher).  
13.2.1. 
Definition of Adverse Events 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered. 
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug.   
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
All serious adverse events that occur after any subject has been enrolled, whether or not they are 
related to the study, must be recorded on forms provided by Sage Therapeutics or designee for 


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the duration of the study (from the signing of the ICF through the Day 28 visit [or early 
termination]). 
13.2.2. 
Pregnancy 
Any pregnancy occurring during this study will be reported within 24 hours of notification of the 
Investigator.  The Investigator will promptly notify the Medical Monitor and withdraw the 
subject from the study.  The Investigator should request permission to contact the subject, the 
subject’s spouse/partner (if the subject is male and his spouse/partner becomes pregnant) or the 
obstetrician for information about the outcome of the pregnancy, and in the case of a live birth, 
about any congenital abnormalities.  If a congenital abnormality is reported, then it should be 
recorded in the source documents and reported as a serious adverse event.   
13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, possibly related or probably related).  
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product.  If no valid reason 
exists for suggesting a relationship, then the adverse event should be classified as “unrelated.”  If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the adverse event, then the 
adverse event should be considered “related.”   
Not 
Related: 
No relationship between the experience and the administration of study drug; related to other 
etiologies such as concomitant medications or subject’s clinical state. 
Possibly 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug and 
follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of therapy 
administered to the subject, but this is not known for sure. 
Probably 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug and 
follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered to be related 
to the investigational product for the purposes of expedited regulatory reporting.   
13.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject 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.  Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event or lead to discontinuation of administration of 
study drug.   


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Information about adverse events will be collected from the signing of the ICF through the 
Day 28 visit (or early termination).  Adverse events that occur after the first administration of 
study drug will be denoted TEAEs.   
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
no expectation of future change.   
The adverse event term should be reported in standard medical terminology when possible.  For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), intensity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study.   
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
13.5. 
Reporting Serious Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 28 visit (14 days following the last dose of study drug) or early termination.  Any 
serious adverse events considered possibly or probably related to the investigational product and 
discovered by the Investigator at any time after the study should be reported.  All serious adverse 
events must be reported to the Sponsor or Sponsor’s designee immediately by phone and in 
writing within 24 hours of the first awareness of the event.  The Investigator must complete, sign 
and date the serious adverse event pages, verify the accuracy of the information recorded on the 
serious adverse event pages with the corresponding source documents, and send a copy to Sage 
Therapeutics or designee.   
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the study file.   
Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
certain events.  It is the Principal Investigator’s responsibility to notify the IRB of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements.  Investigators 
will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) 
that occur during the clinical study.  Each site is responsible for notifying its IRB of these 
additional serious adverse events.   


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14. 
STATISTICAL METHODS AND CONSIDERATIONS 
14.1. 
Data Analysis Sets 
The safety population is defined as all subjects who are administered at least one dose of study 
drug.   
The efficacy population will consist of all subjects in the safety population who complete at least 
one dose and have at least one post-dose efficacy evaluation (Kinesia assessment).   
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations.   
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data.  All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available.  No imputation process will be 
used to estimate missing data.  No sensitivity analysis of missing data will be performed.   
14.3. 
Demographics and Baseline Characteristics 
Demographics, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized.   
Categorical summaries, such as race and ethnicity, will be summarized by frequency and 
percentage.  Continuous summaries, such as age, height, weight, BMI, and baseline vital signs, 
will be summarized using descriptive statistics.   
Hepatitis, HIV, drug, and pregnancy screening results will be listed, but not summarized as they 
are considered part of the inclusion/exclusion criteria.   
Medical history will be listed by subject.   
14.4. 
Primary Efficacy Endpoint 
Analysis will be done separately for each study part.  
For Parts A and B, the change from baseline or randomizationin the accelerometer-based Kinesia 
kinetic tremor combined score (ie, the sum of Kinesia kinetic tremor scores from both sides of 
the body) at Day 14 will be summarized.  In Part C, the change from baseline in the 
accelerometer-based Kinesia™ upper limb tremor combined score (ie, the sum of accelerometer-
based Kinesia forward outstretched postural tremor, lateral "wing beating" postural tremor, and 
kinetic tremor item scores from both sides of the body) at Day 15 will be summarized.   
Change from randomization or baseline to each assessment in Kinesia kinetic tremor combined 
score will be analyzed using a mixed effects repeated measures model, including center, 
treatment, randomization Kinesia kinetic tremor combined score, assessment time point, and 
time point-by-treatment.  All explanatory variables will be treated as fixed effects. 
14.5. 
Secondary Efficacy Endpoints 
Analysis will be done separately for each study part.  


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The change from randomization or baseline in the Kinesia upper limb total and individual item 
scores, TETRAS upper limb total and individual upper limb item scores, and other TETRAS 
Performance Subscale scores at Day 14 or 15 will be summarized by treatment group. 
A mixed effects repeated measures model similar to those described in Section 14.4 will be used 
for the analysis of change from randomization or baseline in the following:  Kinesia upper limb 
total score, Kinesia individual item scores, TETRAS upper limb total score, and TETRAS 
individual upper limb item scores. 
14.6. 
Exploratory Efficacy Endpoints 
Analysis will be done separately for each study part.  
The change from randomization (predose on Day 8) in TETRAS ADL scores at Day 14 or 15 
will be summarized.   
QUEST data will be listed by subject, study day, and time point. 
14.7. 
Safety and Tolerability Analyses 
Data from vital signs, clinical laboratory measures, ECG, and C-SSRS will be summarized using 
descriptive statistics by group and time point, where applicable.  Continuous endpoints will be 
summarized with n, mean, standard deviation, median, minimum, and maximum.  In addition, 
change from baseline values will be calculated at each time point and will be summarized using 
descriptive statistics.  Out-of-range safety endpoints may be categorized as low or high, where 
applicable.  For all categorical endpoints, summaries will include counts and percentages.   
14.7.1. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system (version 18.1 or higher).  The 
analysis of adverse events will be based on the concept of TEAEs.  A TEAE is defined as an 
adverse event with onset after the start of open-label study drug, or any worsening of a pre-
existing medical condition/adverse event with onset after the start of open-label study drug and 
until 14 days after the last dose.  The incidence of TEAEs will be summarized overall and by 
MedDRA System Organ Class, preferred term, and dose group.  Incidences will be presented in 
order of decreasing frequency.  In addition, summaries will be provided by maximum severity 
and relationship to study drug (see Section 13.3).   
TEAEs leading to discontinuation and serious adverse events (see Section 13.2.1.3 for definition) 
with onset after the first dose of open-label study drug will also be summarized. 
All adverse events and serious adverse events (including those with onset or worsening before 
the signing of the ICF) through the Day 28 visit will be listed.   
14.7.2. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection.  Mean changes from 
randomization or baseline in vital signs will be evaluated by time point.   


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14.7.3. 
Physical Examinations 
Screening physical examinations will be documented as done/not done; these results will be 
listed by subject.  Any clinically significant physical examination findings will be recorded as 
medical history.   
14.7.4. 
12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QTcF.  Any clinically significant abnormalities or changes in ECGs should be listed as an 
adverse event.  Electrocardiogram findings will be listed by subject and visit.   
14.7.5. 
Clinical Laboratory Evaluations 
Clinical laboratory results will be listed by subject and timing of collection.  Mean changes from 
baseline or randomization in clinical laboratory measures will be evaluated.   
14.7.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS will be listed for all subjects.  Listings will include 
behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the C-SSRS.   
14.7.7. 
Bond-Lader VAS Mood Scale 
Mood data collected on the Bond-Lader VAS mood scale will be listed by subject, study day, 
and time point.  The scores and change from Day 1 will be summarized by study day and time 
point.   
14.7.8. 
Drug Effects Questionnaire (DEQ-5) 
Results from DEQ-5 will be listed by subject, study day, and time point.  The result for each 
question and change from Day 1 will be summarized by study day and time point.  
14.7.9. 
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 Enhanced (WHO-DDE) version September 2015, or later.   
Medications will be presented according to whether they are being taken prior to and/or during 
the study (concomitant).  Prior medications are defined as those taken within 2 weeks prior to the 
signing of the ICF.  Concomitant medications are defined as those with a start date on or after the 
first dose of open-label study drug, or those with a start date before the first dose of open-label 
study drug that are ongoing or with a stop date on or after the first dose of open-label study drug.  
If medication dates are incomplete and it is not clear whether the medication was concomitant, it 
will be assumed to be concomitant.   
Concomitant medications will be assigned to the part in which they are being taken.  If a 
concomitant medication assigned to a Part A continues to be taken through Part B, then the 
medication will be assigned to both parts of the study as appropriate.  If the start and stop dates 
of the concomitant medications do not clearly define the part during which a medication was 
taken, it will be assumed to be taken in both parts.  Details of prior and concomitant medications 
will be listed by study part, subject, start date, and verbatim term.   


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14.8. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics.  Time to 
reach maximum concentration (tmax) will be summarized using n, mean, standard deviation, 
median, minimum, and maximum.  All other PK parameters will be summarized using n, 
geometric mean, coefficient of variation, median, minimum, and maximum and listed by subject.   
Wherever necessary and appropriate, PK parameters will be dose-adjusted to account for 
individual differences in dose.   
Pharmacokinetic and pharmacodynamic modelling assessment of the relationship between 
plasma exposure of SAGE-217 and change from baseline in Kinesia scores may be assessed.   
14.9. 
Determination of Sample Size 
Parts A and B are closed to enrollment.  Approximately 15 subjects will be enrolled in Part C to 
ensure 10 subjects complete the study (through Day 15).  The sample size for Part C was selected 
based on clinical and not statistical considerations. 
14.10. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
statistical analysis plan.  


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Sage 
Therapeutics or designee will visit the investigational study site to:   
• Determine the adequacy of the facilities; and 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives.  This will be documented in a Clinical Study Agreement between 
Sage Therapeutics and the Investigator.   
During the study, a monitor from Sage Therapeutics or designee 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 CRFs, and that investigational product accountability 
checks are being performed; 
• Perform source data verification. This includes a comparison of the data in the CRFs 
with the subject’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 
subject (eg, clinic charts); 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm adverse events and serious adverse events have been properly documented 
on CRFs and confirm any serious adverse events have been forwarded to Sage 
Therapeutics or designee and those serious adverse events that met criteria for 
reporting have been forwarded to the IRB.   
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification.  The purpose of a Sage Therapeutics or designee audit or 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 guidelines of the International Council on 
Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency about an inspection.   


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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study, including the subject consent form and 
recruitment materials, must be maintained by the Investigator and made available for inspection.   


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
CRFs.   
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements.   
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate.  The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study.   
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  Sage Therapeutics or designee will provide this information to the Principal 
Investigator.   
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines.   
17.2. 
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 the most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements.   
17.3. 
Written Informed Consent 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study.  Subjects must also 
be notified that they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided.   
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures.   
The Principal Investigator(s) must maintain the original, signed ICF.  A copy of the signed ICF 
must be given to the subject.   
 


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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan.   
Electronic CRFs will be completed for each study subject.  It is the Investigator’s responsibility 
to ensure the accuracy, completeness, and timeliness of the data reported in the subject’s eCRF.  
Source documentation supporting the eCRF data should indicate the subject’s participation in the 
study and should document the dates and details of study procedures, adverse events, and subject 
status.   
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study.  For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct.   
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or, if not approved, 2 years following the 
discontinuance of the test article for investigation.  If it becomes necessary for Sage Therapeutics 
or the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records.   
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports and communications will identify the 
subject by the assigned subject number.  The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process.  The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations.   
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used.   


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All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information.  The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor.  It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study.  The information obtained from the clinical study will be used 
towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required.   


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19. 
PUBLICATION POLICY 
All information concerning SAGE-217 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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20.
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2014;6:29-39. eCollection 2014. 
Schmouth JF, Dion PA, Rouleau GA. Genetics of essential tremor: from phenotype to genes, 
insights from both human and mouse studies. Prog Neurobiol. 2014;119-120:1-19.  


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Schnitzler A, Munks C, Butz M, et al. Synchronized brain network associated with essential 
tremor as revealed by magnetoencephalography Mov Disord. 2009;24:1629-35. 
Shill HA, Adler CH, Sabbagh MN, et al. Pathologic findings in prospectively ascertained 
essential tremor subjects. Neurology. 2008;70:1452-5.   
Tröster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of life in Essential Tremor 
Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord. 
2005;11(6):367-73. 
Wills AJ, Thompson PD, Findley LJ, et al. A positron emission tomography study of primary 
orthostatic tremor. Neurol. 1996;46(3):747-52. 
Zappia M, Albanese A, Bruno E, et al. Treatment of essential tremor: a systematic review of 
evidence and recommendations from the Italian Movement Disorders Association. J Neurol. 
2013;260:714–40. 


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21. 
APPENDICES 
Copies of scales and questionnaires included in Appendix 3 through Appendix 7 are for 
reference only; the rating scales and questionnaires are to be used for actual subject assessment 
per the Schedule of Events.   
 


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APPENDIX 1. TREMOROGENIC DRUGS 
The following drug classes are not permitted in the 14 days prior to the Day -1 visit and for the 
duration of the study (up to the Day 28 visit).  The list below gives a non-exhaustive list of 
examples of each drug class. 
Anti-arrhythmics 
 
amiodarone, procainamide 
Antiepileptic drugs 
 
valproic acid, carbamazepine 
Antipsychotic agents 
 
haloperidol, trifluoperazine 
Antimanic agents/mood stabilizer 
 
lithium at toxic levels 
Antivirals 
 
acyclovir, vidarabine 
Beta adrenergic agonists 
 
albuterol, terbutaline 
Calcium Channel blockers 
 
verapamil 
CNS stimulants 
 
methylphenidate, amphetamines, cocaine 
Corticosteroids (local injection topical, or inhalation allowed) 
 
cortisone, hydrocortisone, prednisone 
Cytotoxic agents 
 
cytarabine 
Hormones 
 
calcitonin, levothyroxine (levothyroxine is allowed if on a stable dose and euythroid) 
Immunomodulatory 
 
thalidomide 
Immunosuppressants 
 
cyclosporine, tacrolimus 
Monoamine depleting agents 
 
tetrabenazine 
Oral hypoglycemic agents 
 
metformin, glyburide, glipizide, tolbutamide, pioglitazone, rosiglitazone, acarbose, miglitol 
Prokinetics 
 
metoclopramide 
Tricyclic antidepressants 
 
amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, 
nortriptyline, protriptyline 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
 
Fluoxetine (other SSRIs are allowed) 
Statins 
 
Atorvastatin (other statins are allowed) 


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Sympathomimetics 
 
epinephrine, pseudoephedrine 
Weight loss medication 
 
tiratricol 
Xanthine derivatives 
 
theophylline (caffeine/coffee and theophylline/theobromine/tea require a washout, cocoa 
beans are acceptable) 
 


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APPENDIX 2. STRONG INHIBITORS AND INDUCERS OF CYP3A4 
The following known strong inhibitors/inducers of CYP3A4 are not permitted within the 14 days 
or 5 half-lives (whichever is longer) prior to receiving the first dose of study drug: 
Strong inhibitors of CYP3A4: 
Strong inducers of CYP3A4: 
Indinavir 
Carbamazepine 
Nelfinavir 
Efavirenz 
Ritonavir 
Nevirapine 
Clarithromycin 
Phenobarbital 
Telithromycin 
Phenytoin 
Iitraconazole 
Pioglitazone 
Ketoconazole 
Rifabutin 
Nefazodone 
Rifampin 
Erythromycin 
Troglitazone 
Cobistat 
Enzalutamide 
 
Mitotane 


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APPENDIX 3. TRG ESSENTIAL TREMOR RATING ASSESSMENT 
SCALE (TETRAS) 
 


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Appendix 4. 
QUALITY OF LIFE IN ESSENTIAL TREMOR 
QUESTIONNAIRE (QUEST) 
 


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APPENDIX 5. COLUMBIA – SUICIDE SEVERITY RATING SCALE 
(C-SSRS) 
 


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APPENDIX 6. BOND-LADER VAS (MOOD RATING SCALE) 
 


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APPENDIX 7. DRUG EFFECTS QUESTIONNAIRE (DEQ-5) 
 






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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-217.  I have read the Clinical 
Protocol 217-ETD-201 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 




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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street  
Cambridge, MA  02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
SAGE-217 Capsules 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 2a, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study 
Evaluating the Efficacy, Safety, Tolerability, and Pharmacokinetics of SAGE-217 in the Treatment of 
Subjects with Essential Tremor (ET) 
Study center(s):  Up to 25 centers 
Phase of development: 2a 
Methodology:  
This study will assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of SAGE-217.  
Subjects who consent prior to the approval of Protocol Amendment #3 by the IRB will receive the 
oral solution formulation for the duration of the study.  Subjects who consent after Amendment #3 is 
approved by the IRB will receive the capsule formulation for the duration of the study. 
There are two parts: 
Part A: Open-label with morning dosing (7 days). 
All subjects will start on a 10-mg dose of study drug administered with food on Day 1.  Subjects will 
receive 20 mg with food on Day 2 and 30 mg with food daily on Days 3 to 7.   
Part B: Double-blind, placebo-controlled, randomized withdrawal with morning dosing (7 days). 
In order to qualify for Part B of the study, a subject must tolerate a dose of at least 10 mg of 
SAGE-217, and the subject must have responded to SAGE-217, defined as a 30% reduction from 
baseline in the TRG Essential Tremor Rating Assessment Scale (TETRAS) kinetic tremor combined 
score (ie, the sum of item 4c scores from both sides of the body) predose on Day 8. 
Eligible subjects will be randomized in a 1:1 fashion to SAGE-217 or placebo and will receive their 
maximum dose as determined in Part A in the morning with food.  Subjects randomized to the 
placebo arm will represent randomized withdrawal (withdrawal from treatment they received in 
Part A). 


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Methodology:  
Dose adjustments will only be allowed during the open-label phase of the study (Part A).  If at any 
time the dose is not tolerated in Part A, assessed by occurrence of a severe adverse event judged by 
the investigator to be related to study drug, the dose on the next day will be reduced to the next lowest 
dose and continued for the remainder of the open-label dosing period (ie, subjects who are unable to 
tolerate the 30-mg dose will receive a lower dose of 20 mg, and subjects who are unable to tolerate 
20 mg will be given a 10-mg dose).  The dose tolerated for Days 5, 6, and 7 of the open-label dosing 
period will be determined to be the maximum dose for that subject.  Subjects who require dose 
adjustments on Days 5, 6, or 7 of Part A will not progress to Part B.   
Subjects will be exposed to study drug (SAGE-217 or placebo) for up to 14 days and will be followed 
for an additional 14 days after the administration of the last dose.   
Assessments will be performed periodically during the study as outlined in the Schedule of Events 
(Table 2).   
Objectives:  
Primary: 
• 
The primary objective of this study is to compare the effect of 7 days administration of 
SAGE-217 Capsules to placebo on the change in tremor severity, as measured by the change from 
randomization (Day 8) in the accelerometer-based Kinesia™ kinetic tremor combined score 
(ie, the sum of Kinesia kinetic tremor scores from both sides of the body) at Day 14.   
Secondary: 
The secondary objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Capsules to placebo on the following endpoints: 
• 
Tremor severity, as assessed by the change from randomization (Day 8) in the Kinesia upper limb 
total score (ie, the sum of accelerometer-based Kinesia forward outstretched postural tremor, 
lateral "wing beating" postural tremor, and kinetic tremor item scores from both sides of the 
body) and individual item scores at Day 14.   
• 
Tremor severity, as measured by the change from randomization (Day 8) in the TETRAS upper 
limb total score (ie, the sum of TETRAS Performance Subscale item 4 scores [4a, 4b, and 4c] 
from both sides of the body) and individual TETRAS Performance Subscale upper limb item 
scores at Day 14.   
• 
Tremor severity, as assessed by the change from randomization (Day 8) in other TETRAS 
Performance Subscale scores measured at Day 14.   
• 
Safety and tolerability, as assessed by vital signs measurements, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Severity 
Rating Scale (C-SSRS), and adverse event reporting.   
• 
Sleepiness, as assessed by the Stanford Sleepiness Scale (SSS). 
• 
Mood, as assessed by the Bond-Lader visual analogue scale (VAS) Mood Scale scores.   
• 
How the subject feels after taking the study drug as assessed by Drug Effects Questionnaire 
(DEQ-5) ratings.   
The above endpoints may also be assessed for SAGE-217 Oral Solution if sufficient data are 
available.  
In addition, plasma concentrations of SAGE-217 and SAGE-217 metabolites may be measured.  
Pharmacokinetic parameters, such as area under the concentration-time curve from time zero to last 
time point (AUC0-t), area under the concentration-time curve from time zero to infinity (AUC0-∞), 


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maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), and terminal 
half-life (t1/2), will be derived, where appropriate. 
Exploratory: 
The exploratory objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Capsules to placebo on: 
• 
Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring), as assessed by the Empatica 
Wristband E4.  Tremor oscillation, as assessed by multi-dimensional accelerometer 
measurements (ie, raw accelerometer values) using the Empatica Wristband E4. 
• 
Quality of life (QOL), as assessed by TETRAS activities of daily living (ADL), Quality of Life in 
Essential Tremor Questionnaire (QUEST), and video recording assessment of subjects 
performing three everyday tasks (drinking a glass of water, fastening a button, and one additional 
task that the subject experiences difficulty with on a daily basis).   
In addition, PK/pharmacodynamic (PD) modelling assessment of the relationship between plasma 
exposure of SAGE-217 and change from baseline in Kinesia scores may be assessed. 
The above endpoints may also be assessed for SAGE-217 Oral Solution if sufficient data are 
available.  
Number of subjects (planned):  
Approximately 60 subjects will be enrolled in Part A to yield at least 40 randomized subjects for 
Part B.   
Diagnosis and main criteria for inclusion:  
Inclusion criteria: 
1. Subject has signed an informed consent form before any study-specific procedures are performed. 
2. Subject must be between 18 and 75 years of age, inclusive. 
3. Subject must have a diagnosis of ET, defined as bilateral postural tremor and kinetic tremor, 
involving hands and forearms, that is visible and persistent and the duration is >5 years prior to 
screening. 
4. Subject must have bilateral TETRAS scores of at least two on each side (left and right) for kinetic 
tremor and at least two on each side (left and right) for either wing beating or forward 
outstretched postural tremor.   
5. Subject must be willing to discontinue medications taken for the treatment of ET, alcohol, 
nicotine, and caffeine through Day 21 of the study.   
6. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests.   
7. Female subjects must be post-menopausal, permanently sterile (eg, bilateral tubal occlusion, 
hysterectomy, bilateral oophorectomy), or of childbearing potential with a negative pregnancy 
test, non- breastfeeding, and using two highly effective methods of birth control prior to screening 
through completion of the last follow-up visit (as defined in Section 8.1).  If a subject 
discontinues early after receiving a dose of study drug, they must continue this method of birth 
control for at least 7 days following the last dose of study drug.  Highly effective methods of birth 
control are defined as follows:  hormonal (ie, established use of oral, implantable, injectable, or 
transdermal hormonal methods of conception); placement of an intrauterine device; placement of 
an intrauterine system; and mechanical/barrier method of contraception (ie, condom or occlusive 


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cap [diaphragm or cervical/vault cap] in conjunction with spermicide [foam, gel, film, cream or 
suppository]). 
8. Male subjects must agree to practice a highly effective method of birth control while on study 
drug and for 13 weeks after receiving the last dose of study drug.  Effective methods of birth 
control include sexual abstinence, vasectomy, or a condom with spermicide (men) in combination 
with their partner’s highly effective method. 
9. Males must be willing to abstain from sperm donation and females from donating eggs while on 
study through 13 weeks after receiving the last dose of study drug. 
Exclusion criteria: 
1. Subject has presence of abnormal neurological signs other than tremor or Froment’s sign. 
2. Subject has presence of known causes of enhanced physiological tremor. 
3. Subject has concurrent or recent exposure (14 days prior to Day -1 visit) to tremorogenic drugs, as 
defined in Appendix 1, or the presence of a drug withdrawal state. 
4. Subject has had direct or indirect trauma to the nervous system within 3 months before the onset 
of tremor.  
5. Subject has historical or clinical evidence of tremor with psychogenic origin (including but not 
limited to eating disorders, major depression, etc.). 
6. Subject has convincing evidence of sudden tremor onset or evidence of stepwise deterioration of 
tremor. 
7. Subject has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or oncological disease. 
8. Subject has clinically significant abnormal physical examination or 12-lead ECG at the Screening 
or Day -1 visits.  Note:  A QT interval calculated using the Fridericia method [QTcF] of 
>450 msec in males or >470 msec in females, will be the basis for exclusion from the study.  An 
ECG may be repeated if initial values obtained exceed the limits specified. 
9. Subject has a history, presence, and/or current evidence of serologic positive results for hepatitis 
B surface antigen, hepatitis C antibodies, or human immunodeficiency virus 1 or 2 antibodies. 
10. Subject has hypothyroidism.  Stable thyroid replacement is acceptable. 
11. Subject has used alcohol, caffeine, or nicotine within 3 days prior to the Day -1 visit. 
12. Subject has a known allergy to SAGE-217 or its major excipient hydroxypropyl-β-cyclodextrin 
(HPβCD). 
13. Subject has exposure to another investigational medication or device within the prior 30 days. 
14. Subject has a history of suicidal behavior within 2 years or answers “YES” to questions 3, 4, or 5 
on the C-SSRS at the Screening visit or on Day -1 or is currently at risk of suicide in the opinion 
of the Investigator. 
15. Subject has donated one or more units (1 unit = 450 mL) of blood or acute loss of an equivalent 
amount of blood within 60 days prior to dosing. 
16. Subject is unwilling or unable to comply with study procedures. 
17. Use of any known strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, as defined 
in Appendix 2, within the 14 days or 5 half-lives (whichever is longer) or consumed grapefruit 


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juice, grapefruit, Seville oranges, pomegranates, tangelos, or St. John's Wort or products 
containing these within 30 days prior to receiving the first dose of study drug. 
18. Subject has obstructed venous access and/or has skin disease, rash, acne, or abrasion at venous 
access site that may affect the ability to obtain a PK sample (eg, artificial cardiac valve, joint 
replacement).   
19. Subject has concurrent or recent exposure (14 days prior to the Day -1 visit) to sedative/hypnotic 
(eg, opioids) drugs.   
20. Subject has hyperthyroidism at screening (based on thyroid-stimulating hormone, thyroxine [T4], 
and triiodothyronine [T3]) or clinically significant kidney issues in the opinion of the Investigator.  
Investigational product, dosage and mode of administration:  
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection and administered as an approximate 40 mL solution with a 10 mg, 20 mg, or 
30 mg dose given once daily in the morning with food. 
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white powder.  In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules contain 
croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl fumarate as 
excipients.  Capsules will be available in 5-mg, 10-mg and 20-mg dose strengths.   
Subjects will be administered two capsules per dose.   
Reference therapy, dosage and mode of administration:  
Placebo is available as a solution of 40% HPβCD and 0.0025% sucralose, which is further diluted 
with Sterile Water for Injection and administered as an approximate 40 mL solution given once daily 
in the morning with food in Part B.  Matched placebo capsules containing only the above-listed 
capsule excipients will be provided.  Subjects randomized to placebo treatment will be administered 
2 placebo capsules per day.   
Duration of treatment:  
Screening Duration: up to 28 days; Treatment Period: 14 days; Follow-up: 14 days 
Planned Study Duration per Subject: up to 56 days 
Criteria for evaluation: 
Efficacy: 
Tremor severity will be measured by accelerometer-based Kinesia and clinician-rated TETRAS 
Performance Subscale scores.  Quality-of-life will be evaluated using the TETRAS ADL, QUEST, 
and video recording of subjects performing three everyday tasks.  Physiological activity (ie, 
sympathetic nervous system tone as measured by electrodermal activity, skin temperature monitoring, 
and heart rate monitoring) and tremor oscillation will be assessed by the Empatica Wristband E4.   
Pharmacokinetics: 
Plasma will be collected to assay for concentrations of SAGE-217 and may be assayed for SAGE-217 
metabolites, if deemed necessary.  The following PK parameters will be derived from the plasma 
concentrations (where evaluable): AUC0-t, AUC0-∞, Cmax, tmax, and t½.   
Safety and Tolerability: 
Safety and tolerability of study drug will be evaluated by vital signs measurements, clinical laboratory 
measures, physical examination, ECGs, concomitant medication usage, C-SSRS, SSS, and adverse 
event reporting.  The Bond-Lader Mood Rating Scale and a DEQ-5 will be used to assess mood and 
perception of drug effects, respectively.   


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Statistical methods: 
Study Populations 
The safety population is defined as all subjects who are administered study drug.   
The efficacy population will consist of all subjects in the safety population who complete at least one 
dose in Part B and have at least one post-randomization efficacy evaluation.   
The evaluable population will consist of all randomized subjects with at least one post-randomization 
Kinesia assessment.   
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations.   
Efficacy Analysis 
Efficacy data (including change from randomization values for accelerometer-derived Kinesia and 
clinician-rated TETRAS scores) will be summarized using appropriate descriptive statistics and listed 
by subject. 
The change from randomization (Day 8) in the Kinesia kinetic tremor combined score (ie, the sum of 
Kinesia kinetic tremor scores from both sides of the body) at Day 14 will be summarized by 
treatment.  Additionally, the change from randomization in the Kinesia upper limb total score and 
individual item scores at Day 14 will be summarized by treatment.   
The change from randomization in TETRAS upper limb total score, individual TETRAS Performance 
Subscale upper limb item scores, and other TETRAS Performance Subscale scores at Day 14 will be 
summarized by treatment.   
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics and listed by 
subject.  Wherever necessary and appropriate, PK parameters will be dose-adjusted to account for 
individual differences in dose. 
Safety Analysis 
Adverse events will be coded using Medical Dictionary for Regulatory Activities™.  The overall 
incidence of adverse events will be displayed by System Organ Class, preferred term, and dose group.  
Incidence of adverse events will also be presented by maximum severity and relationship to study 
drug.  Data from vital signs, clinical laboratory measures, ECG, and C-SSRS will be summarized 
using descriptive statistics by dose group, where applicable.  Continuous endpoints will be 
summarized with n, mean, standard deviation, median, minimum, and maximum.  In addition, change 
from baseline values will be calculated at each time point and will be summarized using the same 
summary statistics.  Out-of-range safety endpoints may be categorized as low or high, where 
applicable.  For all categorical endpoints, summaries will include counts and percentages.   
Sample Size 
Up to 60 subjects will be enrolled in Part A to yield at least 40 randomized subjects for Part B.  A 
total sample size of 34 evaluable subjects (ie, 17 per group) will have 80% power to detect a 
difference in means of 3.0 on the primary endpoint assuming that the common standard deviation is 
3.0 using a 2-group t-test with a 0.05 two-sided significance level.  Assuming a 15% non-evaluability 
rate, 20 subjects per group will be randomized.  The number of subjects in each treatment group is 
also thought to be sufficient to assess preliminary safety and tolerability following multiple doses of 
SAGE-217. 
 


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Table 2: 
Schedule of Events:  Part A (Open-Label) 
Visit Days 
Screening 
(Day -28 to Day -1) 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Body weight/height 
X 
 
 
 
 
 
 
 
 
Drug/alcohol screen
a 
X 
X 
 
 
 
 
 
 
 
Complete blood count/ 
serum chemistry
b 
X 
X 
X 
X 
 
 
 
 
 
Pregnancy test  
X 
(serum) 
X 
(urine) 
 
 
 
 
 
 
 
Urinalysisb 
X 
X 
X 
X 
 
 
 
 
 
Hepatitis & HIV screen 
X 
 
 
 
 
 
 
 
 
Exploratory biochemistry 
sample
c 
O 
 
 
 
O 
 
 
 
O 
Genetic sample
d 
O 
 
 
 
 
 
 
 
 
Vital signs
e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetrye 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
f 
X 
 
X 
X 
X 
X 
 
 
X 
C-SSRS
g 
X 
X 
X 
 
 
X 
X 
X 
X 
SSS
h 
 
 
X 
X 
X 
X 
X 
X 
X 
Bond-Lader-VAS
i 
 
 
X 
X 
 
 
 
 
X 
DEQ-5
j 
 
 
X 
 
 
 
 
 
X 


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Table 2: 
Schedule of Events:  Part A (Open-Label) (Continued) 
Visit Days 
Screening 
(Day -28 to Day -1) 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Kinesia (accelerometer)
k 
 
X 
X 
X 
X 
 
 
 
X 
TETRAS upper limb itemsk 
X 
X 
X 
X 
X 
 
 
 
X 
TETRAS (ADL Subscale and 
items 4, 6, 7, and 8 of 
Performance Subscale)
l 
 
X 
 
 
 
 
 
 
X 
Empatica Wristband E4
m 
 
X 
X 
X 
X 
 
 
 
X 
QUEST 
 
X 
 
 
 
 
 
 
X 
Plasma PK samples
n 
 
 
X 
X 
X 
X 
X 
X 
X 
Administer study drug
o 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
Prior/concomitant medications
p 
X 
Videos
q 
 
X 
 
 
 
 
 
 
X 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram; HIV = 
human immunodeficiency virus; O = optional; PK = pharmacokinetic; QUEST = Quality of Life in Essential Tremor Questionnaire; SSS = Stanford Sleepiness 
Scale; TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue score 
a A urine sample for assessment of selected drugs (sedative/hypnotics [eg, opioids], cotinine, and caffeine) and a breath sample for alcohol screen will be 
collected at screening and Day -1. 
b Screening and safety laboratory tests will be performed at screening, Day -1, predose on Day 1, and predose on Day 2. 
c An optional blood sample for exploratory biochemistry, where consent is given. 
d An optional genetic sample for biomarker testing, where consent is given. 
e Vital signs (heart rate, respiratory rate, temperature, and supine [for at least 5 minutes prior to the measurement] and standing [for at least 2 to 3 minutes] 
systolic and diastolic blood pressure) and pulse oximetry will be performed at screening (vital signs only) and Day -1, predose and at 1, 2, 3, 4, 6, and 8 hours 
postdose on Days 1, 2, 3, and 4, and predose on Days 5, 6, and 7.  Vital signs and pulse oximetry assessments will be performed within ±10 minutes of the 
scheduled times. 
f 12-lead ECGs will be performed at screening, predose, and at 1 and 8 hours (±10 minutes) postdose on Days 1, 2, 3, 4, and 7. 
g The C-SSRS will be performed at screening, on Day -1, 8 hours (±1 hour) postdose on Day 1, and predose on Days 4, 5, 6, and 7.  Baseline/Screening version 
of C-SSRS should be used on day of screening and Since Last Visit version should be used on all subsequent time points. 


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h The SSS will be performed predose and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 1, 2, 3, and 4, and predose only on Days 5, 6, and 7.  The SSS is to be 
performed within ±10 minutes of the scheduled times. 
i The Bond-Lader VAS will be performed predose and 2 hours (±10 minutes) postdose on Days 1, 2, and 7. 
j The DEQ-5 will be performed 2 hours (±10 minutes) postdose on Days 1 and 7. 
k Kinesia and TETRAS upper limb items will be performed at screening (TETRAS upper limb items only), on Day -1 (three assessments separated by at least 
30 minutes); single assessments will be performed predose and 2 and 8 hours (±30 minutes) postdose on Days 1, 2, 3, and 7.  In addition, the TETRAS upper 
limb items will be performed, while wearing the Empatica Wristband E4, on Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3, and 7. All three 
maneuvers in the upper limb assessments (items 4a, 4b, and 4c) will be completed for both arms, first for the RIGHT arm and then for the LEFT. 
l TETRAS (ADL Subscale and items 4, 6, 7, and 8 of Performance Subscale) will be performed on Day -1 and predose (±30 minutes) on Day 7. 
m The Empatica Wristband E4 will be worn during the study visits while in clinic on Days -1, 1, 2, 3, and 7.  With the exception of during the TETRAS upper 
limb assessments, the Empatica Wristband E4 will be worn on the wrist that, of the two arms, exhibits more severe tremor symptoms.  During the TETRAS 
upper limb assessments on Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3, and 7, the Empatica Wristband E4 will be worn on the wrist 
corresponding to the side of the body being assessed. 
n Plasma pharmacokinetic samples will be taken predose (±5 minutes) and 0.25, 0.5, 1, 2, 4, and 8 hours postdose on Days 1 and 7 and predose on Days 2, 3, 4, 
5, and 6. 
o Study drug will be administered in the morning with food. 
p To include those taken within 2 weeks prior to informed consent and throughout the study. 
q Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis) will be taken on Day -1and predose on Day 7. 
 


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Table 3: 
Schedule of Events:  Part B (Randomized Withdrawal) 
Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21±1 day
a
(Early 
Termination 
Visit) 
End of Study 
Day 28±1 day 
Randomization 
X 
 
 
 
 
 
 
 
 
Complete blood count/ 
serum chemistry
b 
X 
X 
 
 
 
 
 
X 
 
Pregnancy test
c 
X 
(urine) 
 
 
 
 
 
 
 
X 
(urine) 
Urinalysisb 
X 
X 
 
 
 
 
 
X 
 
Vital signs
d 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pulse oximetryd 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG
e 
X 
X 
X 
 
 
 
X 
X 
 
C-SSRS
f 
X 
 
 
X 
X 
X 
X 
X 
X 
SSS
g 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bond-Lader-VAS
h 
X 
X 
 
 
 
 
X 
X 
 
DEQ-5
i 
X 
 
 
 
 
 
X 
 
 
Kinesia (accelerometer)
j 
X 
X 
 
 
 
 
X 
X 
 
TETRAS upper limb itemsj 
X 
X 
 
 
 
 
X 
X 
 
TETRAS (ADL Subscale and 
items 4, 6, 7, and 8 of 
Performance Subscale)
k 
 
 
 
 
 
 
X 
X 
 
Empatica Wristband E4
l 
X 
X 
 
 
 
 
X 
X 
 
QUEST 
 
 
 
 
 
 
X 
 
 
Plasma PK samples
m 
X 
X 
X 
X 
X 
X 
X 
 
 


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Table 3: 
Schedule of Events:  Part B (Randomized Withdrawal) (Continued) 
Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21±1 day
a
(Early 
Termination 
Visit) 
End of Study 
Day 28±1 day 
Administer study drug
b 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events 
X 
Concomitant medications
c 
X 
Videos
d 
 
 
 
 
 
 
X 
X 
 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram;  
HIV = human immunodeficiency virus; PK = pharmacokinetic; QUEST = Quality of Life in Essential Tremor Questionnaire; SSS = Stanford Sleepiness Scale; 
TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue score 
a In addition to subjects who complete Part B, subjects who receive at least one dose of study drug and do not complete Part B will have a visit 1 week following 
the last dose of study drug to assess safety measures. 
b Safety laboratory tests will be performed predose on Day 8 and Day 9 and anytime during the visit on Day 21. 
c To be performed predose on Day 8 and anytime during the visit on Day 28. 
d Vital signs (heart rate, respiratory rate, temperature, and supine [for at least 5 minutes prior to the measurement] and standing [for at least 2 to 3 minutes] 
systolic and diastolic blood pressure) and pulse oximetry will be performed predose on Day 8 and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 8, 9, and 10, 
predose on Days 11, 12, 13, and 14, and anytime during the visit on Day 21.  Vital signs and pulse oximetry assessments will be performed within ±10 minutes 
of the scheduled times. 
e 12-lead ECGs will be performed at 1 and 8 hours (±10 minutes) postdose on Days 8, 9, 10, and 14, and anytime during the visit on Day 21. 
f The C-SSRS (Since Last Visit version) will be performed 8 hours (±1 hour) postdose on Days 8, 11, 12, 13 and 14 and anytime during the visits on Days 21 
and 28. 
g The SSS will be performed predose and 1, 2, 4, 6, and 8 hours postdose on Days 8, 9, 10, 11, 12, 13, and 14, and anytime during the visit on Day 21.  The SSS 
is to be performed within ±10 minutes of the scheduled times. 
h The Bond-Lader VAS will be performed predose and 2 hours (±10 minutes) postdose on Days 8, 9, and 14 and anytime during the visit on Day 21. 
i The DEQ-5 will be performed 2 hours (±10 minutes) postdose on Days 8 and 14. 
j Kinesia and TETRAS upper limb items will be performed predose, 2 and 8 hours (±30 minutes) postdose on Days 8, 9, and 14, and anytime during the visit on 
Day 21.  In addition, the TETRAS upper limb items will be performed, while wearing the Empatica Wristband E4, 3 hours (±30 minutes) postdose on Days 8, 
9, and 14, and anytime during the visit on Day 21.  All three maneuvers in the upper limb assessments (items 4a, 4b, and 4c) will be completed for both arms, 
first for the RIGHT arm and then for the LEFT. 
k TETRAS ADL Subscale and items 4, 6, 7, and 8 of Performance Subscale will be performed predose (±30 minutes) on Day 14 and anytime during the visit on 
Day 21. 


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l The Empatica Wristband E4 will be worn during the study visits while in clinic on Days 8, 9, 14, and 21.  With the exception of during the TETRAS upper 
limb assessments, the Empatica Wristband E4 will be worn on the wrist that, of the two arms, exhibits more severe tremor symptoms.  During the TETRAS 
upper limb assessments 3 hours (±30 minutes) postdose on Days 8, 9, and 14 and anytime during the visit on Day 21, the Empatica Wristband E4 will be worn 
on the wrist corresponding to the side of the body being assessed. 
m Plasma pharmacokinetic samples will be taken predose (±5 minutes) on Days 8, 9, 10, 11, 12, 13, and 14. 
b Study drug will be administered in the morning with food. 
c To include those taken throughout the study. 
d Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis) will be taken predose on Day 14 and anytime during the visit on Day 21. 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................22 
5. 
INTRODUCTION ......................................................................................................24 
5.1. 
Background of Essential Tremor and Unmet Medical Need ......................................24 
5.2. 
SAGE-217 ...................................................................................................................25 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 ..........................25 
5.3.1. 
Nonclinical Studies with SAGE-217 ..........................................................................25 
5.3.2. 
Clinical Experience .....................................................................................................26 
5.4. 
Potential Risks and Benefits .......................................................................................27 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................29 
6.1. 
Primary Objective .......................................................................................................29 
6.2. 
Secondary Objectives .................................................................................................29 
6.3. 
Exploratory Objectives ...............................................................................................30 
7. 
INVESTIGATIONAL PLAN .....................................................................................31 
7.1. 
Overall Study Design ..................................................................................................31 
7.2. 
Blinding and Randomization ......................................................................................31 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................33 
8.1. 
Subject Inclusion Criteria ...........................................................................................33 
8.2. 
Subject Exclusion Criteria ..........................................................................................33 
8.3. 
Entrance Criteria for Part B ........................................................................................35 
8.4. 
Subject Withdrawal Criteria .......................................................................................35 
8.4.1. 
Study Drug Withdrawal ..............................................................................................35 
8.4.2. 
Criteria for Study Termination ...................................................................................36 
9. 
TREATMENT OF SUBJECTS ..................................................................................37 
9.1. 
Number of Subjects ....................................................................................................37 
9.2. 
Treatment Assignment ................................................................................................37 
9.2.1. 
Part A ..........................................................................................................................37 


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9.2.2. 
Part B ..........................................................................................................................37 
9.3. 
Dose Adjustment Criteria ...........................................................................................37 
9.4. 
Prior/Concomitant Medications and Restrictions .......................................................37 
9.4.1. 
Prior/Concomitant Medications ..................................................................................37 
9.4.2. 
Prohibited Medications ...............................................................................................38 
9.5. 
Treatment Compliance ................................................................................................38 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................39 
10.1. 
Study Drug ..................................................................................................................39 
10.1.1. 
SAGE-217 Oral Solution ............................................................................................39 
10.1.1.1. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL ...................................39 
10.1.2. 
SAGE-217 Capsules ...................................................................................................39 
10.2. 
Study Drug Packaging and Labeling ..........................................................................40 
10.3. 
Study Drug Storage .....................................................................................................40 
10.4. 
Administration and Study Drug Accountability .........................................................41 
10.4.1. 
Study Drug Administration.........................................................................................41 
10.4.2. 
Study Drug Accountability .........................................................................................41 
10.5. 
Study Drug Handling and Disposal ............................................................................41 
11. 
ASSESSMENT OF EFFICACY ................................................................................42 
11.1. 
Kinesia ........................................................................................................................42 
11.2. 
TRG Essential Tremor Rating Assessment Scale (TETRAS) Performance 
Scale ............................................................................................................................42 
11.3. 
Empatica Wristband E4 ..............................................................................................43 
11.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST) ....................................43 
11.5. 
Video Recording .........................................................................................................43 
12. 
PHARMACOKINETICS ...........................................................................................44 
12.1. 
Blood Sample Collection ............................................................................................44 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ..................................................44 
12.3. 
Sample Analysis .........................................................................................................44 
13. 
ASSESSMENT OF SAFETY .....................................................................................45 
13.1. 
Safety and Tolerability Parameters .............................................................................45 
13.1.1. 
Demographic/Medical History ...................................................................................45 
13.1.2. 
Vital Signs ..................................................................................................................45 
13.1.3. 
Weight and Height ......................................................................................................45 


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13.1.4. 
Physical Examination .................................................................................................45 
13.1.5. 
Electrocardiogram (ECG) ...........................................................................................45 
13.1.6. 
Laboratory Assessments .............................................................................................46 
13.1.6.1. 
Hematology .................................................................................................................46 
13.1.6.2. 
Blood Chemistry .........................................................................................................46 
13.1.6.3. 
Urinalysis ....................................................................................................................46 
13.1.6.4. 
Drugs Screen and Alcohol Test ..................................................................................46 
13.1.6.5. 
Virus Serology ............................................................................................................47 
13.1.6.6. 
Pregnancy Test ............................................................................................................47 
13.1.6.7. 
Exploratory Biochemistry ...........................................................................................47 
13.1.6.8. 
Genetic Testing ...........................................................................................................47 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................47 
13.1.8. 
Stanford Sleepiness Scale (SSS) .................................................................................48 
13.1.9. 
Bond-Lader VAS Mood Scale ....................................................................................48 
13.1.10. 
Drug Effects Questionnaire (DEQ-5) .........................................................................48 
13.2. 
Adverse and Serious Adverse Events .........................................................................49 
13.2.1. 
Definition of Adverse Events .....................................................................................49 
13.2.1.1. 
Adverse Event .............................................................................................................49 
13.2.1.2. 
Suspected Adverse Reaction .......................................................................................49 
13.2.1.3. 
Serious Adverse Event ................................................................................................49 
13.2.2. 
Pregnancy ...................................................................................................................49 
13.3. 
Relationship to Study Drug ........................................................................................50 
13.4. 
Recording Adverse Events .........................................................................................50 
13.5. 
Reporting Serious Adverse Events .............................................................................51 
13.6. 
Emergency Identification of Study Drug (Part B) ......................................................51 
14. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................53 
14.1. 
Data Analysis Sets ......................................................................................................53 
14.2. 
Handling of Missing Data ...........................................................................................53 
14.3. 
Demographics and Baseline Characteristics ...............................................................53 
14.4. 
Primary Efficacy Endpoint .........................................................................................53 
14.5. 
Secondary Efficacy Endpoints ....................................................................................53 
14.6. 
Exploratory Efficacy Endpoints .................................................................................54 


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14.7. 
Safety and Tolerability Analyses ................................................................................54 
14.7.1. 
Adverse Events ...........................................................................................................54 
14.7.2. 
Vital Signs ..................................................................................................................54 
14.7.3. 
Physical Examinations ................................................................................................54 
14.7.4. 
12-Lead ECG ..............................................................................................................55 
14.7.5. 
Clinical Laboratory Evaluations .................................................................................55 
14.7.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................55 
14.7.7. 
Stanford Sleepiness Scale (SSS) .................................................................................55 
14.7.8. 
Bond-Lader VAS Mood Scale ....................................................................................55 
14.7.9. 
Drug Effects Questionnaire (DEQ-5) .........................................................................55 
14.7.10. 
Prior and Concomitant Medications ...........................................................................55 
14.8. 
Pharmacokinetic Analysis ..........................................................................................56 
14.9. 
Determination of Sample Size ....................................................................................56 
14.10. 
Changes From Protocol Specified Analyses ...............................................................56 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................57 
15.1. 
Study Monitoring ........................................................................................................57 
15.2. 
Audits and Inspections ................................................................................................57 
15.3. 
Institutional Review Board (IRB) ...............................................................................58 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................59 
17. 
ETHICS ......................................................................................................................60 
17.1. 
Ethics Review .............................................................................................................60 
17.2. 
Ethical Conduct of the Study ......................................................................................60 
17.3. 
Written Informed Consent ..........................................................................................60 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................61 
18.1. 
Inspection of Records .................................................................................................61 
18.2. 
Retention of Records ..................................................................................................61 
18.3. 
Confidentiality ............................................................................................................61 
19. 
PUBLICATION POLICY ..........................................................................................63 
20. 
LIST OF REFERENCES ............................................................................................64 
21. 
APPENDICES ............................................................................................................67 
APPENDIX 1. TREMOROGENIC DRUGS ..............................................................................68 
APPENDIX 2. STRONG INHIBITORS AND INDUCERS OF CYP3A4 ................................70 


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APPENDIX 3. TRG ESSENTIAL TREMOR RATING ASSESSMENT SCALE 
(TETRAS) ..........................................................................................................71 
APPENDIX 4. QUALITY OF LIFE IN ESSENTIAL TREMOR QUESTIONNAIRE 
(QUEST).............................................................................................................77 
APPENDIX 5. COLUMBIA – SUICIDE SEVERITY RATING SCALE (C-SSRS) ................79 
APPENDIX 6. STANFORD SLEEPINESS SCALE (SSS) .......................................................86 
APPENDIX 7. BOND-LADER VAS (MOOD RATING SCALE) ...........................................87 
APPENDIX 8. DRUG EFFECTS QUESTIONNAIRE (DEQ-5) ...............................................88 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events:  Part A (Open-Label) .................................................................11 
Table 3: 
Schedule of Events:  Part B (Randomized Withdrawal) ............................................14 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................22 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL..................39 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
ADL 
activities of daily living 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-t 
area under the concentration-time curve from time zero to last 
time point 
AUC0-∞  
area under the concentration-time curve from time zero to infinity 
BMI 
body mass index 
Cmax  
maximum plasma concentration 
CNS 
central nervous system 
CRF 
case report form 
CS 
clinically significant  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450  
DEQ-5 
Drug Effects Questionnaire 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
ET 
essential tremor 
GABA 
γ-aminobutyric acid 
GABAA 
γ-aminobutyric acid-ligand gated chloride channel 
GABAB 
γ-aminobutyric acid-G protein-coupled 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg  
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxypropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 


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Table 4: 
Abbreviations and Specialist Terms  (Continued) 
Abbreviation or Specialist Term 
Explanation 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
NCS 
not clinically significant 
NF  
National Formulary 
PI 
Principal Investigator 
PK 
pharmacokinetic 
QOL 
quality of life 
QTcF 
QT interval calculated using the Fridericia method 
QUEST 
Quality of Life in Essential Tremor Questionnaire 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAEs 
treatment-emergent adverse events 
TETRAS 
TRG Essential Tremor Rating Assessment Scale 
t1/2 
terminal half-life 
tmax  
time to reach maximum concentration 
USP  
United States Pharmacopeia 
VAS 
visual analogue score 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 
WMA 
World Medical Association 
 


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5. 
INTRODUCTION 
5.1. 
Background of Essential Tremor and Unmet Medical Need 
Essential tremor (ET) is among the most common neurological diseases, with an overall 
prevalence of 0.9%.  Prevalence increases with age and is estimated to be 4.6% in people over 
65 years of age (Louis 2010, Deuschl 2011).  Essential tremor is largely a bilateral, symmetrical 
postural or kinetic tremor involving hands and forearms that is visible and persistent.  Additional 
or isolated tremor of the head or lower limbs may occur, but in the absence of abnormal 
posturing (Deuschl 1998, Habib-ur-Rehman 2000).  The onset of tremor has a bimodal 
distribution, with onset between 15 to 20 and 50 to 70 years.  Over time, tremors can become 
more pronounced and may prevent eating, drinking, and writing, as well as executing personal 
hygiene like shaving or applying make-up.  Voice tremors can be severe enough to inhibit 
talking and singing in public.   
Several lines of evidence suggest that cerebellar dysfunction through the 
cerebellothalamocortical pathway plays a key role in ET (McAuley 2000, Pinto 2003, 
Elble 2009, Schnitzler 2009, Deuschl 2009).  Thalamotomy and deep brain stimulation of the 
ventral intermediate nucleus and of the subthalamic nucleus improve ET (Deuschl 2011, 
Zappia 2013, Rajput 2014).  Microscopic cerebellar pathology has been identified, including 
gliosis, Purkinje cell loss, and increased torpedoes (swellings) in the Purkinje cell axons 
(Louis 2007, Axelrad 2008, Shill 2008, Louis 2009).  Activation studies with positron emission 
tomography indicate abnormally increased regional cerebral blood flow in the cerebellum both at 
rest and when tremor is provoked by unilateral arm extension (Boecker 1994, Wills 1996).   
Essential tremor is associated with impaired γ-aminobutyric acid (GABA)ergic function (and 
consequent hyperactivity) in the cerebellum (Málly 1996, Bucher 1997, Louis 2007, Louis 2008, 
Paris-Robidas 2012).  γ-aminobutyric acid, the major inhibitory neurotransmitter in the central 
nervous system (CNS), is released from GABAergic neurons and binds to several types of 
GABA receptors (γ-aminobutyric acid-ligand gated chloride channel [GABAA] and 
γ-aminobutyric acid-G protein-coupled [GABAB]) on target neurons.  γ-aminobutyric acid-gated 
chloride channel receptors, the major class of inhibitory neurotransmitter receptors in the brain, 
are macromolecular proteins that form a chloride ion channel complex and contain specific 
binding sites for GABA and a number of allosteric regulators, including barbiturates, 
benzodiazepines, and some anesthetic agents.   
Drugs acting on GABAA receptors, such as primidone, benzodiazepines, or ethanol decrease 
tremor amplitude, suggesting that altered GABAergic neurotransmission is involved in ET.  
Postmortem analysis revealed a 35% reduction of GABAA receptors and a 22% to 31% reduction 
of GABAB receptors in the dentate nucleus of cerebella of ET subjects (Paris-Robidas 2012).  
Reduced levels of GABA in the cerebrospinal fluid are also reported in ET subjects 
(Málly 1996).  Moreover, toxins such as aflatrem, penitrem A, or harmaline have been proposed 
to induce tremor in rodents by interacting with GABA receptors (Cavanagh 1998, Miwa 2007), 
and targeted deletion of the α1 subunit of GABAA receptor in knockout mice exhibits a 
15 to 19 Hz action tremor, similar to ET in humans (Kralic 2005).   
Consistent with the role of GABA, the majority of therapeutics for ET act by augmenting 
GABAergic transmission (Louis 2012, Benito-Leon 2007, Pahapill 1999).  First-line treatments 


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for ET include the anticonvulsant primidone and the β-adrenergic blocker propranolol 
(Gorman 1986).  Like primidone, gabapentin is an anticonvulsant found to be effective in the 
treatment of ET (O’Brien 1981, Gironell 1999).  The oldest treatment for ET is ethanol, which 
temporarily ameliorates tremor and is frequently used by subjects to self-medicate; however, 
chronic use of ethanol for tremor management carries the known risks of alcohol dependence and 
overuse (Pahwa 2003).   
These treatments are moderately effective, reducing, though not resolving, tremor amplitudes in 
about 50% of the subjects (Schmouth 2014).  In addition, one out of three patients abandon 
treatment because of side effects or poor efficacy (Louis 2010), illustrating that with few feasible 
treatment options and a range of handicaps in daily living makes ET an area of high unmet 
medical need.   
5.2. 
SAGE-217  
SAGE-217 is a positive allosteric modulator of the GABAA receptor and thus is expected to be 
of benefit for the treatment of ET.  Unlike benzodiazepines that are selective for the γ-subunit-
containing subset of GABAA receptors (Pritchett 1989, Esmaeili 2009), SAGE-217 and other 
neuroactive steroids, which bind to the ubiquitous α-subunit, have a wider range of activity 
(Belelli 2002). 
Two dosage forms of SAGE-217 for oral administration will be used in this study (SAGE-217 
Oral Solution and SAGE-217 Capsules). 
SAGE-217 Oral Solution 6 mg/mL (40% w/w aqueous hydroxypropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a nonviscous, clear solution.   
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white 
powder. In addition to SAGE-217 Drug Substance, the active, SAGE-217 capsules contain 
croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl 
fumarate as excipients. 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 
5.3.1. 
Nonclinical Studies with SAGE-217 
In nonclinical studies of SAGE-217, sedative-hypnotic effects were consistently observed at 
higher doses in both in vivo pharmacology studies as well as in toxicology studies.  The 
sedative-hypnotic impairments seen with SAGE-217 were typical for GABAA positive 
modulators, ranging from hyperexcitability and ataxia at the lower doses through deep sedation 
and ultimately anesthesia at higher doses.  Depth and duration of sedation demonstrated a clear 
dose response over the range tested, with evidence of tolerance occurring with continued 
exposure.  Tolerance to the effects of SAGE-217 on motor incoordination was not observed after 
7 days of dosing.   
The compound has been assessed in 14-day rat and dog toxicology studies with daily 
administration of SAGE-217 as a solution in HPβCD in dogs and Labrasol® in rats.  The no 
observed adverse effect level was 3 mg/kg (females) and 22.5 mg/kg (males) in rats and 
2.5 mg/kg in dogs.  There were no adverse effects in dogs or rats in the main toxicology studies.  
A single observation of mortality occurred in one female rat at the high dose in a toxicokinetic 


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study which was suspected to have been related to exaggerated pharmacology.  Additional 
toxicology and pharmacology information is provided in the Investigator’s Brochure.   
5.3.2. 
Clinical Experience 
To date, two clinical studies employing SAGE-217 Oral Solution are clinically complete and 
final clinical study reports are pending.  Discussions of pharmacokinetic (PK) data are limited to 
the single-ascending dose, food, and essential tremor cohorts from Study 217-CLP-101 and the 
multiple-ascending dose and drug-drug interaction (DDI) cohorts from Study 217-CLP-102.  
Discussions of safety data are limited to the single-ascending dose cohorts in Study 217-CLP-
101 and the multiple-ascending dose cohorts in Study 217-CLP-102.  In addition, one clinical 
study of the safety, tolerability, PK, and relative bioavailability SAGE-217 Capsules is clinically 
complete and the final study report is pending.  The results of this study (217-CLP-103) are 
briefly described below. 
Study 217-CLP-101 was a first-in-human, four-part study that assessed the effects of a single 
dose of SAGE-217 Oral Solution.  The study was a double-blind, placebo-controlled, single-
ascending dose design in healthy adult volunteers, with the objective of identifying the maximum 
tolerated dose (MTD) and PK profiles of SAGE-217 Oral Solution.  Subjects in each of the 
single-ascending dose cohorts received a single dose of study drug, either SAGE-217 Oral 
Solution (six subjects) or placebo (two subjects), with SAGE-217 Oral Solution doses of 
0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 mg, 55 mg, and 66 mg.  Escalation to the 
next dose was undertaken only after safety and PK data were reviewed by the Safety Review 
Committee (SRC) and agreement reached that it was safe to increase the dose.  The MTD was 
determined to be 55 mg.  Two cohorts, 6 subjects each received SAGE-217 Oral Solution in an 
open-label manner (one cohort received 50% of the MTD [22 mg] to study the food effects and 
the other cohort received the MTD [55 mg] to study the effects on subjects with essential 
tremor).  SAGE-217 Oral Solution was orally bioavailable, demonstrated dose-linear PK from 
the lowest (0.25 mg) through the highest (66 mg) dose, and supported once daily oral dosing 
with food.   
Study 217-CLP-102 was a two-part study that assessed the effects of multiple-ascending doses of 
SAGE-217 Oral Solution.  The study was a double-blind, placebo-controlled, multiple-ascending 
dose study in healthy adult volunteers.  Subjects in each of the multiple-ascending dose cohorts 
received study drug, either SAGE-217 Oral Solution (nine subjects) or placebo (three subjects), 
once daily for 7 days, with SAGE-217 Oral Solution doses of 15 mg, 30 mg, and 35 mg.  
Escalation to the next dose was undertaken only after safety and PK data were reviewed by the 
SRC and agreement reached that it was safe to increase the dose.  The MTD was determined to 
be 30 mg.  It was observed that subjects receiving the drug in the evening did better in terms of 
tolerability compared to when they received the drug in the morning.  A fourth cohort of 12 
subjects received 30 mg of SAGE-217 Oral Solution in an open-label manner to study drug-drug 
interactions.  SAGE-217 Oral Solution is not likely to induce the metabolism of CYP2B6 or 
CYP3A4 substrates.  SAGE-217 Oral Solution was orally bioavailable and suitable for once 
daily oral dosing at night time with food.   
SAGE-217 Oral Solution was generally well tolerated.  In both Phase 1 studies (217-CLP-101 
and 217-CLP-102), doses were escalated until the stopping criteria were met.  Most adverse 
events were reported as mild or moderate in intensity, and there were no serious adverse events 


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reported in either study.  In addition, none of the observed adverse events resulted in 
discontinuation of the study drug.  At doses planned for further study, the observed sedation was 
mild, transient, and associated with daily peak exposure.  The most common treatment-emergent 
adverse events were sedation, somnolence, dizziness, euphoric mood, fatigue, tremor, and 
muscle twitching, reported most frequently in the highest dose group (66 mg).  Some changes in 
mean blood pressure and heart rate were observed after single doses of 44 mg and greater.  After 
multiple doses of 30 mg (AM or PM) or 35 mg (PM) over 7 days, there was no evidence of 
changes in mean vital sign measures even though Day 7 plasma concentrations approximated 
that of the highest single dose in the single-ascending dose study.  Subjects seemed to tolerate 
SAGE-217 Oral Solution better when given as night time dosing.   
The safety, tolerability, PK, and relative bioavailability of the SAGE-217 Capsules were 
assessed in a Phase 1 randomized, open-label, cross-over study (Study 217-CLP-103). In the 
fasted state, SAGE-217 Capsules demonstrated reduced exposure in terms of maximum (peak) 
plasma concentration (Cmax) and area under the curve from zero to the time of the last 
quantifiable concentration (AUClast) compared to SAGE-217 Oral Solution.  SAGE-217 Capsules 
administered in the fed state (with standard and high-fat meal) showed increased exposure 
compared to the fasted state and approximately equivalent exposure in terms of geometric mean 
AUClast compared to SAGE-217 Oral Solution; however, the Cmax for SAGE-217 Capsules was 
reduced by approximately 50% when compared with SAGE-217 Oral Solution.  Based on these 
study results, exposures with SAGE-217 Capsules are anticipated to be equal to or less than 
exposures observed at the same dose with SAGE-217 Oral Solution.  
There were no clinical efficacy data of SAGE-217 in ET, since the present study is the first study 
in this indication.   
5.4. 
Potential Risks and Benefits 
Protocol 217-ETD-201 is the first clinical study of SAGE-217 in ET evaluating the efficacy of 
this product.  Thus, the potential benefits in this population are unknown, although the risks are 
likely to be similar to those mentioned in the Investigator’s Brochure.  Many compounds that 
target the GABAA receptors exhibit clinical efficacy in ET, validating this receptor as a 
therapeutic target.  Given the promising SAGE-547 clinical data in conjunction with the shared 
broad receptor selectivity profile, oral bioavailability, long half-life, preclinical evidence of 
anxiolytic activity and safety data of SAGE-217, it is possible that patients may have a clinical 
benefit at the exposures selected for this study.  In view of the few risks associated with 
administration of SAGE-217 that have been identified to date, an intra-patient dose-escalation 
design has been chosen to permit titration of treatment effect vs tolerability (adverse events), 
specifically sedation.  Each subject will start with an initial dose of 10 mg to be escalated to 
20 mg after a day and then escalated further to 30 mg assuming no tolerability issues.  At the end 
of a 7-day exposure, the maximum dose for the subject will be established as will a protocol 
specified response.  Subjects who are responders and tolerate at least the 10-mg dose for a 
minimum of 3 days will qualify for the randomization phase (Part B).  Given the high medical 
need and potential for benefit in ET, there is a favorable benefit-risk evaluation to investigate 
SAGE-217 in ET.   
In the 217-CLP-103 study, SAGE-217 Capsules were found to be generally well-tolerated with 
no serious AEs reported during the treatment and follow-up periods.  The most frequent AE 


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observed was sedation that was mild, transient, and occurred within 1 to 4 hours and generally 
dissipated by 8 hours.  The clinical portion of this study has recently completed; the final report 
is in progress. 
In conclusion, selection criteria for the proposed study take into account the potential safety 
risks.  Continuous safety monitoring, and the implementation of a formal dose-reduction and 
study drug discontinuation scheme also have the potential to mitigate risk.  From a benefit/risk 
perspective, the appropriate measures are being taken in order to ensure the safety of the subjects 
who will be enrolled.   


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of this study is to compare the effect of 7 days administration of 
SAGE-217 Capsules to placebo on the change in tremor severity, as measured by the change 
from randomization (Day 8) in the accelerometer-based Kinesia™ kinetic tremor combined score 
(ie, the sum of Kinesia kinetic tremor scores from both sides of the body) at Day 14. 
6.2. 
Secondary Objectives 
The secondary objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Capsules to placebo on the following endpoints: 
1. Tremor severity as assessed by the change from randomization (Day 8) in the Kinesia 
upper limb total score (ie, the sum of accelerometer-based Kinesia forward outstretched 
postural tremor, lateral “wing beating” postural tremor, and kinetic tremor item scores 
from both sides of the body) and individual item scores at Day 14. 
2. Tremor severity as measured by the change from randomization (Day 8) in TRG 
Essential Tremor Rating Assessment Scale (TETRAS) upper limb total score (ie, the sum 
of TETRAS Performance Subscale item 4 scores [4a, 4b, and 4c] from both sides of the 
body) and individual TETRAS Performance Subscale upper limb item scores at Day 14. 
3. Tremor severity as assessed by the change from randomization (Day 8) in other TETRAS 
Performance Subscale scores measured at Day 14. 
4. Safety and tolerability as assessed by vital signs measurements, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide 
Severity Rating Scale (C-SSRS), and adverse event reporting.   
5. Sleepiness as assessed by the SSS. 
6. Mood as assessed by the Bond-Lader visual analogue score (VAS) Mood Scale. 
7. How the subject feels after taking the study drug as assessed by Drug Effects 
Questionnaire (DEQ-5) ratings. 
The above endpoints may also be assessed for SAGE-217 Oral Solution if sufficient data are 
available.  
In addition, plasma concentrations of SAGE-217 and SAGE-217 metabolites may be measured.  
Pharmacokinetic parameters, such as area under the concentration-time curve from time zero to 
last time point (AUC0-t), area under the concentration-time curve from time zero to infinity 
(AUC0-∞), maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), 
and terminal half-life (t1/2), will be derived, where appropriate.   


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6.3. 
Exploratory Objectives 
The exploratory objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Capsules to placebo on: 
1. Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring) as assessed by the 
Empatica Wristband E4.  Tremor oscillation as assessed by multidimensional 
accelerometer measurements (ie, raw accelerometer values) using the Empatica 
Wristband E4. 
2. Quality of life (QOL) as assessed by TETRAS activities of daily living (ADL), Quality of 
Life in Essential Tremor Questionnaire (QUEST), and video recording assessment of 
subjects performing three everyday tasks (drinking a glass of water, fastening a button, 
and one additional task that the subject experiences difficulty with on a daily basis). 
In addition, PK and pharmacodynamic modelling assessment of the relationship between plasma 
exposure of SAGE-217 and change from baseline in Kinesia scores may be assessed.   
The above endpoints may also be assessed for SAGE-217 Oral Solution if sufficient data are 
available. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study is a two-part, multicenter, Phase 2a study to evaluate the efficacy, safety, tolerability, 
and PK of SAGE-217 in approximately 60 adult subjects with ET.  Subjects who consent prior to 
the approval of Protocol Amendment #3 by the IRB will receive the oral solution formulation for 
the duration of the study.  Subjects who consent after Amendment #3 is approved by the IRB 
will receive the capsule formulation for the duration of the study. 
Part A of the study is an open-label design with morning dosing for 7 days.  Part B of the study is 
a double-blind, placebo-controlled, randomized withdrawal design.  Subjects will be exposed to 
study drug (SAGE-217 or placebo) for up to 14 days and will be followed for an additional 
14 days after the administration of the last dose.   
During the Screening Period (Day -28 to Day -1), after signing the informed consent form (ICF), 
subjects will be assessed for study eligibility and the severity of each subject’s ET will be 
evaluated using TETRAS.  Eligible subjects will return to the clinical study unit on Day -1.   
The study will be conducted in two parts: 
• Part A:  Beginning on Day 1, all subjects will receive open-label SAGE-217 in the 
morning with food (as outlined in Section 9.2) for 7 days.  Subjects will receive 
SAGE-217 10 mg on Day 1, SAGE-217 20 mg on Day 2, and SAGE-217 30 mg from 
Day 3 to Day 7, with dose adjustments for severe adverse events judged by the 
Investigator to be related to study drug (Section 9.3). 
• Part B:  In order to qualify for Part B of the study, a subject must tolerate a dose of 
≥10 mg of SAGE-217, and the subject must have responded to SAGE-217, defined as 
a 30% reduction from baseline in TETRAS kinetic tremor (item 4c) combined score 
predose on Day 8.  Eligible subjects will be randomized in a 1:1 fashion to receive 
SAGE-217 or placebo for 7 days beginning on Day 8.  All doses of study drug will be 
administered with food as outlined in Section 9.2.  Subjects randomized to SAGE-217 
or placebo will receive their maximum dose as determined in Part A in the morning 
with food. 
Dose adjustments will only be allowed during Part A of the study.  A dose will be considered not 
tolerated if the subject experiences a severe adverse event considered to be related to the study 
drug by the Investigator.  If a dose is not tolerated, the dose on the next day will be reduced to 
the next lowest dose and continued for the remainder of the open-label dosing period (ie, subjects 
who are unable to tolerate SAGE-217 30 mg will receive SAGE-217 20 mg and subjects who are 
unable to tolerate SAGE-217 20 mg will receive SAGE-217 10 mg).  The dose tolerated on 
Days 5, 6, and 7 of Part A will be considered the maximum dose for that subject.  Subjects who 
require dose adjustments on Days 5, 6, or 7 of Part A will not progress to Part B.   
7.2. 
Blinding and Randomization 
Part A is open-label with no control group; therefore, there will be no randomization or blinding.   


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Part B of the study is a double-blind, placebo-controlled, randomized withdrawal design.  
Subjects who tolerate a dose of ≥10 mg of SAGE-217 in Part A and respond to SAGE-217, 
defined as a 30% reduction from baseline in TETRAS kinetic tremor combined score predose on 
Day 8, will be randomly assigned in a 1:1 fashion to receive SAGE-217 or placebo according to 
a computer-generated randomization schedule.  Once it has been determined that a subject meets 
eligibility criteria for randomization, the subject will be sequentially assigned a subject number.  
The unblinded pharmacist will then use this randomization number to prepare and allocate 
blinded study drug to the subject. 
The randomization schedule will be generated prior to the start of the study.  The randomization 
schedule will be generated using SAS V9.2 or later.  Only the clinic pharmacist, who is 
responsible for preparing the study drug for administration, will be given a copy of the 
randomization schedule.  In the event of a medical emergency, the pharmacist may reveal actual 
study drug contents to the investigator, who should also alert Sage of the emergency (see 
Section 13.6 for more details related to unblinding).  In all cases where the study drug allocation 
for a subject is unblinded, pertinent information (including the reason for unblinding) must be 
documented in the subject’s records and on the electronic case report form (eCRF).  If the 
subject or study center personnel (other than pharmacist) have been unblinded, the subject will 
be terminated from the study.   
Subjects randomized to SAGE-217 will receive their maximum dose as determined in Part A in 
the morning with food.  Subjects randomized to the placebo arm will represent randomized 
withdrawal (withdrawal from treatment they received in Part A).   


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
It is anticipated that up to 60 subjects will be enrolled at up to 25 study centers.  The following 
inclusion and exclusion criteria will be applied during screening for Part A of the study.  
8.1. 
Subject Inclusion Criteria 
Subjects must meet the following inclusion criteria for enrollment in the study: 
1. Subject has signed an ICF before any study-specific procedures are performed.   
2. Subject must be between 18 and 75 years of age, inclusive. 
3. Subject must have a diagnosis of ET, defined as bilateral postural tremor and kinetic 
tremor, involving hands and forearms, that is visible and persistent and the duration is 
>5 years prior to screening. 
4. Subject must have bilateral TETRAS scores of at least two on each side (left and right) 
for kinetic tremor and at least two on each side (left and right) for either wing beating or 
forward outstretched postural tremor.   
5. Subject must be willing to discontinue medications taken for the treatment of ET, 
alcohol, nicotine, and caffeine through Day 21 of the study.   
6. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. 
7. Female subjects must be post-menopausal, permanently sterile (eg, bilateral tubal 
occlusion, hysterectomy, bilateral oophorectomy), or of childbearing potential with a 
negative pregnancy test, non- breastfeeding, and using two highly effective methods of 
birth control prior to screening through completion of the last follow-up visit.  If a subject 
discontinues early after receiving a dose of study drug, they must continue this method of 
birth control for at least 7 days following the last dose of study drug.  Highly effective 
methods of birth control are defined as follows:  hormonal (ie, established use of oral, 
implantable, injectable, or transdermal hormonal methods of conception); placement of 
an intrauterine device; placement of an intrauterine system; and mechanical/barrier 
method of contraception (ie, condom or occlusive cap [diaphragm or cervical/vault cap] 
in conjunction with spermicide [foam, gel, film, cream or suppository]).   
8. Male subjects must agree to practice a highly effective method of birth control while on 
study drug and for 13 weeks after receiving the last dose of study drug.  Effective 
methods of birth control include sexual abstinence, vasectomy, or a condom with 
spermicide (men) in combination with their partner’s highly effective method. 
9. Males must be willing to abstain from sperm donation and females from donating eggs 
while on study through 13 weeks after receiving the last dose of study drug. 
8.2. 
Subject Exclusion Criteria 
Subjects who met the following exclusion criteria will be excluded from the study: 
1. Subject has presence of abnormal neurological signs other than tremor or Froment’s sign. 


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2. Subject has presence of known causes of enhanced physiological tremor. 
3. Subject has or recent exposure (14 days prior to the Day -1 visit) to tremorogenic drugs, 
as defined in Appendix 1, or the presence of a drug withdrawal state. 
4. Subject has had direct or indirect trauma to the nervous system within 3 months before 
the onset of tremor.   
5. Subject has historical or clinical evidence of tremor with psychogenic origin (including 
but not limited to eating disorders, major depression, etc.).   
6. Subject has convincing evidence of sudden tremor onset or evidence of stepwise 
deterioration of tremor.   
7. Subject has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or 
oncological disease.   
8. Subject has clinically significant abnormal physical examination or 12-lead ECG at the 
Screening or Day -1 visits.  Note:  A QT interval calculated using the Fridericia method 
[QTcF] of >450 msec in males or >470 msec in females, will be the basis for exclusion 
from the study.  An ECG may be repeated if initial values obtained exceed the limits 
specified. 
9. Subject has a 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. 
10. Subject has hypothyroidism.  Stable thyroid replacement is acceptable. 
11. Subject has used alcohol, caffeine, or nicotine within 3 days prior to the Day -1 visit. 
12. Subject has a known allergy to SAGE-217 or its major excipient HPβCD.   
13. Subject has exposure to another investigational medication or device within the prior 
30 days. 
14. Subject has a history of suicidal behavior within 2 years or answers “YES” to questions 
3, 4, or 5 on the C-SSRS at the Screening visit or on Day -1 or is currently at risk of 
suicide in the opinion of the Investigator. 
15. Subject has donated one or more units (1 unit = 450 mL) of blood or acute loss of an 
equivalent amount of blood within 60 days prior to dosing. 
16. Subject is unwilling or unable to comply with study procedures. 
17. Use of any known strong inhibitors and/or inducers of CYP3A4, as defined in 
Appendix 2, within the 14 days or 5 half-lives (whichever is longer) or consumed 
grapefruit juice, grapefruit, Seville oranges, pomegranates, tangelos, or St. John's Wort or 
products containing these within 30 days prior to receiving the first dose of study drug.   
18. Subject has obstructed venous access and/or has skin disease, rash, acne, or abrasion at 
venous access site that may affect the ability to obtain a PK sample (eg, artificial cardiac 
valve, joint replacement).   


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19. Subject has concurrent or recent exposure (14 days prior to the Day -1 visit) to 
sedative/hypnotic (eg, opioids) drugs.   
20. Subject has hyperthyroidism at screening (based on thyroid-stimulating hormone, 
thyroxine [T4], and triiodothyronine [T3]) or clinically significant kidney issues in the 
opinion of the Investigator.   
8.3. 
Entrance Criteria for Part B 
The following entrance criteria will be applied prior to administration of blinded study drug in 
Part B; subjects who require dose adjustments on Days 5, 6, or 7 of Part A will not progress to 
Part B.   
1. Subject must tolerate a dose of ≥10 mg of SAGE-217 in Part A.   
2. Subject must have responded to SAGE-217, defined as a 30% reduction from baseline in 
TETRAS kinetic tremor combined score (ie, the sum of item 4c scores from both sides of 
the body) predose on Day 8.   
8.4. 
Subject Withdrawal Criteria 
If there is an adverse event or medical reason for the withdrawal, the subject should be followed 
medically until the condition has either resolved itself or is stable.  Details of the reason for 
withdrawal should be recorded in the subject’s case report form (CRF).   
Subjects who withdraw should, if possible, have a follow-up examination, including a physical 
examination, the appropriate investigations, vital signs, and clinical laboratory tests, as outlined 
for the Day 21 visit (Table 3).  If the subject cannot return on Day 21 (Early Termination visit), 
their visit can be scheduled at an alternative time, at the discretion of the Investigator and 
subject.  All details of this follow-up examination should be recorded in the subject’s medical 
source documents.   
8.4.1. 
Study Drug Withdrawal 
Participation in the study is strictly voluntary.  Subjects are free to discontinue the study at any 
time without giving their reason(s).   
A subject must be withdrawn from the study treatment in the event of any of the following: 
• Withdrawal of the subject’s consent; 
• New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators and/Sponsor; 
• Occurrence of intolerable adverse events at the lowest dose;  
• Occurrence of pregnancy;  
• Intake of nonpermitted concomitant medication; 
• Subject noncompliance;  
• Significant protocol deviation determined in consultation with the Medical Monitor. 


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If a subject failed to attend scheduled assessments during the course of the study, the 
Investigators must determine the reasons and the circumstances as completely and accurately as 
possible and document this in the subject’s source documents.   
Subjects who withdraw or are withdrawn from the study will be replaced only if they withdraw 
prior to dosing.  Subjects who are withdrawn from the study, fail to return or are no longer 
qualified will not be replaced.   
8.4.2. 
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 adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons.  In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator. Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
participating subjects.   


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Number of Subjects 
Approximately 60 subjects with ET will be recruited into the study to yield at least 
40 randomized subjects for Part B.   
9.2. 
Treatment Assignment 
Study drug will be administered in the morning with food during Part A and Part B. 
9.2.1. 
Part A 
Subjects participating in Part A of the study will take study drug (SAGE-217) in an open-label 
manner.  All subjects will start on a 10-mg dose of study drug administered with food in the 
morning on Day 1.  Subjects will receive 20 mg with food on Day 2 and 30 mg with food daily 
on Days 3 to 7.  Dose adjustments may be allowed per the criteria in Section 9.3.  The dose 
tolerated for Days 5, 6, and 7 of the open-label dosing period will be determined to be the 
maximum dose for that subject.   
9.2.2. 
Part B 
Subjects participating in the double-blind, placebo-controlled, randomized withdrawal portion of 
the study (Part B) will be randomized to SAGE-217 or placebo on Day 8.  Subjects randomized 
to SAGE-217 will receive the maximum dose of SAGE-217 from Part A of the study.  Following 
randomization, subjects will receive 7 days of study drug starting on Day 8.   
9.3. 
Dose Adjustment Criteria 
Dose adjustments will only be allowed during the open-label phase of the study (Part A).  If at 
any time the dose is not tolerated in Part A, assessed by occurrence of a severe adverse event 
judged by the investigator to be related to study drug, the dose on the next day will be reduced to 
the next lowest dose and continued for the remainder of the open-label dosing period (ie, subjects 
who are unable to tolerate the 30-mg dose will receive a lower dose of 20 mg, and subjects who 
are unable to tolerate 20 mg will be given a 10-mg dose).  The dose tolerated for Days 5, 6, and 7 
of the open-label dosing period will be determined to be the maximum dose for that subject.  
Subjects who require dose adjustments on Days 5, 6, or 7 of Part A will not progress to Part B.   
9.4. 
Prior/Concomitant Medications and Restrictions 
9.4.1. 
Prior/Concomitant Medications 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 9.4.2.   
Record the name, start date (if known), indication for use and whether ongoing or stopped of 
medications/treatments taken within 2 weeks prior to informed consent and throughout the study.   


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The charts of all study participants will be reviewed for new concomitant medications through 
discharge from the unit.  Chart reviews will include examination of nursing and physician 
progress notes, vital signs, and medication records in order to identify adverse events that may be 
associated with new concomitant medications.  New concomitant medications, ongoing 
concomitant medications with a change in dose and medical procedures ordered (eg, laboratory 
assessments, computed tomography or magnetic resonance imaging scans) will be reviewed to 
determine if they are associated with an adverse event not previously identified.   
9.4.2. 
Prohibited Medications 
The drug classes listed in Appendix 1 are not permitted in the 14 days prior to the Day -1 visit 
and for the duration of the study (up to the Day 28 visit).  The list provides non-exhaustive 
examples of each drug class.   
Subjects are not permitted to use alcohol, caffeine, or nicotine within 3 days prior to the Day -1 
visit through the Day 21 visit. 
For subjects who have previously received primidone or topiramate, a 1-week washout period 
(prior to Day -1) will be used for subjects with past exposures of ≤1 year and a 2-week washout 
period (prior to Day -1) will be used for subjects with exposures >1 year.  For subjects who have 
previously received propranolol, a 3-day washout period (prior to Day -1) will be used. 
9.5. 
Treatment Compliance 
Investigational product will be prepared by the site pharmacist.  The Investigator(s) or designee 
will record the time and dose of study drug administration in the source documents.  Any reasons 
for non-compliance will also be documented, including: 
• Missed visits;  
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible.   


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
10.1.1. 
SAGE-217 Oral Solution 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose which is further diluted with Sterile 
Water for Injection to achieve the selected dosages.  The 6 mg/mL stock SAGE-217 Oral 
Solution will be compounded from SAGE-217 Drug Substance Powder in the Bottle and 
Excipient (s) in the Bottle (manufactured under clinical Good Manufacturing Practice [GMP] 
conditions at 
) and further admixed at the clinical site in preparation for dosing.  
Placebo oral solution will be matched to SAGE-217 study drug.   
Detailed instructions for study drug preparation will be provided in the Pharmacy Manual.   
10.1.1.1. Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured by 
 and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual.  The batch formula for a 125-mL solution of the 6 mg/mL 
stock solution is shown in Table 5.   
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
Ingredient 
Compendia Specification Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD (Kleptose®) 
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.025 
3.124 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations:  EP = European Pharmacopeia; HPβCD = hydroxypropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
10.1.2. 
SAGE-217 Capsules 
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white 
powder.  In addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 
Capsules contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and 
sodium stearyl fumarate as excipients.  Capsules will be available in 5-mg, 10-mg and 20-mg 
dose strengths.  Subjects will be administered two capsules per dose.   
Matched placebo capsules containing only the above-listed capsule excipients will be provided.  
Subjects randomized to placebo treatment will be administered 2 placebo capsules per day.   
Detailed instructions for study drug preparation will be provided in the Pharmacy Manual.  


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10.2. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation.  Study drug (oral solution) will be provided to the 
site as powder in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy 
at a volume of 125 mL of a 6 mg/mL stock solution and then further diluted to approximately 
40 mL at the identified doses.  Study drug capsules will be provided to the site in appropriately 
labeled bottles.  Study drug labels with all required information and conforming to all applicable 
Code of Federal Regulations and GMP/GCP guidelines will be prepared by the clinical research 
organization.   
10.3. 
Study Drug Storage 
Upon receipt of study drug (SAGE-217 and placebo), the Investigator or designee will inspect 
the medication and complete and return the acknowledgment of receipt form enclosed with the 
parcel.  A copy of the signed receipt will be kept in the study files.  
The study drug must be carefully stored at the temperature specified in the Pharmacy Manual 
(eg, clinical dosing solutions stored at approximately 2 to 8°C for 10 days or room temperature 
for up to 24 hours after preparation), safely and separately from other drugs.   
SAGE-217 Capsules and matched placebo capsules may be stored at room temperature. 
The study drug may not be used for any purpose other than the present study.  After the study is 
completed, all unused study drug must be retained, returned as directed, or destroyed on site per 
the Sponsor’s instructions.   
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies.  An accurate, timely record of 
the disposition of all clinical supplies must be maintained.  The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed; 
• The date(s) and quantity of the drug dispensed to the subject; and 
• The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
A copy of the inventory record and a record of any clinical supplies that have been destroyed 
must be documented.  This documentation must include at least the information below or as 
agreed with the Sponsor: 
• The number of prepared units; 
• The number of administered units; 
• The number of unused units; 


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• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 
10.4. 
Administration and Study Drug Accountability 
Doses of SAGE-217 Oral Solution will be prepared as an approximate 40 mL oral solution to be 
swallowed all at once, followed by approximately 200 mL of water which has been used to rinse 
the dosing bottle.  The start time of swallowing the approximately 40 mL oral solution is time 
zero for all assessments.  Subjects may have assistance from the clinic staff when taking the 
study drug.   
For the capsule formulation, subjects will swallow two capsules per dose with food. 
10.4.1. 
Study Drug Administration 
Subjects in Part A will receive a 10-mg dose of study drug administered in the morning on 
Day 1, 20 mg on Day 2, and 30 mg on Days 3 to 7.   
Subjects in Part B will receive randomized study drug in the morning on Days 8 to 14. 
10.4.2. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol.   
The Investigator or designee must maintain a record of all study drug received, used, and 
discarded.  It must be clear from the records which subject received which dose of active or 
placebo treatment.   
The Sponsor will be permitted access to the study supplies at any time within usual business 
hours and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation.  Only unblinded personnel will be able to access the study drug and 
accountability documentation from first dosing through database hard lock.   
10.5. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding (oral solution only), subsequent admixture (oral solution only), administration of 
test article, and for which subject the study drug was intended (ie, record subject initials and birth 
date or other unique identifier).   
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions; disposition of study drug will be 
documented.   


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11. 
ASSESSMENT OF EFFICACY 
Efficacy assessments include evaluation of subject symptom response by a measurement of 
Kinesia, TETRAS upper limb items, and TETRAS Performance Subscale (items 4, 6, 7, and 8).  
Quality-of-life assessments include TETRAS ADL, QUEST, and video recording of subjects 
performing three everyday tasks.  Physiological activity (ie, sympathetic nervous system tone as 
measured by electrodermal activity, skin temperature monitoring, and heart rate monitoring) and 
tremor oscillation as assessed by multidimensional accelerometer measurements (ie, raw 
accelerometer values) will be assessed by the Empatica Wristband E4.   
11.1. 
Kinesia 
In order to measure tremor amplitude, subjects will wear a wireless ring motion sensor 
(Kinesia, Great Lakes Neuro Technologies).  The motion sensor uses three orthogonal 
accelerometers and three orthogonal gyroscopes to monitor three-dimensional motion.  Data are 
then transmitted from the sensor to a computer using Bluetooth technology.  These measures of 
three-dimensional motion for each maneuver are then converted to Kinesia scores, which have 
been shown to correlate with corresponding clinician-rated TETRAS scores (Giovanni 2010).  
Each Kinesia score ranges from 0 to 4; higher scores indicate more severe tremor.  The Kinesia 
assessment is completed in conjunction with the TETRAS Performance Subscale Item 4 
assessment. 
In Part A, Kinesia will be performed on Day -1 (three assessments separated by at least 
30 minutes); a single assessment will be performed predose and 2 and 8 hours (±30 minutes) 
postdose on Days 1, 2, 3, and 7.  In Part B, a single Kinesia reading will be performed predose 
and 2 and 8 hours (±30 minutes) postdose on Days 8, 9, and 14, and anytime during the visit on 
Day 21. 
11.2. 
TRG Essential Tremor Rating Assessment Scale (TETRAS) 
Performance Scale 
Item #4 (upper limb tremor) of the TETRAS Performance Subscale will be completed using both 
the Kinesia device and clinician assessment.  Testing should be completed within ±10 minutes of 
the planned questionnaire time points.  All three maneuvers in the upper limb assessments 
(items 4a, 4b, and 4c) will be completed for both arms, first for the RIGHT arm and then for the 
LEFT.  Predose assessments can be done any time within 2 hours prior to the start of 
administration of study drug.  The Day 21 follow-up visit assessments can be done at any time 
during the visit. 
In Part A, the TETRAS upper limb items will be performed at screening and on Day -1 (three 
assessments separated by at least 30 minutes); a single assessment of TETRAS upper limb items 
will be performed predose and 2 and 8 hours (±30 minutes) postdose on Days 1, 2, 3, and 7.  In 
addition, the TETRAS upper limb items will be performed, while wearing the Empatica 
Wristband E4, on Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3, and 7. 
The TETRAS ADL Subscale and Performance Subscale (items 4, 6, 7, and 8) will be performed 
on Day -1 and predose (±30 minutes) on Day 7.  On days when the TETRAS ADL and 
Performance Subscale are performed, Item # 4 will not be repeated.   


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In Part B, the TETRAS upper limb items will be performed predose and 2 and 8 hours 
(±30 minutes) postdose on Days 8, 9, and 14, and anytime during the visit on Day 21.  In 
addition, the TETRAS upper limb items will be performed, while wearing the Empatica 
Wristband E4, 3 hours (±30 minutes) postdose on Days 8, 9, and 14, and anytime during the visit 
on Day 21.  The TETRAS ADL Subscale and Performance Subscale (items 4, 6, 7, and 8) will be 
performed predose (±30 minutes) on Day 14 and anytime during the visit on Day 21.  On days 
when the TETRAS ADL Subscale and Performance Subscale are performed, Item #4 will not be 
repeated.   
Note that the TETRAS upper limb scores from the test conducted during screening will be used 
to determine eligibility and must be ≥2 on each side (left and right) for kinetic tremor and ≥2 on 
each side (left and right) for either wing beating or forward outstretched postural tremor.  A copy 
of the TETRAS is provided in Appendix 3.   
11.3. 
Empatica Wristband E4 
Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring) will be assessed by the 
Empatica Wristband E4.  The Empatica Wristband E4 is a wearable device that captures 
motion-based activity and sympathetic nervous system arousal.  In Part A, the Empatica 
Wristband E4 will be worn during the study visits while in clinic on Days -1, 1, 2, 3, and 7.  In 
Part B, the Empatica Wristband E4 will be worn during the study visits while in clinic on Days 8, 
9, 14, and anytime during the visit on Day 21.  With the exception of during the TETRAS upper 
limb assessments, the Empatica Wristband E4 will be worn on the wrist that, of the two arms, 
exhibits more severe tremor symptoms.  During the TETRAS upper limb assessments (Part A:  
Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3 and 7; Part B:  3 hours (±30 minutes) 
postdose on Days 8, 9, and 14 and 21), the Empatica Wristband E4 will be worn on the wrist 
corresponding to the side of the body being assessed.  Data from the Empatica Wristband E4 will 
not be presented in the study report; instead, they will be part of a separate report.   
11.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST) 
The QUEST is a brief, 30-item, ET-specific QOL scale in which subjects rate the extent to which 
tremor impacts a function or state, tremor severity in various body parts, perceived health, and 
overall QOL (Tröster 2005).  The QUEST will be administered on Day -1, Day 7, and on 
Day 14.  A copy of the QUEST is provided in Appendix 4.   
11.5. 
Video Recording 
Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, 
and one additional task that the subject experiences difficulty with on a daily basis) will be taken 
on Day -1 and predose on Day 7 in Part A and predose on Day 14 and anytime during the visit 
on Day 21 in Part B.   


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
In Part A, plasma samples for PK analysis will be collected predose and 0.25, 0.5, 1, 2, 4, and 
8 hours postdose on Days 1 and 7 and predose on Days 2, 3, 4, 5, and 6.  In Part B, plasma 
samples for PK analysis will be collected predose on Days 8, 9, 10, 11, 12, 13, and 14.  The time 
of study drug administration is time zero and all post-dosing sampling times are relative to this 
time.  Samples are to be collected within ±5 minutes of the scheduled sampling time.  The 
Investigator or designee will arrange to have the plasma samples processed, stored, and 
transported as directed for bioanalysis.   
An additional PK sample may be collected at any time if clinically indicated and at the discretion 
of the Investigator (eg, for unusual or severe adverse events).   
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time.  The date and actual time that the blood sample was taken will be 
recorded on the CRF or electronically with a bar code or other method.   
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70°C to -80°C until analyzed.  At 
sites where a -70°C to -80°C freezer is not available, plasma samples may be stored at -20°C 
prior to being transported for bioanalysis.  They should be packed as directed to avoid breakage 
during transit and with sufficient dry ice to prevent thawing for at least 72 hours.  A specimen-
identification form must be completed and sent to the laboratory with each set of samples.  The 
clinical site will arrange to have the plasma samples transported as directed for bioanalysis as 
detailed in the PK instructions.   
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of SAGE-217 will be performed utilizing a 
validated liquid chromatography-tandem mass spectrometry method at a qualified laboratory.   
 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety and Tolerability Parameters 
Safety and tolerability of study drug will be evaluated by vital signs measurements, clinical 
laboratory measures, physical examination, ECGs, concomitant medication usage, C-SSRS, SSS, 
and adverse event reporting.  The Bond-Lader Mood Rating Scale and a DEQ-5 will be used to 
assess mood and perception of drug effects, respectively.   
13.1.1. 
Demographic/Medical History 
Age, gender, race, and ethnic origin will be recorded at the Screening visit.  A full medical 
history including medication history will be recorded at the Screening visit.   
13.1.2. 
Vital Signs 
Vital signs comprise heart rate, respiratory rate, temperature, and supine (supine for at least 
5 minutes prior to the measurement) and standing (for at least 2 to 3 minutes) systolic and 
diastolic blood pressure.   
In Part A, vital signs and pulse oximetry will be performed at screening (vital signs only) and 
Day -1, predose and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 1, 2, 3, and 4, and predose on 
Days 5, 6, and 7.  In Part B, vital signs (both supine for at least 5 minutes prior to the 
measurement and standing for at least 2 to 3 minutes) and pulse oximetry will be performed 
predose on Day 8 and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 8, 9, and 10, predose on 
Days 11, 12, 13, and 14, and anytime during the visit on Day 21.  Vital signs and pulse oximetry 
assessments will be performed within ±10 minutes of the scheduled times.   
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visit.   
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening visit.   
13.1.5. 
Electrocardiogram (ECG) 
A supine (supine for at least 5 minutes prior to the measurement) 12-lead ECG will be performed 
at the times specified below and the standard intervals recorded as well as any abnormalities.   
In Part A, the 12-lead ECG will be assessed at screening, predose and at 1 and 8 hours 
(±10 minutes) postdose on Days 1, 2, 3, 4, and 7.  In Part B, the 12-lead ECG will be assessed at 
1 and 8 hours (±10 minutes) postdose on Days 8, 9, 10, and 14, and anytime during the visit on 
Day 21.   
All time points are relative to the time of dosing.  ECGs will be performed within ±10 minutes of 
the predose and 1- and 8-hour time points. 


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13.1.6. 
Laboratory Assessments 
In Part A, blood and urine samples will be collected for hematology, serum chemistry, and 
urinalysis at the Screening visit, on Day -1, predose on Day 1, and predose on Day 2.  In Part B, 
blood and urine samples will be collected predose on Day 8 and Day 9 and anytime during the 
visit on Day 21.   
Serum and urine samples for pregnancy tests (females only) will also be collected.  These 
assessments should be performed in accordance with the Schedule of Events (Table 2 and 
Table 3) and as outlined individually below.   
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS); or abnormal, clinically significant 
(CS).  Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the medical monitor.  Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to 
Section 13.2.1, and recorded in the eCRF.   
13.1.6.1. Hematology 
Hematology tests will include complete blood count, including red blood cells, white blood cells 
with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets.  The coagulation panel 
will include activated partial thromboplastin time, prothrombin time, and international 
normalized ratio.   
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes, renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide, liver function tests, including total 
bilirubin, AST, and ALT, total protein, and albumin.   
Thyroid-stimulating hormone, thyroxine (T4), and triiodothyronine (T3) will be performed at 
screening to confirm subject eligibility.   
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity.   
13.1.6.4. Drugs Screen and Alcohol Test 
A urine sample for assessment of selected drugs (sedative/hypnotics [eg, opioids], cotinine, and 
caffeine) and a breath sample for alcohol screen will be collected at screening and on Day -1.  
Results may be obtained through subject history.  Subjects who use concomitant 
sedative/hypnotics will be excluded from the study.  Use of alcohol, caffeine, or cotinine is not 
allowed through Day 21. 


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13.1.6.5. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
the study.   
13.1.6.6. Pregnancy Test 
Females of child-bearing potential will be tested for pregnancy by serum pregnancy test at the 
Screening visit and by urine pregnancy test on Day -1, predose on Day 8, and at the follow-up 
visit on Day 28 in Part B.   
13.1.6.7. Exploratory Biochemistry 
Optional blood samples will be collected at screening and on Days 3 and 7 and may be analyzed 
for exploratory biochemistry, where consent is given.  Future research may suggest other 
biochemical markers as candidates for influencing not only response to SAGE-217 but also 
susceptibility to disorders for which SAGE-217 may be evaluated.  Thus, the biochemical 
research may involve study of additional unnamed biochemical biomarkers, but only as related to 
disease susceptibility and drug action.   
13.1.6.8. Genetic Testing 
Where consent is given, an optional genetic sample for biomarker testing will be collected at the 
Screening visit.   
The objective of this research is to collect and store blood samples for possible DNA extraction 
and exploratory research into how genes or specific genetic variation may influence response 
(ie, distribution, safety, tolerability, and efficacy) to SAGE-217.  Specific genetic variations of 
interest include but are not limited to: classes of metabolizing enzymes (eg, cytochrome P450 
supra-family genes), genes encoding enzymes involved in the production and metabolism of 
SAGE-217 (eg, AKR1C4 [3α-hydroxysteroid dehydrogenase]), genes associated with the 
γ-aminobutyric acid (GABA) receptor (eg, GABRA1-A6, GABRB1-B3, GABRD, GABRE, 
GABRG1-3), and genes associated with the production and degradation of GABA.   
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to SAGE-217 but also susceptibility to disorders for which SAGE-217 may be 
evaluated.  Thus, the genetic research may involve study of additional unnamed genes or gene 
categories, but only as related to disease susceptibility and drug action.   
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011).  This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit.  The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).   
If in the opinion of the Investigator, the subject is showing any suicidal tendency, no further 
study drug will be administered and the subject will be referred to a psychologist or psychiatrist 
for further evaluation.  This information will be tracked.   


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The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months).  In Part A, the “Since Last Visit” C-SSRS form will be completed on Day -1, 
8 hours postdose (± 1 hour) on Day 1, predose on Day 4, and on Days 5, 6, and 7.  In Part B, the 
“Since Last Visit” C-SSRS form will be completed 8 hours (± 1 hour) postdose on Days 8, 11, 
12, 13, and 14, and anytime during the visits on Days 21 and 28.  The C-SSRS is provided in 
Appendix 5.   
13.1.8. 
Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling 
(Hoddes 1972).  Degrees of sleepiness and alertness are rated on a scale of 1 to 7, where the 
lowest score of ‘1’ indicates the subject is ‘feeling active, vital, alert, or wide awake’ and the 
highest score of ‘7’ indicates the subject is ‘no longer fighting sleep, sleep onset soon; having 
dream-like thoughts’.   
In Part A, the SSS will be administered predose and at 1, 2, 3, 4, 6, and 8 hours postdose on 
Days 1, 2, 3, and 4, and predose only on Days 5, 6, and 7.  In Part B, the SSS will be 
administered predose and 1, 2, 4, 6, and 8 hours postdose on Days 8, 9, 10, 11, 12, 13, and 14, 
and anytime during the visit on Day 21.  All time points are relative to the time of dosing.  The 
SSS is to be performed within ±10 minutes of the scheduled times.  The SSS is provided in 
Appendix 6. 
13.1.9. 
Bond-Lader VAS Mood Scale 
Mood will be assessed using the Bond-Lader Mood Rating Scale (Bond 1974).  This is a 16-part 
self-administered questionnaire that employs a 100-mm VAS to explore different aspects of self-
reported mood.  In Part A, the mood scale will be administered predose and 2 hours 
(±10 minutes) postdose on Days 1, 2, and 7.  In Part B, the mood scale will be administered 
predose and 2 hours (±10 minutes) postdose on Days 8, 9, 14, and anytime during the visit on 
Day 21.  The Bond-Lader Mood Rating Scale is provided in Appendix 7.   
13.1.10. 
Drug Effects Questionnaire (DEQ-5) 
A DEQ-5 (Morean 2013) will be administered as follows: 
1. Do you FEEL a drug effect right now? 
2. Are you HIGH right now? 
3. Do you DISLIKE any of the effects that you are feeling right now? 
4. Do you LIKE any of the effects that you are feeling right now? 
5. Would you like MORE of the drug you took, right now? 
The answers are recorded on a 100-mm VAS, with the answer for each being “Not at all” and 
“Extremely” at the extremes.  There will be options to record “Not applicable” for 
questions 3 and 4 if no drug effects are felt and for question 5 prior to administration of study 
medication.  The DEQ-5 will be performed 2 hours (±10 minutes) postdose on Days 1 and 7 in 
Part A and 2 hours (±10 minutes) postdose on Days 8 and 14 in Part B.  The DEQ-5 is provided 
in Appendix 8. 


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13.2. 
Adverse and Serious Adverse Events 
Adverse events will be collected after the ICF has been signed.  Medical conditions that occur 
after the ICF has been signed will be captured on the adverse event eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (version 18.1 or higher).  
13.2.1. 
Definition of Adverse Events 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered. 
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug.   
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
All serious adverse events that occur after any subject has been enrolled, whether or not they are 
related to the study, must be recorded on forms provided by Sage Therapeutics or designee for 
the duration of the study (from the signing of the ICF through the Day 28 visit [or early 
termination]). 
13.2.2. 
Pregnancy 
Any pregnancy occurring during this study will be reported within 24 hours of notification of the 
Investigator.  The Investigator will promptly notify the Medical Monitor and withdraw the 


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subject from the study.  The Investigator should request permission to contact the subject, the 
subject’s spouse/partner (if the subject is male and his spouse/partner becomes pregnant) or the 
obstetrician for information about the outcome of the pregnancy, and in the case of a live birth, 
about any congenital abnormalities.  If a congenital abnormality is reported, then it should be 
recorded in the source documents and reported as a serious adverse event.   
13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, possibly related or probably related).  
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product.  If no valid reason 
exists for suggesting a relationship, then the adverse event should be classified as “unrelated.”  If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the adverse event, then the 
adverse event should be considered “related.”   
Not 
Related: 
No relationship between the experience and the administration of study drug; related to other 
etiologies such as concomitant medications or subject’s clinical state. 
Possibly 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug and 
follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of therapy 
administered to the subject, but this is not known for sure. 
Probably 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug and 
follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered to be related 
to the investigational product for the purposes of expedited regulatory reporting.   
13.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject 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.  Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event or lead to discontinuation of administration of 
study drug.   
Information about adverse events will be collected from the signing of the ICF through the 
Day 28 visit (or early termination).  Adverse events that occur after the first administration of 
study drug will be denoted TEAEs.   
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
no expectation of future change.   


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The adverse event term should be reported in standard medical terminology when possible.  For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), intensity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study.   
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
13.5. 
Reporting Serious Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 28 visit (14 days following the last dose of study drug) or early termination.  Any 
serious adverse events considered possibly or probably related to the investigational product and 
discovered by the Investigator at any time after the study should be reported.  All serious adverse 
events must be reported to the Sponsor or Sponsor’s designee immediately by phone and in 
writing within 24 hours of the first awareness of the event.  The Investigator must complete, sign 
and date the serious adverse event pages, verify the accuracy of the information recorded on the 
serious adverse event pages with the corresponding source documents, and send a copy to Sage 
Therapeutics or designee.   
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the study file.   
Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
certain events.  It is the Principal Investigator’s responsibility to notify the IRB of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements.  Investigators 
will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) 
that occur during the clinical study.  Each site is responsible for notifying its IRB of these 
additional serious adverse events.   
13.6. 
Emergency Identification of Study Drug (Part B) 
Part B is a double-blind study.  The pharmacist responsible for preparing the study drug will be 
unblinded and will retain an official paper copy of the randomization schedule. 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received.  Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact the Sponsor prior to unblinding the 
study treatment administered to a subject.  Any request from the Investigator about the treatment 
administered to study subjects must be discussed with the Sponsor.  If the unblinding occurs 
without the Sponsor’s knowledge, the Investigator must notify the Sponsor as soon as possible 
and no later than the next business morning.  All circumstances surrounding a premature 
unblinding must be clearly documented in the source records.  Unless a subject is at immediate 


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risk, any request for the unblinding of individual subjects must be made in writing to the Sponsor 
and approved by the appropriate Sponsor personnel, according to standard operating procedures.  
The blinding of the study will be broken after the database has been locked.  Electronic copies of 
the randomization code will be made available to the laboratory performing the bioanalytical 
analyses in order to allow for limited analysis of samples from subjects receiving placebo.   
In all cases where the study drug allocation for a subject is unblinded, pertinent information must 
be documented in the subject’s records and on the eCRF.  If the subject or study center personnel 
(other than pharmacist) have been unblinded, the subject will be terminated from the study.   


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14. 
STATISTICAL METHODS AND CONSIDERATIONS 
14.1. 
Data Analysis Sets 
The safety population is defined as all subjects who are administered study drug.   
The efficacy population will consist of all subjects in the safety population who complete at least 
one dose in Part B and have at least one post-randomization efficacy evaluation.   
The evaluable population will consist of all randomized subjects with at least one post-
randomization Kinesia assessment.   
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations.   
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data.  All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available.  No imputation process will be 
used to estimate missing data.  No sensitivity analysis of missing data will be performed.   
14.3. 
Demographics and Baseline Characteristics 
Demographics, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized.   
Categorical summaries, such as race and ethnicity, will be summarized by frequency and 
percentage.  Continuous summaries, such as age, height, weight, BMI, and baseline vital signs, 
will be summarized using descriptive statistics.   
Hepatitis, HIV, drug, and pregnancy screening results will be listed, but not summarized as they 
are considered part of the inclusion/exclusion criteria.   
Medical history will be listed by subject.   
14.4. 
Primary Efficacy Endpoint 
The change from randomization (predose on Day 8) in the accelerometer-based Kinesia kinetic 
tremor combined score (ie, the sum of Kinesia kinetic tremor scores from both sides of the body) 
at Day 14 will be summarized by treatment group in Part B. 
Change from randomization to each assessment in Kinesia kinetic tremor combined score will be 
analyzed using a mixed effects repeated measures model, including center, treatment, 
randomization Kinesia kinetic tremor combined score, assessment time point, and time point-by-
treatment.  All explanatory variables will be treated as fixed effects. 
14.5. 
Secondary Efficacy Endpoints 
The change from randomization (predose on Day 8) in the Kinesia upper limb total and 
individual item scores, TETRAS upper limb total and individual upper limb item scores, and 
other TETRAS Performance Subscale scores at Day 14 will be summarized by treatment group 
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A mixed effects repeated measures model similar to those described in Section 14.4 will be used 
for the analysis of change from randomization in the following:  Kinesia upper limb total score, 
Kinesia individual item scores, TETRAS upper limb total score, and TETRAS individual upper 
limb item scores. 
14.6. 
Exploratory Efficacy Endpoints 
The change from randomization (predose on Day 8) in TETRAS ADL scores at Day 14 will be 
summarized by treatment group in Part B.   
QUEST data will be listed by subject, study day, and time point. 
14.7. 
Safety and Tolerability Analyses 
Data from vital signs, clinical laboratory measures, ECG, and C-SSRS will be summarized using 
descriptive statistics by group and time point, where applicable.  Continuous endpoints will be 
summarized with n, mean, standard deviation, median, minimum, and maximum.  In addition, 
change from baseline values will be calculated at each time point and will be summarized using 
descriptive statistics.  Out-of-range safety endpoints may be categorized as low or high, where 
applicable.  For all categorical endpoints, summaries will include counts and percentages.   
14.7.1. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system (version 18.1 or higher).  The 
analysis of adverse events will be based on the concept of TEAEs.  A TEAE is defined as an 
adverse event with onset after the start of open-label study drug, or any worsening of a pre-
existing medical condition/adverse event with onset after the start of open-label study drug and 
until 14 days after the last dose.  The incidence of TEAEs will be summarized overall and by 
MedDRA System Organ Class, preferred term, and dose group.  Incidences will be presented in 
order of decreasing frequency.  In addition, summaries will be provided by maximum severity 
and relationship to study drug (see Section 13.3).   
TEAEs leading to discontinuation and serious adverse events (see Section 13.2.1.3 for definition) 
with onset after the first dose of open-label study drug will also be summarized. 
All adverse events and serious adverse events (including those with onset or worsening before 
the signing of the ICF) through the Day 28 visit will be listed.   
14.7.2. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection.  Mean changes from 
randomization in vital signs will be evaluated by time point.   
14.7.3. 
Physical Examinations 
Screening physical examinations will be documented as done/not done; these results will be 
listed by subject.  Any clinically significant physical examination findings will be recorded as 
medical history.   


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14.7.4. 
12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QTcF.  Any clinically significant abnormalities or changes in ECGs should be listed as an 
adverse event.  Electrocardiogram findings will be listed by subject and visit.   
14.7.5. 
Clinical Laboratory Evaluations 
Clinical laboratory results will be listed by subject and timing of collection.  Mean changes from 
baseline and randomization in clinical laboratory measures will be evaluated.   
14.7.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS will be listed for all subjects.  Listings will include 
behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the C-SSRS.   
14.7.7. 
Stanford Sleepiness Scale (SSS) 
Sleepiness data collected on the SSS will be listed for all subjects.  Changes in score over time 
will be represented graphically, and change from Day 1 will be measured. 
14.7.8. 
Bond-Lader VAS Mood Scale 
Mood data collected on the Bond-Lader VAS mood scale will be listed by subject, study day, 
and time point.  The scores and change from Day 1 will be summarized by study day and time 
point.   
14.7.9. 
Drug Effects Questionnaire (DEQ-5) 
Results from DEQ-5 will be listed by subject, study day, and time point.  The result for each 
question and change from Day 1 will be summarized by study day and time point.  
14.7.10. 
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 Enhanced (WHO-DDE) version September 2015, or later.   
Medications will be presented according to whether they are being taken prior to and/or during 
the study (concomitant).  Prior medications are defined as those taken within 2 weeks prior to the 
signing of the ICF.  Concomitant medications are defined as those with a start date on or after the 
first dose of open-label study drug, or those with a start date before the first dose of open-label 
study drug that are ongoing or with a stop date on or after the first dose of open-label study drug.  
If medication dates are incomplete and it is not clear whether the medication was concomitant, it 
will be assumed to be concomitant.   
Concomitant medications will be assigned to the part in which they are being taken.  If a 
concomitant medication assigned to a Part A continues to be taken through Part B, then the 
medication will be assigned to both parts of the study as appropriate.  If the start and stop dates 
of the concomitant medications do not clearly define the part during which a medication was 
taken, it will be assumed to be taken in both parts.  Details of prior and concomitant medications 
will be listed by study part, subject, start date, and verbatim term.   


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14.8. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics.  Time to 
reach maximum concentration (tmax) will be summarized using n, mean, standard deviation, 
median, minimum, and maximum.  All other PK parameters will be summarized using n, 
geometric mean, coefficient of variation, median, minimum, and maximum and listed by subject.   
Wherever necessary and appropriate, PK parameters will be dose-adjusted to account for 
individual differences in dose.   
Pharmacokinetic and pharmacodynamic modelling assessment of the relationship between 
plasma exposure of SAGE-217 and change from baseline in Kinesia scores may be assessed.   
14.9. 
Determination of Sample Size 
Up to 60 subjects will be enrolled in Part A to yield at least 40 randomized subjects for Part B.  
A total sample size of 34 evaluable subjects (ie, 17 per group) will have 80% power to detect a 
difference in means of 3.0 on the primary endpoint assuming that the common standard deviation 
is 3.0 using a 2-group t-test with a 0.05 two-sided significance level.  Assuming a 15% non-
evaluability rate, 20 subjects per group will be randomized.  The number of subjects in each 
treatment group is also thought to be sufficient to assess preliminary safety and tolerability 
following multiple doses of SAGE-217. 
14.10. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
statistical analysis plan.  


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Sage 
Therapeutics or designee will visit the investigational study site to:   
• Determine the adequacy of the facilities; and 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives.  This will be documented in a Clinical Study Agreement between 
Sage Therapeutics and the Investigator.   
During the study, a monitor from Sage Therapeutics or designee 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 CRFs, and that investigational product accountability 
checks are being performed; 
• Perform source data verification. This includes a comparison of the data in the CRFs 
with the subject’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 
subject (eg, clinic charts); 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm adverse events and serious adverse events have been properly documented 
on CRFs and confirm any serious adverse events have been forwarded to Sage 
Therapeutics or designee and those serious adverse events that met criteria for 
reporting have been forwarded to the IRB.   
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification.  The purpose of a Sage Therapeutics or designee audit or 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 guidelines of the International Council on 
Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency about an inspection.   


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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study, including the subject consent form and 
recruitment materials, must be maintained by the Investigator and made available for inspection.   


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
CRFs.   
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements.   
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate.  The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study.   
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  Sage Therapeutics or designee will provide this information to the Principal 
Investigator.   
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines.   
17.2. 
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 the most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements.   
17.3. 
Written Informed Consent 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study.  Subjects must also 
be notified that they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided.   
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures.   
The Principal Investigator(s) must maintain the original, signed ICF.  A copy of the signed ICF 
must be given to the subject.   
 


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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan.   
Electronic CRFs will be completed for each study subject.  It is the Investigator’s responsibility 
to ensure the accuracy, completeness, and timeliness of the data reported in the subject’s eCRF.  
Source documentation supporting the eCRF data should indicate the subject’s participation in the 
study and should document the dates and details of study procedures, adverse events, and subject 
status.   
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study.  For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct.   
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or, if not approved, 2 years following the 
discontinuance of the test article for investigation.  If it becomes necessary for Sage Therapeutics 
or the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records.   
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports and communications will identify the 
subject by the assigned subject number.  The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process.  The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations.   
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used.   


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All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information.  The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor.  It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study.  The information obtained from the clinical study will be used 
towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required.   


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19. 
PUBLICATION POLICY 
All information concerning SAGE-217 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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20. 
LIST OF REFERENCES 
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interaction of neurosteroids with GABA(A) receptors. Neuropharmacology. 2002;43(4):651-61. 
Benito-Leon J, Louis ED. Clinical update: diagnosis and treatment of essential tremor. Lancet. 
2007;369(9568):1152-4. 
Boecker H, Kleinschmidt A, Requardt M, Hänicke W, Merboldt KD, Frahm J. Functional 
cooperativity of human cortical motor areas during self-paced simple finger movements. A high 
resolution MRI study. Brain. 1994;117(Pt 6):1231-9. 
Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Med Psychol. 
1974;47:211-218. 
Bucher SF, Seelos KC, Dodel RC, et al. Activation mapping in essential tremor with functional 
magnetic resonance imaging. Ann Neurol. 1997;41:32-40. 
Cavanagh JB, Holton JL, Nolan CC, Ray DE, Naik JT, Mantle PG. The effects of the 
tremorgenic mycotoxin penitrem A on the rat cerebellum. Vet Pathol. 1998;35:53–63. 
Deuschl G, Bain P, Brin M. Adhoc-Scientific-Committee. Consensus Statement of the 
Movement Disorder Society on Tremor. Mov Disord. 1998;13(suppl 3):2-23. 
Deuschl G, Elble R. Essential tremor—neurodegenerative or nondegenerative disease towards a 
working definition of ET. Mov Disord. 2009;24(14):2033–41. 
Deuschl G, Raethjen J, Hellriegel H, et al. Treatment of patients with essential tremor. Lancet 
Neurol. 2011;10:148–61. 
Elble RJ, Deuschl G. An update on essential tremor. Curr Neurol Neurosci Rep. 2009;9:273–7. 
Esmaeili A, Lynch JW, Sah P.  GABAA receptors containing gamma1 subunits contribute to 
inhibitory transmission in the central amygdala. J Neurophysiol. 2009;101(1):341-9.  
Giovanni M, Giuffrida J, Adam O, Davidson A, Jankovic J. Correlation between Kinesia system 
assessments and clinical tremor scores in patients with essential tremor. Mov Disord. 
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Gironell A, Kulisevsky J, Barbanoj M, et al. A randomized placebo controlled comparative trial 
of gabapentin and propranolol in essential tremor. Arch Neurol. 1999;56:475–80. 
Gorman WP, Cooper R, Pocock P, et al. A comparison of primidone, propranolol, and placebo in 
essential tremor, using quantitative analysis. J Neurol Neurosurg Psychiatry. 1986;49:64–8. 
Habib-ur-Rehman. Diagnosis and management of tremor. Arch Intern Med. 
2000;160(16):2438-44. 
Hoddes E, Dement W, Zarcone V. The development and use of the Stanford Sleepiness Scale 
(SSS). Psychophysiology. 1972;9:150. 
Kralic JE, Criswell HE, Osterman JL, et al. Genetic essential tremor in gamma-aminobutyric 
acid A receptor alpha1 subunit knockout mice. J Clin Invest. 2005;115:774–9. 


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Louis ED, Faust PL, Vonsattel JP, et al. Neuropathological changes in essential tremor: 33 cases 
compared with 21 controls. Brain. 2007;130:3297–307. 
Louis ED, Vonsattel JPG. The emerging neuropathology of essential tremor. Mov Disord. 
2008;23(2):174-82. 
Louis ED. Essential tremors: a family of neurodegenerative disorders? Arch Neurol. 
2009;66:1202–8. 
Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on 
the worldwide prevalence of essential tremor. Mov Disord. 2010;25:534–41. 
Louis ED. Treatment of essential tremor: are there issues we are overlooking? Front Neurol. 
2012;2:91. 
Málly J, Baranyi M, Vizi ES. Change in the concentrations of amino acids in CSF and serum of 
patients with essential tremor. J Neural Transm. 1996;103:555-60. 
McAuley JH, Marsden CD. Physiological and pathological tremors and rhythmic central motor 
control. Brain. 2000;123 (Pt 8):1545-67. 
Miwa H. Rodent models of tremor. Cerebellum. 2007;6:66-72. 
Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, O’Malley SS. The drug effects 
questionnaire: psychometric support across three drug types. Psychopharmacology. 
2013;227:177-92. 
O'Brien MD, Upton AR, Toseland PA. Benign familial tremor treated with primidone. Br Med J 
(Clin Res Ed). 1981;82(6259):178-80. 
Pahapill PA, Levy R, Dostrovsky JO, et al. Tremor arrest with thalamic microinjections of 
muscimol in patients with essential tremor. Ann Neurol. 1999;46(2):249-52. 
Pahwa R, Lyons KE. Essential tremor: differential diagnosis and current therapy. Am J Med. 
2003;115(2):134-42. 
Paris-Robidas S, Brochu E, Sintes M, et al. Defective dentate nucleus GABA receptors in 
essential tremor. Brain. 2012;135:105-16. 
Pinto AD, Lang AE, Chen R. The cerebellothalamocortical pathway in essential tremor. 
Neurology. 2003;60(12):1985-7. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 
Pritchett DB, Sontheimer H, Shivers BD, et al.  Importance of a novel GABAA receptor subunit 
for benzodiazepine pharmacology.  Nature. 1989;338(6216):582-5. 
Rajput AH, Rajput A. Medical Treatment of Essential Tremor. J Cent Nerv Syst Dis. 
2014;6:29-39. eCollection 2014. 
Schmouth JF, Dion PA, Rouleau GA. Genetics of essential tremor: from phenotype to genes, 
insights from both human and mouse studies. Prog Neurobiol. 2014;119-120:1-19.  


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Schnitzler A, Munks C, Butz M, et al. Synchronized brain network associated with essential 
tremor as revealed by magnetoencephalography Mov Disord. 2009;24:1629-35. 
Shill HA, Adler CH, Sabbagh MN, et al. Pathologic findings in prospectively ascertained 
essential tremor subjects. Neurology. 2008;70:1452-5.   
Tröster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of life in Essential Tremor 
Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord. 
2005;11(6):367-73. 
Wills AJ, Thompson PD, Findley LJ, et al. A positron emission tomography study of primary 
orthostatic tremor. Neurol. 1996;46(3):747-52. 
Zappia M, Albanese A, Bruno E, et al. Treatment of essential tremor: a systematic review of 
evidence and recommendations from the Italian Movement Disorders Association. J Neurol. 
2013;260:714–40. 


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21. 
APPENDICES 
Copies of scales and questionnaires included in Appendix 3 through Appendix 7 are for 
reference only; the rating scales and questionnaires are to be used for actual subject assessment 
per the Schedule of Events.   
 


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APPENDIX 1. TREMOROGENIC DRUGS 
The following drug classes are not permitted in the 14 days prior to the Day -1 visit and for the 
duration of the study (up to the Day 28 visit).  The list below gives a non-exhaustive list of 
examples of each drug class. 
Anti-arrhythmics 
 
amiodarone, procainamide 
Antiepileptic drugs 
 
valproic acid, carbamazepine 
Antipsychotic agents 
 
haloperidol, trifluoperazine 
Antimanic agents/mood stabilizer 
 
lithium at toxic levels 
Antivirals 
 
acyclovir, vidarabine 
Beta adrenergic agonists 
 
albuterol, terbutaline 
Calcium Channel blockers 
 
verapamil 
CNS stimulants 
 
methylphenidate, amphetamines, cocaine 
Corticosteroids (local injection topical, or inhalation allowed) 
 
cortisone, hydrocortisone, prednisone 
Cytotoxic agents 
 
cytarabine 
Hormones 
 
calcitonin, levothyroxine (levothyroxine is allowed if on a stable dose and euythroid) 
Immunomodulatory 
 
thalidomide 
Immunosuppressants 
 
cyclosporine, tacrolimus 
Monoamine depleting agents 
 
tetrabenazine 
Oral hypoglycemic agents 
 
metformin, glyburide, glipizide, tolbutamide, pioglitazone, rosiglitazone, acarbose, miglitol 
Prokinetics 
 
metoclopramide 
Tricyclic antidepressants 
 
amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, 
nortriptyline, protriptyline 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
 
Fluoxetine (other SSRIs are allowed) 
Statins 
 
Atorvastatin (other statins are allowed) 


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Sympathomimetics 
 
epinephrine, pseudoephedrine 
Weight loss medication 
 
tiratricol 
Xanthine derivatives 
 
theophylline (caffeine/coffee and theophylline/theobromine/tea require a washout, cocoa 
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APPENDIX 2. STRONG INHIBITORS AND INDUCERS OF CYP3A4 
The following known strong inhibitors/inducers of CYP3A4 are not permitted within the 14 days 
or 5 half-lives (whichever is longer) prior to receiving the first dose of study drug: 
Strong inhibitors of CYP3A4: 
Strong inducers of CYP3A4: 
Indinavir 
Carbamazepine 
Nelfinavir 
Efavirenz 
Ritonavir 
Nevirapine 
Clarithromycin 
Phenobarbital 
Telithromycin 
Phenytoin 
Iitraconazole 
Pioglitazone 
Ketoconazole 
Rifabutin 
Nefazodone 
Rifampin 
Erythromycin 
Troglitazone 
Cobistat 
Enzalutamide 
 
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APPENDIX 3. TRG ESSENTIAL TREMOR RATING ASSESSMENT 
SCALE (TETRAS) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
  
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 


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Appendix 4. 
QUALITY OF LIFE IN ESSENTIAL TREMOR 
QUESTIONNAIRE (QUEST) 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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APPENDIX 5. COLUMBIA – SUICIDE SEVERITY RATING SCALE 
(C-SSRS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
  
 


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Appendix 6. 
STANFORD SLEEPINESS SCALE (SSS) 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  


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APPENDIX 7. BOND-LADER VAS (MOOD RATING SCALE) 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 8. DRUG EFFECTS QUESTIONNAIRE (DEQ-5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-217.  I have read the Clinical 
Protocol 217-ETD-201 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 




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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street  
Cambridge, MA  02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 2a, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study 
Evaluating the Efficacy, Safety, Tolerability, and Pharmacokinetics of SAGE-217 Oral Solution in the 
Treatment of Subjects with Essential Tremor (ET) 
Study center(s):  Up to 25 centers 
Phase of development: 2a 
Methodology:  
This study will assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of SAGE-217 Oral 
Solution.   
There are two parts: 
Part A: Open-label with morning dosing (7 days). 
All subjects will start on a 10-mg dose of study drug administered with food on Day 1.  Subjects will 
receive 20 mg with food on Day 2 and 30 mg with food daily on Days 3 to 7.   
Part B: Double-blind, placebo-controlled, randomized withdrawal with morning dosing (7 days). 
In order to qualify for Part B of the study, a subject must tolerate a dose of at least 10 mg of 
SAGE-217, and the subject must have responded to SAGE-217, defined as a 30% reduction from 
baseline in the TRG Essential Tremor Rating Assessment Scale (TETRAS) kinetic tremor combined 
score (ie, the sum of item 4c scores from both sides of the body) predose on Day 8. 
Eligible subjects will be randomized in a 1:1 fashion to SAGE-217 or placebo and will receive their 
maximum dose as determined in Part A in the morning with food.  Subjects randomized to the placebo 
arm will represent randomized withdrawal (withdrawal from treatment they received in Part A). 


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Methodology:  
Dose adjustments will only be allowed during the open-label phase of the study (Part A).  If at any time 
the dose is not tolerated in Part A, assessed by occurrence of a severe adverse event judged by the 
investigator to be related to study drug, the dose on the next day will be reduced to the next lowest dose 
and continued for the remainder of the open-label dosing period (ie, subjects who are unable to tolerate 
the 30-mg dose will receive a lower dose of 20 mg, and subjects who are unable to tolerate 20 mg will 
be given a 10-mg dose).  The dose tolerated for Days 5, 6, and 7 of the open-label dosing period will be 
determined to be the maximum dose for that subject.  Subjects who require dose adjustments on 
Days 5, 6, or 7 of Part A will not progress to Part B.   
Subjects will be exposed to study drug (SAGE-217 or placebo) for up to 14 days and will be followed 
for an additional 14 days after the administration of the last dose.   
Assessments will be performed periodically during the study as outlined in the Schedule of Events 
(Table 2).   
Objectives:  
Primary: 
• 
The primary objective of this study is to compare the effect of 7 days administration of SAGE-217 
Oral Solution to placebo on the change in tremor severity, as measured by the change from 
randomization (Day 8) in the accelerometer-based Kinesia™ kinetic tremor combined score (ie, the 
sum of Kinesia kinetic tremor scores from both sides of the body) at Day 14.   
Secondary: 
The secondary objectives of the study are to compare the effect of 7 days administration of SAGE-217 
Oral Solution to placebo on the following endpoints: 
• 
Tremor severity, as assessed by the change from randomization (Day 8) in the Kinesia upper limb 
total score (ie, the sum of accelerometer-based Kinesia forward outstretched postural tremor, lateral 
"wing beating" postural tremor, and kinetic tremor item scores from both sides of the body) and 
individual item scores at Day 14.   
• 
Tremor severity, as measured by the change from randomization (Day 8) in the TETRAS upper 
limb total score (ie, the sum of TETRAS Performance Subscale item 4 scores [4a, 4b, and 4c] from 
both sides of the body) and individual TETRAS Performance Subscale upper limb item scores at 
Day 14.   
• 
Tremor severity, as assessed by the change from randomization (Day 8) in other TETRAS 
Performance Subscale scores measured at Day 14.   
• 
Safety and tolerability, as assessed by vital signs measurements, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Severity 
Rating Scale (C-SSRS), and adverse event reporting.   
• 
Sleepiness, as assessed by the Stanford Sleepiness Scale (SSS). 
• 
Mood, as assessed by the Bond-Lader visual analogue scale (VAS) Mood Scale scores.   
• 
How the subject feels after taking the study drug as assessed by Drug Effects Questionnaire 
(DEQ-5) ratings.   
In addition, plasma concentrations of SAGE-217 and SAGE-217 metabolites may be measured.  
Pharmacokinetic parameters, such as area under the concentration-time curve from time zero to last 
time point (AUC0-t), area under the concentration-time curve from time zero to infinity (AUC0-∞), 
maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), and terminal half-
life (t1/2), will be derived, where appropriate. 
 


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Exploratory: 
The exploratory objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on: 
• 
Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal activity, 
skin temperature monitoring, and heart rate monitoring), as assessed by the Empatica Wristband 
E4.  Tremor oscillation, as assessed by multi-dimensional accelerometer measurements (ie, raw 
accelerometer values) using the Empatica Wristband E4. 
• 
Quality of life (QOL), as assessed by TETRAS activities of daily living (ADL), Quality of Life in 
Essential Tremor Questionnaire (QUEST), and video recording assessment of subjects performing 
three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the 
subject experiences difficulty with on a daily basis).   
In addition, PK/pharmacodynamic (PD) modelling assessment of the relationship between plasma 
exposure of SAGE-217 and change from baseline in Kinesia scores may be assessed. 
Number of subjects (planned):  
Up to 60 subjects will be enrolled in Part A to yield at least 40 randomized subjects for Part B.   
Diagnosis and main criteria for inclusion:  
Inclusion criteria: 
1. Subject has signed an informed consent form before any study-specific procedures are performed. 
2. Subject must be between 18 and 75 years of age, inclusive. 
3. Subject must have a diagnosis of ET, defined as bilateral postural tremor and kinetic tremor, 
involving hands and forearms, that is visible and persistent and the duration is >5 years prior to 
screening. 
4. Subject must have bilateral TETRAS scores of at least two on each side (left and right) for kinetic 
tremor and at least two on each side (left and right) for either wing beating or forward outstretched 
postural tremor.   
5. Subject must be willing to discontinue medications taken for the treatment of ET, alcohol, nicotine, 
and caffeine through Day 21 of the study.   
6. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests.   
7. Female subjects must be post-menopausal, permanently sterile (eg, bilateral tubal occlusion, 
hysterectomy, bilateral oophorectomy), or of childbearing potential with a negative pregnancy test, 
non- breastfeeding, and using two highly effective methods of birth control prior to screening 
through completion of the last follow-up visit (as defined in Section 8.1).  If a subject discontinues 
early after receiving a dose of study drug, they must continue this method of birth control for at 
least 7 days following the last dose of study drug.  Highly effective methods of birth control are 
defined as follows:  hormonal (ie, established use of oral, implantable, injectable, or transdermal 
hormonal methods of conception); placement of an intrauterine device; placement of an intrauterine 
system; and mechanical/barrier method of contraception (ie, condom or occlusive cap [diaphragm 
or cervical/vault cap] in conjunction with spermicide [foam, gel, film, cream or suppository]). 
8. Male subjects must agree to practice a highly effective method of birth control while on study drug 
and for 13 weeks after receiving the last dose of study drug.  Effective methods of birth control 
include sexual abstinence, vasectomy, or a condom with spermicide (men) in combination with 
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9. Males must be willing to abstain from sperm donation and females from donating eggs while on 
study through 13 weeks after receiving the last dose of study drug. 
Exclusion criteria: 
1. Subject has presence of abnormal neurological signs other than tremor or Froment’s sign. 
2. Subject has presence of known causes of enhanced physiological tremor. 
3. Subject has concurrent or recent exposure (14 days prior to Day -1 visit) to tremorogenic drugs, as 
defined in Appendix 1, or the presence of a drug withdrawal state. 
4. Subject has had direct or indirect trauma to the nervous system within 3 months before the onset of 
tremor.  
5. Subject has historical or clinical evidence of tremor with psychogenic origin (including but not 
limited to eating disorders, major depression, etc.). 
6. Subject has convincing evidence of sudden tremor onset or evidence of stepwise deterioration of 
tremor. 
7. Subject has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or oncological disease. 
8. Subject has clinically significant abnormal physical examination or 12-lead ECG at the Screening 
or Day -1 visits.  Note:  A QT interval calculated using the Fridericia method [QTcF] of >450 msec 
in males or >470 msec in females, will be the basis for exclusion from the study.  An ECG may be 
repeated if initial values obtained exceed the limits specified. 
9. Subject has a history, presence, and/or current evidence of serologic positive results for hepatitis B 
surface antigen, hepatitis C antibodies, or human immunodeficiency virus 1 or 2 antibodies. 
10. Subject has hypothyroidism.  Stable thyroid replacement is acceptable. 
11. Subject has used alcohol, caffeine, or nicotine within 3 days prior to the Day -1 visit. 
12. Subject has a known allergy to SAGE-217 or its major excipient hydroxypropyl-β-cyclodextrin 
(HPβCD). 
13. Subject has exposure to another investigational medication or device within the prior 30 days. 
14. Subject has a history of suicidal behavior within 2 years or answers “YES” to questions 3, 4, or 5 
on the C-SSRS at the Screening visit or on Day -1 or is currently at risk of suicide in the opinion of 
the Investigator. 
15. Subject has donated one or more units (1 unit = 450 mL) of blood or acute loss of an equivalent 
amount of blood within 60 days prior to dosing. 
16. Subject is unwilling or unable to comply with study procedures. 
17. Use of any known strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, pomegranates, tangelos, or St. John's Wort or products containing these within 30 days 
prior to receiving the first dose of study drug. 
18. Subject has obstructed venous access and/or has skin disease, rash, acne, or abrasion at venous 
access site that may affect the ability to obtain a PK sample (eg, artificial cardiac valve, joint 
replacement).   
19. Subject has concurrent or recent exposure (14 days prior to the Day -1 visit) to sedative/hypnotic 
(eg, opioids) drugs.   


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20. Subject has hyperthyroidism at screening (based on thyroid-stimulating hormone, thyroxine [T4], 
and triiodothyronine [T3]) or clinically significant kidney issues in the opinion of the Investigator.   
Investigational product, dosage and mode of administration:  
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile Water 
for Injection and administered as an approximate 40 mL solution with a 10 mg, 20 mg, or 30 mg dose 
given once daily in the morning with food. 
Duration of treatment:  
Screening Duration: approximately 28 days; Treatment Period: 14 days; Follow-up: 14 days 
Planned Study Duration per Subject: approximately 56 days 
Reference therapy, dosage and mode of administration:  
Placebo is available as a solution of 40% HPβCD and 0.0025% sucralose, which is further diluted with 
Sterile Water for Injection and administered as an approximate 40 mL solution given once daily in the 
morning with food in Part B. 
Criteria for evaluation: 
Efficacy: 
Tremor severity will be measured by accelerometer-based Kinesia and clinician-rated TETRAS 
Performance Subscale scores.  Quality-of-life will be evaluated using the TETRAS ADL, QUEST, and 
video recording of subjects performing three everyday tasks.  Physiological activity (ie, sympathetic 
nervous system tone as measured by electrodermal activity, skin temperature monitoring, and heart rate 
monitoring) and tremor oscillation will be assessed by the Empatica Wristband E4.   
Pharmacokinetics: 
Plasma will be collected to assay for concentrations of SAGE-217 and may be assayed for SAGE-217 
metabolites, if deemed necessary.  The following PK parameters will be derived from the plasma 
concentrations (where evaluable): AUC0-t, AUC0-∞, Cmax, tmax, and t½.   
Safety and Tolerability: 
Safety and tolerability of study drug will be evaluated by vital signs measurements, clinical laboratory 
measures, physical examination, ECGs, concomitant medication usage, C-SSRS, SSS, and adverse 
event reporting.  The Bond-Lader Mood Rating Scale and a DEQ-5 will be used to assess mood and 
perception of drug effects, respectively.   
Statistical methods: 
Study Populations 
The safety population is defined as all subjects who are administered study drug.   
The efficacy population will consist of all subjects in the safety population who complete at least one 
dose in Part B and have at least one post-randomization efficacy evaluation.   
The evaluable population will consist of all randomized subjects with at least one post-randomization 
Kinesia assessment.   
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations.   
Efficacy Analysis 
Efficacy data (including change from randomization values for accelerometer-derived Kinesia and 
clinician-rated TETRAS scores) will be summarized using appropriate descriptive statistics and listed 
by subject. 
 


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The change from randomization (Day 8) in the Kinesia kinetic tremor combined score (ie, the sum of 
Kinesia kinetic tremor scores from both sides of the body) at Day 14 will be summarized by treatment.  
Additionally, the change from randomization in the Kinesia upper limb total score and individual item 
scores at Day 14 will be summarized by treatment.   
The change from randomization in TETRAS upper limb total score, individual TETRAS Performance 
Subscale upper limb item scores, and other TETRAS Performance Subscale scores at Day 14 will be 
summarized by treatment.   
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics and listed by 
subject.  Wherever necessary and appropriate, PK parameters will be dose-adjusted to account for 
individual differences in dose. 
Safety Analysis 
Adverse events will be coded using Medical Dictionary for Regulatory Activities™.  The overall 
incidence of adverse events will be displayed by System Organ Class, preferred term, and dose group.  
Incidence of adverse events will also be presented by maximum severity and relationship to study drug.  
Data from vital signs, clinical laboratory measures, ECG, and C-SSRS will be summarized using 
descriptive statistics by dose group, where applicable.  Continuous endpoints will be summarized with 
n, mean, standard deviation, median, minimum, and maximum.  In addition, change from baseline 
values will be calculated at each time point and will be summarized using the same summary statistics.  
Out-of-range safety endpoints may be categorized as low or high, where applicable.  For all categorical 
endpoints, summaries will include counts and percentages.   
Sample Size 
Up to 60 subjects will be enrolled in Part A to yield at least 40 randomized subjects for Part B.  A total 
sample size of 34 evaluable subjects (ie, 17 per group) will have 80% power to detect a difference in 
means of 3.0 on the primary endpoint assuming that the common standard deviation is 3.0 using a 
2-group t-test with a 0.05 two-sided significance level.  Assuming a 15% non-evaluability rate, 
20 subjects per group will be randomized.  The number of subjects in each treatment group is also 
thought to be sufficient to assess preliminary safety and tolerability following multiple doses of 
SAGE-217 Oral Solution. 
 


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Table 2: 
Schedule of Events:  Part A (Open-Label) 
Visit Days 
Screening 
(Day -28 to Day -1) 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Body weight/height 
X 
 
 
 
 
 
 
 
 
Drug/alcohol screen
a 
X 
X 
 
 
 
 
 
 
 
Complete blood count/ 
serum chemistry
b 
X 
X 
X 
X 
 
 
 
 
 
Pregnancy test  
X 
(serum) 
X 
(urine) 
 
 
 
 
 
 
 
Urinalysisb 
X 
X 
X 
X 
 
 
 
 
 
Hepatitis & HIV screen 
X 
 
 
 
 
 
 
 
 
Exploratory biochemistry 
sample
c 
O 
 
 
 
O 
 
 
 
O 
Genetic sample
d 
O 
 
 
 
 
 
 
 
 
Vital signs
e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetrye 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
f 
X 
 
X 
X 
X 
X 
 
 
X 
C-SSRS
g 
X 
X 
X 
 
 
X 
X 
X 
X 
SSS
h 
 
 
X 
X 
X 
X 
X 
X 
X 
Bond-Lader-VAS
i 
 
 
X 
X 
 
 
 
 
X 
DEQ-5
j 
 
 
X 
 
 
 
 
 
X 


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Visit Days 
Screening 
(Day -28 to Day -1) 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Kinesia (accelerometer)
k 
 
X 
X 
X 
X 
 
 
 
X 
TETRAS upper limb itemsk 
X 
X 
X 
X 
X 
 
 
 
X 
TETRAS (ADL Subscale and 
items 4, 6, 7, and 8 of 
Performance Subscale)
l 
 
X 
 
 
 
 
 
 
X 
Empatica Wristband E4
m 
 
X 
X 
X 
X 
 
 
 
X 
QUEST 
 
X 
 
 
 
 
 
 
X 
Plasma PK samples
n 
 
 
X 
X 
X 
X 
X 
X 
X 
Administer study drug
o 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
Prior/concomitant medications
p 
X 
Videos
q 
 
X 
 
 
 
 
 
 
X 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram; HIV = 
human immunodeficiency virus; O = optional; PK = pharmacokinetic; QUEST = Quality of Life in Essential Tremor Questionnaire; SSS = Stanford Sleepiness 
Scale; TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue score 
a A urine sample for assessment of selected drugs (sedative/hypnotics [eg, opioids], cotinine, and caffeine) and a breath sample for alcohol screen will be 
collected at screening and Day -1. 
b Screening and safety laboratory tests will be performed at screening, Day -1, predose on Day 1, and predose on Day 2. 
c An optional blood sample for exploratory biochemistry, where consent is given. 
d An optional genetic sample for biomarker testing, where consent is given. 
e Vital signs (heart rate, respiratory rate, temperature, and supine [for at least 5 minutes prior to the measurement] and standing [for at least 2 to 3 minutes] 
systolic and diastolic blood pressure) and pulse oximetry will be performed at screening (vital signs only) and Day -1, predose and at 1, 2, 3, 4, 6, and 8 hours 
postdose on Days 1, 2, 3, and 4, and predose on Days 5, 6, and 7.  Vital signs and pulse oximetry assessments will be performed within ±10 minutes of the 
scheduled times. 
f 12-lead ECGs will be performed at screening, predose, and at 1 and 8 hours (±10 minutes) postdose on Days 1, 2, 3, 4, and 7. 
g The C-SSRS will be performed at screening, on Day -1, 8 hours (±1 hour) postdose on Day 1, predose on Day 4, and on Days 5, 6, and 7.  Baseline/Screening 
version of C-SSRS should be used on day of screening and Since Last Visit version should be used on all subsequent time points. 
h The SSS will be performed predose and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 1, 2, 3, and 4, and predose only on Days 5, 6, and 7.  The SSS is to be 
performed within ±10 minutes of the scheduled times. 
i The Bond-Lader VAS will be performed predose and 2 hours (±10 minutes) postdose on Days 1, 2, and 7. 
j The DEQ-5 will be performed 2 hours (±10 minutes) postdose on Days 1 and 7. 


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k Kinesia and TETRAS upper limb items will be performed at screening (TETRAS upper limb items only), on Day -1 (three assessments separated by at least 
30 minutes); single assessments will be performed predose and 2 and 8 hours (±30 minutes) postdose on Days 1, 2, 3, and 7.  In addition, the TETRAS upper 
limb items will be performed, while wearing the Empatica Wristband E4, on Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3, and 7. All three 
maneuvers in the upper limb assessments (items 4a, 4b, and 4c) will be completed for both arms, first for the RIGHT arm and then for the LEFT. 
l TETRAS (ADL Subscale and items 4, 6, 7, and 8 of Performance Subscale) will be performed on Day -1 and predose (±30 minutes) on Day 7. 
m The Empatica Wristband E4 will be worn during the study visits while in clinic on Days -1, 1, 2, 3, and 7.  With the exception of during the TETRAS upper 
limb assessments, the Empatica Wristband E4 will be worn on the wrist that, of the two arms, exhibits more severe tremor symptoms.  During the TETRAS 
upper limb assessments on Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3, and 7, the Empatica Wristband E4 will be worn on the wrist 
corresponding to the side of the body being assessed. 
n Plasma pharmacokinetic samples will be taken predose (±5 minutes) and 0.25, 0.5, 1, 2, 4, and 8 hours postdose on Days 1 and 7 and predose on Days 2, 3, 4, 
5, and 6. 
o Study drug will be administered in the morning with food. 
p To include those taken within 2 weeks prior to informed consent and throughout the study. 
q Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis) will be taken on Day -1and predose on Day 7. 
 


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Table 3: 
Schedule of Events:  Part B (Randomized Withdrawal) 
Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21±1 day
a
(Early 
Termination 
Visit) 
End of Study 
Day 28±1 day 
Randomization 
X 
 
 
 
 
 
 
 
 
Complete blood count/ 
serum chemistry
b 
X 
X 
 
 
 
 
 
X 
 
Pregnancy test
c 
X 
(urine) 
 
 
 
 
 
 
 
X 
(urine) 
Urinalysisb 
X 
X 
 
 
 
 
 
X 
 
Vital signs
d 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pulse oximetryd 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG
e 
X 
X 
X 
 
 
 
X 
X 
 
C-SSRS
f 
X 
 
 
X 
X 
X 
X 
X 
X 
SSS
g 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bond-Lader-VAS
h 
X 
X 
 
 
 
 
X 
X 
 
DEQ-5
i 
X 
 
 
 
 
 
X 
 
 
Kinesia (accelerometer)
j 
X 
X 
 
 
 
 
X 
X 
 
TETRAS upper limb itemsj 
X 
X 
 
 
 
 
X 
X 
 
TETRAS (ADL Subscale and 
items 4, 6, 7, and 8 of 
Performance Subscale)
k 
 
 
 
 
 
 
X 
X 
 
Empatica Wristband E4
l 
X 
X 
 
 
 
 
X 
X 
 
QUEST 
 
 
 
 
 
 
X 
 
 
Plasma PK samples
m 
X 
X 
X 
X 
X 
X 
X 
 
 


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Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21±1 day
a
(Early 
Termination 
Visit) 
End of Study 
Day 28±1 day 
Administer study drug
n 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events 
X 
Concomitant medications
o 
X 
Videos
p 
 
 
 
 
 
 
X 
X 
 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram;  
HIV = human immunodeficiency virus; PK = pharmacokinetic; QUEST = Quality of Life in Essential Tremor Questionnaire; SSS = Stanford Sleepiness Scale; 
TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue score 
a In addition to subjects who complete Part B, subjects who receive at least one dose of study drug and do not complete Part B will have a visit 1 week following 
the last dose of study drug to assess safety measures. 
b Safety laboratory tests will be performed predose on Day 8 and Day 9 and anytime during the visit on Day 21. 
c To be performed predose on Day 8 and anytime during the visit on Day 28. 
d Vital signs (heart rate, respiratory rate, temperature, and supine [for at least 5 minutes prior to the measurement] and standing [for at least 2 to 3 minutes] 
systolic and diastolic blood pressure) and pulse oximetry will be performed predose on Day 8 and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 8, 9, and 10, 
predose on Days 11, 12, 13, and 14, and anytime during the visit on Day 21.  Vital signs and pulse oximetry assessments will be performed within ±10 minutes 
of the scheduled times. 
e 12-lead ECGs will be performed at 1 and 8 hours (±10 minutes) postdose on Days 8, 9, 10, and 14, and anytime during the visit on Day 21. 
f The C-SSRS (Since Last Visit version) will be performed 8 hours (±1 hour) postdose on Days 8, 11, 12, 13 and 14 and anytime during the visits on Days 21 
and 28. 
g The SSS will be performed predose and 1, 2, 4, 6, and 8 hours postdose on Days 8, 9, 10, 11, 12, 13, and 14, and anytime during the visit on Day 21.  The SSS 
is to be performed within ±10 minutes of the scheduled times. 
h The Bond-Lader VAS will be performed predose and 2 hours (±10 minutes) postdose on Days 8, 9, and 14 and anytime during the visit on Day 21. 
i The DEQ-5 will be performed 2 hours (±10 minutes) postdose on Days 8 and 14. 
j Kinesia and TETRAS upper limb items will be performed predose, 2 and 8 hours (±30 minutes) postdose on Days 8, 9, and 14, and anytime during the visit on 
Day 21.  In addition, the TETRAS upper limb items will be performed, while wearing the Empatica Wristband E4, 3 hours (±30 minutes) postdose on Days 8, 
9, and 14, and anytime during the visit on Day 21.  All three maneuvers in the upper limb assessments (items 4a, 4b, and 4c) will be completed for both arms, 
first for the RIGHT arm and then for the LEFT. 
k TETRAS ADL Subscale and items 4, 6, 7, and 8 of Performance Subscale will be performed predose (±30 minutes) on Day 14 and anytime during the visit on 
Day 21. 
l The Empatica Wristband E4 will be worn during the study visits while in clinic on Days 8, 9, 14, and 21.  With the exception of during the TETRAS upper 
limb assessments, the Empatica Wristband E4 will be worn on the wrist that, of the two arms, exhibits more severe tremor symptoms.  During the TETRAS 


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16 
upper limb assessments 3 hours (±30 minutes) postdose on Days 8, 9, and 14 and anytime during the visit on Day 21, the Empatica Wristband E4 will be worn 
on the wrist corresponding to the side of the body being assessed. 
m Plasma pharmacokinetic samples will be taken predose (±5 minutes) on Days 8, 9, 10, 11, 12, 13, and 14. 
n Study drug will be administered in the morning with food. 
o To include those taken throughout the study. 
p Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis) will be taken predose on Day 14 and anytime during the visit on Day 21. 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................22 
5. 
INTRODUCTION ......................................................................................................24 
5.1. 
Background of Essential Tremor and Unmet Medical Need ......................................24 
5.2. 
SAGE-217 Oral Solution ............................................................................................25 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 ..........................25 
5.3.1. 
Nonclinical Studies with SAGE-217 ..........................................................................25 
5.3.2. 
Clinical Experience .....................................................................................................26 
5.4. 
Potential Risks and Benefits .......................................................................................27 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................28 
6.1. 
Primary Objective .......................................................................................................28 
6.2. 
Secondary Objectives .................................................................................................28 
6.3. 
Exploratory Objectives ...............................................................................................29 
7. 
INVESTIGATIONAL PLAN .....................................................................................30 
7.1. 
Overall Study Design ..................................................................................................30 
7.2. 
Blinding and Randomization ......................................................................................30 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................32 
8.1. 
Subject Inclusion Criteria ...........................................................................................32 
8.2. 
Subject Exclusion Criteria ..........................................................................................32 
8.3. 
Entrance Criteria for Part B ........................................................................................34 
8.4. 
Subject Withdrawal Criteria .......................................................................................34 
8.4.1. 
Study Drug Withdrawal ..............................................................................................34 
8.4.2. 
Criteria for Study Termination ...................................................................................35 
9. 
TREATMENT OF SUBJECTS ..................................................................................36 
9.1. 
Number of Subjects ....................................................................................................36 
9.2. 
Treatment Assignment ................................................................................................36 
9.2.1. 
Part A ..........................................................................................................................36 


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9.2.2. 
Part B ..........................................................................................................................36 
9.3. 
Dose Adjustment Criteria ...........................................................................................36 
9.4. 
Prior/Concomitant Medications and Restrictions .......................................................36 
9.4.1. 
Prior/Concomitant Medications ..................................................................................36 
9.4.2. 
Prohibited Medications ...............................................................................................37 
9.5. 
Treatment Compliance ................................................................................................37 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................38 
10.1. 
Study Drug ..................................................................................................................38 
10.2. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL ...................................38 
10.3. 
Study Drug Packaging and Labeling ..........................................................................38 
10.4. 
Study Drug Storage .....................................................................................................38 
10.5. 
Administration and Study Drug Accountability .........................................................39 
10.5.1. 
Study Drug Administration.........................................................................................39 
10.5.2. 
Study Drug Accountability .........................................................................................39 
10.6. 
Study Drug Handling and Disposal ............................................................................40 
11. 
ASSESSMENT OF EFFICACY ................................................................................41 
11.1. 
Kinesia ........................................................................................................................41 
11.2. 
TRG Essential Tremor Rating Assessment Scale (TETRAS) Performance 
Scale ............................................................................................................................41 
11.3. 
Empatica Wristband E4 ..............................................................................................42 
11.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST) ....................................42 
11.5. 
Video Recording .........................................................................................................42 
12. 
PHARMACOKINETICS ...........................................................................................43 
12.1. 
Blood Sample Collection ............................................................................................43 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ..................................................43 
12.3. 
Sample Analysis .........................................................................................................43 
13. 
ASSESSMENT OF SAFETY .....................................................................................44 
13.1. 
Safety and Tolerability Parameters .............................................................................44 
13.1.1. 
Demographic/Medical History ...................................................................................44 
13.1.2. 
Vital Signs ..................................................................................................................44 
13.1.3. 
Weight and Height ......................................................................................................44 
13.1.4. 
Physical Examination .................................................................................................44 
13.1.5. 
Electrocardiogram (ECG) ...........................................................................................44 


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13.1.6. 
Laboratory Assessments .............................................................................................45 
13.1.6.1. 
Hematology .................................................................................................................45 
13.1.6.2. 
Blood Chemistry .........................................................................................................45 
13.1.6.3. 
Urinalysis ....................................................................................................................45 
13.1.6.4. 
Drugs Screen and Alcohol Test ..................................................................................45 
13.1.6.5. 
Virus Serology ............................................................................................................45 
13.1.6.6. 
Pregnancy Test ............................................................................................................46 
13.1.6.7. 
Exploratory Biochemistry ...........................................................................................46 
13.1.6.8. 
Genetic Testing ...........................................................................................................46 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................46 
13.1.8. 
Stanford Sleepiness Scale (SSS) .................................................................................47 
13.1.9. 
Bond-Lader VAS Mood Scale ....................................................................................47 
13.1.10. 
Drug Effects Questionnaire (DEQ-5) .........................................................................47 
13.2. 
Adverse and Serious Adverse Events .........................................................................47 
13.2.1. 
Definition of Adverse Events .....................................................................................48 
13.2.1.1. 
Adverse Event .............................................................................................................48 
13.2.1.2. 
Suspected Adverse Reaction .......................................................................................48 
13.2.1.3. 
Serious Adverse Event ................................................................................................48 
13.2.2. 
Pregnancy ...................................................................................................................48 
13.3. 
Relationship to Study Drug ........................................................................................49 
13.4. 
Recording Adverse Events .........................................................................................49 
13.5. 
Reporting Serious Adverse Events .............................................................................50 
13.6. 
Emergency Identification of Study Drug (Part B) ......................................................50 
14. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................52 
14.1. 
Data Analysis Sets ......................................................................................................52 
14.2. 
Handling of Missing Data ...........................................................................................52 
14.3. 
Demographics and Baseline Characteristics ...............................................................52 
14.4. 
Primary Efficacy Endpoint .........................................................................................52 
14.5. 
Secondary Efficacy Endpoints ....................................................................................52 
14.6. 
Exploratory Efficacy Endpoints .................................................................................53 
14.7. 
Safety and Tolerability Analyses ................................................................................53 
14.7.1. 
Adverse Events ...........................................................................................................53 
14.7.2. 
Vital Signs ..................................................................................................................53 


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14.7.3. 
Physical Examinations ................................................................................................53 
14.7.4. 
12-Lead ECG ..............................................................................................................54 
14.7.5. 
Clinical Laboratory Evaluations .................................................................................54 
14.7.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................54 
14.7.7. 
Stanford Sleepiness Scale (SSS) .................................................................................54 
14.7.8. 
Bond-Lader VAS Mood Scale ....................................................................................54 
14.7.9. 
Drug Effects Questionnaire (DEQ-5) .........................................................................54 
14.7.10. 
Prior and Concomitant Medications ...........................................................................54 
14.8. 
Pharmacokinetic Analysis ..........................................................................................55 
14.9. 
Determination of Sample Size ....................................................................................55 
14.10. 
Changes From Protocol Specified Analyses ...............................................................55 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................56 
15.1. 
Study Monitoring ........................................................................................................56 
15.2. 
Audits and Inspections ................................................................................................56 
15.3. 
Institutional Review Board (IRB) ...............................................................................57 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................58 
17. 
ETHICS ......................................................................................................................59 
17.1. 
Ethics Review .............................................................................................................59 
17.2. 
Ethical Conduct of the Study ......................................................................................59 
17.3. 
Written Informed Consent ..........................................................................................59 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................60 
18.1. 
Inspection of Records .................................................................................................60 
18.2. 
Retention of Records ..................................................................................................60 
18.3. 
Confidentiality ............................................................................................................60 
19. 
PUBLICATION POLICY ..........................................................................................62 
20. 
LIST OF REFERENCES ............................................................................................63 
21. 
APPENDICES ............................................................................................................66 
APPENDIX 1. TREMOROGENIC DRUGS ..............................................................................67 
APPENDIX 2. TRG ESSENTIAL TREMOR RATING ASSESSMENT SCALE 
(TETRAS) ...................................................................................................................69 
APPENDIX 3. QUALITY OF LIFE IN ESSENTIAL TREMOR QUESTIONNAIRE 
(QUEST) .....................................................................................................................75 
APPENDIX 4. COLUMBIA – SUICIDE SEVERITY RATING SCALE (C-SSRS) ................77 


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APPENDIX 5. STANFORD SLEEPINESS SCALE (SSS) .......................................................84 
APPENDIX 6. BOND-LADER VAS (MOOD RATING SCALE) ...........................................85 
APPENDIX 7. DRUG EFFECTS QUESTIONNAIRE (DEQ-5) ...............................................86 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events:  Part A (Open-Label) .................................................................11 
Table 3: 
Schedule of Events:  Part B (Randomized Withdrawal) ............................................14 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................22 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL..................38 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
ADL 
activities of daily living 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-t 
area under the concentration-time curve from time zero to 
last time point 
AUC0-∞  
area under the concentration-time curve from time zero to 
infinity 
BMI 
body mass index 
Cmax  
maximum plasma concentration 
CNS 
central nervous system 
CRF 
case report form 
CS 
clinically significant  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450  
DEQ-5 
Drug Effects Questionnaire 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
ET 
essential tremor 
GABA 
γ-aminobutyric acid 
GABAA 
γ-aminobutyric acid-ligand gated chloride channel 
GABAB 
γ-aminobutyric acid-G protein-coupled 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg  
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxypropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 


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Abbreviation or Specialist Term 
Explanation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
NCS 
not clinically significant 
NF  
National Formulary 
PI 
Principal Investigator 
PK 
pharmacokinetic 
QOL 
quality of life 
QTcF 
QT interval calculated using the Fridericia method 
QUEST 
Quality of Life in Essential Tremor Questionnaire 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAEs 
treatment-emergent adverse events 
TETRAS 
TRG Essential Tremor Rating Assessment Scale 
t1/2 
terminal half-life 
tmax  
time to reach maximum concentration 
USP  
United States Pharmacopeia 
VAS 
visual analogue score 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 
WMA 
World Medical Association 
 


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5. 
INTRODUCTION 
5.1. 
Background of Essential Tremor and Unmet Medical Need 
Essential tremor (ET) is among the most common neurological diseases, with an overall 
prevalence of 0.9%.  Prevalence increases with age and is estimated to be 4.6% in people over 
65 years of age (Louis 2010, Deuschl 2011).  Essential tremor is largely a bilateral, symmetrical 
postural or kinetic tremor involving hands and forearms that is visible and persistent.  Additional 
or isolated tremor of the head or lower limbs may occur, but in the absence of abnormal 
posturing (Deuschl 1998, Habib-ur-Rehman 2000).  The onset of tremor has a bimodal 
distribution, with onset between 15 to 20 and 50 to 70 years.  Over time, tremors can become 
more pronounced and may prevent eating, drinking, and writing, as well as executing personal 
hygiene like shaving or applying make-up.  Voice tremors can be severe enough to inhibit 
talking and singing in public.   
Several lines of evidence suggest that cerebellar dysfunction through the 
cerebellothalamocortical pathway plays a key role in ET (McAuley 2000, Pinto 2003, 
Elble 2009, Schnitzler 2009, Deuschl 2009).  Thalamotomy and deep brain stimulation of the 
ventral intermediate nucleus and of the subthalamic nucleus improve ET (Deuschl 2011, 
Zappia 2013, Rajput 2014).  Microscopic cerebellar pathology has been identified, including 
gliosis, Purkinje cell loss, and increased torpedoes (swellings) in the Purkinje cell axons 
(Louis 2007, Axelrad 2008, Shill 2008, Louis 2009).  Activation studies with positron emission 
tomography indicate abnormally increased regional cerebral blood flow in the cerebellum both at 
rest and when tremor is provoked by unilateral arm extension (Boecker 1994, Wills 1996).   
Essential tremor is associated with impaired γ-aminobutyric acid (GABA)ergic function (and 
consequent hyperactivity) in the cerebellum (Málly 1996, Bucher 1997, Louis 2007, Louis 2008, 
Paris-Robidas 2012).  γ-aminobutyric acid, the major inhibitory neurotransmitter in the central 
nervous system (CNS), is released from GABAergic neurons and binds to several types of 
GABA receptors (γ-aminobutyric acid-ligand gated chloride channel [GABAA] and 
γ-aminobutyric acid-G protein-coupled [GABAB]) on target neurons.  γ-aminobutyric acid-gated 
chloride channel receptors, the major class of inhibitory neurotransmitter receptors in the brain, 
are macromolecular proteins that form a chloride ion channel complex and contain specific 
binding sites for GABA and a number of allosteric regulators, including barbiturates, 
benzodiazepines, and some anesthetic agents.   
Drugs acting on GABAA receptors, such as primidone, benzodiazepines, or ethanol decrease 
tremor amplitude, suggesting that altered GABAergic neurotransmission is involved in ET.  
Postmortem analysis revealed a 35% reduction of GABAA receptors and a 22% to 31% reduction 
of GABAB receptors in the dentate nucleus of cerebella of ET subjects (Paris-Robidas 2012).  
Reduced levels of GABA in the cerebrospinal fluid are also reported in ET subjects 
(Málly 1996).  Moreover, toxins such as aflatrem, penitrem A, or harmaline have been proposed 
to induce tremor in rodents by interacting with GABA receptors (Cavanagh 1998, Miwa 2007), 
and targeted deletion of the α1 subunit of GABAA receptor in knockout mice exhibits a 
15 to 19 Hz action tremor, similar to ET in humans (Kralic 2005).   


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Consistent with the role of GABA, the majority of therapeutics for ET act by augmenting 
GABAergic transmission (Louis 2012, Benito-Leon 2007, Pahapill 1999).  First-line treatments 
for ET include the anticonvulsant primidone and the β-adrenergic blocker propranolol 
(Gorman 1986).  Like primidone, gabapentin is an anticonvulsant found to be effective in the 
treatment of ET (O’Brien 1981, Gironell 1999).  The oldest treatment for ET is ethanol, which 
temporarily ameliorates tremor and is frequently used by subjects to self-medicate; however, 
chronic use of ethanol for tremor management carries the known risks of alcohol dependence and 
overuse (Pahwa 2003).   
These treatments are moderately effective, reducing, though not resolving, tremor amplitudes in 
about 50% of the subjects (Schmouth 2014).  In addition, one out of three patients abandon 
treatment because of side effects or poor efficacy (Louis 2010), illustrating that with few feasible 
treatment options and a range of handicaps in daily living makes ET an area of high unmet 
medical need.   
5.2. 
SAGE-217 Oral Solution 
SAGE-217 is a positive allosteric modulator of the GABAA receptor and thus is expected to be 
of benefit for the treatment of ET.  Unlike benzodiazepines that are selective for the γ-subunit-
containing subset of GABAA receptors (Pritchett 1989, Esmaeili 2009), SAGE-217 and other 
neuroactive steroids, which bind to the ubiquitous α-subunit, have a wider range of activity 
(Belelli 2002). 
SAGE-217 Oral Solution 6 mg/mL (40% w/w aqueous hydroxypropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a nonviscous, clear solution.   
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 
5.3.1. 
Nonclinical Studies with SAGE-217 
In nonclinical studies of SAGE-217, sedative-hypnotic effects were consistently observed at 
higher doses in both in vivo pharmacology studies as well as in toxicology studies.  The 
sedative-hypnotic impairments seen with SAGE-217 were typical for GABAA positive 
modulators, ranging from hyperexcitability and ataxia at the lower doses through deep sedation 
and ultimately anesthesia at higher doses.  Depth and duration of sedation demonstrated a clear 
dose response over the range tested, with evidence of tolerance occurring with continued 
exposure.  Tolerance to the effects of SAGE-217 on motor incoordination was not observed after 
7 days of dosing.   
The compound has been assessed in 14-day rat and dog toxicology studies with daily 
administration of SAGE-217 as a solution in HPβCD in dogs and Labrasol® in rats.  The no 
observed adverse effect level was 3 mg/kg (females) and 22.5 mg/kg (males) in rats and 
2.5 mg/kg in dogs.  There were no adverse effects in dogs or rats in the main toxicology studies.  
A single observation of mortality occurred in one female rat at the high dose in a toxicokinetic 
study which was suspected to have been related to exaggerated pharmacology.  Additional 
toxicology and pharmacology information is provided in the Investigator’s Brochure.   


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5.3.2. 
Clinical Experience 
To date, two clinical studies employing SAGE-217 are clinically complete and final clinical 
study reports are pending.  Discussions of pharmacokinetic (PK) data are limited to the single-
ascending dose, food, and essential tremor cohorts from Study 217-CLP-101 and the multiple-
ascending dose and drug-drug interaction (DDI) cohorts from Study 217-CLP-102.  Discussions 
of safety data are limited to the single-ascending dose cohorts in Study 217-CLP-101 and the 
multiple-ascending dose cohorts in Study 217-CLP-102.   
Study 217-CLP-101 was a first-in-human, four-part study that assessed the effects of a single 
dose of SAGE-217.  The study was a double-blind, placebo-controlled, single-ascending dose 
design in healthy adult volunteers, with the objective of identifying the maximum tolerated dose 
(MTD) and PK profiles of SAGE-217 Oral Solution.  Subjects in each of the single-ascending 
dose cohorts received a single dose of study drug, either SAGE-217 (six subjects) or placebo 
(two subjects), with SAGE-217 doses of 0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 mg, 
55 mg, and 66 mg.  Escalation to the next dose was undertaken only after safety and PK data 
were reviewed by the Safety Review Committee (SRC) and agreement reached that it was safe to 
increase the dose.  The MTD was determined to be 55 mg.  Two cohorts, 6 subjects each 
received SAGE-217 in an open-label manner (one cohort received 50% of the MTD [22 mg] to 
study the food effects and the other cohort received the MTD [55 mg] to study the effects on 
subjects with essential tremor).  SAGE-217 was orally bioavailable, demonstrated dose-linear 
PK from the lowest (0.25 mg) through the highest (66 mg) dose, and supported once daily oral 
dosing with food.   
Study 217-CLP-102 was a two-part study that assessed the effects of multiple-ascending doses of 
SAGE-217.  The study was a double-blind, placebo-controlled, multiple-ascending dose study in 
healthy adult volunteers.  Subjects in each of the multiple-ascending dose cohorts received study 
drug, either SAGE-217 (nine subjects) or placebo (three subjects), once daily for 7 days, with 
SAGE-217 doses of 15 mg, 30 mg, and 35 mg.  Escalation to the next dose was undertaken only 
after safety and PK data were reviewed by the SRC and agreement reached that it was safe to 
increase the dose.  The MTD was determined to be 30 mg.  It was observed that subjects 
receiving the drug in the evening did better in terms of tolerability compared to when they 
received the drug in the morning.  A fourth cohort of 12 subjects received 30 mg of SAGE-217 
in an open-label manner to study drug-drug interactions.  SAGE-217 is not likely to induce the 
metabolism of CYP2B6 or CYP3A4 substrates.  SAGE-217 was orally bioavailable and suitable 
for once daily oral dosing at night time with food.   
SAGE-217 was generally well tolerated.  In both Phase 1 studies (217-CLP-101 and  
217-CLP-102), doses were escalated until the stopping criteria were met.  Most adverse events 
were reported as mild or moderate in intensity, and there were no serious adverse events reported 
in either study.  In addition, none of the observed adverse events resulted in discontinuation of 
the study drug.  At doses planned for further study, the observed sedation was mild, transient, 
and associated with daily peak exposure.  The most common treatment-emergent adverse events 
were sedation, somnolence, dizziness, euphoric mood, fatigue, tremor, and muscle twitching, 
reported most frequently in the highest dose group (66 mg).  Some changes in mean blood 
pressure and heart rate were observed after single doses of 44 mg and greater.  After multiple 
doses of 30 mg (AM or PM) or 35 mg (PM) over 7 days, there was no evidence of changes in 
mean vital sign measures even though Day 7 plasma concentrations approximated that of the 


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highest single dose in the single-ascending dose study.  Subjects seemed to tolerate SAGE-217 
better when given as night time dosing.   
There were no clinical efficacy data of SAGE-217 in ET, since the present study is the first study 
in this indication.   
5.4. 
Potential Risks and Benefits 
Protocol 217-ETD-201 is the first clinical study of SAGE-217 Oral Solution in ET evaluating the 
efficacy of this product.  Thus, the potential benefits in this population are unknown, although 
the risks are likely to be similar to those mentioned in the Investigator’s Brochure.  Many 
compounds that target the GABAA receptors exhibit clinical efficacy in ET, validating this 
receptor as a therapeutic target.  Given the promising SAGE-547 clinical data in conjunction 
with the shared broad receptor selectivity profile, oral bioavailability, long half-life, preclinical 
evidence of anxiolytic activity and safety data of SAGE-217, it is possible that patients may have 
a clinical benefit at the exposures selected for this study.  In view of the few risks associated with 
administration of SAGE-217 Oral Solution that have been identified to date, an intra-patient 
dose-escalation design has been chosen to permit titration of treatment effect vs tolerability 
(adverse events), specifically sedation.  Each subject will start with an initial dose of 10 mg to be 
escalated to 20 mg after a day and then escalated further to 30 mg assuming no tolerability 
issues.  At the end of a 7-day exposure, the maximum dose for the subject will be established as 
will a protocol specified response.  Subjects who are responders and tolerate at least the 10-mg 
dose for a minimum of 3 days will qualify for the randomization phase (Part B).  Given the high 
medical need and potential for benefit in ET, there is a favorable benefit-risk evaluation to 
investigate SAGE-217 Oral Solution in ET.   
In conclusion, selection criteria for the proposed study take into account the potential safety 
risks.  Continuous safety monitoring, and the implementation of a formal dose-reduction and 
study drug discontinuation scheme also have the potential to mitigate risk.  From a benefit/risk 
perspective, the appropriate measures are being taken in order to ensure the safety of the subjects 
who will be enrolled.   


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of this study is to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on the change in tremor severity, as measured by the change 
from randomization (Day 8) in the accelerometer-based Kinesia™ kinetic tremor combined score 
(ie, the sum of Kinesia kinetic tremor scores from both sides of the body) at Day 14. 
6.2. 
Secondary Objectives 
The secondary objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on the following endpoints: 
1. Tremor severity as assessed by the change from randomization (Day 8) in the Kinesia 
upper limb total score (ie, the sum of accelerometer-based Kinesia forward outstretched 
postural tremor, lateral “wing beating” postural tremor, and kinetic tremor item scores 
from both sides of the body) and individual item scores at Day 14. 
2. Tremor severity as measured by the change from randomization (Day 8) in TRG 
Essential Tremor Rating Assessment Scale (TETRAS) upper limb total score (ie, the sum 
of TETRAS Performance Subscale item 4 scores [4a, 4b, and 4c] from both sides of the 
body) and individual TETRAS Performance Subscale upper limb item scores at Day 14. 
3. Tremor severity as assessed by the change from randomization (Day 8) in other TETRAS 
Performance Subscale scores measured at Day 14. 
4. Safety and tolerability as assessed by vital signs measurements, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide 
Severity Rating Scale (C-SSRS), and adverse event reporting.   
5. Sleepiness as assessed by the SSS. 
6. Mood as assessed by the Bond-Lader visual analogue score (VAS) Mood Scale. 
7. How the subject feels after taking the study drug as assessed by Drug Effects 
Questionnaire (DEQ-5) ratings. 
In addition, plasma concentrations of SAGE-217 and SAGE-217 metabolites may be measured.  
Pharmacokinetic parameters, such as area under the concentration-time curve from time zero to 
last time point (AUC0-t), area under the concentration-time curve from time zero to infinity 
(AUC0-∞), maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), 
and terminal half-life (t1/2), will be derived, where appropriate.   


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6.3. 
Exploratory Objectives 
The exploratory objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on: 
1. Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring) as assessed by the 
Empatica Wristband E4.  Tremor oscillation as assessed by multidimensional 
accelerometer measurements (ie, raw accelerometer values) using the Empatica 
Wristband E4. 
2. Quality of life (QOL) as assessed by TETRAS activities of daily living (ADL), Quality of 
Life in Essential Tremor Questionnaire (QUEST), and video recording assessment of 
subjects performing three everyday tasks (drinking a glass of water, fastening a button, 
and one additional task that the subject experiences difficulty with on a daily basis). 
In addition, PK and pharmacodynamic modelling assessment of the relationship between plasma 
exposure of SAGE-217 and change from baseline in Kinesia scores may be assessed.   


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study is a two-part, multicenter, Phase 2a study to evaluate the efficacy, safety, tolerability, 
and PK of SAGE-217 Oral Solution in up to 60 adult subjects with ET.  Part A of the study is an 
open-label design with morning dosing for 7 days.  Part B of the study is a double-blind, 
placebo-controlled, randomized withdrawal design.  Subjects will be exposed to study drug 
(SAGE-217 or placebo) for up to 14 days and will be followed for an additional 14 days after the 
administration of the last dose.   
During the Screening Period (Day -28 to Day -1), after signing the informed consent form (ICF), 
subjects will be assessed for study eligibility and the severity of each subject’s ET will be 
evaluated using TETRAS.  Eligible subjects will return to the clinical study unit on Day -1.   
The study will be conducted in two parts: 
• Part A:  Beginning on Day 1, all subjects will receive open-label SAGE-217 in the 
morning with food (as outlined in Section 9.2) for 7 days.  Subjects will receive 
SAGE-217 10 mg on Day 1, SAGE-217 20 mg on Day 2, and SAGE-217 30 mg from 
Day 3 to Day 7, with dose adjustments for severe adverse events judged by the 
Investigator to be related to study drug (Section 9.3). 
• Part B:  In order to qualify for Part B of the study, a subject must tolerate a dose of 
≥10 mg of SAGE-217, and the subject must have responded to SAGE-217, defined as 
a 30% reduction from baseline in TETRAS kinetic tremor (item 4c) combined score 
predose on Day 8.  Eligible subjects will be randomized in a 1:1 fashion to receive 
SAGE-217 or placebo for 7 days beginning on Day 8.  All doses of study drug will be 
administered with food as outlined in Section 9.2.  Subjects randomized to SAGE-217 
or placebo will receive their maximum dose as determined in Part A in the morning 
with food. 
Dose adjustments will only be allowed during Part A of the study.  A dose will be considered not 
tolerated if the subject experiences a severe adverse event considered to be related to the study 
drug by the Investigator.  If a dose is not tolerated, the dose on the next day will be reduced to 
the next lowest dose and continued for the remainder of the open-label dosing period (ie, subjects 
who are unable to tolerate SAGE-217 30 mg will receive SAGE-217 20 mg and subjects who are 
unable to tolerate SAGE-217 20 mg will receive SAGE-217 10 mg).  The dose tolerated on 
Days 5, 6, and 7 of Part A will be considered the maximum dose for that subject.  Subjects who 
require dose adjustments on Days 5, 6, or 7 of Part A will not progress to Part B.   
7.2. 
Blinding and Randomization 
Part A is open-label with no control group; therefore, there will be no randomization or blinding.   
Part B of the study is a double-blind, placebo-controlled, randomized withdrawal design.  
Subjects who tolerate a dose of ≥10 mg of SAGE-217 in Part A and respond to SAGE-217, 
defined as a 30% reduction from baseline in TETRAS kinetic tremor combined score predose on 
Day 8, will be randomly assigned in a 1:1 fashion to receive SAGE-217 or placebo according to 


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a computer-generated randomization schedule.  Once it has been determined that a subject meets 
eligibility criteria for randomization, the subject will be sequentially assigned a subject number.  
The unblinded pharmacist will then use this randomization number to prepare and allocate 
blinded study drug to the subject. 
The randomization schedule will be generated prior to the start of the study.  The randomization 
schedule will be generated using SAS V9.2 or later.  Only the clinic pharmacist, who is 
responsible for preparing the solutions, will be given a copy of the randomization schedule.  In 
the event of a medical emergency, the pharmacist may reveal actual solution contents to the 
investigator, who should also alert Sage of the emergency (see Section 13.6 for more details 
related to unblinding).  In all cases where the study drug allocation for a subject is unblinded, 
pertinent information (including the reason for unblinding) must be documented in the subject’s 
records and on the electronic case report form (eCRF).  If the subject or study center personnel 
(other than pharmacist) have been unblinded, the subject will be terminated from the study.   
Subjects randomized to SAGE-217 will receive their maximum dose as determined in Part A in 
the morning with food.  Subjects randomized to the placebo arm will represent randomized 
withdrawal (withdrawal from treatment they received in Part A).   


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
It is anticipated that up to 60 subjects will be enrolled at up to 25 study centers.  The following 
inclusion and exclusion criteria will be applied during screening for Part A of the study.  
8.1. 
Subject Inclusion Criteria 
Subjects must meet the following inclusion criteria for enrollment in the study: 
1. Subject has signed an ICF before any study-specific procedures are performed.   
2. Subject must be between 18 and 75 years of age, inclusive. 
3. Subject must have a diagnosis of ET, defined as bilateral postural tremor and kinetic 
tremor, involving hands and forearms, that is visible and persistent and the duration is 
>5 years prior to screening. 
4. Subject must have bilateral TETRAS scores of at least two on each side (left and right) 
for kinetic tremor and at least two on each side (left and right) for either wing beating or 
forward outstretched postural tremor.   
5. Subject must be willing to discontinue medications taken for the treatment of ET, 
alcohol, nicotine, and caffeine through Day 21 of the study.   
6. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. 
7. Female subjects must be post-menopausal, permanently sterile (eg, bilateral tubal 
occlusion, hysterectomy, bilateral oophorectomy), or of childbearing potential with a 
negative pregnancy test, non- breastfeeding, and using two highly effective methods of 
birth control prior to screening through completion of the last follow-up visit.  If a subject 
discontinues early after receiving a dose of study drug, they must continue this method of 
birth control for at least 7 days following the last dose of study drug.  Highly effective 
methods of birth control are defined as follows:  hormonal (ie, established use of oral, 
implantable, injectable, or transdermal hormonal methods of conception); placement of 
an intrauterine device; placement of an intrauterine system; and mechanical/barrier 
method of contraception (ie, condom or occlusive cap [diaphragm or cervical/vault cap] 
in conjunction with spermicide [foam, gel, film, cream or suppository]).   
8. Male subjects must agree to practice a highly effective method of birth control while on 
study drug and for 13 weeks after receiving the last dose of study drug.  Effective 
methods of birth control include sexual abstinence, vasectomy, or a condom with 
spermicide (men) in combination with their partner’s highly effective method. 
9. Males must be willing to abstain from sperm donation and females from donating eggs 
while on study through 13 weeks after receiving the last dose of study drug. 
8.2. 
Subject Exclusion Criteria 
Subjects who met the following exclusion criteria will be excluded from the study: 
1. Subject has presence of abnormal neurological signs other than tremor or Froment’s sign. 


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2. Subject has presence of known causes of enhanced physiological tremor. 
3. Subject has or recent exposure (14 days prior to the Day -1 visit) to tremorogenic drugs, 
as defined in Appendix 1, or the presence of a drug withdrawal state. 
4. Subject has had direct or indirect trauma to the nervous system within 3 months before 
the onset of tremor.   
5. Subject has historical or clinical evidence of tremor with psychogenic origin (including 
but not limited to eating disorders, major depression, etc.).   
6. Subject has convincing evidence of sudden tremor onset or evidence of stepwise 
deterioration of tremor.   
7. Subject has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or 
oncological disease.   
8. Subject has clinically significant abnormal physical examination or 12-lead ECG at the 
Screening or Day -1 visits.  Note:  A QT interval calculated using the Fridericia method 
[QTcF] of >450 msec in males or >470 msec in females, will be the basis for exclusion 
from the study.  An ECG may be repeated if initial values obtained exceed the limits 
specified. 
9. Subject has a 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. 
10. Subject has hypothyroidism.  Stable thyroid replacement is acceptable. 
11. Subject has used alcohol, caffeine, or nicotine within 3 days prior to the Day -1 visit. 
12. Subject has a known allergy to SAGE-217 or its major excipient HPβCD.   
13. Subject has exposure to another investigational medication or device within the prior 
30 days. 
14. Subject has a history of suicidal behavior within 2 years or answers “YES” to questions 
3, 4, or 5 on the C-SSRS at the Screening visit or on Day -1 or is currently at risk of 
suicide in the opinion of the Investigator. 
15. Subject has donated one or more units (1 unit = 450 mL) of blood or acute loss of an 
equivalent amount of blood within 60 days prior to dosing. 
16. Subject is unwilling or unable to comply with study procedures. 
17. Use of any known strong inhibitors and/or inducers of CYP3A4 within the 14 days or 
5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, pomegranates, tangelos, or St. John's Wort or products containing these within 
30 days prior to receiving the first dose of study drug.   
18. Subject has obstructed venous access and/or has skin disease, rash, acne, or abrasion at 
venous access site that may affect the ability to obtain a PK sample (eg, artificial cardiac 
valve, joint replacement).   


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19. Subject has concurrent or recent exposure (14 days prior to the Day -1 visit) to 
sedative/hypnotic (eg, opioids) drugs.   
20. Subject has hyperthyroidism at screening (based on thyroid-stimulating hormone, 
thyroxine [T4], and triiodothyronine [T3]) or clinically significant kidney issues in the 
opinion of the Investigator.   
8.3. 
Entrance Criteria for Part B 
The following entrance criteria will be applied prior to administration of blinded study drug in 
Part B; subjects who require dose adjustments on Days 5, 6, or 7 of Part A will not progress to 
Part B.   
1. Subject must tolerate a dose of ≥10 mg of SAGE-217 in Part A.   
2. Subject must have responded to SAGE-217, defined as a 30% reduction from baseline in 
TETRAS kinetic tremor combined score (ie, the sum of item 4c scores from both sides of 
the body) predose on Day 8.   
8.4. 
Subject Withdrawal Criteria 
If there is an adverse event or medical reason for the withdrawal, the subject should be followed 
medically until the condition has either resolved itself or is stable.  Details of the reason for 
withdrawal should be recorded in the subject’s case report form (CRF).   
Subjects who withdraw should, if possible, have a follow-up examination, including a physical 
examination, the appropriate investigations, vital signs, and clinical laboratory tests, as outlined 
for the Day 21 visit (Table 3).  If the subject cannot return on Day 21 (Early Termination visit), 
their visit can be scheduled at an alternative time, at the discretion of the Investigator and 
subject.  All details of this follow-up examination should be recorded in the subject’s medical 
source documents.   
8.4.1. 
Study Drug Withdrawal 
Participation in the study is strictly voluntary.  Subjects are free to discontinue the study at any 
time without giving their reason(s).   
A subject must be withdrawn from the study treatment in the event of any of the following: 
• Withdrawal of the subject’s consent; 
• New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators and/Sponsor; 
• Occurrence of intolerable adverse events at the lowest dose;  
• Occurrence of pregnancy;  
• Intake of nonpermitted concomitant medication; 
• Subject noncompliance;  
• Significant protocol deviation determined in consultation with the Medical Monitor. 


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If a subject failed to attend scheduled assessments during the course of the study, the 
Investigators must determine the reasons and the circumstances as completely and accurately as 
possible and document this in the subject’s source documents.   
Subjects who withdraw or are withdrawn from the study will be replaced only if they withdraw 
prior to dosing.  Subjects who are withdrawn from the study, fail to return or are no longer 
qualified will not be replaced.   
8.4.2. 
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 adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons.  In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator. Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
participating subjects.   


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Number of Subjects 
Approximately 60 subjects with ET will be recruited into the study to yield at least 
40 randomized subjects for Part B.   
9.2. 
Treatment Assignment 
Study drug will be administered in the morning with food during Part A and Part B. 
9.2.1. 
Part A 
Subjects participating in Part A of the study will take study drug (SAGE-217) in an open-label 
manner.  All subjects will start on a 10-mg dose of study drug administered with food in the 
morning on Day 1.  Subjects will receive 20 mg with food on Day 2 and 30 mg with food daily 
on Days 3 to 7.  Dose adjustments may be allowed per the criteria in Section 9.3.  The dose 
tolerated for Days 5, 6, and 7 of the open-label dosing period will be determined to be the 
maximum dose for that subject.   
9.2.2. 
Part B 
Subjects participating in the double-blind, placebo-controlled, randomized withdrawal portion of 
the study (Part B) will be randomized to SAGE-217 or placebo on Day 8.  Subjects randomized 
to SAGE-217 will receive the maximum dose of SAGE-217 from Part A of the study.  Following 
randomization, subjects will receive 7 days of study drug starting on Day 8.   
9.3. 
Dose Adjustment Criteria 
Dose adjustments will only be allowed during the open-label phase of the study (Part A).  If at 
any time the dose is not tolerated in Part A, assessed by occurrence of a severe adverse event 
judged by the investigator to be related to study drug, the dose on the next day will be reduced to 
the next lowest dose and continued for the remainder of the open-label dosing period (ie, subjects 
who are unable to tolerate the 30-mg dose will receive a lower dose of 20 mg, and subjects who 
are unable to tolerate 20 mg will be given a 10-mg dose).  The dose tolerated for Days 5, 6, and 7 
of the open-label dosing period will be determined to be the maximum dose for that subject.  
Subjects who require dose adjustments on Days 5, 6, or 7 of Part A will not progress to Part B.   
9.4. 
Prior/Concomitant Medications and Restrictions 
9.4.1. 
Prior/Concomitant Medications 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 9.4.2.   
Record the name, start date (if known), indication for use and whether ongoing or stopped of 
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The charts of all study participants will be reviewed for new concomitant medications through 
discharge from the unit.  Chart reviews will include examination of nursing and physician 
progress notes, vital signs, and medication records in order to identify adverse events that may be 
associated with new concomitant medications.  New concomitant medications, ongoing 
concomitant medications with a change in dose and medical procedures ordered (eg, laboratory 
assessments, computed tomography or magnetic resonance imaging scans) will be reviewed to 
determine if they are associated with an adverse event not previously identified.   
9.4.2. 
Prohibited Medications 
The drug classes listed in Appendix 1 are not permitted in the 14 days prior to the Day -1 visit 
and for the duration of the study (up to the Day 28 visit).  The list provides non-exhaustive 
examples of each drug class.   
Subjects are not permitted to use alcohol, caffeine, or nicotine within 3 days prior to the Day -1 
visit through the Day 21 visit. 
For subjects who have previously received primidone or topiramate, a 1-week washout period 
(prior to Day -1) will be used for subjects with past exposures of ≤1 year and a 2-week washout 
period (prior to Day -1) will be used for subjects with exposures >1 year.  For subjects who have 
previously received propranolol, a 3-day washout period (prior to Day -1) will be used. 
9.5. 
Treatment Compliance 
Investigational product will be prepared by the site pharmacist.  The Investigator(s) or designee 
will record the time and dose of study drug administration in the source documents.  Any reasons 
for non-compliance will also be documented, including: 
• Missed visits;  
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible.   


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose which is further diluted with Sterile 
Water for Injection to achieve the selected dosages.  The 6 mg/mL stock SAGE-217 Oral 
Solution will be compounded from SAGE-217 Drug Substance Powder in the Bottle and 
Excipient (s) in the Bottle (manufactured under clinical Good Manufacturing Practice [GMP] 
conditions at 
) and further admixed at the clinical site in preparation for dosing.  
Placebo will be matched to SAGE-217 study drug.  Detailed instructions for study drug 
preparation will be provided in the Pharmacy Manual.   
10.2. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured by 
 and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual.  The batch formula for a 125-mL solution of the 6 mg/mL 
stock solution is shown in Table 5.   
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
Ingredient 
Compendia Specification Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD (Kleptose®) 
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.025 
3.124 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations:  EP = European Pharmacopeia; HPβCD = hydroxypropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
10.3. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation.  Study drug will be provided to the site as powder 
in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy at a volume of 
125 mL of a 6 mg/mL stock solution and then further diluted to approximately 40 mL at the 
identified doses.  Study drug labels with all required information and conforming to all 
applicable Code of Federal Regulations and GMP/GCP guidelines will be prepared by the 
clinical research organization.   
10.4. 
Study Drug Storage 
Upon receipt of study drug (SAGE-217 and placebo), the Investigator or designee will inspect 
the medication and complete and return the acknowledgment of receipt form enclosed with the 
parcel.  A copy of the signed receipt will be kept in the study files.  


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The study drug must be carefully stored at the temperature specified in the Pharmacy Manual 
(eg, clinical dosing solutions stored at approximately 2 to 8°C for 10 days or room temperature 
for up to 24 hours after preparation), safely and separately from other drugs.  The study drug 
may not be used for any purpose other than the present study.  After the study is completed, all 
unused study drug must be retained, returned as directed, or destroyed on site per the Sponsor’s 
instructions.   
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies.  An accurate, timely record of 
the disposition of all clinical supplies must be maintained.  The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed; 
• The date(s) and quantity of the drug dispensed to the subject; and 
• The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
A copy of the inventory record and a record of any clinical supplies that have been destroyed 
must be documented.  This documentation must include at least the information below or as 
agreed with the Sponsor: 
• The number of prepared units; 
• The number of administered units; 
• The number of unused units; 
• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 
10.5. 
Administration and Study Drug Accountability 
Doses will be prepared as an approximate 40 mL oral solution to be swallowed all at once, 
followed by approximately 200 mL of water which has been used to rinse the dosing bottle.  The 
start time of swallowing the approximately 40 mL oral solution is time zero for all assessments.  
Subjects may have assistance from the clinic staff when taking the study drug.   
10.5.1. 
Study Drug Administration 
Subjects in Part A will receive a 10-mg dose of study drug administered in the morning on 
Day 1, 20 mg on Day 2, and 30 mg on Days 3 to 7.   
Subjects in Part B will receive randomized study drug in the morning on Days 8 to 14. 
10.5.2. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol.   


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The Investigator or designee must maintain a record of all study drug received, used, and 
discarded.  It must be clear from the records which subject received which dose of active or 
placebo treatment.   
The Sponsor will be permitted access to the study supplies at any time within usual business 
hours and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation.  Only unblinded personnel will be able to access the study drug and 
accountability documentation from first dosing through database hard lock.   
10.6. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding, subsequent admixture, administration of test article, and for which subject the 
study drug was intended (ie, record subject initials and birth date or other unique identifier).   
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions; disposition of study drug will be 
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11. 
ASSESSMENT OF EFFICACY 
Efficacy assessments include evaluation of subject symptom response by a measurement of 
Kinesia, TETRAS upper limb items, and TETRAS Performance Subscale (items 4, 6, 7, and 8).  
Quality-of-life assessments include TETRAS ADL, QUEST, and video recording of subjects 
performing three everyday tasks.  Physiological activity (ie, sympathetic nervous system tone as 
measured by electrodermal activity, skin temperature monitoring, and heart rate monitoring) and 
tremor oscillation as assessed by multidimensional accelerometer measurements (ie, raw 
accelerometer values) will be assessed by the Empatica Wristband E4.   
11.1. 
Kinesia 
In order to measure tremor amplitude, subjects will wear a wireless ring motion sensor 
(Kinesia, Great Lakes Neuro Technologies).  The motion sensor uses three orthogonal 
accelerometers and three orthogonal gyroscopes to monitor three-dimensional motion.  Data are 
then transmitted from the sensor to a computer using Bluetooth technology.  These measures of 
three-dimensional motion for each maneuver are then converted to Kinesia scores, which have 
been shown to correlate with corresponding clinician-rated TETRAS scores (Giovanni 2010).  
Each Kinesia score ranges from 0 to 4; higher scores indicate more severe tremor.  The Kinesia 
assessment is completed in conjunction with the TETRAS Performance Subscale Item 4 
assessment. 
In Part A, Kinesia will be performed on Day -1 (three assessments separated by at least 
30 minutes); a single assessment will be performed predose and 2 and 8 hours (±30 minutes) 
postdose on Days 1, 2, 3, and 7.  In Part B, a single Kinesia reading will be performed predose 
and 2 and 8 hours (±30 minutes) postdose on Days 8, 9, and 14, and anytime during the visit on 
Day 21. 
11.2. 
TRG Essential Tremor Rating Assessment Scale (TETRAS) 
Performance Scale 
Item #4 (upper limb tremor) of the TETRAS Performance Subscale will be completed using both 
the Kinesia device and clinician assessment.  Testing should be completed within ±10 minutes of 
the planned questionnaire time points.  All three maneuvers in the upper limb assessments 
(items 4a, 4b, and 4c) will be completed for both arms, first for the RIGHT arm and then for the 
LEFT.  Predose assessments can be done any time within 2 hours prior to the start of 
administration of solution.  The Day 21 follow-up visit assessments can be done at any time 
during the visit. 
In Part A, the TETRAS upper limb items will be performed at screening and on Day -1 (three 
assessments separated by at least 30 minutes); a single assessment of TETRAS upper limb items 
will be performed predose and 2 and 8 hours (±30 minutes) postdose on Days 1, 2, 3, and 7.  In 
addition, the TETRAS upper limb items will be performed, while wearing the Empatica 
Wristband E4, on Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3, and 7. 
The TETRAS ADL Subscale and Performance Subscale (items 4, 6, 7, and 8) will be performed 
on Day -1 and predose (±30 minutes) on Day 7.  On days when the TETRAS ADL and 
Performance Subscale are performed, Item # 4 will not be repeated.   


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In Part B, the TETRAS upper limb items will be performed predose and 2 and 8 hours 
(±30 minutes) postdose on Days 8, 9, and 14, and anytime during the visit on Day 21.  In 
addition, the TETRAS upper limb items will be performed, while wearing the Empatica 
Wristband E4, 3 hours (±30 minutes) postdose on Days 8, 9, and 14, and anytime during the visit 
on Day 21.  The TETRAS ADL Subscale and Performance Subscale (items 4, 6, 7, and 8) will be 
performed predose (±30 minutes) on Day 14 and anytime during the visit on Day 21.  On days 
when the TETRAS ADL Subscale and Performance Subscale are performed, Item #4 will not be 
repeated.   
Note that the TETRAS upper limb scores from the test conducted during screening will be used 
to determine eligibility and must be ≥2 on each side (left and right) for kinetic tremor and ≥2 on 
each side (left and right) for either wing beating or forward outstretched postural tremor.  A copy 
of the TETRAS is provided in Appendix 2.   
11.3. 
Empatica Wristband E4 
Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring) will be assessed by the 
Empatica Wristband E4.  The Empatica Wristband E4 is a wearable device that captures 
motion-based activity and sympathetic nervous system arousal.  In Part A, the Empatica 
Wristband E4 will be worn during the study visits while in clinic on Days -1, 1, 2, 3, and 7.  In 
Part B, the Empatica Wristband E4 will be worn during the study visits while in clinic on Days 8, 
9, 14, and anytime during the visit on Day 21.  With the exception of during the TETRAS upper 
limb assessments, the Empatica Wristband E4 will be worn on the wrist that, of the two arms, 
exhibits more severe tremor symptoms.  During the TETRAS upper limb assessments (Part A:  
Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3 and 7; Part B:  3 hours (±30 minutes) 
postdose on Days 8, 9, and 14 and 21), the Empatica Wristband E4 will be worn on the wrist 
corresponding to the side of the body being assessed.  Data from the Empatica Wristband E4 will 
not be presented in the study report; instead, they will be part of a separate report.   
11.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST) 
The QUEST is a brief, 30-item, ET-specific QOL scale in which subjects rate the extent to which 
tremor impacts a function or state, tremor severity in various body parts, perceived health, and 
overall QOL (Tröster 2005).  The QUEST will be administered on Day -1, Day 7, and on 
Day 14.  A copy of the QUEST is provided in Appendix 3.   
11.5. 
Video Recording 
Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, 
and one additional task that the subject experiences difficulty with on a daily basis) will be taken 
on Day -1 and predose on Day 7 in Part A and predose on Day 14 and anytime during the visit 
on Day 21 in Part B.   


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
In Part A, plasma samples for PK analysis will be collected predose and 0.25, 0.5, 1, 2, 4, and 
8 hours postdose on Days 1 and 7 and predose on Days 2, 3, 4, 5, and 6.  In Part B, plasma 
samples for PK analysis will be collected predose on Days 8, 9, 10, 11, 12, 13, and 14.  The time 
of study drug administration is time zero and all post-dosing sampling times are relative to this 
time.  Samples are to be collected within ±5 minutes of the scheduled sampling time.  The 
Investigator or designee will arrange to have the plasma samples processed, stored, and 
transported as directed for bioanalysis.   
An additional PK sample may be collected at any time if clinically indicated and at the discretion 
of the Investigator (eg, for unusual or severe adverse events).   
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time.  The date and actual time that the blood sample was taken will be 
recorded on the CRF or electronically with a bar code or other method.   
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70°C to -80°C until analyzed.  
They should be packed as directed to avoid breakage during transit and with sufficient dry ice to 
prevent thawing for at least 72 hours.  A specimen-identification form must be completed and 
sent to the laboratory with each set of samples.  The clinical site will arrange to have the plasma 
samples transported as directed for bioanalysis as detailed in the PK instructions.   
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of SAGE-217 will be performed utilizing a 
validated liquid chromatography-tandem mass spectrometry method at a qualified laboratory.   
 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety and Tolerability Parameters 
Safety and tolerability of study drug will be evaluated by vital signs measurements, clinical 
laboratory measures, physical examination, ECGs, concomitant medication usage, C-SSRS, SSS, 
and adverse event reporting.  The Bond-Lader Mood Rating Scale and a DEQ-5 will be used to 
assess mood and perception of drug effects, respectively.   
13.1.1. 
Demographic/Medical History 
Age, gender, race, and ethnic origin will be recorded at the Screening visit.  A full medical 
history including medication history will be recorded at the Screening visit.   
13.1.2. 
Vital Signs 
Vital signs comprise heart rate, respiratory rate, temperature, and supine (supine for at least 
5 minutes prior to the measurement) and standing (for at least 2 to 3 minutes) systolic and 
diastolic blood pressure.   
In Part A, vital signs and pulse oximetry will be performed at screening (vital signs only) and 
Day -1, predose and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 1, 2, 3, and 4, and predose on 
Days 5, 6, and 7.  In Part B, vital signs (both supine for at least 5 minutes prior to the 
measurement and standing for at least 2 to 3 minutes) and pulse oximetry will be performed 
predose on Day 8 and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 8, 9, and 10, predose on 
Days 11, 12, 13, and 14, and anytime during the visit on Day 21.  Vital signs and pulse oximetry 
assessments will be performed within ±10 minutes of the scheduled times.   
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visit.   
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening visit.   
13.1.5. 
Electrocardiogram (ECG) 
A supine (supine for at least 5 minutes prior to the measurement) 12-lead ECG will be performed 
at the times specified below and the standard intervals recorded as well as any abnormalities.   
In Part A, the 12-lead ECG will be assessed at screening, predose and at 1 and 8 hours 
(±10 minutes) postdose on Days 1, 2, 3, 4, and 7.  In Part B, the 12-lead ECG will be assessed at 
1 and 8 hours (±10 minutes) postdose on Days 8, 9, 10, and 14, and anytime during the visit on 
Day 21.   
All time points are relative to the time of dosing.  ECGs will be performed within ±10 minutes of 
the predose and 1- and 8-hour time points. 


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13.1.6. 
Laboratory Assessments 
In Part A, blood and urine samples will be collected for hematology, serum chemistry, and 
urinalysis at the Screening visit, on Day -1, predose on Day 1, and predose on Day 2.  In Part B, 
blood and urine samples will be collected predose on Day 8 and Day 9 and anytime during the 
visit on Day 21.   
Serum and urine samples for pregnancy tests (females only) will also be collected.  These 
assessments should be performed in accordance with the Schedule of Events (Table 2 and 
Table 3) and as outlined individually below.   
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS); or abnormal, clinically significant 
(CS).  Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the medical monitor.  Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to 
Section 13.2.1, and recorded in the eCRF.   
13.1.6.1. Hematology 
Hematology tests will include complete blood count, including red blood cells, white blood cells 
with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets.  The coagulation panel 
will include activated partial thromboplastin time, prothrombin time, and international 
normalized ratio.   
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes, renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide, liver function tests, including total 
bilirubin, AST, and ALT, total protein, and albumin.   
Thyroid-stimulating hormone, thyroxine (T4), and triiodothyronine (T3) will be performed at 
screening to confirm subject eligibility.   
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity.   
13.1.6.4. Drugs Screen and Alcohol Test 
A urine sample for assessment of selected drugs (sedative/hypnotics [eg, opioids], cotinine, and 
caffeine) and a breath sample for alcohol screen will be collected at screening and on Day -1.  
Results may be obtained through subject history.  Subjects who use concomitant 
sedative/hypnotics will be excluded from the study.  Use of alcohol, caffeine, or cotinine is not 
allowed through Day 21. 
13.1.6.5. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
the study.   


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13.1.6.6. Pregnancy Test 
Females of child-bearing potential will be tested for pregnancy by serum pregnancy test at the 
Screening visit and by urine pregnancy test on Day -1, predose on Day 8, and at the follow-up 
visit on Day 28 in Part B.   
13.1.6.7. Exploratory Biochemistry 
Optional blood samples will be collected at screening and on Days 3 and 7 and may be analyzed 
for exploratory biochemistry, where consent is given.  Future research may suggest other 
biochemical markers as candidates for influencing not only response to SAGE-217 but also 
susceptibility to disorders for which SAGE-217 may be evaluated.  Thus, the biochemical 
research may involve study of additional unnamed biochemical biomarkers, but only as related to 
disease susceptibility and drug action.   
13.1.6.8. Genetic Testing 
Where consent is given, an optional genetic sample for biomarker testing will be collected at the 
Screening visit.   
The objective of this research is to collect and store blood samples for possible DNA extraction 
and exploratory research into how genes or specific genetic variation may influence response 
(ie, distribution, safety, tolerability, and efficacy) to SAGE-217.  Specific genetic variations of 
interest include but are not limited to: classes of metabolizing enzymes (eg, cytochrome P450 
supra-family genes), genes encoding enzymes involved in the production and metabolism of 
SAGE-217 (eg, AKR1C4 [3α-hydroxysteroid dehydrogenase]), genes associated with the 
γ-aminobutyric acid (GABA) receptor (eg, GABRA1-A6, GABRB1-B3, GABRD, GABRE, 
GABRG1-3), and genes associated with the production and degradation of GABA.   
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to SAGE-217 but also susceptibility to disorders for which SAGE-217 may be 
evaluated.  Thus, the genetic research may involve study of additional unnamed genes or gene 
categories, but only as related to disease susceptibility and drug action.   
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011).  This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit.  The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).   
If in the opinion of the Investigator, the subject is showing any suicidal tendency, no further 
study drug will be administered and the subject will be referred to a psychologist or psychiatrist 
for further evaluation.  This information will be tracked.   
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months).  In Part A, the “Since Last Visit” C-SSRS form will be completed on Day -1, 
8 hours postdose (± 1 hour) on Day 1, predose on Day 4, and on Days 5, 6, and 7.  In Part B, the 
“Since Last Visit” C-SSRS form will be completed 8 hours (± 1 hour) postdose on Days 8, 11, 


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12, 13, and 14, and anytime during the visits on Days 21 and 28.  The C-SSRS is provided in 
Appendix 4.   
13.1.8. 
Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling 
(Hoddes 1972).  Degrees of sleepiness and alertness are rated on a scale of 1 to 7, where the 
lowest score of ‘1’ indicates the subject is ‘feeling active, vital, alert, or wide awake’ and the 
highest score of ‘7’ indicates the subject is ‘no longer fighting sleep, sleep onset soon; having 
dream-like thoughts’.   
In Part A, the SSS will be administered predose and at 1, 2, 3, 4, 6, and 8 hours postdose on 
Days 1, 2, 3, and 4, and predose only on Days 5, 6, and 7.  In Part B, the SSS will be 
administered predose and 1, 2,  4, 6, and 8 hours postdose on Days 8, 9, 10, 11, 12, 13, and 14, 
and anytime during the visit on Day 21.  All time points are relative to the time of dosing.  The 
SSS is to be performed within ±10 minutes of the scheduled times.  The SSS is provided in 
Appendix 5. 
13.1.9. 
Bond-Lader VAS Mood Scale 
Mood will be assessed using the Bond-Lader Mood Rating Scale (Bond 1974).  This is a 16-part 
self-administered questionnaire that employs a 100-mm VAS to explore different aspects of self-
reported mood.  In Part A, the mood scale will be administered predose and 2 hours 
(±10 minutes) postdose on Days 1, 2, and 7.  In Part B, the mood scale will be administered 
predose and 2 hours (±10 minutes) postdose on Days 8, 9, 14, and anytime during the visit on 
Day 21.  The Bond-Lader Mood Rating Scale is provided in Appendix 6.   
13.1.10. 
Drug Effects Questionnaire (DEQ-5) 
A DEQ-5 (Morean 2013) will be administered as follows: 
1. Do you FEEL a drug effect right now? 
2. Are you HIGH right now? 
3. Do you DISLIKE any of the effects that you are feeling right now? 
4. Do you LIKE any of the effects that you are feeling right now? 
5. Would you like MORE of the drug you took, right now? 
The answers are recorded on a 100-mm VAS, with the answer for each being “Not at all” and 
“Extremely” at the extremes.  There will be options to record “Not applicable” for 
questions 3 and 4 if no drug effects are felt and for question 5 prior to administration of study 
medication.  The DEQ-5 will be performed 2 hours (±10 minutes) postdose on Days 1 and 7 in 
Part A and 2 hours (±10 minutes) postdose on Days 8 and 14 in Part B.  The DEQ-5 is provided 
in Appendix 7. 
13.2. 
Adverse and Serious Adverse Events 
Adverse events will be collected after the ICF has been signed.  Medical conditions that occur 
after the ICF has been signed will be captured on the adverse event eCRF. 


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Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (version 18.1 or higher).  
13.2.1. 
Definition of Adverse Events 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered. 
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug.   
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
All serious adverse events that occur after any subject has been enrolled, whether or not they are 
related to the study, must be recorded on forms provided by Sage Therapeutics or designee for 
the duration of the study (from the signing of the ICF through the Day 28 visit [or early 
termination]). 
13.2.2. 
Pregnancy 
Any pregnancy occurring during this study will be reported within 24 hours of notification of the 
Investigator.  The Investigator will promptly notify the Medical Monitor and withdraw the 
subject from the study.  The Investigator should request permission to contact the subject, the 
subject’s spouse/partner (if the subject is male and his spouse/partner becomes pregnant) or the 
obstetrician for information about the outcome of the pregnancy, and in the case of a live birth, 
about any congenital abnormalities.  If a congenital abnormality is reported, then it should be 
recorded in the source documents and reported as a serious adverse event.   


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13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, possibly related or probably related).  
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product.  If no valid reason 
exists for suggesting a relationship, then the adverse event should be classified as “unrelated.”  If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the adverse event, then the 
adverse event should be considered “related.”   
Not 
Related: 
No relationship between the experience and the administration of study drug; related to other 
etiologies such as concomitant medications or subject’s clinical state. 
Possibly 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug and 
follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of therapy 
administered to the subject, but this is not known for sure. 
Probably 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug and 
follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s clinical 
state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered to be related 
to the investigational product for the purposes of expedited regulatory reporting.   
13.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject 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.  Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event or lead to discontinuation of administration of 
study drug.   
Information about adverse events will be collected from the signing of the ICF through the 
Day 28 visit (or early termination).  Adverse events that occur after the first administration of 
study drug will be denoted TEAEs.   
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
no expectation of future change.   
The adverse event term should be reported in standard medical terminology when possible.  For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), intensity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study.   
Intensity will be assessed according to the following scale: 


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• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
13.5. 
Reporting Serious Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 28 visit (14 days following the last dose of study drug) or early termination.  Any 
serious adverse events considered possibly or probably related to the investigational product and 
discovered by the Investigator at any time after the study should be reported.  All serious adverse 
events must be reported to the Sponsor or Sponsor’s designee immediately by phone and in 
writing within 24 hours of the first awareness of the event.  The Investigator must complete, sign 
and date the serious adverse event pages, verify the accuracy of the information recorded on the 
serious adverse event pages with the corresponding source documents, and send a copy to Sage 
Therapeutics or designee.   
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the study file.   
Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
certain events.  It is the Principal Investigator’s responsibility to notify the IRB of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements.  Investigators 
will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) 
that occur during the clinical study.  Each site is responsible for notifying its IRB of these 
additional serious adverse events.   
13.6. 
Emergency Identification of Study Drug (Part B) 
Part B is a double-blind study.  The pharmacist responsible for preparing the solutions will be 
unblinded and will retain an official paper copy of the randomization schedule. 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received.  Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact the Sponsor prior to unblinding the 
study treatment administered to a subject.  Any request from the Investigator about the treatment 
administered to study subjects must be discussed with the Sponsor.  If the unblinding occurs 
without the Sponsor’s knowledge, the Investigator must notify the Sponsor as soon as possible 
and no later than the next business morning.  All circumstances surrounding a premature 
unblinding must be clearly documented in the source records.  Unless a subject is at immediate 
risk, any request for the unblinding of individual subjects must be made in writing to the Sponsor 
and approved by the appropriate Sponsor personnel, according to standard operating procedures.  
The blinding of the study will be broken after the database has been locked.  Electronic copies of 
the randomization code will be made available to the laboratory performing the bioanalytical 
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In all cases where the study drug allocation for a subject is unblinded, pertinent information must 
be documented in the subject’s records and on the eCRF.  If the subject or study center personnel 
(other than pharmacist) have been unblinded, the subject will be terminated from the study.   


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14. 
STATISTICAL METHODS AND CONSIDERATIONS 
14.1. 
Data Analysis Sets 
The safety population is defined as all subjects who are administered study drug.   
The efficacy population will consist of all subjects in the safety population who complete at least 
one dose in Part B and have at least one post-randomization efficacy evaluation.   
The evaluable population will consist of all randomized subjects with at least one post-
randomization Kinesia assessment.   
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations.   
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data.  All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available.  No imputation process will be 
used to estimate missing data.  No sensitivity analysis of missing data will be performed.   
14.3. 
Demographics and Baseline Characteristics 
Demographics, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized.   
Categorical summaries, such as race and ethnicity, will be summarized by frequency and 
percentage.  Continuous summaries, such as age, height, weight, BMI, and baseline vital signs, 
will be summarized using descriptive statistics.   
Hepatitis, HIV, drug, and pregnancy screening results will be listed, but not summarized as they 
are considered part of the inclusion/exclusion criteria.   
Medical history will be listed by subject.   
14.4. 
Primary Efficacy Endpoint 
The change from randomization (predose on Day 8) in the accelerometer-based Kinesia kinetic 
tremor combined score (ie, the sum of Kinesia kinetic tremor scores from both sides of the body) 
at Day 14 will be summarized by treatment group in Part B. 
Change from randomization to each assessment in Kinesia kinetic tremor combined score will be 
analyzed using a mixed effects repeated measures model, including center, treatment, 
randomization Kinesia kinetic tremor combined score, assessment time point, and time point-by-
treatment.  All explanatory variables will be treated as fixed effects. 
14.5. 
Secondary Efficacy Endpoints 
The change from randomization (predose on Day 8) in the Kinesia upper limb total and 
individual item scores, TETRAS upper limb total and individual upper limb item scores, and 


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other TETRAS Performance Subscale scores at Day 14 will be summarized by treatment group 
in Part B. 
A mixed effects repeated measures model similar to those described in Section 14.4 will be used 
for the analysis of change from randomization in the following:  Kinesia upper limb total score, 
Kinesia individual item scores, TETRAS upper limb total score, and TETRAS individual upper 
limb item scores. 
14.6. 
Exploratory Efficacy Endpoints 
The change from randomization (predose on Day 8) in TETRAS ADL scores at Day 14 will be 
summarized by treatment group in Part B.   
QUEST data will be listed by subject, study day, and time point. 
14.7. 
Safety and Tolerability Analyses 
Data from vital signs, clinical laboratory measures, ECG, and C-SSRS will be summarized using 
descriptive statistics by group and time point, where applicable.  Continuous endpoints will be 
summarized with n, mean, standard deviation, median, minimum, and maximum.  In addition, 
change from baseline values will be calculated at each time point and will be summarized using 
descriptive statistics.  Out-of-range safety endpoints may be categorized as low or high, where 
applicable.  For all categorical endpoints, summaries will include counts and percentages.   
14.7.1. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system (version 18.1 or higher).  The 
analysis of adverse events will be based on the concept of TEAEs.  A TEAE is defined as an 
adverse event with onset after the start of open-label study drug, or any worsening of a pre-
existing medical condition/adverse event with onset after the start of open-label study drug and 
until 14 days after the last dose.  The incidence of TEAEs will be summarized overall and by 
MedDRA System Organ Class, preferred term, and dose group.  Incidences will be presented in 
order of decreasing frequency.  In addition, summaries will be provided by maximum severity 
and relationship to study drug (see Section 13.3).   
TEAEs leading to discontinuation and serious adverse events (see Section 13.2.1.3 for definition) 
with onset after the first dose of open-label study drug will also be summarized. 
All adverse events and serious adverse events (including those with onset or worsening before 
the signing of the ICF) through the Day 28 visit will be listed.   
14.7.2. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection.  Mean changes from 
randomization in vital signs will be evaluated by time point.   
14.7.3. 
Physical Examinations 
Screening physical examinations will be documented as done/not done; these results will be 
listed by subject.  Any clinically significant physical examination findings will be recorded as 
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14.7.4. 
12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QTcF.  Any clinically significant abnormalities or changes in ECGs should be listed as an 
adverse event.  Electrocardiogram findings will be listed by subject and visit.   
14.7.5. 
Clinical Laboratory Evaluations 
Clinical laboratory results will be listed by subject and timing of collection.  Mean changes from 
baseline and randomization in clinical laboratory measures will be evaluated.   
14.7.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS will be listed for all subjects.  Listings will include 
behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the C-SSRS.   
14.7.7. 
Stanford Sleepiness Scale (SSS) 
Sleepiness data collected on the SSS will be listed for all subjects.  Changes in score over time 
will be represented graphically, and change from Day 1 will be measured. 
14.7.8. 
Bond-Lader VAS Mood Scale 
Mood data collected on the Bond-Lader VAS mood scale will be listed by subject, study day, 
and time point.  The scores and change from Day 1 will be summarized by study day and time 
point.   
14.7.9. 
Drug Effects Questionnaire (DEQ-5) 
Results from DEQ-5 will be listed by subject, study day, and time point.  The result for each 
question and change from Day 1 will be summarized by study day and time point.  
14.7.10. 
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 Enhanced (WHO-DDE) version September 2015, or later.   
Medications will be presented according to whether they are being taken prior to and/or during 
the study (concomitant).  Prior medications are defined as those taken within 2 weeks prior to the 
signing of the ICF.  Concomitant medications are defined as those with a start date on or after the 
first dose of open-label study drug, or those with a start date before the first dose of open-label 
study drug that are ongoing or with a stop date on or after the first dose of open-label study drug.  
If medication dates are incomplete and it is not clear whether the medication was concomitant, it 
will be assumed to be concomitant.   
Concomitant medications will be assigned to the part in which they are being taken.  If a 
concomitant medication assigned to a Part A continues to be taken through Part B, then the 
medication will be assigned to both parts of the study as appropriate.  If the start and stop dates 
of the concomitant medications do not clearly define the part during which a medication was 
taken, it will be assumed to be taken in both parts.  Details of prior and concomitant medications 
will be listed by study part, subject, start date, and verbatim term.   


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14.8. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics.  Time to 
reach maximum concentration (tmax) will be summarized using n, mean, standard deviation, 
median, minimum, and maximum.  All other PK parameters will be summarized using n, 
geometric mean, coefficient of variation, median, minimum, and maximum and listed by subject.   
Wherever necessary and appropriate, PK parameters will be dose-adjusted to account for 
individual differences in dose.   
Pharmacokinetic and pharmacodynamic modelling assessment of the relationship between 
plasma exposure of SAGE-217 and change from baseline in Kinesia scores may be assessed.   
14.9. 
Determination of Sample Size 
Up to 60 subjects will be enrolled in Part A to yield at least 40 randomized subjects for Part B.  
A total sample size of 34 evaluable subjects (ie, 17 per group) will have 80% power to detect a 
difference in means of 3.0 on the primary endpoint assuming that the common standard deviation 
is 3.0 using a 2-group t-test with a 0.05 two-sided significance level.  Assuming a 15% non-
evaluability rate, 20 subjects per group will be randomized.  The number of subjects in each 
treatment group is also thought to be sufficient to assess preliminary safety and tolerability 
following multiple doses of SAGE-217 Oral Solution. 
14.10. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Sage 
Therapeutics or designee will visit the investigational study site to:   
• Determine the adequacy of the facilities; and 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives.  This will be documented in a Clinical Study Agreement between 
Sage Therapeutics and the Investigator.   
During the study, a monitor from Sage Therapeutics or designee 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 CRFs, and that investigational product accountability 
checks are being performed; 
• Perform source data verification. This includes a comparison of the data in the CRFs 
with the subject’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 
subject (eg, clinic charts); 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm adverse events and serious adverse events have been properly documented 
on CRFs and confirm any serious adverse events have been forwarded to Sage 
Therapeutics or designee and those serious adverse events that met criteria for 
reporting have been forwarded to the IRB.   
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification.  The purpose of a Sage Therapeutics or designee audit or 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 guidelines of the International Council on 
Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency about an inspection.   


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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study, including the subject consent form and 
recruitment materials, must be maintained by the Investigator and made available for inspection.   


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
CRFs.   
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements.   
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate.  The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study.   
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  Sage Therapeutics or designee will provide this information to the Principal 
Investigator.   
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines.   
17.2. 
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 the most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements.   
17.3. 
Written Informed Consent 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study.  Subjects must also 
be notified that they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided.   
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures.   
The Principal Investigator(s) must maintain the original, signed ICF.  A copy of the signed ICF 
must be given to the subject.   
 


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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan.   
Electronic CRFs will be completed for each study subject.  It is the Investigator’s responsibility 
to ensure the accuracy, completeness, and timeliness of the data reported in the subject’s eCRF.  
Source documentation supporting the eCRF data should indicate the subject’s participation in the 
study and should document the dates and details of study procedures, adverse events, and subject 
status.   
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study.  For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct.   
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or, if not approved, 2 years following the 
discontinuance of the test article for investigation.  If it becomes necessary for Sage Therapeutics 
or the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records.   
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports and communications will identify the 
subject by the assigned subject number.  The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process.  The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations.   
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used.   


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All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information.  The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor.  It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study.  The information obtained from the clinical study will be used 
towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required.   


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19. 
PUBLICATION POLICY 
All information concerning SAGE-217 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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20. 
LIST OF REFERENCES 
Axelrad JE, Louis ED, Honig LS, et al. Reduced Purkinje cell number in essential tremor: A 
postmortem study. Arch Neurol. 2008;65(1):101–7. 
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. 
Benito-Leon J, Louis ED. Clinical update: diagnosis and treatment of essential tremor. Lancet. 
2007;369(9568):1152-4. 
Boecker H, Kleinschmidt A, Requardt M, Hänicke W, Merboldt KD, Frahm J. Functional 
cooperativity of human cortical motor areas during self-paced simple finger movements. A high 
resolution MRI study. Brain. 1994;117(Pt 6):1231-9. 
Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Med Psychol. 
1974;47:211-218. 
Bucher SF, Seelos KC, Dodel RC, et al. Activation mapping in essential tremor with functional 
magnetic resonance imaging. Ann Neurol. 1997;41:32-40. 
Cavanagh JB, Holton JL, Nolan CC, Ray DE, Naik JT, Mantle PG. The effects of the 
tremorgenic mycotoxin penitrem A on the rat cerebellum. Vet Pathol. 1998;35:53–63. 
Deuschl G, Bain P, Brin M. Adhoc-Scientific-Committee. Consensus Statement of the 
Movement Disorder Society on Tremor. Mov Disord. 1998;13(suppl 3):2-23. 
Deuschl G, Elble R. Essential tremor—neurodegenerative or nondegenerative disease towards a 
working definition of ET. Mov Disord. 2009;24(14):2033–41. 
Deuschl G, Raethjen J, Hellriegel H, et al. Treatment of patients with essential tremor. Lancet 
Neurol. 2011;10:148–61. 
Elble RJ, Deuschl G. An update on essential tremor. Curr Neurol Neurosci Rep. 2009;9:273–7. 
Esmaeili A, Lynch JW, Sah P.  GABAA receptors containing gamma1 subunits contribute to 
inhibitory transmission in the central amygdala. J Neurophysiol. 2009;101(1):341-9.  
Giovanni M, Giuffrida J, Adam O, Davidson A, Jankovic J. Correlation between Kinesia system 
assessments and clinical tremor scores in patients with essential tremor. Mov Disord. 
2010;25(12):1938-43. 
Gironell A, Kulisevsky J, Barbanoj M, et al. A randomized placebo controlled comparative trial 
of gabapentin and propranolol in essential tremor. Arch Neurol. 1999;56:475–80. 
Gorman WP, Cooper R, Pocock P, et al. A comparison of primidone, propranolol, and placebo in 
essential tremor, using quantitative analysis. J Neurol Neurosurg Psychiatry. 1986;49:64–8. 
Habib-ur-Rehman. Diagnosis and management of tremor. Arch Intern Med. 
2000;160(16):2438-44. 
Hoddes E, Dement W, Zarcone V. The development and use of the Stanford Sleepiness Scale 
(SSS). Psychophysiology. 1972;9:150. 


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Kralic JE, Criswell HE, Osterman JL, et al. Genetic essential tremor in gamma-aminobutyric 
acid A receptor alpha1 subunit knockout mice. J Clin Invest. 2005;115:774–9. 
Louis ED, Faust PL, Vonsattel JP, et al. Neuropathological changes in essential tremor: 33 cases 
compared with 21 controls. Brain. 2007;130:3297–307. 
Louis ED, Vonsattel JPG. The emerging neuropathology of essential tremor. Mov Disord. 
2008;23(2):174-82. 
Louis ED. Essential tremors: a family of neurodegenerative disorders? Arch Neurol. 
2009;66:1202–8. 
Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on 
the worldwide prevalence of essential tremor. Mov Disord. 2010;25:534–41. 
Louis ED. Treatment of essential tremor: are there issues we are overlooking? Front Neurol. 
2012;2:91. 
Málly J, Baranyi M, Vizi ES. Change in the concentrations of amino acids in CSF and serum of 
patients with essential tremor. J Neural Transm. 1996;103:555-60. 
McAuley JH, Marsden CD. Physiological and pathological tremors and rhythmic central motor 
control. Brain. 2000;123 (Pt 8):1545-67. 
Miwa H. Rodent models of tremor. Cerebellum. 2007;6:66-72. 
Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, O’Malley SS. The drug effects 
questionnaire: psychometric support across three drug types. Psychopharmacology. 
2013;227:177-92. 
O'Brien MD, Upton AR, Toseland PA. Benign familial tremor treated with primidone. Br Med J 
(Clin Res Ed). 1981;82(6259):178-80. 
Pahapill PA, Levy R, Dostrovsky JO, et al. Tremor arrest with thalamic microinjections of 
muscimol in patients with essential tremor. Ann Neurol. 1999;46(2):249-52. 
Pahwa R, Lyons KE. Essential tremor: differential diagnosis and current therapy. Am J Med. 
2003;115(2):134-42. 
Paris-Robidas S, Brochu E, Sintes M, et al. Defective dentate nucleus GABA receptors in 
essential tremor. Brain. 2012;135:105-16. 
Pinto AD, Lang AE, Chen R. The cerebellothalamocortical pathway in essential tremor. 
Neurology. 2003;60(12):1985-7. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
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Pritchett DB, Sontheimer H, Shivers BD, et al.  Importance of a novel GABAA receptor subunit 
for benzodiazepine pharmacology.  Nature. 1989;338(6216):582-5. 
Rajput AH, Rajput A. Medical Treatment of Essential Tremor. J Cent Nerv Syst Dis. 
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Schmouth JF, Dion PA, Rouleau GA. Genetics of essential tremor: from phenotype to genes, 
insights from both human and mouse studies. Prog Neurobiol. 2014;119-120:1-19.  
Schnitzler A, Munks C, Butz M, et al. Synchronized brain network associated with essential 
tremor as revealed by magnetoencephalography Mov Disord. 2009;24:1629-35. 
Shill HA, Adler CH, Sabbagh MN, et al. Pathologic findings in prospectively ascertained 
essential tremor subjects. Neurology. 2008;70:1452-5.   
Tröster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of life in Essential Tremor 
Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord. 
2005;11(6):367-73. 
Wills AJ, Thompson PD, Findley LJ, et al. A positron emission tomography study of primary 
orthostatic tremor. Neurol. 1996;46(3):747-52. 
Zappia M, Albanese A, Bruno E, et al. Treatment of essential tremor: a systematic review of 
evidence and recommendations from the Italian Movement Disorders Association. J Neurol. 
2013;260:714–40. 


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21. 
APPENDICES 
Copies of scales and questionnaires included in Appendix 2 through Appendix 7 are for 
reference only; the rating scales and questionnaires are to be used for actual subject assessment 
per the Schedule of Events.   
 


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APPENDIX 1. TREMOROGENIC DRUGS 
The following drug classes are not permitted in the 14 days prior to the Day -1 visit and for the 
duration of the study (up to the Day 28 visit).  The list below gives a non-exhaustive list of 
examples of each drug class. 
Anti-arrhythmics 
 
amiodarone, procainamide 
Antiepileptic drugs 
 
valproic acid, carbamazepine 
Antipsychotic agents 
 
haloperidol, trifluoperazine 
Antimanic agents/mood stabilizer 
 
lithium at toxic levels 
Antivirals 
 
acyclovir, vidarabine 
Beta adrenergic agonists 
 
albuterol, terbutaline 
Calcium Channel blockers 
 
verapamil 
CNS stimulants 
 
methylphenidate, amphetamines, cocaine 
Corticosteroids (local injection topical, or inhalation allowed) 
 
cortisone, hydrocortisone, prednisone 
Cytotoxic agents 
 
cytarabine 
Hormones 
 
calcitonin, levothyroxine (levothyroxine is allowed if on a stable dose and euythroid) 
Immunomodulatory 
 
thalidomide 
Immunosuppressants 
 
cyclosporine, tacrolimus 
Monoamine depleting agents 
 
tetrabenazine 
Oral hypoglycemic agents 
 
metformin, glyburide, glipizide, tolbutamide, pioglitazone, rosiglitazone, acarbose, miglitol 
Prokinetics 
 
metoclopramide 
Tricyclic antidepressants 
 
amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, 
nortriptyline, protriptyline 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
 
Fluoxetine (other SSRIs are allowed) 
Statins 
 
Atorvastatin (other statins are allowed) 


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Sympathomimetics 
 
epinephrine, pseudoephedrine 
Weight loss medication 
 
tiratricol 
Xanthine derivatives 
 
theophylline (caffeine/coffee and theophylline/theobromine/tea require a washout, cocoa 
beans are acceptable) 
 


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APPENDIX 2. TRG ESSENTIAL TREMOR RATING ASSESSMENT 
SCALE (TETRAS) 
 


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Appendix 3. 
QUALITY OF LIFE IN ESSENTIAL TREMOR 
QUESTIONNAIRE (QUEST) 
 


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APPENDIX 4. COLUMBIA – SUICIDE SEVERITY RATING SCALE 
(C-SSRS) 
 


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Appendix 5. 
STANFORD SLEEPINESS SCALE (SSS) 
 
 


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APPENDIX 6. BOND-LADER VAS (MOOD RATING SCALE) 
 


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APPENDIX 7. DRUG EFFECTS QUESTIONNAIRE (DEQ-5) 
 


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1. 
TITLE PAGE 
 
PROTOCOL NUMBER: 217-ETD-201 
A PHASE 2A, DOUBLE-BLIND, PLACEBO-
CONTROLLED, RANDOMIZED WITHDRAWAL STUDY 
EVALUATING THE EFFICACY, SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS OF 
SAGE-217 ORAL SOLUTION IN THE TREATMENT OF 
SUBJECTS WITH ESSENTIAL TREMOR (ET) 
IND NUMBER:  131,258 
Investigational Product 
SAGE-217 
Clinical Phase 
2a 
Sponsor 
Sage Therapeutics, Inc. 
Sponsor Contact 
, M.S.H.S. 
 
Sage Therapeutics 
215 First Street  
Cambridge, MA  02142 
Phone: 
 
Email:  
   
Medical Monitor 
, M.D., M.P.H. 
Study Physician 
Sage Therapeutics 
215 First Street  
Cambridge, MA  02142 
Phone:  
  
Email: 
 
Date of Original Protocol 
Date of Amendment One 
Version 1.0, 19 August 2016 
Version 2.0, 28 October 2016 
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 the Sponsor. 




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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-217.  I have read the Clinical 
Protocol 217-ETD-201 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 


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CONTACTS IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sponsor Physician 
, M.D., M.P.H. 
 
Sage Therapeutics 
 
215 First Street, Suite 220 
Cambridge, MA 02142 
Cell: 
 
Sponsor Signatory 
, M.D., Ph.D. 
 
  
 
215 First Street, Suite 220 
Cambridge, MA 02142 
Office:
 
Cell: 
 
Medical Monitor 
, M.D. 
 
  
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street  
Cambridge, MA  02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 2a, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study 
Evaluating the Efficacy, Safety, Tolerability, and Pharmacokinetics of SAGE-217 Oral Solution in the 
Treatment of Subjects with Essential Tremor (ET) 
Study center(s):  Up to 30 centers 
Phase of development: 2a 
Methodology:  
This study will assess the efficacy, safety, tolerability, and PK of SAGE-217 Oral Solution.   
There are two parts: 
Part A: Open-label with morning dosing (7 days). 
All subjects will start on a 10 mg dose of study drug administered with food in the morning on Day 1.  
Subjects will receive 20 mg with food on Day 2 and 30 mg with food daily on Days 3 to 7.   
Part B: Double-blind, placebo-controlled, randomized withdrawal with morning and evening dosing 
(7 days). 
In order to qualify for Part B of the study, a subject must tolerate a maximum dose of at least 10 mg of 
SAGE-217, and the subject must have responded to SAGE-217, defined as a 30% reduction from 
baseline in the TRG Essential Tremor Rating Assessment Scale (TETRAS) kinetic tremor combined 
score (ie, the sum of item 4c scores from both sides of the body) predose on Day 8.   
Eligible subjects will be randomized in a 1:1:1 fashion to SAGE-217 morning dosing, SAGE-217 
evening dosing, or placebo.  In order to preserve the blind, those randomized to SAGE-217 morning 
dosing will receive placebo for the evening dose, those randomized to SAGE-217 evening dosing will 
receive placebo for the morning dose, and those randomized to placebo will receive placebo for both 
morning and evening dosing.  Subjects randomized to SAGE-217 will receive their maximum dose as 
determined in Part A.  Subjects randomized to the placebo arm will represent randomized withdrawal 
(withdrawal from treatment they received in Part A).  Subjects will be administered study drug with 
meals in the morning and in the evening for 7 consecutive days.   
  


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Methodology:  
Dose adjustments will only be allowed during the open-label phase of the study (Part A).  If at any time 
the dose is not tolerated in Part A, assessed by occurrence of a severe adverse event judged by the 
investigator to be related to study drug, the dose on the next day will be reduced to the next lowest dose 
and continued for the remainder of the open-label dosing period (ie, subjects who are unable to tolerate 
the 30 mg dose will receive a lower dose of 20 mg, and subjects who are unable to tolerate 20 mg will 
be given a 10 mg dose).  The dose tolerated for Days 5, 6, and 7 of the open-label dosing period will be 
determined to be the maximum dose for that subject.  Subjects who require dose adjustments on Days 
5, 6, and 7 of Part A will not progress to Part B.   
Subjects will be exposed to study drug (SAGE-217 or placebo) for up to 14 days and will be followed 
for an additional 14 days after the administration of the last dose.   
Assessments will be performed periodically during the study as outlined in the Schedule of Events 
(Table 2).   
Objectives:  
Primary: 
 
The primary objective of this study is to compare the effect of 7 days administration of SAGE-217 
Oral Solution to placebo on the change in tremor severity.   
Secondary: 
The secondary objectives of the study are to compare the effect of 7 days administration of SAGE-217 
Oral Solution to placebo on the following endpoints: 
 
Tremor severity, as assessed by the change from randomization (Day 8) in the accelerometer-based 
Kinesia upper limb total score (ie, the sum of forward outstretched postural tremor, lateral "wing 
beating" postural tremor, and kinetic tremor item scores across both sides of the body) and 
individual item scores at Day 14.   
 
Tremor severity, as measured by the change from randomization (Day 8) in the TETRAS upper 
limb total score (ie, the sum of item 4c scores from both sides of the body) and individual TETRAS 
upper limb item scores at Day 14.   
 
Tremor severity, as assessed by the change from randomization (Day 8) in TETRAS Performance 
Subscale scores measured at Day 14.   
 
Safety and tolerability, as assessed by vital signs measurements, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Severity 
Rating Scale (C-SSRS), and adverse event reporting.   
 
Sleepiness/sedation, as assessed by the Stanford Sleepiness Scale (SSS) and Modified Observer's 
Assessment of Alertness/Sedation (MOAA/S) scores.   
 
Mood, as assessed by the Bond-Lader visual analogue scale (VAS) Mood Scale scores.   
 
How the subject feels after taking the study drug as assessed by Drug Effects Questionnaire 
(DEQ-5) ratings.   
In addition, plasma concentrations of SAGE-217 and SAGE-217 metabolites may be measured.  
Pharmacokinetic (PK) parameters, such as area under the concentration-time curve from time zero to 
last time point (AUC0-t), area under the concentration-time curve from time zero to infinity (AUC0-∞), 
maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), and terminal half-
life (t1/2), will be derived, where appropriate.   
Exploratory: 
The exploratory objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on: 


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 
Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal activity, 
skin temperature monitoring, and heart rate monitoring), as assessed by the Empatica Wristband 
E4.  Tremor oscillation, as assessed by multi-dimensional accelerometer measurements (ie, raw 
accelerometer values). 
 
Quality of life (QOL), as assessed by TETRAS activities of daily living (ADL), Quality of Life in 
Essential Tremor Questionnaire (QUEST), and video recording assessment of subjects performing 
three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the 
subject experiences difficulty with on a daily basis).   
In addition, PK/pharmacodynamics (PD) modelling assessment of the relationship between plasma 
exposure of SAGE-217 and change from baseline in accelerometer-based Kinesia scores. 
Endpoints:  
The primary endpoint of this study is the change from randomization (Day 8) in the accelerometer-
based Kinesia kinetic tremor combined score (ie, the sum of item 4c scores from both sides of the 
body) at Day 14.   
Number of subjects (planned):  
Up to 80 subjects will be enrolled in Part A to yield at least 60 randomized subjects for Part B.   
Diagnosis and main criteria for inclusion:  
Inclusion criteria: 
1. Subject has signed an informed consent form before any study-specific procedures are performed.   
2. Subject must be between 18 and 75 years of age, inclusive. 
3. Subject must have a diagnosis of ET, defined as bilateral postural tremor and kinetic tremor, 
involving hands and forearms, that is visible and persistent and the duration is >5 years prior to 
screening. 
4. Subject must have bilateral TETRAS scores of at least two on each side (left and right) for kinetic 
tremor and at least two on each side (left and right) for either wing beating or forward outstretched 
postural tremor.   
5. Subject must be willing to discontinue medications taken for the treatment of ET, alcohol, nicotine, 
and caffeine through Day 21 of the study.   
6. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests.   
7. Female subjects must be post-menopausal, permanently sterile (bilateral tubal occlusion), or of 
childbearing potential with a negative pregnancy test, non- breastfeeding, and using two highly 
effective methods of birth control prior to screening through completion of the last follow-up visit 
(as defined in Section 8.1).  If a subject discontinues early after receiving a dose of study drug, they 
must continue this method of birth control for at least 7 days following the last dose of study drug.   
8. Male subjects must agree to practice a highly effective method of birth control while on study drug 
and for 13 weeks after receiving the last dose of study drug.  Effective methods of birth control 
include sexual abstinence, vasectomy, or a condom with spermicide (men) in combination with 
their partner’s highly effective method. 
9. Males must be willing to abstain from sperm donation while on study through 13 weeks after 
receiving the last dose of study drug. 


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Exclusion criteria: 
1. Subject has presence of abnormal neurological signs other than tremor or Froment’s sign. 
2. Subject has presence of known causes of enhanced physiological tremor. 
3. Subject has concurrent or recent exposure (14 days prior to admission visit) to tremorogenic drugs, 
as defined in Appendix 1, or the presence of a drug withdrawal state. 
4. Subject has had direct or indirect trauma to the nervous system within 3 months before the onset of 
tremor.  
5. Subject has historical or clinical evidence of tremor with psychogenic origin (including but not 
limited to eating disorders, major depression, etc.). 
6. Subject has convincing evidence of sudden tremor onset or evidence of stepwise deterioration of 
tremor. 
7. Subject has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or oncological disease. 
8. Subject has clinically significant abnormal physical examination or 12-lead ECG at the Screening 
or Admission Visits.  Note:  A QT interval calculated using the Fridericia method [QTcF] of 
>450 msec in males or >470 msec in females, will be the basis for exclusion from the study.  An 
ECG may be repeated if initial values obtained exceed the limits specified. 
9. Subject has a history, presence, and/or current evidence of serologic positive results for hepatitis B 
surface antigen, hepatitis C antibodies, or human immunodeficiency virus 1 or 2 antibodies. 
10. Subject has hyperthyroidism.   
11. Subject has used alcohol, caffeine, or nicotine within 3 days prior to Admission visit. 
12. Subject has a known allergy to SAGE-217 and its major excipient hydroxypropyl-β-cyclodextrin 
(HPβCD). 
13. Subject has exposure to another investigational medication or device within the prior 30 days. 
14. Subject has a history of suicidal behavior within 2 years or answers “YES” to questions 3, 4, or 5 
on the C-SSRS at the Screening Visit or on Day -1 or is currently at risk of suicide in the opinion of 
the Investigator. 
15. Subject has donated one or more units (1 unit = 450 mL) of blood or acute loss of an equivalent 
amount of blood within 60 days prior to dosing. 
16. Subject is unwilling or unable to comply with study procedures. 
17. Use of any known strong inhibitors and/or inducers of cytochrome P450 (CYP)3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or St. John's Wort or products containing these within 30 days prior to receiving the first 
dose of study drug.   
18. Subject has obstructed venous access and/or has skin disease, rash, acne, or abrasion at venous 
access site that may affect the ability to obtain a PK sample (eg, artificial cardiac valve, joint 
replacement).   
19. Subject has concurrent or recent exposure (14 days prior to admission visit) to sedative/hypnotic 
(eg, opioids) drugs.   
20. Subject has hyperthyroidism at screening (based on thyroid-stimulating hormone, thyroxine [T4], 
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Investigational product, dosage and mode of administration:  
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile Water 
for Injection to achieve the selected dose. 
Duration of treatment:  
Screening Duration: approximately 28 days; Treatment Period: 14 days; Follow-up: 14 days 
Planned Study Duration per Subject: approximately 56 days 
Reference therapy, dosage and mode of administration:  
Placebo will be matched to study drug in Part B.   
Criteria for evaluation: 
Efficacy: 
Transducer measurement of tremor amplitude using an accelerometer and TETRAS Performance 
Subscale.  Quality-of-life will be evaluated using the TETRAS ADL, QUEST, and video recording of 
subjects performing three everyday tasks.  Physiological activity (ie, sympathetic nervous system tone 
as measured by electrodermal activity, skin temperature monitoring, and heart rate monitoring) will be 
assessed by the Empatica Wristband E4.   
Pharmacokinetics: 
Plasma will be collected to assay for concentrations of SAGE-217 and may be assayed for SAGE-217 
metabolites, if deemed necessary.  The following PK parameters will be derived from the plasma 
concentrations (where evaluable): AUC0-t, AUC0-∞, Cmax, tmax, and t½.   
Safety and Tolerability: 
Safety and tolerability of study drug will be evaluated by vital signs measurements, clinical laboratory 
measures, physical examination, ECGs, concomitant medication usage, C-SSRS, SSS, MOAA/S 
scores, and adverse event reporting.  The Bond-Lader Mood Rating Scale and a DEQ-5 will be used to 
assess mood and perception of drug effects, respectively.   
Statistical methods: 
Study Populations 
The safety population is defined as all subjects who are administered study drug.   
The efficacy population will consist of all subjects in the safety population who complete at least one 
dose in Part B and have at least one post-randomization efficacy evaluation.   
The evaluable population will consist of all randomized subjects with at least one post-randomization 
Kinesia assessment.   
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations.   
Efficacy Analysis 
Efficacy data (including change from randomization values for accelerometer-derived Kinesia and 
clinician-rated TETRAS scores) will be summarized using appropriate descriptive statistics and listed 
by subject.   
The change from randomization (Day 8) in the accelerometer-based Kinesia kinetic tremor combined 
score (ie, the sum of item 4c scores from both sides of the body) at Day 14 will be summarized by 
treatment.  Additionally, the change from randomization in the accelerometer-based Kinesia upper limb 
total score and individual item scores at Day 14 will be summarized by treatment.   
The change from randomization in TETRAS upper limb total score, individual TETRAS upper limb 
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Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics and listed by 
subject.  Wherever necessary and appropriate, PK parameters will be dose-adjusted to account for 
individual differences in dose.   
  
Safety Analysis 
Adverse events will be coded using Medical Dictionary for Regulatory Activities™.  The overall 
incidence of adverse events will be displayed by System Organ Class, preferred term, and dose group.  
Incidence of adverse events will also be presented by maximum severity and relationship to study drug.  
Data from vital signs, clinical laboratory measures, ECG, and C-SSRS will be summarized using 
descriptive statistics by dose group, where applicable.  Continuous endpoints will be summarized with 
n, mean, standard deviation, median, minimum, and maximum.  In addition, change from baseline 
values will be calculated at each time point and will be summarized using the same summary statistics.  
Out-of-range safety endpoints may be categorized as low or high, where applicable.  For all categorical 
endpoints, summaries will include counts and percentages.   
Sample Size 
Up to 80 subjects will be enrolled in Part A to yield at least 60 randomized subjects for Part B.  A total 
sample size of 51 evaluable subjects (ie, 17 per group) will have 80% power to detect a difference in 
means of 3.0 on the primary endpoint assuming that the common standard deviation is 3.0 using a 
2-group t-test with a 0.05 two-sided significance level.  Assuming a 15% non-evaluability rate, 
20 subjects per group will be randomized.  The number of subjects in each treatment group is also 
thought to be sufficient to assess preliminary safety and tolerability following multiple doses of 
SAGE-217 Oral Solution. 
 


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Table 2: 
Schedule of Events:  Part A (Open-Label) 
Visit Days 
Screening 
(Day -28 to Day -1) 
Admit 
(Day -1) 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
Confined to unit 
 
X 
X 
X 
X 
 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Body weight/height 
X 
 
 
 
 
 
 
 
 
Drug/alcohol screen
a 
X 
X 
 
 
 
 
 
 
 
Complete blood count/ 
serum chemistry
b 
X 
X 
X 
X 
 
 
 
 
 
Pregnancy test  
X 
(serum) 
X 
(urine) 
 
 
 
 
 
 
 
Urinalysisb 
X 
X 
X 
X 
 
 
 
 
 
Hepatitis & HIV screen 
X 
 
 
 
 
 
 
 
 
Hormone Sample
c 
O 
 
 
 
O 
 
 
 
O 
Genetic Sample
d 
O 
 
 
 
 
 
 
 
 
Vital signs
e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetrye 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
f 
X 
 
X 
X 
X 
 
 
 
X 
C-SSRS
g 
X 
X 
X 
 
 
X 
X 
X 
X 
SSS
h 
 
 
X 
X 
X 
X 
X 
X 
X 
MOAA/S
i 
 
 
X 
X 
X 
X 
X 
X 
X 
Bond-Lader-VAS
j 
 
 
X 
X 
 
 
 
 
X 


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Visit Days 
Screening 
(Day -28 to Day -1) 
Admit 
(Day -1) 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
DEQ-5
k 
 
 
X 
 
 
 
 
 
X 
Kinesia (accelerometer)
l 
 
X 
X 
X 
 
 
 
 
X 
TETRAS upper limb subscalel 
X 
X 
X 
X 
 
 
 
 
X 
TETRAS (all ADL and all 
Performance Subscale)
m 
 
X 
 
 
 
 
 
 
X 
Empatica Wristband E4
n 
 
X 
X 
X 
X 
 
 
 
X 
QUEST 
 
X 
 
 
 
 
 
 
X 
Plasma PK samples
o 
 
 
X 
X 
X 
X 
X 
X 
X 
Administer study drug
p 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
Prior/concomitant medications
q 
X 
Videos
r 
 
X 
 
 
 
 
 
 
X 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram; HIV = 
human immunodeficiency virus; MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; O = optional; PK = pharmacokinetic; QUEST = Quality of 
Life in Essential Tremor Questionnaire; SSS = Stanford Sleepiness Scale; TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue 
score 
a A urine sample for assessment of selected drugs (sedative/hypnotics [eg, opioids], cotinine, and caffeine) and a breath sample for alcohol screen will be 
collected at screening and Day -1. 
b Screening and safety laboratory tests will be performed at screening, Day -1 (Admission), predose on Day 1, and predose on Day 2. 
c An optional blood sample for stress hormone levels, kynurenine biochemistry, and markers of inflammation, where consent is given.   
d An optional genetic sample for biomarker testing, where consent is given. 
e Vital signs (both supine for at least 5 minutes prior to the measurement and standing) and pulse oximetry will be performed at screening (vital signs only) and 
Day -1 (Admission), predose on Day 1 and at 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose on Days 1, 2, and 3, and predose on Days 5, 6, and 7.  Vital signs 
and pulse oximetry assessments will be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the 
scheduled times thereafter. 
f 12-lead ECGs will be performed at screening, predose on Day 1 and Day 7, and at 1 (±10 minutes), 12, and 24 (±15 minutes) hours postdose on Days 1, 2, 3, 
and 7. 
g The C-SSRS will be performed at screening, on Day -1 (Admission), 12 hours postdose on Day 1, predose on Day 4, and on Days 5, 6, and 7.  
Baseline/Screening version of C-SSRS should be used on day of screening and since last visit version should be used on all subsequent time points. 


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h The SSS will be performed predose on Day 1 and 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose on Days 1, 2, and 3, and predose only on Days 5, 6, and 7.  The 
SSS is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
i The MOAA/S will be performed predose on Day 1 and 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose on Days 1, 2, and 3, and predose only on Days 5, 6, and 7.  
The MOAA/S is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times 
thereafter. 
j The Bond-Lader VAS will be at performed predose on Days 1, 2, and 7. 
k The DEQ-5 will be performed 2 hours postdose on Days 1 and 7. 
l Kinesia and TETRAS upper limb subscale will be performed at screening (TETRAS upper limb subscale only), on Day -1 (Admission; three assessments 
separated by at least 30 minutes); single assessments will be performed predose and 2, 12, and 14 hours postdose on Days 1, 2, and 7.  All three tests in the 
upper limb tremor series of assessments (Item 4) will be completed for both arms, first for the RIGHT arm and then for the LEFT.  For each test, the maximum 
score is four, with a resulting maximum score of 24. 
m TETRAS (all ADL) will be performed on Day -1 (Admission) and predose on Day 7.   
n The Empatica Wristband E4 will be worn during the Confinement Periods. 
o Plasma pharmacokinetic samples (±5 minutes) will be taken predose and 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours postdose on Day 1 and predose on Days 3, 4, 5, 
6, and 7. 
p Study drug will be administered in the morning with food during Part A. 
q To include those taken within 2 weeks prior to informed consent and throughout the study. 
r Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis) will be taken on Day -1 (Admission) and predose on Day 7. 


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Table 3: 
Schedule of Events:  Part B (Randomized Withdrawal) 
Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21±1 day
a 
End of Study 
Day 28±1 day 
Randomization 
X 
 
 
 
 
 
 
 
 
Confined to unit 
X 
X 
X 
 
 
 
 
 
 
Complete blood count/ 
serum chemistry
b 
X 
X 
 
 
 
 
 
X 
 
Pregnancy test 
c 
X 
(urine) 
 
 
 
 
 
 
 
X 
(urine) 
Urinalysisb 
X 
X 
 
 
 
 
 
X 
 
Vital signs
d 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pulse oximetryd  
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG
e 
X 
X 
X 
 
 
 
X 
X 
 
C-SSRS
f 
X 
 
 
X 
X 
X 
X 
X 
X 
SSS
g 
X 
X 
X 
X 
X 
X 
X 
X 
 
MOAA/S
h 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bond-Lader-VAS
i 
X 
X 
 
 
 
 
X 
X 
 
DEQ-5
j 
X 
 
 
 
 
 
X 
 
 
Kinesia (accelerometer)
k 
X 
X 
 
 
 
 
X 
X 
 
TETRAS upper limb subscalel 
X 
X 
 
 
 
 
X 
X 
 
TETRAS (all ADL and all 
Performance Subscale)
l 
 
 
 
 
 
 
X 
X 
 
Empatica Wristband E4
m 
X 
X 
X 
 
 
 
 
 
 
QUEST 
 
 
 
 
 
 
X 
 
 
Plasma PK samples
n 
X 
X 
X 
X 
X 
X 
X 
 
 
Administer study drug
o 
X 
X 
X 
X 
X 
X 
X 
 
 


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Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21±1 day
a 
End of Study 
Day 28±1 day 
Adverse events 
X 
Concomitant medications
p 
X 
Videos
q 
 
 
 
 
 
 
X 
X 
 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram;  
HIV = human immunodeficiency virus; MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; PK = pharmacokinetic; QUEST = Quality of Life in 
Essential Tremor Questionnaire; SSS = Stanford Sleepiness Scale; TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue score 
±1 daya In addition to subjects who complete Part B, subjects who receive at least one dose of study drug and do not complete Part B will have a visit 1 week 
following the last dose of study drug to assess safety measures.   
b Safety laboratory tests will be performed predose (morning and evening doses) on Day 8, Day 9, and on Day 21. 
c To be performed predose (morning dose) on Day 8 and on Day 28.   
d For morning dose, vital signs (both supine for at least 5 minutes prior to the measurement and standing) and pulse oximetry will be performed predose on 
Day 8 and at 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose on Days 8, 9, and 10, predose on Days 12, 13, and 14, and on Day 21.  Vital signs and pulse 
oximetry assessments will be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled 
times thereafter. 
e 12-lead ECGs will be performed at 1 (±10 minutes), 12, and 24 (±15 minutes) hours postdose on Days 8, 9, and 10, 1 (±10 minutes) and 12 (±15 minutes) 
hours post morning dose and 1 hour (±10 minutes) post evening dose on Day 14, and on Day 21.   
f The C-SSRS will be performed 12 hours postdose (morning and evening doses) on Day 8, predose (morning and evening doses) on Day 11, and on Days 12, 
13, 14, 21, and 28.   
g The SSS will be performed predose (morning dose) on Day 8 and 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose (morning dose) and 1, 3, 4, 6, and 8 hours 
postdose (evening dose) on Days 8, 9, and 10, predose (morning and evening doses) only on Days 12, 13, and 14, and on Day 21.  The SSS is to be performed 
within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
i The MOAA/S will be performed predose (morning dose) on Day 8 and 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose (morning dose) and 1, 3, 4, 6, and 8 hours 
postdose (evening dose) on Days 8, 9, and 10, predose (morning and evening doses) only on Days 12, 13, and 14, and on Day 21.  The MOAA/S is to be 
performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
j The Bond-Lader VAS will be at performed predose (morning and evening doses) on Days 8, 9, 14, and 21. 
k The DEQ-5 will be performed 2 hours postdose (morning and evening doses) on Days 8 and 14. 
l Kinesia and TETRAS upper limb subscale will be performed before morning dose, after morning dose (2 hours post morning dose), before evening dose 
(12 hours post morning dose), and after evening dose (14 hours post morning dose) on Days 8, 9, and 14, and on Day 21.  Item 4c (kinetic tremor) of the 
TETRAS upper limb subscale will be performed after morning dose (3 hours post morning dose) on Days 8 and 9.  All three tests in the upper limb tremor 
series of assessments (Item 4) will be completed for both arms, first for the RIGHT arm and then for the LEFT.  For each test, the maximum score is four, with 
a resulting maximum score of 24. 
m TETRAS (all ADL) will be performed predose (morning and evening doses) on Day 14 and on Day 21.   
n The Empatica Wristband E4 will be worn during the Confinement Period and will be removed prior to discharge from the unit on Day 10.  The Empatica 
device will be worn during the corresponding 3-hour postdose TETRAS upper limb subscale (Item 4c [kinetic tremor]) assessments.   


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o Plasma pharmacokinetic samples (±5 minutes) will be taken 0.25, 0.5, 1, 2, 4, 8 (morning dose only), 12, and 24 hours postdose (morning and evening doses) 
on Day 8 and predose (morning and evening doses) on Days 10, 11, 12, 13, and 14. 
p Study drug will be administered in the morning with food during Part A and in the morning and evening (every 12 hours) with food during Part B. 
p To include those taken throughout the study.   
r Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis) will be taken predose (morning and evening doses) on Day 14 and on Day 21.   


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................22 
5. 
INTRODUCTION ......................................................................................................24 
5.1. 
Background of Essential Tremor and Unmet Medical Need ......................................24 
5.2. 
SAGE-217 Oral Solution ............................................................................................25 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 ..........................25 
5.3.1. 
Nonclinical Studies with SAGE-217 ..........................................................................25 
5.3.2. 
Clinical Experience .....................................................................................................26 
5.4. 
Potential Risks and Benefits .......................................................................................27 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................28 
6.1. 
Primary Objective .......................................................................................................28 
6.2. 
Secondary Objectives .................................................................................................28 
6.3. 
Exploratory Objectives ...............................................................................................29 
7. 
INVESTIGATIONAL PLAN .....................................................................................30 
7.1. 
Overall Study Design ..................................................................................................30 
7.2. 
Blinding and Randomization ......................................................................................31 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................32 
8.1. 
Subject Inclusion Criteria ...........................................................................................32 
8.2. 
Subject Exclusion Criteria ..........................................................................................32 
8.3. 
Entrance Criteria for Part B ........................................................................................34 
8.4. 
Subject Withdrawal Criteria .......................................................................................34 
8.4.1. 
Study Drug Withdrawal ..............................................................................................34 
8.4.2. 
Criteria for Study Termination ...................................................................................35 
9. 
TREATMENT OF SUBJECTS ..................................................................................36 
9.1. 
Number of Subjects ....................................................................................................36 
9.2. 
Treatment Assignment ................................................................................................36 
9.2.1. 
Part A ..........................................................................................................................36 


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9.2.2. 
Part B ..........................................................................................................................36 
9.3. 
Dose Adjustment Criteria ...........................................................................................36 
9.4. 
Prior/Concomitant Medications and Restrictions .......................................................37 
9.4.1. 
Prior/Concomitant Medications ..................................................................................37 
9.4.2. 
Prohibited Medications ...............................................................................................37 
9.5. 
Treatment Compliance ................................................................................................37 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................38 
10.1. 
Study Drug ..................................................................................................................38 
10.2. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL ...................................38 
10.3. 
Study Drug Packaging and Labeling ..........................................................................38 
10.4. 
Study Drug Storage .....................................................................................................38 
10.5. 
Administration and Study Drug Accountability .........................................................39 
10.5.1. 
Study Drug Administration.........................................................................................39 
10.5.2. 
Study Drug Accountability .........................................................................................40 
10.6. 
Study Drug Handling and Disposal ............................................................................40 
11. 
ASSESSMENT OF EFFICACY ................................................................................41 
11.1. 
Measurements of Tremor Amplitude ..........................................................................41 
11.2. 
TRG Essential Tremor Rating Assessment Scale (TETRAS) Performance 
Scale ............................................................................................................................41 
11.3. 
Empatica Wristband E4 ..............................................................................................42 
11.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST) ....................................42 
11.5. 
Video Recording .........................................................................................................42 
12. 
PHARMACOKINETICS ...........................................................................................43 
12.1. 
Blood Sample Collection ............................................................................................43 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ..................................................43 
12.3. 
Sample Analysis .........................................................................................................43 
13. 
ASSESSMENT OF SAFETY .....................................................................................44 
13.1. 
Safety and Tolerability Parameters .............................................................................44 
13.1.1. 
Demographic/Medical History ...................................................................................44 
13.1.2. 
Vital Signs ..................................................................................................................44 
13.1.3. 
Weight and Height ......................................................................................................44 
13.1.4. 
Physical Examination .................................................................................................44 
13.1.5. 
Electrocardiogram (ECG) ...........................................................................................44 


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13.1.6. 
Laboratory Assessments .............................................................................................45 
13.1.6.1. 
Hematology .................................................................................................................45 
13.1.6.2. 
Blood Chemistry .........................................................................................................45 
13.1.6.3. 
Urinalysis ....................................................................................................................45 
13.1.6.4. 
Drugs Screen and Alcohol Test ..................................................................................45 
13.1.6.5. 
Virus Serology ............................................................................................................45 
13.1.6.6. 
Pregnancy Test ............................................................................................................46 
13.1.6.7. 
Hormones and Exploratory Biochemistry ..................................................................46 
13.1.6.8. 
Genetic Testing ...........................................................................................................46 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................46 
13.1.8. 
Stanford Sleepiness Scale (SSS) .................................................................................47 
13.1.9. 
Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) ...............47 
13.1.10. 
Bond-Lader VAS Mood Scale ....................................................................................47 
13.1.11. 
Drug Effects Questionnaire (DEQ-5) .........................................................................47 
13.2. 
Adverse and Serious Adverse Events .........................................................................48 
13.2.1. 
Definition of Adverse Events .....................................................................................48 
13.2.1.1. 
Adverse Event .............................................................................................................48 
13.2.1.2. 
Suspected Adverse Reaction .......................................................................................48 
13.2.1.3. 
Serious Adverse Event ................................................................................................48 
13.2.1.4. 
Recording Sedation as an Adverse Event ...................................................................49 
13.2.2. 
Pregnancy ...................................................................................................................49 
13.3. 
Relationship to Study Drug ........................................................................................49 
13.4. 
Recording Adverse Events .........................................................................................50 
13.5. 
Reporting Serious Adverse Events .............................................................................50 
13.6. 
Emergency Identification of Study Drug (Part B) ......................................................51 
14. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................52 
14.1. 
Data Analysis Sets ......................................................................................................52 
14.2. 
Handling of Missing Data ...........................................................................................52 
14.3. 
Demographics and Baseline Characteristics ...............................................................52 
14.4. 
Primary Efficacy Endpoint .........................................................................................52 
14.5. 
Secondary Efficacy Endpoints ....................................................................................52 
14.6. 
Exploratory Efficacy Endpoints .................................................................................53 
14.7. 
Safety and Tolerability Analyses ................................................................................53 


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14.7.1. 
Adverse Events ...........................................................................................................53 
14.7.2. 
Vital Signs ..................................................................................................................53 
14.7.3. 
Physical Examinations ................................................................................................53 
14.7.4. 
12-Lead ECG ..............................................................................................................53 
14.7.5. 
Clinical Laboratory Evaluations .................................................................................54 
14.7.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................54 
14.7.7. 
Stanford Sleepiness Scale (SSS) .................................................................................54 
14.7.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) ........................54 
14.7.9. 
Bond-Lader VAS Mood Scale ....................................................................................54 
14.7.10. 
Drug Effects Questionnaire (DEQ-5) .........................................................................54 
14.7.11. 
Prior and Concomitant Medications ...........................................................................54 
14.8. 
Pharmacokinetic Analysis ..........................................................................................55 
14.9. 
Determination of Sample Size ....................................................................................55 
14.10. 
Changes From Protocol Specified Analyses ...............................................................55 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................56 
15.1. 
Study Monitoring ........................................................................................................56 
15.2. 
Audits and Inspections ................................................................................................56 
15.3. 
Institutional Review Board (IRB) ...............................................................................57 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................58 
17. 
ETHICS ......................................................................................................................59 
17.1. 
Ethics Review .............................................................................................................59 
17.2. 
Ethical Conduct of the Study ......................................................................................59 
17.3. 
Written Informed Consent ..........................................................................................59 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................60 
18.1. 
Inspection of Records .................................................................................................60 
18.2. 
Retention of Records ..................................................................................................60 
18.3. 
Confidentiality ............................................................................................................60 
19. 
PUBLICATION POLICY ..........................................................................................62 
20. 
LIST OF REFERENCES ............................................................................................63 
21. 
APPENDICES ............................................................................................................66 
APPENDIX 1. TREMOROGENIC DRUGS ..............................................................................67 
APPENDIX 2. TRG ESSENTIAL TREMOR RATING ASSESSMENT SCALE 
(TETRAS) ...................................................................................................................69 


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APPENDIX 3. QUALITY OF LIFE IN ESSENTIAL TREMOR QUESTIONNAIRE 
(QUEST) .....................................................................................................................75 
APPENDIX 4. COLUMBIA – SUICIDE SEVERITY RATING SCALE (C-SSRS) ................77 
APPENDIX 5. STANFORD SLEEPINESS SCALE (SSS) .......................................................83 
APPENDIX 6. MODIFIED OBSERVER'S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) .....................................................................84 
APPENDIX 7. BOND-LADER VAS (MOOD RATING SCALE) ...........................................85 
APPENDIX 8. DRUG EFFECTS QUESTIONNAIRE (DEQ-5) ...............................................86 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events:  Part A (Open-Label) .................................................................11 
Table 3: 
Schedule of Events:  Part B (Randomized Withdrawal) ............................................14 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................22 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL..................38 
 


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22 
 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
ADL 
activities of daily living 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-t 
area under the concentration-time curve from time zero to 
last time point 
AUC0-∞  
area under the concentration-time curve from time zero to 
infinity 
BMI 
body mass index 
Cmax  
maximum plasma concentration 
CNS 
central nervous system 
CRF 
case report form 
CS 
clinically significant  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450  
DEQ-5 
Drug Effects Questionnaire 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
ET 
essential tremor 
GABA 
γ-aminobutyric acid 
GABAA 
γ-aminobutyric acid-ligand gated chloride channel 
GABAB 
γ-aminobutyric acid-G protein-coupled 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg  
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxypropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 


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23 
 
Abbreviation or Specialist Term 
Explanation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
MTD 
maximum tolerated dose 
NCS 
not clinically significant 
NF  
National Formulary 
PI 
Principal Investigator 
PK 
pharmacokinetic 
QOL 
quality of life 
QTcF 
QT interval calculated using the Fridericia method 
QUEST 
Quality of Life in Essential Tremor Questionnaire 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAEs 
treatment-emergent adverse events 
TETRAS 
TRG Essential Tremor Rating Assessment Scale 
t1/2 
terminal half-life 
tmax  
time to reach maximum concentration 
USP  
United States Pharmacopeia 
VAS 
visual analogue score 
WHO 
World Health Organization 
WMA 
World Medical Association 
 


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5. 
INTRODUCTION 
5.1. 
Background of Essential Tremor and Unmet Medical Need 
Essential tremor (ET) is among the most common neurological diseases, with an overall 
prevalence of 0.9%.  Prevalence increases with age and is estimated to be 4.6% in people over 
65 years of age (Louis 2010, Deuschl 2011).  Essential tremor is largely a bilateral, symmetrical 
postural or kinetic tremor involving hands and forearms that is visible and persistent.  Additional 
or isolated tremor of the head or lower limbs may occur, but in the absence of abnormal 
posturing (Deuschl 1998, Habib-ur-Rehman 2000).  The onset of tremor has a bimodal 
distribution, with onset between 15 to 20 and 50 to 70 years.  Over time, tremors can become 
more pronounced and may prevent eating, drinking, and writing, as well as executing personal 
hygiene like shaving or applying make-up.  Voice tremors can be severe enough to inhibit 
talking and singing in public.   
Several lines of evidence suggest that cerebellar dysfunction through the 
cerebellothalamocortical pathway plays a key role in ET (McAuley 2000; Pinto 2003; 
Elble 2009, Schnitzler 2009, Deuschl 2009).  Thalamotomy and deep brain stimulation of the 
ventral intermediate nucleus and of the subthalamic nucleus improve ET (Deuschl 2011, 
Zappia 2013, Rajput 2014).  Microscopic cerebellar pathology has been identified, including 
gliosis, Purkinje cell loss, and increased torpedoes (swellings) in the Purkinje cell axons 
(Louis 2007, Axelrad 2008, Shill 2008, Louis 2009).  Activation studies with positron emission 
tomography indicate abnormally increased regional cerebral blood flow in the cerebellum both at 
rest and when tremor is provoked by unilateral arm extension (Boecker 1994, Wills 1996).   
Essential tremor is associated with impaired γ-aminobutyric acid (GABA)ergic function (and 
consequent hyperactivity) in the cerebellum (Málly 1996, Bucher 1997, Louis 2007, Louis 2008, 
Paris-Robidas 2012).  γ-aminobutyric acid, the major inhibitory neurotransmitter in the central 
nervous system (CNS), is released from GABAergic neurons and binds to several types of 
GABA receptors (γ-aminobutyric acid-ligand gated chloride channel [GABAA] and 
γ-aminobutyric acid-G protein-coupled [GABAB]) on target neurons.  γ-aminobutyric acid-gated 
chloride channel receptors, the major class of inhibitory neurotransmitter receptors in the brain, 
are macromolecular proteins that form a chloride ion channel complex and contain specific 
binding sites for GABA and a number of allosteric regulators, including barbiturates, 
benzodiazepines, and some anesthetic agents.   
Drugs acting on GABAA receptors, such as primidone, benzodiazepines, or ethanol decrease 
tremor amplitude, suggesting that altered GABAergic neurotransmission is involved in ET.  
Postmortem analysis revealed a 35% reduction of GABAA receptors and a 22% to 31% reduction 
of GABAB receptors in the dentate nucleus of cerebella of ET subjects (Paris-Robidas 2012).  
Reduced levels of GABA in the cerebrospinal fluid are also reported in ET subjects 
(Málly 1996).  Moreover, toxins such as aflatrem, penitrem A, or harmaline have been proposed 
to induce tremor in rodents by interacting with GABA receptors (Cavanagh 1998; Miwa 2007), 
and targeted deletion of the α1 subunit of GABAA receptor in knockout mice exhibits a 
15 to 19 Hz action tremor, similar to ET in humans (Kralic 2005).   


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Consistent with the role of GABA, the majority of therapeutics for ET act by augmenting 
GABAergic transmission (Louis 2012, Benito-Leon 2007, Pahapill 1999).  First-line treatments 
for ET include the anticonvulsant primidone and the β-adrenergic blocker propranolol 
(Gorman 1986).  Like primidone, gabapentin is an anticonvulsant found to be effective in the 
treatment of ET (O’Brien 1981; Gironell 1999).  The oldest treatment for ET is ethanol, which 
temporarily ameliorates tremor and is frequently used by subjects to self-medicate; however, 
chronic use of ethanol for tremor management carries the known risks of alcohol dependence and 
overuse (Pahwa 2003).   
These treatments are moderately effective, reducing, though not resolving, tremor amplitudes in 
about 50% of the subjects (Schmouth 2014).  In addition, one out of three patients abandon 
treatment because of side effects or poor efficacy (Louis 2010), illustrating that with few feasible 
treatment options and a range of handicaps in daily living makes ET an area of high unmet 
medical need.   
5.2. 
SAGE-217 Oral Solution 
SAGE-217 is a positive allosteric modulator of the GABAA receptor and thus is expected to be 
of benefit for the treatment of ET.  Unlike benzodiazepines that are selective for the γ-subunit-
containing subset of GABAA receptors (Pritchett 1989, Esmaeili 2009), SAGE-217 and other 
neuroactive steroids, which bind to the ubiquitous α-subunit, have a wider range of activity 
(Belelli 2002). 
SAGE-217 Oral Solution 6 mg/mL (40% w/w aqueous hydroxypropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a nonviscous, clear solution.   
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 
5.3.1. 
Nonclinical Studies with SAGE-217 
In nonclinical studies of SAGE-217, sedative-hypnotic effects were consistently observed at 
higher doses in both in vivo pharmacology studies as well as in toxicology studies.  The 
sedative-hypnotic impairments seen with SAGE-217 were typical for GABAA positive 
modulators, ranging from hyperexcitability and ataxia at the lower doses through deep sedation 
and ultimately anesthesia at higher doses.  Depth and duration of sedation demonstrated a clear 
dose response over the range tested, with evidence of tolerance occurring with continued 
exposure.  Tolerance to the effects of SAGE-217 on motor incoordination was not observed after 
7 days of dosing.   
The compound has been assessed in 14-day rat and dog toxicology studies with daily 
administration of SAGE-217 as a solution in HPβCD in dogs and Labrasol® in rats.  The no 
observed adverse effect level was 3 mg/kg (females) and 22.5 mg/kg (males) in rats and 
2.5 mg/kg in dogs.  There were no adverse effects in dogs or rats in the main toxicology studies.  
A single observation of mortality occurred in one female rat at the high dose in a toxicokinetic 
study which was suspected to have been related to exaggerated pharmacology.  Additional 
toxicology and pharmacology information is provided in the Investigator’s Brochure.   


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5.3.2. 
Clinical Experience 
To date, two clinical studies employing SAGE-217 are clinically complete and final clinical 
study reports are pending.  Discussions of pharmacokinetic (PK) data are limited to the single-
ascending dose, food, and essential tremor cohorts from Study 217-CLP-101 and the multiple-
ascending dose and drug-drug interaction (DDI) cohorts from Study 217-CLP-102.  Discussions 
of safety data are limited to the single-ascending dose cohorts in Study 217-CLP-101 and the 
multiple-ascending dose cohorts in Study 217-CLP-102.   
Study 217-CLP-101 was a first-in-human, four-part study that assessed the effects of a single 
dose of SAGE-217.  The study was a double-blind, placebo-controlled, single-ascending dose 
design in healthy adult volunteers, with the objective of identifying the maximum tolerated dose 
(MTD) and PK profiles of SAGE-217 Oral Solution.  Subjects in each of the single-ascending 
dose cohorts received a single dose of study drug, either SAGE-217 (six subjects) or placebo 
(two subjects), with SAGE-217 doses of 0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 mg, 
55 mg, and 66 mg.  Escalation to the next dose was undertaken only after safety and PK data 
were reviewed by the Safety Review Committee (SRC) and agreement reached that it was safe to 
increase the dose.  The MTD was determined to be 55 mg.  Two cohorts, 6 subjects each 
received SAGE-217 in an open-label manner (one cohort received 50% of the MTD [22 mg] to 
study the food effects and the other cohort received the MTD [55 mg] to study the effects on 
subjects with essential tremor).  SAGE-217 was orally bioavailable, demonstrated dose-linear 
PK from the lowest (0.25 mg) through the highest (66 mg) dose, and supported once daily oral 
dosing with food.   
Study 217-CLP-102 was a two-part study that assessed the effects of multiple-ascending doses of 
SAGE-217.  The study was a double-blind, placebo-controlled, multiple-ascending dose study in 
healthy adult volunteers.  Subjects in each of the multiple-ascending dose cohorts received study 
drug, either SAGE-217 (nine subjects) or placebo (three subjects), once daily for 7 days, with 
SAGE-217 doses of 15 mg, 30 mg, and 35 mg.  Escalation to the next dose was undertaken only 
after safety and PK data were reviewed by the SRC and agreement reached that it was safe to 
increase the dose.  The MTD was determined to be 30 mg.  It was observed that subjects 
receiving the drug in the evening did better in terms of tolerability compared to when they 
received the drug in the morning.  A fourth cohort of 12 subjects received 30 mg of SAGE-217 
in an open-label manner to study drug-drug interactions.  SAGE-217 is not likely to induce the 
metabolism of CYP2B6 or CYP3A4 substrates.  SAGE-217 was orally bioavailable and suitable 
for once daily oral dosing at night time with food.   
SAGE-217 was generally well tolerated.  In both Phase 1 studies (217-CLP-101 and  
217-CLP-102), doses were escalated until the stopping criteria were met.  Most adverse events 
were reported as mild or moderate in intensity, and there were no serious adverse events reported 
in either study.  In addition, none of the observed adverse events resulted in discontinuation of 
the study drug.  At doses planned for further study, the observed sedation was mild, transient, 
and associated with daily peak exposure.  The most common treatment-emergent adverse events 
were sedation, somnolence, dizziness, euphoric mood, fatigue, tremor, and muscle twitching, 
reported most frequently in the highest dose group (66 mg).  Some changes in mean blood 
pressure and heart rate were observed after single doses of 44 mg and greater.  After multiple 
doses of 30 mg (AM or PM) or 35 mg (PM) over 7 days, there was no evidence of changes in 
mean vital sign measures even though Day 7 plasma concentrations approximated that of the 


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highest single dose in the single-ascending dose study.  Subjects seemed to tolerate SAGE-217 
better when given as night time dosing.   
There were no clinical efficacy data of SAGE-217 in ET, since the present study is the first study 
in this indication.   
5.4. 
Potential Risks and Benefits 
Protocol 217-ETD-201 is the first clinical study of SAGE-217 Oral Solution in ET evaluating the 
efficacy of this product.  Thus, the potential benefits in this population are unknown, although 
the risks are likely to be similar to those mentioned in the Investigator’s Brochure.  Many 
compounds that target the GABAA receptors exhibit clinical efficacy in ET, validating this 
receptor as a therapeutic target.  Given the promising SAGE-547 clinical data in conjunction 
with the shared broad receptor selectivity profile, oral bioavailability, long half-life, preclinical 
evidence of anxiolytic activity and safety data of SAGE-217, it is possible that patients may have 
a clinical benefit at the exposures selected for this study.  In view of the few risks associated with 
administration of SAGE-217 Oral Solution that have been identified to date, an intra-patient 
dose-escalation design has been chosen to permit titration of treatment effect vs tolerability 
(adverse events), specifically sedation.  Each subject will start with an initial dose of 10 mg to be 
escalated to 20 mg after a day and then escalated further to 30 mg assuming no tolerability 
issues.  At the end of a 7-day exposure, the maximum dose for the subject will be established as 
will a protocol specified response.  Subjects who are responders and tolerate at least the 10 mg 
dose for a minimum of 3 days will qualify for the randomization phase (Part B).  Given the high 
medical need and potential for benefit in ET, there is a favorable benefit-risk evaluation to 
investigate SAGE-217 Oral Solution in ET.   
In conclusion, selection criteria for the proposed study take into account the potential safety 
risks.  Continuous safety monitoring, and the implementation of a formal dose-reduction and 
study drug discontinuation scheme also have the potential to mitigate risk.  From a benefit/risk 
perspective, the appropriate measures are being taken in order to ensure the safety of the subjects 
who will be enrolled.   


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of this study is to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on the change in tremor severity.   
The primary endpoint of this study is the change from randomization (Day 8) in the 
accelerometer-based Kinesia kinetic tremor combined score (ie, the sum of item 4c scores from 
both sides of the body) at Day 14.   
6.2. 
Secondary Objectives 
The secondary objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on the following endpoints: 
1. Tremor severity as assessed by the change from randomization (Day 8) in the 
accelerometer-based Kinesia upper limb total score (ie, the sum of forward outstretched 
postural tremor, lateral “wing beating” postural tremor, and kinetic tremor item scores 
across both sides of the body) and individual item scores at Day 14. 
2. Tremor severity as measured by the change from randomization (Day 8) in TRG 
Essential Tremor Rating Assessment Scale (TETRAS) upper limb total score (ie, the sum 
of item 4c scores from both sides of the body) and individual TETRAS upper limb item 
scores at Day 14. 
3. Tremor severity as assessed by the change from randomization (Day 8) in TETRAS 
Performance Subscale scores measured at Day 14. 
4. Safety and tolerability as assessed by vital signs measurements, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide 
Severity Rating Scale (C-SSRS), and adverse event reporting.   
5. Sleepiness/sedation as assessed by the SSS and MOAA/S scores. 
6. Mood as assessed by the Bond-Lader visual analogue score (VAS) Mood Scale. 
7. How the subject feels after taking the study drug as assessed by Drug Effects 
Questionnaire (DEQ-5) ratings. 
In addition, plasma concentrations of SAGE-217 and SAGE-217 metabolites may be measured.  
Pharmacokinetic parameters, such as area under the concentration-time curve from time zero to 
last time point (AUC0-t), area under the concentration-time curve from time zero to infinity 
(AUC0-∞), maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), 
and terminal half-life (t1/2), will be derived, where appropriate.   


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6.3. 
Exploratory Objectives 
The exploratory objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on: 
1. Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring) as assessed by the 
Empatica Wristband E4.  Tremor oscillation as assessed by multidimensional 
accelerometer measurements (ie, raw accelerometer values). 
2. Quality of life (QOL) as assessed by TETRAS activities of daily living (ADL), Quality of 
Life in Essential Tremor Questionnaire (QUEST), and video recording assessment of 
subjects performing three everyday tasks (drinking a glass of water, fastening a button, 
and one additional task that the subject experiences difficulty with on a daily basis). 
In addition, PK and pharmacodynamic modelling assessment of the relationship between plasma 
exposure of SAGE-217 and change from baseline in accelerometer-based Kinesia scores may be 
assessed.   


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study is a two-part, multicenter, Phase 2a study to evaluate the efficacy, safety, tolerability, 
and PK of SAGE-217 Oral Solution in up to 80 adult subjects with ET.  Part A of the study is an 
open-label design with morning dosing for 7 days.  Part B of the study is a double-blind, 
placebo-controlled, randomized withdrawal design.  Subjects will be exposed to study drug 
(SAGE-217 or placebo) for up to 14 days and will be followed for an additional 14 days after the 
administration of the last dose.   
During the Screening Period (Day -28 to Day -1), after signing the informed consent form (ICF), 
subjects will be assessed for study eligibility and the severity of each subject’s ET will be 
evaluated using TETRAS.  Eligible subjects will be admitted to the clinical study unit on Day -1.   
The study will be conducted in two parts: 
 Part A:  Beginning on Day 1, all subjects will receive open-label SAGE-217 in the 
morning with food (as outlined in Section 9.2) for 7 days.  Subjects will receive 
SAGE-217 10 mg on Day 1, SAGE-217 20 mg on Day 2, and SAGE-217 30 mg from 
Day 3 to Day 7, with dose adjustments for severe adverse events judged by the 
Investigator to be related to study drug (Section 9.3).  Subjects will be confined on 
Day -1 through Day 3.   
 Part B:  In order to qualify for Part B of the study, a subject must tolerate a maximum 
dose of ≥10 mg of SAGE-217, and the subject must have responded to SAGE-217, 
defined as a 30% reduction from baseline in TETRAS kinetic tremor combined score 
predose on Day 8.  Eligible subjects will be randomized in a 1:1:1 fashion to receive 
SAGE-217 in the morning or in the evening or to receive placebo for 7 days 
beginning on Day 8.  All doses of study drug will be administered with food as 
outlined in Section 9.2.  Subjects randomized to SAGE-217 will receive their 
maximum dose as determined in Part A.  In order to preserve the blind, those 
randomized to SAGE-217 in the morning will receive placebo in the evening, those 
randomized to receive SAGE-217 in the evening will receive placebo in the morning, 
and those randomized to receive placebo will receive placebo in both morning and 
evening.  Subjects randomized to the placebo arm will represent randomized 
withdrawal (ie, withdrawal from treatment they received in Part A).  Subjects will be 
confined on Day 7 through Day 10.   
Dose adjustments will only be allowed during Part A of the study.  A dose will be considered not 
tolerated if the subject experiences a severe adverse event considered to be related to the study 
drug by the Investigator.  If a dose is not tolerated, the dose on the next day will be reduced to 
the next lowest dose and continued for the remainder of the open-label dosing period (ie, subjects 
who are unable to tolerate SAGE-217 30 mg will receive SAGE-217 20 mg and subjects who are 
unable to tolerate SAGE-217 20 mg will receive SAGE-217 10 mg).  The dose tolerated on 
Days 5, 6, and 7 of Part A will be considered the maximum dose for that subject.  Subjects who 
require dose adjustments on Days 5, 6, and 7 of Part A will not progress to Part B.   


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7.2. 
Blinding and Randomization 
Part A is open-label with no control group; therefore, there will be no randomization or blinding.   
Part B of the study is a double-blind, placebo-controlled, randomized withdrawal study.  Subjects 
who tolerate a maximum dose of ≥10 mg of SAGE-217 in Part A and respond to SAGE-217, 
defined as a 30% reduction from baseline in TETRAS kinetic tremor combined score predose on 
Day 8, will be randomly assigned in a 1:1:1 fashion to receive SAGE-217 in the morning or in 
the evening or placebo according to a computer-generated randomization schedule.  Once it has 
been determined that a subject meets eligibility criteria, the subject will be sequentially assigned 
a subject number from the randomization schedule provided to the unblinded pharmacist.  
Subject identification numbers will consist of the site number (eg, “01”) followed by numbering 
starting with double zero (eg, 01-001, 01-002, 01-003, etc.).   
A randomization schedule will be generated prior to the start of the study.  The randomization 
schedule will be generated using SAS V9.2 or later.  Only the clinic pharmacist, who is 
responsible for preparing the solutions, will be given a copy of the randomization schedule.  In 
the event of a medical emergency, the pharmacist may reveal actual solution contents to the 
investigator, who should also alert Sage of the emergency (see Section 13.6 for more details 
related to unblinding).  In all cases where the study drug allocation for a subject is unblinded, 
pertinent information (including the reason for unblinding) must be documented in the subject’s 
records and on the electronic case report form (eCRF).  If the subject or study center personnel 
(other than pharmacist) have been unblinded, the subject will be terminated from the study.   
In order to preserve the blind in Part B, those randomized to SAGE-217 morning dosing will 
receive placebo for the evening dose, those randomized to SAGE-217 evening dosing will 
receive placebo for the morning dose, and those randomized to placebo will receive placebo for 
both morning and evening dosing.  Subjects randomized to SAGE-217 will receive their 
maximum dose as determined in Part A.  Subjects randomized to the placebo arm will represent 
randomized withdrawal (withdrawal from treatment they received in Part A).   


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
It is anticipated that up to 80 subjects will be enrolled at up to 30 study centers.  The following 
inclusion and exclusion criteria will be applied during screening for Part A of the study.  
8.1. 
Subject Inclusion Criteria 
Subjects must meet the following inclusion criteria for enrollment in the study: 
1. Subject has signed an ICF before any study-specific procedures are performed.   
2. Subject must be between 18 and 75 years of age, inclusive. 
3. Subject must have a diagnosis of ET, defined as bilateral postural tremor and kinetic 
tremor, involving hands and forearms, that is visible and persistent and the duration is 
>5 years prior to screening. 
4. Subject must have bilateral TETRAS scores of at least two on each side (left and right) 
for kinetic tremor and at least two on each side (left and right) for either wing beating or 
forward outstretched postural tremor.   
5. Subject must be willing to discontinue medications taken for the treatment of ET, 
alcohol, nicotine, and caffeine through Day 21 of the study.   
6. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. 
7. Female subjects must be post-menopausal, permanently sterile (bilateral tubal occlusion), 
or of childbearing potential with a negative pregnancy test, non- breastfeeding, and using 
two highly effective methods of birth control prior to screening through completion of the 
last follow-up visit.  If a subject discontinues early after receiving a dose of study drug, 
they must continue this method of birth control for at least 7 days following the last dose 
of study drug.  Highly effective methods of birth control are defined as follows:  
hormonal (ie, established use of oral, implantable, injectable, or transdermal hormonal 
methods of conception); placement of an intrauterine device; placement of an intrauterine 
system; and mechanical/barrier method of contraception (ie, condom or occlusive cap 
[diaphragm or cervical/vault cap] in conjunction with spermicide [foam, gel, film, cream 
or suppository]).   
8. Male subjects must agree to practice a highly effective method of birth control while on 
study drug and for 13 weeks after receiving the last dose of study drug.  Effective 
methods of birth control include sexual abstinence, vasectomy, or a condom with 
spermicide (men) in combination with their partner’s highly effective method. 
9. Males must be willing to abstain from sperm donation while on study through 13 weeks 
after receiving the last dose of study drug. 
8.2. 
Subject Exclusion Criteria 
Subjects who met the following exclusion criteria will be excluded from the study: 
1. Subject has presence of abnormal neurological signs other than tremor or Froment’s sign. 


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2. Subject has presence of known causes of enhanced physiological tremor. 
3. Subject has or recent exposure (14 days prior to admission visit) to tremorogenic drugs, 
as defined in Appendix 1, or the presence of a drug withdrawal state. 
4. Subject has had direct or indirect trauma to the nervous system within 3 months before 
the onset of tremor.   
5. Subject has historical or clinical evidence of tremor with psychogenic origin (including 
but not limited to eating disorders, major depression, etc.).   
6. Subject has convincing evidence of sudden tremor onset or evidence of stepwise 
deterioration of tremor.   
7. Subject has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or 
oncological disease.   
8. Subject has clinically significant abnormal physical examination or 12-lead ECG at the 
Screening or Admission Visits.  Note:  A QT interval calculated using the Fridericia 
method [QTcF] of >450 msec in males or >470 msec in females, will be the basis for 
exclusion from the study.  An ECG may be repeated if initial values obtained exceed the 
limits specified. 
9. Subject has a 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. 
10. Subject has hyperthyroidism.   
11. Subject has used alcohol, caffeine, or nicotine within 3 days prior to Admission visit. 
12. Subject has a known allergy to SAGE-217 and its major excipient HPβCD.   
13. Subject has exposure to another investigational medication or device within the prior 
30 days. 
14. Subject has a history of suicidal behavior within 2 years or answers “YES” to questions 
3, 4, or 5 on the C-SSRS at the Screening Visit or on Day -1 or is currently at risk of 
suicide in the opinion of the Investigator. 
15. Subject has donated one or more units (1 unit = 450 mL) of blood or acute loss of an 
equivalent amount of blood within 60 days prior to dosing. 
16. Subject is unwilling or unable to comply with study procedures. 
17. Use of any known strong inhibitors and/or inducers of CYP3A4 within the 14 days or 
5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or St. John's Wort or products containing these within 30 days prior to receiving 
the first dose of study drug.   
18. Subject has obstructed venous access and/or has skin disease, rash, acne, or abrasion at 
venous access site that may affect the ability to obtain a PK sample (eg, artificial cardiac 
valve, joint replacement).   


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19. Subject has concurrent or recent exposure (14 days prior to admission visit) to 
sedative/hypnotic (eg, opioids) drugs.   
20. Subject has hyperthyroidism at screening (based on thyroid-stimulating hormone, 
thyroxine [T4], and triiodothyronine [T3]) or clinically significant kidney issues in the 
opinion of the Investigator.   
8.3. 
Entrance Criteria for Part B 
The following entrance criteria will be applied prior to administration of blinded study drug in 
Part B; subjects who require dose adjustments on Days 5, 6, and 7 of Part A will not progress to 
Part B.   
1. Subject must tolerate a maximum dose of ≥10 mg of SAGE-217 in Part A.   
2. Subject must have responded to SAGE-217, defined as a 30% reduction from baseline in 
TETRAS kinetic tremor combined score (ie, the sum of item 4c scores from both sides of 
the body) predose on Day 8.   
8.4. 
Subject Withdrawal Criteria 
If there is an adverse event or medical reason for the withdrawal, the subject should be followed 
medically until the condition has either resolved itself or is stable.  Details of the reason for 
withdrawal should be recorded in the subject’s case report form (CRF).   
Subjects who withdraw should, if possible, have a follow-up examination, including a physical 
examination, the appropriate investigations, vital signs, and clinical laboratory tests, as outlined 
for the Day 21 visit (Table 3).  All details of this follow-up examination should be recorded in 
the subject’s medical source documents.   
8.4.1. 
Study Drug Withdrawal 
Participation in the study is strictly voluntary.  Subjects are free to discontinue the study at any 
time without giving their reason(s).   
A subject must be withdrawn from the study treatment in the event of any of the following: 
 Withdrawal of the subject’s consent; 
 New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators and/Sponsor; 
 Occurrence of intolerable adverse events;  
 Occurrence of pregnancy;  
 Intake of nonpermitted concomitant medication; 
 Subject noncompliance;  
 Significant protocol deviation determined in consultation with the Medical Monitor. 


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If a subject failed to attend scheduled assessments during the course of the study, the 
Investigators must determine the reasons and the circumstances as completely and accurately as 
possible and document this in the subject’s source documents.   
Subjects may be withdrawn from the study if there is concern for the subject’s safety or it is 
determined that the subject is no longer a qualified participant.  Any subject who is withdrawn 
from the study for any reason is to have the final visit assessments performed.   
Subjects who withdraw or are withdrawn from the study will be replaced only if they withdraw 
prior to dosing.  Subjects who are withdrawn from the study, fail to return or are no longer 
qualified will not be replaced.   
8.4.2. 
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 adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons.  In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator. Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
participating subjects.   


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Number of Subjects 
Approximately 80 subjects with ET will be recruited into the study to yield at least 
60 randomized subjects for Part B.   
9.2. 
Treatment Assignment 
Study drug will be administered in the morning with food during Part A and in the morning and 
evening (every 12 hours) with food during Part B.  Food intake was standardized as specified by 
the Sponsor.   
9.2.1. 
Part A 
Subjects participating in Part A of the study will take study drug (SAGE-217) in an open-label 
manner.  All subjects will start on a 10 mg dose of study drug administered with food in the 
morning on Day 1.  Subjects will receive 20 mg with food on Day 2 and 30 mg with food daily 
on Days 3 to 7.  Dose adjustments will only be allowed any time the dose is not tolerated, 
assessed by occurrence of a severe adverse event judged by the investigator to be related to study 
drug (Section 9.3).  The dose tolerated for Days 5, 6, and 7 of the open-label dosing period will 
be determined to be the maximum dose for that subject.   
9.2.2. 
Part B 
Subjects participating in the double-blind, placebo-controlled, randomized withdrawal portion of 
the study (Part B) will be randomized to SAGE-217 morning dosing, SAGE-217 evening dosing, 
or placebo.  Subjects randomized to SAGE-217 will receive the maximum dose of SAGE-217 
from Part A of the study.  Following randomization, subjects will receive 7 days of study drug 
starting on Day 8.   
9.3. 
Dose Adjustment Criteria 
Dose adjustments will only be allowed during the open-label phase of the study (Part A).  If at 
any time the dose is not tolerated in Part A, assessed by occurrence of a severe adverse event 
judged by the investigator to be related to study drug, the dose on the next day will be reduced to 
the next lowest dose and continued for the remainder of the open-label dosing period (ie, subjects 
who are unable to tolerate the 30 mg dose will receive a lower dose of 20 mg, and subjects who 
are unable to tolerate 20 mg will be given a 10 mg dose).  The dose tolerated for Days 5, 6, and 7 
of the open-label dosing period will be determined to be the maximum dose for that subject.  
Subjects who require dose adjustments on Days 5, 6, and 7 of Part A will not progress to Part B.   


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9.4. 
Prior/Concomitant Medications and Restrictions 
9.4.1. 
Prior/Concomitant Medications 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 9.4.2.   
Record the name, start date (if known), indication for use and whether ongoing or stopped of 
medications/treatments taken within 2 weeks prior to informed consent and throughout the study.   
The charts of all study participants will be reviewed for new concomitant medications through 
discharge from the unit.  Chart reviews will include examination of nursing and physician 
progress notes, vital signs, and medication records in order to identify adverse events that may be 
associated with new concomitant medications.  New concomitant medications, ongoing 
concomitant medications with a change in dose and medical procedures ordered (eg, laboratory 
assessments, computed tomography or magnetic resonance imaging scans) will be reviewed to 
determine if they are associated with an adverse event not previously identified.   
9.4.2. 
Prohibited Medications 
The drug classes listed in Appendix 1 are not permitted in the 14 days prior to the admission visit 
and for the duration of the study (up to the Day 28 visit).  The list provides non-exhaustive 
examples of each drug class.   
Subjects are not permitted to use alcohol, caffeine, or nicotine within 3 days prior to Admission 
visit through the Day 21 visit.   
9.5. 
Treatment Compliance 
Investigational product will be prepared by the site pharmacist.  The Investigator(s) or designee 
will record the time and dose of study drug administration in the source documents.  Any reasons 
for non-compliance will also be documented, including: 
 Missed visits;  
 Interruptions in the schedule of administration; and 
 Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible.   


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose which is further diluted with Sterile 
Water for Injection to achieve the selected dosages.  The 6 mg/mL stock SAGE-217 Oral 
Solution will be compounded from SAGE-217 Drug Substance Powder in the Bottle and 
Excipient (s) in the Bottle (manufactured under clinical Good Manufacturing Practice [GMP] 
conditions at 
) and further admixed at the clinical site in preparation for dosing.  
Placebo will be matched to SAGE-217 study drug.  Detailed instructions for study drug 
preparation will be provided in the Pharmacy Manual.   
10.2. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured by 
 and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual.  The batch formula for a 125 mL solution of the 6 mg/mL 
stock solution is shown in Table 5.   
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
Ingredient 
Compendia Specification Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD (Kleptose®) 
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.025 
3.124 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations:  EP = European Pharmacopeia; HPβCD = hydroxypropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
10.3. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation.  Study drug will be provided to the site as powder 
in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy at a volume of 
125 mL of a 6 mg/mL stock solution and then further diluted to approximately 40 mL at the 
identified doses.  Study drug labels with all required information and conforming to all 
applicable Code of Federal Regulations and GMP/GCP guidelines will be prepared by the 
clinical research organization.   
10.4. 
Study Drug Storage 
Upon receipt of study drug (SAGE-217 and placebo), the Investigator or designee will inspect 
the medication and complete and return the acknowledgment of receipt form enclosed with the 
parcel.  A copy of the signed receipt will be kept in the study files.  


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The study drug must be carefully stored at the temperature specified in the Pharmacy Manual 
(eg, clinical dosing solutions stored at approximately 2 to 8°C for 10 days or room temperature 
for up to 24 hours after preparation), safely and separately from other drugs.  The study drug 
may not be used for any purpose other than the present study.  After the study is completed, all 
unused study drug must be retained, returned as directed, or destroyed on site per the Sponsor’s 
instructions.   
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies.  An accurate, timely record of 
the disposition of all clinical supplies must be maintained.  The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
 The identification of the subject to whom the drug was dispensed; 
 The date(s) and quantity of the drug dispensed to the subject; and 
 The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
A copy of the inventory record and a record of any clinical supplies that have been destroyed 
must be documented.  This documentation must include at least the information below or as 
agreed with the Sponsor: 
 The number of prepared units; 
 The number of administered units; 
 The number of unused units; 
 The number of units destroyed at the end of the study; 
 The date, method, and location of destruction. 
10.5. 
Administration and Study Drug Accountability 
Doses will be prepared as an approximate 40 mL oral solution to be swallowed all at once, 
followed by approximately 200 mL of water which has been used to rinse the dosing bottle.  The 
start time of swallowing the approximately 40 mL oral solution is time zero for all assessments.  
Subjects may have assistance from the clinic staff when taking the study drug.   
10.5.1. 
Study Drug Administration 
While confined in the clinical unit (Day -1 through Day 3), subjects in Part A will receive a 
10 mg dose of study drug administered in the morning on Day 1, 20 mg on Day 2, and 30 mg on 
Day 3.   
While confined in the clinical unit in Part B (Day 7 through Day 10), subjects will receive 
randomized study drug in the morning and in the evening on Days 8, 9, and 10.   
For non-confinement days (Days 4 through 6 [Part A] and Days 11 through 14 [Part B]), dosing 
will be done at the clinical site or, if suitable arrangements can be made, via home administration 


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where local regulations allow.  Home administration of study drug will be performed according 
to a site-specific plan by a healthcare professional trained on the protocol and delivery of the 
study drug.   
10.5.2. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol.   
The Investigator or designee must maintain a record of all study drug received, used, and 
discarded.  It must be clear from the records which subject received which dose of active or 
placebo treatment.   
The Sponsor will be permitted access to the study supplies at any time within usual business 
hours and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation.  Only unblinded personnel will be able to access the study drug and 
accountability documentation from first dosing through database hard lock.   
10.6. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding, subsequent admixture, administration of test article, and for which subject the 
study drug was intended (ie, record subject initials and birth date or other unique identifier).   
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions; disposition of study drug will be 
documented.   


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11. 
ASSESSMENT OF EFFICACY 
Efficacy assessments include evaluation of subject symptom response by a measurement of 
tremor amplitude, TETRAS upper limb subscale, and TETRAS Performance Subscale (items 4, 
6, 7, and 8).  Quality-of-life assessments include TETRAS ADL, QUEST, and video recording 
of subjects performing three everyday tasks.  Physiological activity (ie, sympathetic nervous 
system tone as measured by electrodermal activity, skin temperature monitoring, and heart rate 
monitoring) and tremor oscillation as assessed by multidimensional accelerometer measurements 
(ie, raw accelerometer values) will be assessed by the Empatica Wristband E4.   
11.1. 
Measurements of Tremor Amplitude 
In order to measure essential tremor amplitude, subjects will wear a wireless ring motion sensor.  
The motion sensor measures linear acceleration and angular velocity (the Kinesia score).  
Amplitudes from the motion sensor data are collected for three upper limb maneuvers (postural 
tremor, wing beating, kinetic tremor) on each side of the body, for a total of six amplitude 
measures per assessment.  Data are transmitted from the sensor to a computer using Bluetooth 
technology.  Information from the motion sensor data correlates to symptoms of tremor. The 
Kinesia score ranges from 0 to 4 in 0.5 step increments.  Higher scores indicate more tremors.  
The accelerometer assessment is completed in conjunction with the TETRAS Performance 
Subscale Item 4.   
In Part A, Kinesia will be performed at screening and on Day -1 (Admission; three assessments 
separated by at least 30 minutes); a single assessment will be performed predose and 2, 12, and 
14 hours postdose on Days 1, 2, and 7.  In Part B, a single Kinesia reading will be performed 
before morning dose, after morning dose (2 hours post morning dose), before evening dose 
(12 hours post morning dose), and after evening dose (14 hours post morning dose) on Days 8, 9, 
and 14, and on Day 21.   
11.2. 
TRG Essential Tremor Rating Assessment Scale (TETRAS) 
Performance Scale 
Item #4 (upper limb tremor) of the TETRAS Performance Subscale will be completed using both 
the accelerometer and clinician assessment.  Testing should be completed within ±10 minutes of 
the planned questionnaire time points.  All three tests in the upper limb tremor series of 
assessments (Item 4) will be completed for both arms, first for the RIGHT arm and then for the 
LEFT.  For each test, the maximum score is four, with a resulting maximum score of 24.  
Predose assessments can be done any time within 2 hours prior to the start of administration of 
solution.  The Day 21 follow-up visit assessments can be done at any time during the visit.  
Subjects will complete the TETRAS Performance Subscale, Item #4 (upper limb tremor) while 
wearing the accelerometer.  Simultaneous clinician assessment of Item #4 will occur.  The 
accelerometer assessment is completed in conjunction with the TETRAS Performance Subscale 
at the same time points during the study.   
In Part A, the TETRAS upper limb subscale will be performed at screening and on Day -1 
(Admission; three assessments separated by at least 30 minutes); a single assessment of 
TETRAS upper limb subscale will be performed predose and 2, 12, and 14 hours postdose on 


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Days 1, 2, and 7.  The TETRAS (all ADL and Performance Subscale [Items 4, 6, 7, and 8]) will 
be performed on Day -1 (Admission) and predose on Day 7.  On days when the TETRAS all 
ADL and Performance Subscale are performed, Item # 4 will not be repeated.   
In Part B, the TETRAS upper limb subscale will be before morning dose, after morning dose 
(2 hours post morning dose), before evening dose (12 hours post morning dose), and after 
evening dose (14 hours post morning dose) on Days 8, 9, and 14, and on Day 21.  Item 4c 
(kinetic tremor) of the TETRAS upper limb subscale will be performed after morning dose 
(3 hours post morning dose) on Days 8 and 9.  The TETRAS (all ADL and Performance 
Subscale [Items 4, 6, 7, and 8]) will be performed predose (morning and evening doses) on Day 
14 and on Day 21.  On days when the TETRAS all ADL and Performance Subscale are 
performed, Item # 4 will not be repeated.   
Note that the bilateral TETRAS score for the test conducted during screening will be used to 
determine eligibility and must be ≥2 on each side (left and right) for kinetic tremor and ≥2 on 
each side (left and right) for either wing beating or forward outstretched postural tremor.  A copy 
of the TETRAS is provided in Appendix 2.   
11.3. 
Empatica Wristband E4 
Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring) will be assessed by the 
Empatica Wristband E4.  The Empatica Wristband E4 is a wearable device that captures 
motion-based activity and sympathetic nervous system arousal.  In Part A, the Empatica 
Wristband E4 will be worn during the Confinement Period.  In Part B, the Empatica 
Wristband E4 will be worn during the Confinement Period and will be removed prior to 
discharge from the unit on Day 10.  The Empatica device will be worn during the corresponding 
3-hour postdose TETRAS upper limb subscale (Item 4c [kinetic tremor]) assessments.  Data 
from the Empatica Wristband E4 will not be presented in the study report; instead, they will be 
part of a separate report.   
11.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST) 
The QUEST is a brief, 30-item, ET-specific QOL scale in which subjects rate the extent to which 
tremor impacts a function or state, tremor severity in various body parts, perceived health, and 
overall QOL (Tröster 2005).  The QUEST will be administered on Day -1 (Admission), Day 7, 
and on Day 14.  A copy of the QUEST is provided in Appendix 3.   
11.5. 
Video Recording 
Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, 
and one additional task that the subject experiences difficulty with on a daily basis) will be taken 
on Day -1 (Admission) and predose on Day 7 in Part A and predose (morning and evening 
doses) on Day 14 and on Day 21 in Part B.   


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
In Part A, plasma samples for PK analysis will be collected predose and 0.25, 0.5, 1, 2, 4, 8, 12, 
and 24 hours postdose on Day 1 and predose on Days 3, 4, 5, 6, and 7.  In Part B, plasma 
samples for PK analysis will be collected 0.25, 0.5, 1, 2, 4, 8 (morning dose only), 12, and 
24 hours postdose (morning and evening doses) on Day 8 and predose (morning and evening 
doses) on Days 10, 11, 12, 13, and 14.  The time of study drug administration is time zero and all 
post-dosing sampling times are relative to this time.  Samples are to be collected within 
±5 minutes of the scheduled sampling time.  The Investigator or designee will arrange to have 
the plasma samples processed, stored, and transported as directed for bioanalysis.   
An additional PK sample may be collected at any time if clinically indicated and at the discretion 
of the Investigator (eg, for unusual or severe adverse events).   
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time.  The date and actual time that the blood sample was taken will be 
recorded on the CRF or electronically with a bar code or other method.   
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70°C to -80°C until analyzed.  
They should be packed as directed to avoid breakage during transit and with sufficient dry ice to 
prevent thawing for at least 72 hours.  A specimen-identification form must be completed and 
sent to the laboratory with each set of samples.  The clinical site will arrange to have the plasma 
samples transported as directed for bioanalysis as detailed in the PK instructions.   
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of SAGE-217 will be performed utilizing a 
validated liquid chromatography-tandem mass spectrometry method at a qualified laboratory.   
 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety and Tolerability Parameters 
Safety and tolerability of study drug will be evaluated by vital signs measurements, clinical 
laboratory measures, physical examination, ECGs, concomitant medication usage, C-SSRS, SSS, 
MOAA/S scores, and adverse event reporting.  The Bond-Lader Mood Rating Scale and a 
DEQ-5 will be used to assess mood and perception of drug effects, respectively.   
13.1.1. 
Demographic/Medical History 
Age, gender, race, and ethnic origin will be recorded at the Screening Visit.  A full medical 
history including medication history will be recorded at the Screening Visit.   
13.1.2. 
Vital Signs 
Vital signs comprise supine (supine for at least 5 minutes prior to the measurement) and standing 
systolic and diastolic blood pressure and heart rate, respiratory rate and temperature.   
In Part A, vital signs and pulse oximetry will be performed at screening (vital signs only) and 
Day -1 (Admission), predose on Day 1 and at 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose on 
Days 1, 2, and 3, and predose on Days 5, 6, and 7.  In Part B, for morning dose, vital signs (both 
supine for at least 5 minutes prior to the measurement and standing) and pulse oximetry will be 
performed predose on Day 8 and at 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose on Days 8, 9, 
and 10, predose on Days 12, 13, and 14, and on Day 21.  Vital signs and pulse oximetry 
assessments will be performed within ±10 minutes of the scheduled times through the 4-hour 
time point and within ±15 minutes of the scheduled times thereafter.   
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening Visit.   
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening Visit.   
13.1.5. 
Electrocardiogram (ECG) 
A supine 12-lead ECG will be performed at the times specified below and the standard intervals 
recorded as well as any abnormalities.   
In Part A, the 12-lead ECG will be assessed at screening, predose on Day 1 and Day 7, and at 1 
(±10 minutes), 12, and 24 (±15 minutes) hours postdose on Days 1, 2, 3, and 7.  In Part B, the 
12-lead ECG will be assessed at 1 (±10 minutes), 12, and 24 (±15 minutes) hours postdose on 
Days 8, 9, and 10, 1 (±10 minutes) and 12 (±15 minutes) hours post morning dose and 1 hour 
(±10 minutes) post evening dose on Day 14, and on Day 21.   
All time points are relative to the time of dosing.  ECGs will be performed within ±10 minutes of 
the predose and 1-hour time points and within ±15 minutes of the 12-hour time point. 


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13.1.6. 
Laboratory Assessments 
In Part A, blood and urine samples will be collected for hematology, serum chemistry, and 
urinalysis at the Screening Visit, on Day -1 (Admission), predose on Day 1, and predose on 
Day 2.  In Part B, blood and urine samples will be collected predose (morning and evening 
doses) on Day 8, Day 9, and on Day 21.   
Serum and urine samples for pregnancy tests (females only) will also be collected.  These 
assessments should be performed in accordance with the Schedule of Events (Table 2 and 
Table 3) and as outlined individually below.   
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS); or abnormal, clinically significant 
(CS).  Screening results considered abnormal, CS recorded at the Screening Visit may make the 
subject ineligible for the study pending review by the medical monitor.  Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to 
Section 13.2.1, and recorded in the eCRF.   
13.1.6.1. Hematology 
Hematology tests will include complete blood count, including red blood cells, white blood cells 
with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets.  The coagulation panel 
will include activated partial thromboplastin time, prothrombin time, and international 
normalized ratio.   
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes, renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide, liver function tests, including total 
bilirubin, AST, and ALT, total protein, and albumin.   
Thyroid-stimulating hormone, thyroxine (T4), and triiodothyronine (T3) will be performed at 
screening to confirm subject eligibility.   
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity.   
13.1.6.4. Drugs Screen and Alcohol Test 
A urine sample for assessment of selected drugs (sedative/hypnotics [eg, opioids], cotinine, and 
caffeine) and a breath sample for alcohol screen will be collected at screening and on Day -1.  
Results may be obtained through subject history.  Subjects who use concomitant 
sedative/hypnotics will be excluded from the study.  Use of alcohol, caffeine, or cotinine was not 
allowed for the duration of the study.   
13.1.6.5. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
the study.   


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13.1.6.6. Pregnancy Test 
Females of child-bearing potential will be tested for pregnancy by serum pregnancy test at the 
Screening Visit and by urine pregnancy test on Day -1 (Admission), predose (morning dose) on 
Day 8, and at the follow-up visit on Day 28 in Part B.   
13.1.6.7. Hormones and Exploratory Biochemistry 
Optional blood samples will be collected at screening and on Days 3 and 7 and may be analyzed 
for stress hormone levels, kynurenine biochemistry, and markers of inflammation.  Future 
research may suggest other biochemical markers as candidates for influencing not only response 
to SAGE-217 but also susceptibility to disorders for which SAGE-217 may be evaluated.  Thus, 
the biochemical research may involve study of additional unnamed biochemical biomarkers, but 
only as related to disease susceptibility and drug action.   
13.1.6.8. Genetic Testing 
Where consent is given, an optional genetic sample for biomarker testing will be collected at the 
Screening Visit.   
The objective of this research is to collect and store blood samples for possible DNA extraction 
and exploratory research into how genes or specific genetic variation may influence response 
(ie, distribution, safety, tolerability, and efficacy) to SAGE-217.  Specific genetic variations of 
interest include but are not limited to: classes of metabolizing enzymes (eg, cytochrome P450 
supra-family genes), genes encoding enzymes involved in the production and metabolism of 
SAGE-217 (eg, AKR1C4 [3α-hydroxysteroid dehydrogenase]), genes associated with the 
γ-aminobutyric acid (GABA) receptor (eg, GABRA1-A6, GABRB1-B3, GABRD, GABRE, 
GABRG1-3), and genes associated with the production and degradation of GABA.   
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to SAGE-217 but also susceptibility to disorders for which SAGE-217 may be 
evaluated.  Thus, the genetic research my involve study of additional unnamed genes or gene 
categories, but only as related to disease susceptibility and drug action.   
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011).  This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit.  The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).   
If in the opinion of the Investigator, the subject is showing any suicidal tendency, no further 
study drug will be administered and the subject will be referred to a psychologist or psychiatrist 
for further evaluation.  This information will be tracked.   
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months).  In Part A, the “Since Last Visit” C-SSRS form will be completed on Day -1 
(Admission), 12 hours postdose on Day 1, predose on Day 4, and on Days 5, 6, and 7.  In Part B, 
the “Since Last Visit” C-SSRS form will be completed 12 hours postdose (morning and evening 


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doses) on Day 8, predose (morning and evening doses) on Day 11, and on Days 12, 13, 14, 21, 
and 28.  The C-SSRS is provided in Appendix 4.   
13.1.8. 
Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling.  Degrees 
of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of ‘1’ indicates 
the subject is ‘feeling active, vital, alert, or wide awake’ and the highest score of ‘7’ indicates the 
subject is ‘no longer fighting sleep, sleep onset soon; having dream-like thoughts’.   
In Part A, the SSS will be administered predose on Day 1 and 1, 2, 3, 4, 6, 8, 12, 14, and 
24 hours postdose on Days 1, 2, and 3, and predose only on Days 5, 6, and 7.  In Part B, the SSS 
will be administered predose (morning dose) on Day 8 and 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours 
postdose (morning dose) and 1, 3, 4, 6, and 8 hours postdose (evening dose) on Days 8, 9, and 
10, predose (morning and evening doses) only on Days 12, 13, and 14, and on Day 21.  All time 
points are relative to the time of dosing.  The SSS is to be performed within ±10 minutes of the 
scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times 
thereafter.  The SSS is provided in Appendix 5.  The SSS should be performed prior to the 
MOAA/S score. 
13.1.9. 
Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) 
The MOAA/S allows exploration of deeper sedation states than the SSS.  If a MOAA/S score of 
3 or less was observed, the score was to be confirmed by waiting approximately 10 minutes and 
re-administering the MOAA/S assessment.  In Part A, the MOAA/S assessment should be 
conducted after other assessments that are scheduled at the same time point.  In Part A, the 
MOAA/S will be performed predose on Day 1 and 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose 
on Days 1, 2, and 3, predose only on Days 5, 6, and 7.  In Part B, the MOAA/S will be 
performed predose (morning dose) on Day 8 and 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose 
(morning dose) and 1, 3, 4, 6, and 8 hours postdose (evening dose) on Days 8, 9, and 10, predose 
(morning and evening doses) only on Days 12, 13, and 14, and on Day 21.  The MOAA/S 
assessments will be performed within ±10 minutes of the scheduled times through the 4-hour 
time point and within ±15 minutes of the scheduled times for the 6-hour through 24-hour time 
points.  The MOAA/S is provided in Appendix 6.   
13.1.10. 
Bond-Lader VAS Mood Scale 
Mood will be assessed using the Bond-Lader Mood Rating Scale.  This is a 16-part self-
administered questionnaire that employs a 100-mm VAS to explore different aspects of self-
reported mood.  In Part A, the mood scale will be administered predose on Days 1, 2, and 7.  In 
Part B, the mood scale will be administered predose (morning and evening doses) on Days 8, 9, 
14 and 21.  The Bond-Lader Mood Rating Scale is provided in Appendix 7.   
13.1.11. 
Drug Effects Questionnaire (DEQ-5) 
A DEQ-5 will be administered as follows: 
1. Do you FEEL a drug effect right now? 
2. Are you HIGH right now? 


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3. Do you DISLIKE any of the effects that you are feeling right now? 
4. Do you LIKE any of the effects that you are feeling right now? 
5. Would you like MORE of the drug you took, right now? 
The answers are recorded on a 100-mm VAS, with the answer for each being “Not at all” and 
“Extremely” at the extremes.  There will be options to record “Not applicable” for questions 3 
and 4 if no drug effects are felt and for question 5 prior to administration of study medication.  
The DEQ-5 will be performed 2 hours postdose on Days 1 and 7 in Part A and 2 hours postdose 
(morning and evening doses) on Days 8 and 14 in Part B.  The DEQ-5 is provided in 
Appendix 8.   
13.2. 
Adverse and Serious Adverse Events 
Adverse events will be collected after the ICF has been signed.  Medical conditions that occur 
after the ICF has been signed will be captured on the adverse event eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (version 18.1 or higher).  
13.2.1. 
Definition of Adverse Events 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered. 
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug.   
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
 It results in death 
 It is immediately life-threatening 
 It requires inpatient hospitalization or prolongation of existing hospitalization 
 It results in persistent or significant disability or incapacity 
 It results in a congenital abnormality or birth defect 


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 It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
All serious adverse events that occur after any subject has been enrolled, whether or not they are 
related to the study, must be recorded on forms provided by Sage Therapeutics or designee for 
the duration of the study (from the signing of the ICF through the Day 28 visit [or early 
termination]). 
13.2.1.4. Recording Sedation as an Adverse Event 
Sedation will be assessed using protocol-specified rating scales.  In order to standardize the 
reporting of sedation as adverse events, Investigators need not record sedation as an adverse 
event unless there is a score of >5 on the SSS and/or a score of ≤2 on the MOAA/S.  
Consideration should be given to the most appropriate term to describe the sedation 
characteristics.   
13.2.2. 
Pregnancy 
Any pregnancy occurring during this study will be reported within 24 hours of notification of the 
Investigator.  The Investigator will promptly notify the Medical Monitor and withdraw the 
subject from the study.  The Investigator should request permission to contact the subject, the 
subject’s spouse/partner (if the subject is male and his spouse/partner becomes pregnant) or the 
obstetrician for information about the outcome of the pregnancy, and in the case of a live birth, 
about any congenital abnormalities.  If a congenital abnormality is reported, then it should be 
recorded in the source documents and reported as a serious adverse event.   
13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, possibly related or probably related).  
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product.  If no valid reason 
exists for suggesting a relationship, then the adverse event should be classified as “unrelated.”  If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the adverse event, then the 
adverse event should be considered “related.”   
Not 
Related: 
No relationship between the experience and the administration of study drug; related to other 
etiologies such as concomitant medications or subject’s clinical state. 
Possibly 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug and 
follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of therapy 
administered to the subject, but this is not known for sure. 
Probably 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug and 
follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s clinical 
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If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered to be related 
to the investigational product for the purposes of expedited regulatory reporting.   
13.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject 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.  Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event or lead to discontinuation of administration of 
study drug.   
Information about adverse events will be collected from the signing of the ICF through the 
Day 28 visit (or early termination).  Adverse events that occur after the first administration of 
study drug will be denoted TEAEs.   
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
no expectation of future change.   
The adverse event term should be reported in standard medical terminology when possible.  For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), intensity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study.   
Intensity will be assessed according to the following scale: 
 Mild (awareness of sign or symptom, but easily tolerated) 
 Moderate (discomfort sufficient to cause interference with normal activities) 
 Severe (incapacitating, with inability to perform normal activities) 
13.5. 
Reporting Serious Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 28 visit (14 days following the last dose of study drug) or early termination.  Any 
serious adverse events considered possibly or probably related to the investigational product and 
discovered by the Investigator at any time after the study should be reported.  All serious adverse 
events must be reported to the Sponsor or Sponsor’s designee immediately by phone and in 
writing within 24 hours of the first awareness of the event.  The Investigator must complete, sign 
and date the serious adverse event pages, verify the accuracy of the information recorded on the 
serious adverse event pages with the corresponding source documents, and send a copy to Sage 
Therapeutics or designee.   
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the study file.   
Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
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adverse events that occur at his or her site if applicable per the IRB’s requirements.  Investigators 
will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) 
that occur during the clinical study.  Each site is responsible for notifying its IRB of these 
additional serious adverse events.   
13.6. 
Emergency Identification of Study Drug (Part B) 
Part B is a double-blind study.  The pharmacist responsible for preparing the solutions will be 
unblinded and will retain an official paper copy of the randomization schedule. 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received.  Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact the Sponsor prior to unblinding the 
study treatment administered to a subject.  Any request from the Investigator about the treatment 
administered to study subjects must be discussed with the Sponsor.  If the unblinding occurs 
without the Sponsor’s knowledge, the Investigator must notify the Sponsor as soon as possible 
and no later than the next business morning.  All circumstances surrounding a premature 
unblinding must be clearly documented in the source records.  Unless a subject is at immediate 
risk, any request for the unblinding of individual subjects must be made in writing to the Sponsor 
and approved by the appropriate Sponsor personnel, according to standard operating procedures.  
The blinding of the study will be broken after the database has been locked.  Electronic copies of 
the randomization code will be made available to the laboratory performing the bioanalytical 
analyses in order to allow for limited analysis of samples from subjects receiving placebo.   
In all cases where the study drug allocation for a subject is unblinded, pertinent information must 
be documented in the subject’s records and on the eCRF.  If the subject or study center personnel 
(other than pharmacist) have been unblinded, the subject will be terminated from the study.   


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14. 
STATISTICAL METHODS AND CONSIDERATIONS 
14.1. 
Data Analysis Sets 
The safety population is defined as all subjects who are administered study drug.   
The efficacy population will consist of all subjects in the safety population who complete at least 
one dose in Part B and have at least one post-randomization efficacy evaluation.   
The evaluable population will consist of all randomized subjects with at least one post-
randomization Kinesia assessment.   
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations.   
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data.  All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available.  No imputation process will be 
used to estimate missing data.  No sensitivity analysis of missing data will be performed.   
14.3. 
Demographics and Baseline Characteristics 
Demographics, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized.   
Categorical summaries, such as race and ethnicity, will be summarized by frequency and 
percentage.  Continuous summaries, such as age, height, weight, BMI, and baseline vital signs, 
will be summarized using descriptive statistics.   
Hepatitis, HIV, drug, and pregnancy screening results will be listed, but not summarized as they 
are considered part of the inclusion/exclusion criteria.   
Medical history will be listed by subject.   
14.4. 
Primary Efficacy Endpoint 
The change from randomization (predose on Day 8) in the accelerometer-based Kinesia kinetic 
tremor combined score (ie, the sum of item 4c scores from both sides of the body) at Day 14 will 
be summarized by treatment group in Part B.   
14.5. 
Secondary Efficacy Endpoints 
The change from randomization (predose on Day 8) in the accelerometer-based Kinesia upper 
limb total and individual item scores, TETRAS total and individual upper limb item scores, and 
TETRAS Performance Subscale scores at Day 14 will be summarized by treatment group in 
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14.6. 
Exploratory Efficacy Endpoints 
The change from randomization (predose on Day 8) in TETRAS ADL scores at Day 14 will be 
summarized by treatment group in Part B.   
Empatica Wristband E4 Tremor oscillation and QUEST data will be listed by subject, study day, 
and time point.   
A summary of clinical ratings of video recordings will be presented by group in Part B.   
14.7. 
Safety and Tolerability Analyses 
Data from vital signs, clinical laboratory measures, ECG, C-SSRS, and MOAA/S will be 
summarized using descriptive statistics by group and time point, where applicable.  Continuous 
endpoints will be summarized with n, mean, standard deviation, median, minimum, and 
maximum.  In addition, change from baseline values will be calculated at each time point and 
will be summarized using descriptive statistics.  Out-of-range safety endpoints may be 
categorized as low or high, where applicable.  For all categorical endpoints, summaries will 
include counts and percentages.   
14.7.1. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system (version 18.1 or higher).  The 
analysis of adverse events will be based on the concept of TEAEs.  A TEAE is defined as an 
adverse event with onset after the start of open-label study drug, or any worsening of a pre-
existing medical condition/adverse event with onset after the start of open-label study drug and 
until 14 days after the last dose.  The incidence of TEAEs will be summarized overall and by 
MedDRA System Organ Class, preferred term, and dose group.  Incidences will be presented in 
order of decreasing frequency.  In addition, summaries will be provided by maximum severity 
and relationship to study drug (see Section 13.3).   
TEAEs leading to discontinuation and serious adverse events (see Section 13.2.1.3 for definition) 
with onset after the first dose of open-label study drug will also be summarized. 
All adverse events and serious adverse events (including those with onset or worsening before 
the signing of the ICF) through the Day 28 visit will be listed.   
14.7.2. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection.  Mean changes from 
randomization in vital signs will be evaluated by time point.   
14.7.3. 
Physical Examinations 
Screening physical examination results will be listed by subject.  Any clinically significant 
physical examination will be recorded in medical history.   
14.7.4. 
12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QTcF.  Any clinically significant abnormalities or changes in ECGs should be listed as an 
adverse event.  Electrocardiogram findings will be listed by subject and visit.   


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14.7.5. 
Clinical Laboratory Evaluations 
Clinical laboratory results will be listed by subject and timing of collection.  Mean changes from 
baseline and randomization in clinical laboratory measures will be evaluated.   
14.7.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS will be listed for all subjects.  Listings will include 
behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the C-SSRS.   
14.7.7. 
Stanford Sleepiness Scale (SSS) 
Sedation data collected on the SSS will be listed for all subjects.  Changes in score over time will 
be represented graphically, and change from Day 1 will be measured. 
14.7.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) 
Sedation data collected on the MOAA/S will be listed for all subjects.  Changes in score over 
time will be represented graphically, and change from Day 1 will be measured. 
14.7.9. 
Bond-Lader VAS Mood Scale 
Mood data collected on the Bond-Lader VAS mood scale will be listed by subject, study day, 
and time point.  The scores and change from Day 1 will be summarized by study day and time 
point.   
14.7.10. 
Drug Effects Questionnaire (DEQ-5) 
Results from DEQ-5 will be listed by subject, study day, and time point.  The result for each 
question and change from Day 1 will be summarized by study day and time point.  
14.7.11. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization (WHO)-Drug dictionary September 2015, or later.   
Medications will be presented according to whether they are being taken prior to and/or during 
the study (concomitant).  Prior medications are defined as those taken within 2 weeks prior to the 
signing of the ICF.  Concomitant medications are defined as those with a start date on or after the 
first dose of open-label study drug, or those with a start date before the first dose of open-label 
study drug that are ongoing or with a stop date on or after the first dose of open-label study drug.  
If medication dates are incomplete and it is not clear whether the medication was concomitant, it 
will be assumed to be concomitant.   
Concomitant medications will be assigned to the part in which they are being taken.  If a 
concomitant medication assigned to a Part A continues to be taken through Part B, then the 
medication will be assigned to both parts of the study as appropriate.  If the start and stop dates 
of the concomitant medications do not clearly define the part during which a medication was 
taken, it will be assumed to be taken in both parts.  Details of prior and concomitant medications 
will be listed by study part, subject, start date, and verbatim term.   


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14.8. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics.  Time to 
reach maximum concentration (tmax) will be summarized using n, mean, standard deviation, 
median, minimum, and maximum.  All other PK parameters will be summarized using n, 
geometric mean, coefficient of variation, median, minimum, and maximum and listed by subject.   
Wherever necessary and appropriate, PK parameters will be dose-adjusted to account for 
individual differences in dose.   
Pharmacokinetic and pharmacodynamic modelling assessment of the relationship between 
plasma exposure of SAGE-217 and change from baseline in accelerometer-based Kinesia scores 
may be assessed.   
14.9. 
Determination of Sample Size 
Up to 80 subjects will be enrolled in Part A to yield at least 60 randomized subjects for Part B.  
A total sample size of 51 evaluable subjects (ie, 17 per group) will have 80% power to detect a 
difference in means of 3.0 on the primary endpoint assuming that the common standard deviation 
is 3.0 using a 2-group t-test with a 0.05 two-sided significance level.  Assuming a 15% non-
evaluability rate, 20 subjects per group will be randomized.  The number of subjects in each 
treatment group is also thought to be sufficient to assess preliminary safety and tolerability 
following multiple doses of SAGE-217 Oral Solution. 
14.10. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Sage 
Therapeutics or designee will visit the investigational study site to:   
 Determine the adequacy of the facilities; and 
 Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives.  This will be documented in a Clinical Study Agreement between 
Sage Therapeutics and the Investigator.   
During the study, a monitor from Sage Therapeutics or designee 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 CRFs, and that investigational product accountability 
checks are being performed; 
 Perform source data verification. This includes a comparison of the data in the CRFs 
with the subject’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 
subject (eg, clinic charts); 
 Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
 Confirm adverse events and serious adverse events have been properly documented 
on CRFs and confirm any serious adverse events have been forwarded to Sage 
Therapeutics or designee and those serious adverse events that met criteria for 
reporting have been forwarded to the IRB.   
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification.  The purpose of a Sage Therapeutics or designee audit or 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 guidelines of the International Council on 
Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency about an inspection.   


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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study, including the subject consent form and 
recruitment materials, must be maintained by the Investigator and made available for inspection.   


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
CRFs.   
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements.   
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate.  The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study.   
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  Sage Therapeutics or designee will provide this information to the Principal 
Investigator.   
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines.   
17.2. 
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 the most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements.   
17.3. 
Written Informed Consent 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study.  Subjects must also 
be notified that they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided.   
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures.   
The Principal Investigator(s) must maintain the original, signed ICF.  A copy of the signed ICF 
must be given to the subject.   
 


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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan.   
Electronic CRFs will be completed for each study subject.  It is the Investigator’s responsibility 
to ensure the accuracy, completeness, and timeliness of the data reported in the subject’s eCRF.  
Source documentation supporting the eCRF data should indicate the subject’s participation in the 
study and should document the dates and details of study procedures, adverse events, and subject 
status.   
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study.  For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct.   
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or, if not approved, 2 years following the 
discontinuance of the test article for investigation.  If it becomes necessary for Sage Therapeutics 
or the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records.   
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports and communications will identify the 
subject by the assigned subject number.  The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process.  The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations.   
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used.   


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All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information.  The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor.  It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study.  The information obtained from the clinical study will be used 
towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required.   


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19. 
PUBLICATION POLICY 
All information concerning SAGE-217 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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20. 
LIST OF REFERENCES 
Axelrad JE, Louis ED, Honig LS, et al. Reduced Purkinje cell number in essential tremor: A 
postmortem study. Arch Neurol. 2008;65(1):101–7. 
Belelli D, Casula A, Ling A, Lambert JJ.  The influence of subunit composition on the 
interaction of neurosteroids with GABA(A) receptors. Neuropharmacology. 2002 
Sep;43(4):651-61. 
Benito-Leon J, Louis ED. Clinical update: diagnosis and treatment of essential tremor. Lancet. 
2007;369(9568):1152-4. 
Boecker H, Kleinschmidt A, Requardt M, Hänicke W, Merboldt KD, Frahm J. Functional 
cooperativity of human cortical motor areas during self-paced simple finger movements. A high 
resolution MRI study. Brain. 1994;117(Pt 6):1231-9. 
Bucher SF, Seelos KC, Dodel RC, et al. Activation mapping in essential tremor with functional 
magnetic resonance imaging. Ann Neurol. 1997;41:32-40. 
Cavanagh JB, Holton JL, Nolan CC, Ray DE, Naik JT, Mantle PG. The effects of the 
tremorgenic mycotoxin penitrem A on the rat cerebellum. Vet Pathol. 1998;35:53–63. 
Deuschl G, Bain P, Brin M. Adhoc-Scientific-Committee. Consensus Statement of the 
Movement Disorder Society on Tremor. Mov Disord. 1998;13(suppl 3):2-23. 
Deuschl G, Elble R. Essential tremor—neurodegenerative or nondegenerative disease towards a 
working definition of ET. Mov Disord. 2009;24(14):2033–41. 
Deuschl G, Raethjen J, Hellriegel H, et al. Treatment of patients with essential tremor. Lancet 
Neurol. 2011;10:148–61. 
Elble RJ, Deuschl G. An update on essential tremor. Curr Neurol Neurosci Rep. 2009;9:273–7. 
Esmaeili A, Lynch JW, Sah P.  GABAA receptors containing gamma1 subunits contribute to 
inhibitory transmission in the central amygdala. J Neurophysiol. 2009;101(1):341-9.  
Gironell A, Kulisevsky J, Barbanoj M, et al. A randomized placebo controlled comparative trial 
of gabapentin and propranolol in essential tremor. Arch Neurol. 1999;56:475–80. 
Gorman WP, Cooper R, Pocock P, et al. A comparison of primidone, propranolol, and placebo in 
essential tremor, using quantitative analysis. J Neurol Neurosurg Psychiatry. 1986;49:64–8. 
Habib-ur-Rehman. Diagnosis and management of tremor. Arch Intern Med. 
2000;160(16):2438-44. 
Kralic JE, Criswell HE, Osterman JL, et al. Genetic essential tremor in gamma-aminobutyric 
acid A receptor alpha1 subunit knockout mice. J Clin Invest. 2005;115:774–9. 
Louis ED, Faust PL, Vonsattel JP, et al. Neuropathological changes in essential tremor: 33 cases 
compared with 21 controls. Brain. 2007;130:3297–307. 
Louis ED, Vonsattel JPG. The emerging neuropathology of essential tremor. Mov Disord. 
2008;23(2):174-82. 


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Louis ED. Essential tremors: a family of neurodegenerative disorders? Arch Neurol. 
2009;66:1202–8. 
Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on 
the worldwide prevalence of essential tremor. Mov Disord. 2010;25:534–41. 
Louis ED. Treatment of essential tremor: are there issues we are overlooking? Front Neurol. 
2012;2:91. 
Málly J, Baranyi M, Vizi ES. Change in the concentrations of amino acids in CSF and serum of 
patients with essential tremor. J Neural Transm. 1996;103:555-60. 
McAuley JH, Marsden CD. Physiological and pathological tremors and rhythmic central motor 
control. Brain. 2000;123 (Pt 8):1545-67. 
Miwa H. Rodent models of tremor. Cerebellum. 2007;6:66-72. 
O'Brien MD, Upton AR, Toseland PA. Benign familial tremor treated with primidone. Br Med J 
(Clin Res Ed). 1981;82(6259):178-80. 
Pahapill PA, Levy R, Dostrovsky JO, et al. Tremor arrest with thalamic microinjections of 
muscimol in patients with essential tremor. Ann Neurol. 1999;46(2):249-52. 
Pahwa R, Lyons KE. Essential tremor: differential diagnosis and current therapy. Am J Med. 
2003;115(2):134-42. 
Paris-Robidas S, Brochu E, Sintes M, et al. Defective dentate nucleus GABA receptors in 
essential tremor. Brain. 2012;135:105-16. 
Pinto AD, Lang AE, Chen R. The cerebellothalamocortical pathway in essential tremor. 
Neurology. 2003;60(12):1985-7. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 
Pritchett DB, Sontheimer H, Shivers BD, et al.  Importance of a novel GABAA receptor subunit 
for benzodiazepine pharmacology.  Nature. 1989;338(6216):582-5. 
Rajput AH, Rajput A. Medical Treatment of Essential Tremor. J Cent Nerv Syst Dis. 
2014;6:29-39. eCollection 2014. 
Schmouth JF, Dion PA, Rouleau GA. Genetics of essential tremor: from phenotype to genes, 
insights from both human and mouse studies. Prog Neurobiol. 2014 Aug-Sep;119-120:1-19.  
Schnitzler A, Munks C, Butz M, et al. Synchronized brain network associated with essential 
tremor as revealed by magnetoencephalography Mov Disord. 2009;24:1629-35. 
Shill HA, Adler CH, Sabbagh MN, et al. Pathologic findings in prospectively ascertained 
essential tremor subjects. Neurology. 2008;70:1452-5.   
Tröster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of life in Essential Tremor 
Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord. 2005 
Sep;11(6):367-73. 


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Wills AJ, Thompson PD, Findley LJ, et al. A positron emission tomography study of primary 
orthostatic tremor. Neurol. 1996;46(3):747-52. 
Zappia M, Albanese A, Bruno E, et al. Treatment of essential tremor: a systematic review of 
evidence and recommendations from the Italian Movement Disorders Association. J Neurol. 
2013;260:714–40. 


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21. 
APPENDICES 
Copies of scales and questionnaires included in Appendix 2 through Appendix 8 are for 
reference only; the rating scales and questionnaires reproduced in the eCRFs are to be used for 
actual subject assessment per the Schedule of Events.   
 


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APPENDIX 1. TREMOROGENIC DRUGS 
The following drug classes are not permitted in the 14 days prior to the admission visit and for 
the duration of the study (up to the Day 21 visit).  The list below gives a non-exhaustive list of 
examples of each drug class. 
Anti-arrhythmics 
 
amiodarone, procainamide 
Antiepileptic drugs 
 
valproic acid, carbamazepine 
Antipsychotic agents 
 
haloperidol, trifluoperazine 
Antimanic agents/mood stabilizer 
 
lithium at toxic levels 
Antivirals 
 
acyclovir, vidarabine 
Beta adrenergic agonists 
 
albuterol, terbutaline 
Calcium Channel blockers 
 
verapamil 
CNS stimulants 
 
methylphenidate, amphetamines, cocaine 
Corticosteroids (local injection topical, or inhalation allowed) 
 
cortisone, hydrocortisone, prednisone 
Cytotoxic agents 
 
cytarabine 
Hormones 
 
calcitonin, levothyroxine 
Immunomodulatory 
 
thalidomide 
Immunosuppressants 
 
cyclosporine, tacrolimus 
Monoamine depleting agents 
 
tetrabenazine 
Oral hypoglycemic agents 
 
metformin, glyburide, glipizide, tolbutamide, pioglitazone, rosiglitazone, acarbose, miglitol 
Prokinetics 
 
metoclopramide 
Tricyclic antidepressants 
 
amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, 
nortriptyline, protriptyline 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
 
fluoxetine 
Statins 
 
atorvastatin 


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Sympathomimetics 
 
epinephrine, pseudoephedrine 
Weight loss medication 
 
tiratricol 
Xanthine derivatives 
 
theophylline  
 


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APPENDIX 2. TRG ESSENTIAL TREMOR RATING ASSESSMENT 
SCALE (TETRAS) 
 


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Appendix 3. 
QUALITY OF LIFE IN ESSENTIAL TREMOR 
QUESTIONNAIRE (QUEST) 
 


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APPENDIX 4. COLUMBIA – SUICIDE SEVERITY RATING SCALE 
(C-SSRS) 
 
 


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APPENDIX 5. STANFORD SLEEPINESS SCALE (SSS) 
 
 


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APPENDIX 6. MODIFIED OBSERVER'S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) 
 
 


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APPENDIX 7. BOND-LADER VAS (MOOD RATING SCALE) 
 


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APPENDIX 8. DRUG EFFECTS QUESTIONNAIRE (DEQ-5) 
 






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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-217.  I have read the Clinical 
Protocol 217-ETD-201 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 




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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street  
Cambridge, MA  02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 2a, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study 
Evaluating the Efficacy, Safety, Tolerability, and Pharmacokinetics of SAGE-217 Oral Solution in the 
Treatment of Subjects with Essential Tremor (ET) 
Study center(s):  Up to 30 centers 
Phase of development: 2a 
Methodology:  
This study will assess the efficacy, safety, tolerability, and PK of SAGE-217 Oral Solution.   
There are two parts: 
Part A: Open-label with morning dosing (7 days). 
All subjects will start on a 10 mg dose of study drug administered with food in the morning on Day 1.  
Subjects will receive 20 mg with food on Day 2 and 30 mg with food daily on Days 3 to 7.   
Part B: Double-blind, placebo-controlled, randomized withdrawal with morning and evening dosing 
(7 days). 
In order to qualify for Part B of the study, a subject must tolerate a maximum dose of at least 10 mg of 
SAGE-217, and the subject must have responded to SAGE-217, defined as a 30% reduction from 
baseline in the TRG Essential Tremor Rating Assessment Scale (TETRAS) kinetic tremor combined 
score (ie, the sum of item 4c scores from both sides of the body) on Day 7.   
Eligible subjects will be randomized in a 1:1:1 fashion to SAGE-217 morning dosing, SAGE-217 
evening dosing, or placebo.  In order to preserve the blind, those randomized to SAGE-217 morning 
dosing will receive placebo for the evening dose, those randomized to SAGE-217 evening dosing will 
receive placebo for the morning dose, and those randomized to placebo will receive placebo for both 
morning and evening dosing.  Subjects randomized to SAGE-217 will receive their maximum dose as 
determined in Part A.  Subjects randomized to the placebo arm will represent randomized withdrawal 
(withdrawal from treatment they received in Part A).  Subjects will be administered study drug with 
meals in the morning and in the evening for 7 consecutive days.   
  


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Methodology:  
Dose adjustments will only be allowed during the open-label phase of the study (Part A).  If at any time 
the dose is not tolerated in Part A, assessed by occurrence of a severe adverse event judged by the 
investigator to be related to study drug, the dose on the next day will be reduced to the next lowest dose 
and continued for the remainder of the open-label dosing period (ie, subjects who are unable to tolerate 
the 30 mg dose will receive a lower dose of 20 mg, and subjects who are unable to tolerate 20 mg will 
be given a 10 mg dose).  The dose tolerated for Days 5, 6, and 7 of the open-label dosing period will be 
determined to be the maximum dose for that subject.  Subjects who require dose adjustments on Days 
5, 6, and 7 of Part A will not progress to Part B.   
Subjects will be exposed to study drug (SAGE-217 or placebo) for up to 14 days and will be followed 
for an additional 14 days after the administration of the last dose.   
Assessments will be performed periodically during the study as outlined in the Schedule of Events 
(Table 2).   
Objectives:  
Primary: 
• 
The primary objective of this study is to compare the effect of 7 days administration of SAGE-217 
Oral Solution to placebo on the change in tremor severity.   
Secondary: 
The secondary objectives of the study are to compare the effect of 7 days administration of SAGE-217 
Oral Solution to placebo on the following endpoints: 
• 
Tremor severity, as assessed by the change from randomization (Day 8) in the accelerometer-based 
Kinesia upper limb total score (ie, the sum of forward outstretched postural tremor, lateral "wing 
beating" postural tremor, and kinetic tremor item scores across both sides of the body) and 
individual item scores at Day 14.   
• 
Tremor severity, as measured by the change from randomization (Day 8) in the TETRAS upper 
limb total score (ie, the sum of item 4c scores from both sides of the body) and individual TETRAS 
upper limb item scores at Day 14.   
• 
Tremor severity, as assessed by the change from randomization (Day 8) in TETRAS Performance 
Subscale scores measured at Day 14.   
• 
Safety and tolerability, as assessed by vital signs measurements, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Severity 
Rating Scale (C-SSRS), and adverse event reporting.   
• 
Sleepiness/sedation, as assessed by the Stanford Sleepiness Scale (SSS) and Modified Observer's 
Assessment of Alertness/Sedation (MOAA/S) scores.   
• 
Mood, as assessed by the Bond-Lader visual analogue scale (VAS) Mood Scale scores.   
• 
How the subject feels after taking the study drug as assessed by Drug Effects Questionnaire 
(DEQ-5) ratings.   
In addition, plasma concentrations of SAGE-217 and SAGE-217 metabolites may be measured.  
Pharmacokinetic (PK) parameters, such as area under the concentration-time curve from time zero to 
last time point (AUC0-t), area under the concentration-time curve from time zero to infinity (AUC0-∞), 
maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), and terminal half-
life (t1/2), will be derived, where appropriate.   
Exploratory: 
The exploratory objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on: 


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• 
Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal activity, 
skin temperature monitoring, and heart rate monitoring), as assessed by the Empatica Wristband 
E4.  Tremor oscillation, as assessed by multi-dimensional accelerometer measurements (ie, raw 
accelerometer values). 
• 
Quality of life (QOL), as assessed by TETRAS activities of daily living (ADL), Quality of Life in 
Essential Tremor Questionnaire (QUEST), and video recording assessment of subjects performing 
three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the 
subject experiences difficulty with on a daily basis).   
In addition, PK/pharmacodynamics (PD) modelling assessment of the relationship between plasma 
exposure of SAGE-217 and change from baseline in accelerometer-based Kinesia scores. 
Endpoints:  
The primary endpoint of this study is the change from randomization (Day 8) in the accelerometer-
based Kinesia kinetic tremor combined score (ie, the sum of item 4c scores from both sides of the 
body) at Day 14.   
Number of subjects (planned):  
Up to 80 subjects will be enrolled in Part A to yield at least 60 randomized subjects for Part B.   
Diagnosis and main criteria for inclusion:  
Inclusion criteria: 
1. Subject has signed an informed consent form before any study-specific procedures are performed.   
2. Subject must be between 18 and 75 years of age, inclusive. 
3. Subject must have a diagnosis of ET, defined as bilateral postural tremor and kinetic tremor, 
involving hands and forearms, that is visible and persistent and the duration is >5 years prior to 
screening. 
4. Subject must have bilateral TETRAS scores of at least two on each side (left and right) for kinetic 
tremor and at least two on each side (left and right) for either wing beating or forward outstretched 
postural tremor.   
5. Subject must be willing to discontinue medications taken for the treatment of ET, alcohol, nicotine, 
and caffeine through Day 21 of the study.   
6. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests.   
7. Female subjects must be post-menopausal, permanently sterile (bilateral tubal occlusion), or of 
childbearing potential with a negative pregnancy test, non- breastfeeding, and using two highly 
effective methods of birth control prior to screening, throughout study participation and for 14 days 
after the last dose of study drug (as defined in Section 8.1).   
8. Male subjects must agree to practice a highly effective method of birth control while on study and 
for 13 weeks after receiving the last dose of study drug.  Effective methods of birth control include 
sexual abstinence, vasectomy, or a condom with spermicide (men) in combination with female 
partner’s highly effective method. 
9. Males must be willing to abstain from sperm donation while on study through 13 weeks after 
receiving the last dose of study drug. 


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Exclusion criteria: 
1. Subject has presence of abnormal neurological signs other than tremor or Froment’s sign. 
2. Subject has presence of known causes of enhanced physiological tremor. 
3. Subject has concurrent or recent exposure (14 days prior to admission visit) to tremorogenic drugs, 
as defined in Appendix 1, or the presence of a drug withdrawal state. 
4. Subject has had direct or indirect trauma to the nervous system within 3 months before the onset of 
tremor.  
5. Subject has historical or clinical evidence of tremor with psychogenic origin (including but not 
limited to eating disorders, major depression, etc.). 
6. Subject has convincing evidence of sudden tremor onset or evidence of stepwise deterioration of 
tremor. 
7. Subject has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or oncological disease. 
8. Subject has clinically significant abnormal physical examination or 12-lead ECG at the Screening 
or Admission Visits.  Note:  A QT interval calculated using the Fridericia method [QTcF] of 
>450 msec in males or >470 msec in females, will be the basis for exclusion from the study.  An 
ECG may be repeated if initial values obtained exceed the limits specified. 
9. Subject has a history, presence, and/or current evidence of serologic positive results for hepatitis B 
surface antigen, hepatitis C antibodies, or human immunodeficiency virus 1 or 2 antibodies. 
10. Subject has hyperthyroidism.   
11. Subject has used alcohol, caffeine, or nicotine within 3 days prior to Admission visit. 
12. Subject has a known allergy to SAGE-217 and its major excipient hydroxylpropyl-β-cyclodextrin 
(HPβCD). 
13. Subject has exposure to another investigational medication or device within the prior 30 days. 
14. Subject has a history of suicidal behavior within 2 years or answers “YES” to questions 3, 4, or 5 
on the C-SSRS at the Screening Visit or on Day -1 or is currently at risk of suicide in the opinion of 
the Investigator. 
15. Subject has donated one or more units (1 unit = 450 mL) of blood or acute loss of an equivalent 
amount of blood within 60 days prior to dosing. 
16. Subject is unwilling or unable to comply with study procedures. 
17. Use of any known strong inhibitors and/or inducers of cytochrome P450 (CYP)3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or St. John's Wort or products containing these within 30 days prior to receiving the first 
dose of study drug.   
Investigational product, dosage and mode of administration:  
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile Water 
for Injection to achieve the selected dose. 
Duration of treatment:  
Screening Duration: approximately 28 days; Treatment Period: 14 days; Follow-up: 14 days 


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Planned Study Duration per Subject: approximately 56 days 
Reference therapy, dosage and mode of administration:  
Placebo will be matched to study drug in Part B.   
Criteria for evaluation: 
Efficacy: 
Transducer measurement of tremor amplitude using an accelerometer and TETRAS Performance 
Subscale.  Quality-of-life will be evaluated using the TETRAS ADL, QUEST, and video recording of 
subjects performing three everyday tasks.  Physiological activity (ie, sympathetic nervous system tone 
as measured by electrodermal activity, skin temperature monitoring, and heart rate monitoring) will be 
assessed by the Empatica Wristband E4.   
Pharmacokinetics: 
Plasma will be collected to assay for concentrations of SAGE-217 and may be assayed for SAGE-217 
metabolites, if deemed necessary.  The following PK parameters will be derived from the plasma 
concentrations (where evaluable): AUC0-t, AUC0-∞, Cmax, tmax, and t½.   
Safety and Tolerability: 
Safety and tolerability of study drug will be evaluated by vital signs measurements, clinical laboratory 
measures, physical examination, ECGs, concomitant medication usage, C-SSRS, SSS, MOAA/S 
scores, and adverse event reporting.  The Bond-Lader Mood Rating Scale and a DEQ-5 will be used to 
assess mood and perception of drug effects, respectively.   
Statistical methods: 
Study Populations 
The safety population is defined as all subjects who are administered study drug.   
The efficacy population will consist of all subjects in the safety population who complete at least one 
dose in Part B and have at least one post-randomization efficacy evaluation.   
The evaluable population will consist of all randomized subjects with at least one post-randomization 
Kinesia assessment.   
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations.   
Efficacy Analysis 
Efficacy data (including change from randomization values for accelerometer-derived Kinesia and 
clinician-rated TETRAS scores) will be summarized using appropriate descriptive statistics and listed 
by subject.   
The change from randomization (Day 8) in the accelerometer-based Kinesia kinetic tremor combined 
score (ie, the sum of item 4c scores from both sides of the body) at Day 14 will be summarized by 
treatment.  Additionally, the change from randomization in the accelerometer-based Kinesia upper limb 
total score and individual item scores at Day 14 will be summarized by treatment.   
The change from randomization in TETRAS upper limb total score, individual TETRAS upper limb 
item scores, and TETRAS Performance Subscale scores at Day 14 will be summarized by treatment.   
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics and listed by 
subject.  Wherever necessary and appropriate, PK parameters will be dose-adjusted to account for 
individual differences in dose.   
  


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Safety Analysis 
Adverse events will be coded using Medical Dictionary for Regulatory Activities™.  The overall 
incidence of adverse events will be displayed by System Organ Class, preferred term, and dose group.  
Incidence of adverse events will also be presented by maximum severity and relationship to study drug.  
Data from vital signs, clinical laboratory measures, ECG, and C-SSRS will be summarized using 
descriptive statistics by dose group, where applicable.  Continuous endpoints will be summarized with 
n, mean, standard deviation, median, minimum, and maximum.  In addition, change from baseline 
values will be calculated at each time point and will be summarized using the same summary statistics.  
Out-of-range safety endpoints may be categorized as low or high, where applicable.  For all categorical 
endpoints, summaries will include counts and percentages.   
Sample Size 
Up to 80 subjects will be enrolled in Part A to yield at least 60 randomized subjects for Part B.  A total 
sample size of 51 evaluable subjects (ie, 17 per group) will have 80% power to detect a difference in 
means of 3.0 on the primary endpoint assuming that the common standard deviation is 3.0 using a 
2-group t-test with a 0.05 two-sided significance level.  Assuming a 15% non-evaluability rate, 
20 subjects per group will be randomized.  The number of subjects in each treatment group is also 
thought to be sufficient to assess preliminary safety and tolerability following multiple doses of 
SAGE-217 Oral Solution. 
 


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Table 2: 
Schedule of Events:  Part A (Open-Label) 
Visit Days 
Screening 
(Day -28 to Day -1) 
Admit 
(Day -1) 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
Confined to unit 
 
X 
X 
X 
X 
 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Body weight/height 
X 
 
 
 
 
 
 
 
 
Complete blood count/ 
serum chemistry
a 
X 
X 
X 
X 
 
 
 
 
 
Pregnancy test  
X 
(serum) 
X 
(urine) 
 
 
 
 
 
 
 
Urinalysisa 
X 
X 
X 
X 
 
 
 
 
 
Hepatitis & HIV screen 
X 
 
 
 
 
 
 
 
 
Vital signs
b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryb 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
c 
X 
 
X 
X 
X 
 
 
 
X 
C-SSRS
d 
 
X 
X 
 
 
X 
X 
X 
X 
SSS
e 
 
 
X 
X 
X 
X 
X 
X 
X 
MOAA/S
f 
 
 
X 
X 
X 
X 
X 
X 
X 
Bond-Lader-VAS
g 
 
 
X 
X 
 
 
 
 
X 
DEQ-5
h 
 
 
X 
 
 
 
 
 
X 
Kinesia (accelerometer)
i 
 
X 
X 
X 
 
 
 
 
X 
TETRAS upper limb subscalei 
X 
X 
X 
X 
 
 
 
 
X 


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Visit Days 
Screening 
(Day -28 to Day -1) 
Admit 
(Day -1) 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
TETRAS (all ADL and all 
Performance Subscale)
j 
 
X 
 
 
 
 
 
 
X 
Empatica Wristband E4
k 
 
X 
X 
X 
X 
 
 
 
X 
QUEST 
 
X 
 
 
 
 
 
 
X 
Plasma PK samples
l 
 
 
X 
X 
X 
X 
X 
X 
X 
Administer study drug
m 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Videos
n 
 
X 
 
 
 
 
 
 
X 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram; HIV = 
human immunodeficiency virus; MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; PK = pharmacokinetic; QUEST = Quality of Life in 
Essential Tremor Questionnaire; SSS = Stanford Sleepiness Scale; TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue score 
a Screening and safety laboratory tests will be performed at Screening, Day -1 (Admission), Day 1, and predose on Day 2. 
b Vital signs (both supine for at least 5 minutes prior to the measurement and standing) and pulse oximetry will be performed at Screening (vital signs only) and 
Day -1 (Admission), predose and at 1, 2, 3, 4, 6, 8, 12, 14, 16, and 24 hours postdose on Days 1, 2, and 3, and predose only on Days 4, 5, 6, and 7. 
c 12-lead ECGs will be performed at Screening, predose on Day 1, and at 1, 12, and 24 hours postdose on Days 1, 2, 3, and 7. 
d The C-SSRS will be performed on Day -1 (Admission), 12 hours postdose on Day 1, predose on Day 4, and on Days 5, 6, and 7. 
e The SSS will be performed predose and 1, 2, 3, 4, 6, 8, 12, 14, 16, and 24 hours postdose on Days 1, 2, and 3, and predose only on Days 4, 5, 6, and 7. 
f The MOAA/S will be performed predose and 1, 2, 3, 4, 6, 8, 12, 14, 16, and 24 hours postdose on Days 1, 2, and 3, and predose only on Days 4, 5, 6, and 7. 
g The Bond-Lader VAS will be at performed predose on Days 1, 2, and 7. 
h The DEQ-5 will be performed 2 hours postdose on Days 1 and 7. 
i Kinesia and TETRAS upper limb subscale will be performed at Screening (TETRAS upper limb subscale only), predose on Day -1 (Admission; three 
assessments separated by at least 30 minutes), and predose and 2, 12, and 14 hours postdose (three assessments separated by at least 30 minutes) on Days 1, 2, 
and 7.   
j TETRAS (all ADL) will be performed on Day -1 (Admission) and Day 7.   
k The Empatica Wristband E4 will be worn during the Confinement Periods. 
l Plasma pharmacokinetic samples will be taken predose and 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours postdose on Day 1 and predose on Days 2, 3, 4, 5, 6, and 7. 
m Study drug will be administered in the morning with food during Part A. 
n Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis) will be taken on Day -1 (Admission) and predose on Day 7. 


Protocol 217-ETD-201 
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13 
 
Table 3: 
Schedule of Events:  Part B (Randomized Withdrawal) 
Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21 
End of Study 
Day 28 
Randomization 
X 
 
 
 
 
 
 
 
 
Confined to unit 
X 
X 
X 
 
 
 
 
 
 
Complete blood count/ 
serum chemistry
a 
X 
X 
 
 
 
 
 
X 
 
Pregnancy test  
 
 
 
 
 
 
 
 
X 
Urinalysisa 
X 
X 
 
 
 
 
 
X 
 
Vital signs
b 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pulse oximetryb 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG
c 
X 
X 
X 
 
 
 
X 
X 
 
C-SSRS
d 
X 
 
 
X 
X 
X 
X 
X 
X 
SSS
e 
X 
X 
X 
X 
X 
X 
X 
X 
 
MOAA/S
f 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bond-Lader-VAS
g 
X 
X 
 
 
 
 
X 
X 
 
DEQ-5
h 
X 
 
 
 
 
 
X 
 
 
Kinesia (accelerometer)
i 
X 
X 
 
 
 
 
X 
X 
 
TETRAS upper limb subscalei 
X 
X 
 
 
 
 
X 
X 
 
TETRAS (all ADL and all 
Performance Subscale)
j 
 
 
 
 
 
 
X 
X 
 
Empatica Wristband E4
k 
X 
X 
X 
 
 
 
X 
 
 
QUEST 
 
 
 
 
 
 
X 
 
 
Plasma PK samples
l 
X 
X 
X 
X 
X 
X 
X 
 
 
Administer study drug
m 
X 
X 
X 
X 
X 
X 
X 
 
 


Protocol 217-ETD-201 
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Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21 
End of Study 
Day 28 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Videos
n 
 
 
 
 
 
 
X 
X 
 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram;  
HIV = human immunodeficiency virus; MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; PK = pharmacokinetic; QUEST = Quality of Life 
in Essential Tremor Questionnaire; SSS = Stanford Sleepiness Scale; TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue 
score 
a Safety laboratory tests will be performed predose on Day 8, Day 9, and on Day 21. 
b Vital signs (both supine for at least 5 minutes prior to the measurement and standing) and pulse oximetry will be performed predose and at 1, 2, 3, 4, 6, 8, 12, 
14, 16, and 24 hours postdose on Days 8, 9, and 10, predose only on Days 11, 12, 13, and 14, and on Day 21. 
c 12-lead ECGs will be performed at 1, 12, and 24 hours postdose on Days 8, 9, and 10, on Day 14, and Day 21. 
d The C-SSRS will be performed on Days 8, 11, 12, 13, and 14, on Day 21, and on Day 28. 
e The SSS will be performed predose and 1, 2, 3, 4, 6, 8, 12, 14, 16, and 24 hours postdose on Days 8, 9, and 10, predose only on Days 11, 12, 13, and 14, and on 
Day 21. 
f The MOAA/S will be performed predose and 1, 2, 3, 4, 6, 8, 12, 14, 16, and 24 hours postdose on Days 8, 9, and 10, predose only on Days 11, 12, 13, and 14, 
and on Day 21. 
g The Bond-Lader VAS will be at performed predose on Days 8, 9, and 14 and on Day 21. 
h The DEQ-5 will be performed 2 hours postdose on Days 8 and 14. 
i Kinesia and TETRAS upper limb subscale will be performed before morning dose, after morning dose (2 hours post morning dose), before evening dose (12 
hours post morning dose), and after evening dose (14 hours post evening dose) (three assessments separated by at least 30 minutes) on Days 8, 9, and 14, and 
on Day 21.   
j TETRAS (all ADL) will be performed on Day 14 and Day 21.   
k The Empatica Wristband E4 will be worn during the Confinement Periods and on Day 14. 
l Plasma pharmacokinetic samples will be taken predose and 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours postdose on Day 8 and predose on Days 9, 10, 11, 12, 13, and 
14. 
m Study drug will be administered in the morning with food during Part A and in the morning and evening (every 12 hours) with food during Part B. 
n Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences difficulty 
with on a daily basis) will be taken on Day 14 and Day 21. 
 
 


Protocol 217-ETD-201 
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15 
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF
FIGURES
TABLE OF CONTENTS 
1.
TITLE PAGE ................................................................................................................1 
2.
SYNOPSIS ...................................................................................................................5 
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............15 
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................21 
5.
INTRODUCTION ......................................................................................................23
5.1. 
Background of Essential Tremor and Unmet Medical Need ......................................23 
5.2. 
SAGE-217 Oral Solution ............................................................................................24 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 ..........................24 
5.3.1. 
Nonclinical Studies with SAGE-217 ..........................................................................24 
5.3.2. 
Clinical Experience .....................................................................................................25 
5.4. 
Potential Risks and Benefits .......................................................................................26 
6.
STUDY OBJECTIVES AND PURPOSE ..................................................................27 
6.1. 
Primary Objective .......................................................................................................27 
6.2. 
Secondary Objectives .................................................................................................27 
6.3. 
Exploratory Objectives ...............................................................................................28 
7.
INVESTIGATIONAL PLAN .....................................................................................29 
7.1. 
Overall Study Design ..................................................................................................29 
7.2. 
Blinding and Randomization ......................................................................................30 
8.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................31 
8.1. 
Subject Inclusion Criteria ...........................................................................................31 
8.2. 
Subject Exclusion Criteria ..........................................................................................31 
8.3. 
Entrance Criteria for Part B ........................................................................................32 
8.4. 
Subject Withdrawal Criteria .......................................................................................33 
8.4.1. 
Study Drug Withdrawal ..............................................................................................33 
8.4.2. 
Criteria for Study Termination ...................................................................................34 
9.
TREATMENT OF SUBJECTS ..................................................................................35 
9.1. 
Number of Subjects ....................................................................................................35 
9.2. 
Treatment Assignment ................................................................................................35 
9.2.1. 
Part A ..........................................................................................................................35 


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9.2.2. 
Part B ..........................................................................................................................35 
9.3. 
Dose Adjustment Criteria ...........................................................................................35 
9.4. 
Prior/Concomitant Medications and Restrictions .......................................................36 
9.4.1. 
Prior/Concomitant Medications ..................................................................................36 
9.4.2. 
Prohibited Medications ...............................................................................................36 
9.5. 
Treatment Compliance ................................................................................................36 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................37 
10.1. 
Study Drug ..................................................................................................................37 
10.2. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL ...................................37 
10.3. 
Study Drug Packaging and Labeling ..........................................................................37 
10.4. 
Study Drug Storage .....................................................................................................37 
10.5. 
Administration and Study Drug Accountability .........................................................38 
10.5.1. 
Study Drug Administration.........................................................................................38 
10.5.2. 
Study Drug Accountability .........................................................................................39 
10.6. 
Study Drug Handling and Disposal ............................................................................39 
11. 
ASSESSMENT OF EFFICACY ................................................................................40 
11.1. 
Measurements of Tremor Amplitude ..........................................................................40 
11.2. 
TRG Essential Tremor Rating Assessment Scale (TETRAS) Performance 
Scale ............................................................................................................................40 
11.3. 
Empatica Wristband E4 ..............................................................................................41 
11.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST) ....................................41 
11.5. 
Video Recording .........................................................................................................41 
12. 
PHARMACOKINETICS ...........................................................................................42 
12.1. 
Blood Sample Collection ............................................................................................42 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ..................................................42 
12.3. 
Sample Analysis .........................................................................................................42 
13. 
ASSESSMENT OF SAFETY .....................................................................................43 
13.1. 
Safety and Tolerability Parameters .............................................................................43 
13.1.1. 
Demographic/Medical History ...................................................................................43 
13.1.2. 
Vital Signs ..................................................................................................................43 
13.1.3. 
Weight and Height ......................................................................................................43 
13.1.4. 
Physical Examination .................................................................................................43 
13.1.5. 
Electrocardiogram (ECG) ...........................................................................................43 


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13.1.6. 
Laboratory Assessments .............................................................................................43 
13.1.6.1. 
Hematology .................................................................................................................44 
13.1.6.2. 
Blood Chemistry .........................................................................................................44 
13.1.6.3. 
Urinalysis ....................................................................................................................44 
13.1.6.4. 
Virus Serology ............................................................................................................44 
13.1.6.5. 
Pregnancy Test ............................................................................................................44 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................44 
13.1.8. 
Stanford Sleepiness Scale (SSS) .................................................................................45 
13.1.9. 
Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) ...............45 
13.1.10. 
Bond-Lader VAS Mood Scale ....................................................................................45 
13.1.11. 
Drug Effects Questionnaire (DEQ-5) .........................................................................45 
13.2. 
Adverse and Serious Adverse Events .........................................................................46 
13.2.1. 
Definition of Adverse Events .....................................................................................46 
13.2.1.1. 
Adverse Event .............................................................................................................46 
13.2.1.2. 
Suspected Adverse Reaction .......................................................................................46 
13.2.1.3. 
Serious Adverse Event ................................................................................................46 
13.2.1.4. 
Recording Sedation as an Adverse Event ...................................................................47 
13.2.2. 
Pregnancy ...................................................................................................................47 
13.3. 
Relationship to Study Drug ........................................................................................47 
13.4. 
Recording Adverse Events .........................................................................................48 
13.5. 
Reporting Serious Adverse Events .............................................................................48 
13.6. 
Emergency Identification of Study Drug (Part B) ......................................................49 
14. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................50 
14.1. 
Data Analysis Sets ......................................................................................................50 
14.2. 
Handling of Missing Data ...........................................................................................50 
14.3. 
Demographics and Baseline Characteristics ...............................................................50 
14.4. 
Primary Efficacy Endpoint .........................................................................................50 
14.5. 
Secondary Efficacy Endpoints ....................................................................................50 
14.6. 
Exploratory Efficacy Endpoints .................................................................................50 
14.7. 
Safety and Tolerability Analyses ................................................................................51 
14.7.1. 
Adverse Events ...........................................................................................................51 
14.7.2. 
Vital Signs ..................................................................................................................51 
14.7.3. 
Physical Examinations ................................................................................................51 


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14.7.4. 
12-Lead ECG ..............................................................................................................51 
14.7.5. 
Clinical Laboratory Evaluations .................................................................................51 
14.7.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................52 
14.7.7. 
Stanford Sleepiness Scale (SSS) .................................................................................52 
14.7.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) ........................52 
14.7.9. 
Bond-Lader VAS Mood Scale ....................................................................................52 
14.7.10. 
Drug Effects Questionnaire (DEQ-5) .........................................................................52 
14.7.11. 
Prior and Concomitant Medications ...........................................................................52 
14.8. 
Pharmacokinetic Analysis ..........................................................................................52 
14.9. 
Determination of Sample Size ....................................................................................53 
14.10. 
Changes From Protocol Specified Analyses ...............................................................53 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................54 
15.1. 
Study Monitoring ........................................................................................................54 
15.2. 
Audits and Inspections ................................................................................................54 
15.3. 
Institutional Review Board (IRB) ...............................................................................55 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
17. 
ETHICS ......................................................................................................................57 
17.1. 
Ethics Review .............................................................................................................57 
17.2. 
Ethical Conduct of the Study ......................................................................................57 
17.3. 
Written Informed Consent ..........................................................................................57 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................58 
18.1. 
Inspection of Records .................................................................................................58 
18.2. 
Retention of Records ..................................................................................................58 
18.3. 
Confidentiality ............................................................................................................58 
19. 
PUBLICATION POLICY ..........................................................................................60 
20. 
LIST OF REFERENCES ............................................................................................61 
21. 
APPENDICES ............................................................................................................64 
APPENDIX 1. TREMOROGENIC DRUGS ..............................................................................65 
APPENDIX 2. TRG ESSENTIAL TREMOR RATING ASSESSMENT SCALE 
(TETRAS) ...................................................................................................................67 
APPENDIX 3. QUALITY OF LIFE IN ESSENTIAL TREMOR QUESTIONNAIRE 
(QUEST) .....................................................................................................................73 
APPENDIX 4. COLUMBIA – SUICIDE SEVERITY RATING SCALE (C-SSRS) ................75 


Protocol 217-ETD-201 
 
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19 
 
APPENDIX 5. STANFORD SLEEPINESS SCALE (SSS) .......................................................81 
APPENDIX 6. MODIFIED OBSERVER'S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) .....................................................................82 
APPENDIX 7. BOND-LADER VAS (MOOD RATING SCALE) ...........................................83 
APPENDIX 8. DRUG EFFECTS QUESTIONNAIRE (DEQ-5) ...............................................84 
 


Protocol 217-ETD-201 
 
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20 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events:  Part A (Open-Label) .................................................................11 
Table 3: 
Schedule of Events:  Part B (Randomized Withdrawal) ............................................13 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................21 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL..................37 
 


Protocol 217-ETD-201 
 
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21 
 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
ADL 
activities of daily living 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-t 
area under the concentration-time curve from time zero to 
last time point 
AUC0-∞  
area under the concentration-time curve from time zero to 
infinity 
BMI 
body mass index 
Cmax  
maximum plasma concentration 
CNS 
central nervous system 
CRF 
case report form 
CS 
clinically significant  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450  
DEQ-5 
Drug Effects Questionnaire 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
ET 
essential tremor 
GABA 
γ-aminobutyric acid 
GABAA 
γ-aminobutyric acid-ligand gated chloride channel 
GABAB 
γ-aminobutyric acid-G protein-coupled 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg  
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxylpropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 


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Abbreviation or Specialist Term 
Explanation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
MTD 
maximum tolerated dose 
NCS 
not clinically significant 
NF  
National Formulary 
PI 
Principal Investigator 
PK 
pharmacokinetic 
QOL 
quality of life 
QTcF 
QT interval calculated using the Fridericia method 
QUEST 
Quality of Life in Essential Tremor Questionnaire 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAEs 
treatment-emergent adverse events 
TETRAS 
TRG Essential Tremor Rating Assessment Scale 
t1/2 
terminal half-life 
tmax  
time to reach maximum concentration 
USP  
United States Pharmacopeia 
VAS 
visual analogue score 
WHO 
World Health Organization 
WMA 
World Medical Association 
 


Protocol 217-ETD-201 
 
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23 
 
5. 
INTRODUCTION 
5.1. 
Background of Essential Tremor and Unmet Medical Need 
Essential tremor (ET) is among the most common neurological diseases, with an overall 
prevalence of 0.9%.  Prevalence increases with age and is estimated to be 4.6% in people over 
65 years of age (Louis 2010, Deuschl 2011).  Essential tremor is largely a bilateral, symmetrical 
postural or kinetic tremor involving hands and forearms that is visible and persistent.  Additional 
or isolated tremor of the head or lower limbs may occur, but in the absence of abnormal 
posturing (Deuschl 1998, Habib-ur-Rehman 2000).  The onset of tremor has a bimodal 
distribution, with onset between 15 to 20 and 50 to 70 years.  Over time, tremors can become 
more pronounced and may prevent eating, drinking, and writing, as well as executing personal 
hygiene like shaving or applying make-up.  Voice tremors can be severe enough to inhibit 
talking and singing in public.   
Several lines of evidence suggest that cerebellar dysfunction through the 
cerebellothalamocortical pathway plays a key role in ET (McAuley 2000; Pinto 2003; 
Elble 2009, Schnitzler 2009, Deuschl 2009).  Thalamotomy and deep brain stimulation of the 
ventral intermediate nucleus and of the subthalamic nucleus improve ET (Deuschl 2011, 
Zappia 2013, Rajput 2014).  Microscopic cerebellar pathology has been identified, including 
gliosis, Purkinje cell loss, and increased torpedoes (swellings) in the Purkinje cell axons 
(Louis 2007, Axelrad 2008, Shill 2008, Louis 2009).  Activation studies with positron emission 
tomography indicate abnormally increased regional cerebral blood flow in the cerebellum both at 
rest and when tremor is provoked by unilateral arm extension (Boecker 1994, Wills 1996).   
Essential tremor is associated with impaired γ-aminobutyric acid (GABA)ergic function (and 
consequent hyperactivity) in the cerebellum (Málly 1996, Bucher 1997, Louis 2007, Louis 2008, 
Paris-Robidas 2012).  γ-aminobutyric acid, the major inhibitory neurotransmitter in the central 
nervous system (CNS), is released from GABAergic neurons and binds to several types of 
GABA receptors (γ-aminobutyric acid-ligand gated chloride channel [GABAA] and 
γ-aminobutyric acid-G protein-coupled [GABAB]) on target neurons.  γ-aminobutyric acid-gated 
chloride channel receptors, the major class of inhibitory neurotransmitter receptors in the brain, 
are macromolecular proteins that form a chloride ion channel complex and contain specific 
binding sites for GABA and a number of allosteric regulators, including barbiturates, 
benzodiazepines, and some anesthetic agents.   
Drugs acting on GABAA receptors, such as primidone, benzodiazepines, or ethanol decrease 
tremor amplitude, suggesting that altered GABAergic neurotransmission is involved in ET.  
Postmortem analysis revealed a 35% reduction of GABAA receptors and a 22% to 31% reduction 
of GABAB receptors in the dentate nucleus of cerebella of ET subjects (Paris-Robidas 2012).  
Reduced levels of GABA in the cerebrospinal fluid are also reported in ET subjects 
(Málly 1996).  Moreover, toxins such as aflatrem, penitrem A, or harmaline have been proposed 
to induce tremor in rodents by interacting with GABA receptors (Cavanagh 1998; Miwa 2007), 
and targeted deletion of the α1 subunit of GABAA receptor in knockout mice exhibits a 
15 to 19 Hz action tremor, similar to ET in humans (Kralic 2005).   


Protocol 217-ETD-201 
 
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24 
 
Consistent with the role of GABA, the majority of therapeutics for ET act by augmenting 
GABAergic transmission (Louis 2012, Benito-Leon 2007, Pahapill 1999).  First-line treatments 
for ET include the anticonvulsant primidone and the β-adrenergic blocker propranolol (Gorman 
1986).  Like primidone, gabapentin is an anticonvulsant found to be effective in the treatment of 
ET (O’Brien 1981; Gironell 1999).  The oldest treatment for ET is ethanol, which temporarily 
ameliorates tremor and is frequently used by subjects to self-medicate; however, chronic use of 
ethanol for tremor management carries the known risks of alcohol dependence and overuse 
(Pahwa 2003).   
These treatments are moderately effective, reducing, though not resolving, tremor amplitudes in 
about 50% of the subjects (Schmouth 2014).  In addition, one out of three patients abandon 
treatment because of side effects or poor efficacy (Louis 2010), illustrating that with few feasible 
treatment options and a range of handicaps in daily living makes ET an area of high unmet 
medical need.   
5.2. 
SAGE-217 Oral Solution 
SAGE-217 is a positive allosteric modulator of the GABAA receptor and thus is expected to be 
of benefit for the treatment of ET.  Unlike benzodiazepines that are selective for the γ-subunit-
containing subset of GABAA receptors (Pritchett 1989, Esmaeili 2009), SAGE-217 and other 
neuroactive steroids, which bind to the ubiquitous α-subunit, have a wider range of activity 
(Belelli 2002). 
SAGE-217 Oral Solution 6 mg/mL (40% w/w aqueous hydroxylpropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a nonviscous, clear solution.   
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 
5.3.1. 
Nonclinical Studies with SAGE-217 
In nonclinical studies of SAGE-217, sedative-hypnotic effects were consistently observed at 
higher doses in both in vivo pharmacology studies as well as in toxicology studies.  The 
sedative-hypnotic impairments seen with SAGE-217 were typical for GABAA positive 
modulators, ranging from hyperexcitability and ataxia at the lower doses through deep sedation 
and ultimately anesthesia at higher doses.  Depth and duration of sedation demonstrated a clear 
dose response over the range tested, with evidence of tolerance occurring with continued 
exposure.  Tolerance to the effects of SAGE-217 on motor incoordination was not observed after 
7 days of dosing.   
The compound has been assessed in 14-day rat and dog toxicology studies with daily 
administration of SAGE-217 as a solution in HPβCD in dogs and Labrasol® in rats.  The no 
observed adverse effect level was 3 mg/kg (females) and 22.5 mg/kg (males) in rats and 
2.5 mg/kg in dogs.  There were no adverse effects in dogs or rats in the main toxicology studies.  
A single observation of mortality occurred in one female rat at the high dose in a toxicokinetic 
study which was suspected to have been related to exaggerated pharmacology.  Additional 
toxicology and pharmacology information is provided in the Investigator’s Brochure.   


Protocol 217-ETD-201 
 
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25 
 
5.3.2. 
Clinical Experience 
To date, two clinical studies employing SAGE-217 are clinically complete and final clinical 
study reports are pending.  Discussions of pharmacokinetic (PK) data are limited to the single-
ascending dose, food, and essential tremor cohorts from Study 217-CLP-101 and the multiple-
ascending dose and drug-drug interaction (DDI) cohorts from Study 217-CLP-102.  Discussions 
of safety data are limited to the single-ascending dose cohorts in Study 217-CLP-101 and the 
multiple-ascending dose cohorts in Study 217-CLP-102.   
Study 217-CLP-101 was a first-in-human, four-part study that assessed the effects of a single 
dose of SAGE-217.  The study was a double-blind, placebo-controlled, single-ascending dose 
design in healthy adult volunteers, with the objective of identifying the maximum tolerated dose 
(MTD) and PK profiles of SAGE-217 Oral Solution.  Subjects in each of the single-ascending 
dose cohorts received a single dose of study drug, either SAGE-217 (six subjects) or placebo 
(two subjects), with SAGE-217 doses of 0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 mg, 
55 mg, and 66 mg.  Escalation to the next dose was undertaken only after safety and PK data 
were reviewed by the Safety Review Committee (SRC) and agreement reached that it was safe to 
increase the dose.  The MTD was determined to be 55 mg.  Two cohorts, 6 subjects each 
received SAGE-217 in an open-label manner (one cohort received 50% of the MTD [22 mg] to 
study the food effects and the other cohort received the MTD [55 mg] to study the effects on 
subjects with essential tremor).  SAGE-217 was orally bioavailable, demonstrated dose-linear 
PK from the lowest (0.25 mg) through the highest (66 mg) dose, and supported once daily oral 
dosing with food.   
Study 217-CLP-102 was a two-part study that assessed the effects of multiple-ascending doses of 
SAGE-217.  The study was a double-blind, placebo-controlled, multiple-ascending dose study in 
healthy adult volunteers.  Subjects in each of the multiple-ascending dose cohorts received study 
drug, either SAGE-217 (nine subjects) or placebo (three subjects), once daily for 7 days, with 
SAGE-217 doses of 15 mg, 30 mg, and 35 mg.  Escalation to the next dose was undertaken only 
after safety and PK data were reviewed by the SRC and agreement reached that it was safe to 
increase the dose.  The MTD was determined to be 30 mg.  It was observed that subjects 
receiving the drug in the evening did better in terms of tolerability compared to when they 
received the drug in the morning.  A fourth cohort of 12 subjects received 30 mg of SAGE-217 
in an open-label manner to study drug-drug interactions.  SAGE-217 is not likely to induce the 
metabolism of CYP2B6 or CYP3A4 substrates.  SAGE-217 was orally bioavailable and suitable 
for once daily oral dosing at night time with food.   
SAGE-217 was generally well tolerated.  In both Phase 1 studies (217-CLP-101 and  
217-CLP-102), doses were escalated until the stopping criteria were met.  Most adverse events 
were reported as mild or moderate in intensity, and there were no serious adverse events reported 
in either study.  In addition, none of the observed adverse events resulted in discontinuation of 
the study drug.  At doses planned for further study, the observed sedation was mild, transient, 
and associated with daily peak exposure.  The most common treatment-emergent adverse events 
were sedation, somnolence, dizziness, euphoric mood, fatigue, tremor, and muscle twitching, 
reported most frequently in the highest dose group (66 mg).  Some changes in mean blood 
pressure and heart rate were observed after single doses of 44 mg and greater.  After multiple 
doses of 30 mg (AM or PM) or 35 mg (PM) over 7 days, there was no evidence of changes in 
mean vital sign measures even though Day 7 plasma concentrations approximated that of the 


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highest single dose in the single-ascending dose study.  Subjects seemed to tolerate SAGE-217 
better when given as night time dosing.   
There were no clinical efficacy data of SAGE-217 in ET, since the present study is the first study 
in this indication.   
5.4. 
Potential Risks and Benefits 
Protocol 217-ETD-201 is the first clinical study of SAGE-217 Oral Solution in ET evaluating the 
efficacy of this product.  Thus, the potential benefits in this population are unknown, although 
the risks are likely to be similar to those mentioned in the Investigator’s Brochure.  Many 
compounds that target the GABAA receptors exhibit clinical efficacy in ET, validating this 
receptor as a therapeutic target.  Given the promising SAGE-547 clinical data in conjunction 
with the shared broad receptor selectivity profile, oral bioavailability, long half-life, preclinical 
evidence of anxiolytic activity and safety data of SAGE-217, it is possible that patients may have 
a clinical benefit at the exposures selected for this study.  In view of the few risks associated with 
administration of SAGE-217 Oral Solution that have been identified to date, an intra-patient 
dose-escalation design has been chosen to permit titration of treatment effect vs tolerability 
(adverse events), specifically sedation.  Each subject will start with an initial dose of 10 mg to be 
escalated to 20 mg after a day and then escalated further to 30 mg assuming no tolerability 
issues.  At the end of a 7-day exposure, the maximum dose for the subject will be established as 
will a protocol specified response.  Subjects who are responders and tolerate at least the 10 mg 
dose for a minimum of 3 days will qualify for the randomization phase (Part B).  Given the high 
medical need and potential for benefit in ET, there is a favorable benefit-risk evaluation to 
investigate SAGE-217 Oral Solution in ET.   
In conclusion, selection criteria for the proposed study take into account the potential safety 
risks.  Continuous safety monitoring, and the implementation of a formal dose-reduction and 
study drug discontinuation scheme also have the potential to mitigate risk.  From a benefit/risk 
perspective, the appropriate measures are being taken in order to ensure the safety of the subjects 
who will be enrolled.   


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of this study is to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on the change in tremor severity.   
The primary endpoint of this study is the change from randomization (Day 8) in the 
accelerometer-based Kinesia kinetic tremor combined score (ie, the sum of item 4c scores from 
both sides of the body) at Day 14.   
6.2. 
Secondary Objectives 
The secondary objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on the following endpoints: 
1. Tremor severity as assessed by the change from randomization (Day 8) in the 
accelerometer-based Kinesia upper limb total score (ie, the sum of forward outstretched 
postural tremor, lateral “wing beating” postural tremor, and kinetic tremor item scores 
across both sides of the body) and individual item scores at Day 14. 
2. Tremor severity as measured by the change from randomization (Day 8) in TRG 
Essential Tremor Rating Assessment Scale (TETRAS) upper limb total score (ie, the sum 
of item 4c scores from both sides of the body) and individual TETRAS upper limb item 
scores at Day 14. 
3. Tremor severity as assessed by the change from randomization (Day 8) in TETRAS 
Performance Subscale scores measured at Day 14. 
4. Safety and tolerability as assessed by vital signs measurements, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide 
Severity Rating Scale (C-SSRS), and adverse event reporting.   
5. Sleepiness/sedation as assessed by the SSS and MOAA/S scores. 
6. Mood as assessed by the Bond-Lader visual analogue score (VAS) Mood Scale. 
7. How the subject feels after taking the study drug as assessed by Drug Effects 
Questionnaire (DEQ-5) ratings. 
In addition, plasma concentrations of SAGE-217 and SAGE-217 metabolites may be measured.  
Pharmacokinetic parameters, such as area under the concentration-time curve from time zero to 
last time point (AUC0-t), area under the concentration-time curve from time zero to infinity 
(AUC0-∞), maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), 
and terminal half-life (t1/2), will be derived, where appropriate.   


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6.3. 
Exploratory Objectives 
The exploratory objectives of the study are to compare the effect of 7 days administration of 
SAGE-217 Oral Solution to placebo on: 
1. Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring) as assessed by the 
Empatica Wristband E4.  Tremor oscillation as assessed by multidimensional 
accelerometer measurements (ie, raw accelerometer values). 
2. Quality of life (QOL) as assessed by TETRAS activities of daily living (ADL), Quality of 
Life in Essential Tremor Questionnaire (QUEST), and video recording assessment of 
subjects performing three everyday tasks (drinking a glass of water, fastening a button, 
and one additional task that the subject experiences difficulty with on a daily basis). 
In addition, PK and pharmacodynamic modelling assessment of the relationship between plasma 
exposure of SAGE-217 and change from baseline in accelerometer-based Kinesia scores may be 
assessed.   


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study is a two-part, multicenter, Phase 2a study to evaluate the efficacy, safety, tolerability, 
and PK of SAGE-217 Oral Solution in up to 80 adult subjects with ET.  Part A of the study is an 
open-label design with morning dosing for 7 days.  Part B of the study is a double-blind, 
placebo-controlled, randomized withdrawal design.  Subjects will be exposed to study drug 
(SAGE-217 or placebo) for up to 14 days and will be followed for an additional 14 days after the 
administration of the last dose.   
During the Screening Period (Day -28 to Day -1), after signing the informed consent form (ICF), 
subjects will be assessed for study eligibility and the severity of each subject’s ET will be 
evaluated using TETRAS.  Eligible subjects will be admitted to the clinical study unit on Day -1.   
The study will be conducted in two parts: 
• Part A:  Beginning on Day 1, all subjects will receive open-label SAGE-217 in the 
morning with food (as outlined in Section 9.2) for 7 days.  Subjects will receive 
SAGE-217 10 mg on Day 1, SAGE-217 20 mg on Day 2, and SAGE-217 30 mg from 
Day 3 to Day 7, with dose adjustments for severe adverse events judged by the 
Investigator to be related to study drug (Section 9.3).  Subjects will be confined on 
Day -1 through Day 3.   
• Part B:  In order to qualify for Part B of the study, a subject must tolerate a maximum 
dose of ≥10 mg of SAGE-217, and the subject must have responded to SAGE-217, 
defined as a 30% reduction from baseline in TETRAS kinetic tremor combined score 
on Day 7.  Eligible subjects will be randomized in a 1:1:1 fashion to receive 
SAGE-217 in the morning or in the evening or to receive placebo for 7 days 
beginning on Day 8.  All doses of study drug will be administered with food as 
outlined in Section 9.2.  Subjects randomized to SAGE-217 will receive their 
maximum dose as determined in Part A.  In order to preserve the blind, those 
randomized to SAGE-217 in the morning will receive placebo in the evening, those 
randomized to receive SAGE-217 in the evening will receive placebo in the morning, 
and those randomized to receive placebo will receive placebo in both morning and 
evening.  Subjects randomized to the placebo arm will represent randomized 
withdrawal (ie, withdrawal from treatment they received in Part A).  Subjects will be 
confined on Day 7 through Day 10.   
Dose adjustments will only be allowed during Part A of the study.  A dose will be considered not 
tolerated if the subject experiences a severe adverse event considered to be related to the study 
drug by the Investigator.  If a dose is not tolerated, the dose on the next day will be reduced to 
the next lowest dose and continued for the remainder of the open-label dosing period (ie, subjects 
who are unable to tolerate SAGE-217 30 mg will receive SAGE-217 20 mg and subjects who are 
unable to tolerate SAGE-217 20 mg will receive SAGE-217 10 mg).  The dose tolerated on 
Days 5, 6, and 7 of Part A will be considered the maximum dose for that subject.  Subjects who 
require dose adjustments on Days 5, 6, and 7 of Part A will not progress to Part B.   


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7.2. 
Blinding and Randomization 
Part A is open-label with no control group; therefore, there will be no randomization or blinding.   
Part B of the study is a double-blind, placebo-controlled, randomized withdrawal study.  Subjects 
who tolerate a maximum dose of ≥10 mg of SAGE-217 in Part A and respond to SAGE-217, 
defined as a 30% reduction from baseline in TETRAS kinetic tremor combined score on Day 7, 
will be randomly assigned in a 1:1:1 fashion to receive SAGE-217 in the morning or in the 
evening or placebo according to a computer-generated randomization schedule.  Once it has been 
determined that a subject meets eligibility criteria, the subject will be sequentially assigned a 
subject number from the randomization schedule provided to the unblinded pharmacist.  Subject 
identification numbers will consist of the site number (eg, “01”) followed by numbering starting 
with double zero (eg, 01-001, 01-002, 01-003, etc.).   
A randomization schedule will be generated by an independent statistical consultant for the 
study.  This schedule will be prepared prior to the start of the study.  The randomization schedule 
will be generated using SAS V9.2 or later.  Only the clinic pharmacist, who is responsible for 
preparing the solutions, will be given a copy of the randomization schedule.  In the event of a 
medical emergency, the pharmacist may reveal actual solution contents to the investigator, who 
should also alert Sage of the emergency (see Section 13.6 for more details related to unblinding).  
In all cases where the study drug allocation for a subject is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the subject’s records and on the 
electronic case report form (eCRF).  If the subject or study center personnel (other than 
pharmacist) have been unblinded, the subject will be terminated from the study.   
In order to preserve the blind in Part B, those randomized to SAGE-217 morning dosing will 
receive placebo for the evening dose, those randomized to SAGE-217 evening dosing will 
receive placebo for the morning dose, and those randomized to placebo will receive placebo for 
both morning and evening dosing.  Subjects randomized to SAGE-217 will receive their 
maximum dose as determined in Part A.  Subjects randomized to the placebo arm will represent 
randomized withdrawal (withdrawal from treatment they received in Part A).   


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
It is anticipated that up to 80 subjects will be enrolled at up to 30 study centers.  The following 
inclusion and exclusion criteria will be applied during screening for Part A of the study.  
8.1. 
Subject Inclusion Criteria 
Subjects must meet the following inclusion criteria for enrollment in the study: 
1. Subject has signed an ICF before any study-specific procedures are performed.   
2. Subject must be between 18 and 75 years of age, inclusive. 
3. Subject must have a diagnosis of ET, defined as bilateral postural tremor and kinetic 
tremor, involving hands and forearms, that is visible and persistent and the duration is 
>5 years prior to screening. 
4. Subject must have bilateral TETRAS scores of at least two on each side (left and right) 
for kinetic tremor and at least two on each side (left and right) for either wing beating or 
forward outstretched postural tremor.   
5. Subject must be willing to discontinue medications taken for the treatment of ET, 
alcohol, nicotine, and caffeine through Day 21 of the study.   
6. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. 
7. Female subjects must be post-menopausal, permanently sterile (bilateral tubal occlusion), 
or of childbearing potential with a negative pregnancy test, non- breastfeeding, and using 
two highly effective methods of birth control prior to screening, throughout study 
participation and for 14 days after the last dose of study drug.  Highly effective methods 
of birth control are defined as follows:  hormonal (ie, established use of oral, implantable, 
injectable, or transdermal hormonal methods of conception); placement of an intrauterine 
device; placement of an intrauterine system; and mechanical/barrier method of 
contraception (ie, condom or occlusive cap [diaphragm or cervical/vault cap] in 
conjunction with spermicide [foam, gel, film, cream or suppository]).   
8. Male subjects must agree to practice a highly effective method of birth control while on 
study and for 13 weeks after receiving the last dose of study drug.  Effective methods of 
birth control include sexual abstinence, vasectomy, or a condom with spermicide (men) 
in combination with female partner’s highly effective method. 
9. Males must be willing to abstain from sperm donation while on study through 13 weeks 
after receiving the last dose of study drug. 
8.2. 
Subject Exclusion Criteria 
Subjects who met the following exclusion criteria will be excluded from the study: 
1. Subject has presence of abnormal neurological signs other than tremor or Froment’s sign. 
2. Subject has presence of known causes of enhanced physiological tremor. 


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3. Subject has or recent exposure (14 days prior to admission visit) to tremorogenic drugs, 
as defined in Appendix 1, or the presence of a drug withdrawal state. 
4. Subject has had direct or indirect trauma to the nervous system within 3 months before 
the onset of tremor.   
5. Subject has historical or clinical evidence of tremor with psychogenic origin (including 
but not limited to eating disorders, major depression, etc.).   
6. Subject has convincing evidence of sudden tremor onset or evidence of stepwise 
deterioration of tremor.   
7. Subject has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or 
oncological disease.   
8. Subject has clinically significant abnormal physical examination or 12-lead ECG at the 
Screening or Admission Visits.  Note:  A QT interval calculated using the Fridericia 
method [QTcF] of >450 msec in males or >470 msec in females, will be the basis for 
exclusion from the study.  An ECG may be repeated if initial values obtained exceed the 
limits specified. 
9. Subject has a 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. 
10. Subject has hyperthyroidism.   
11. Subject has used alcohol, caffeine, or nicotine within 3 days prior to Admission visit. 
12. Subject has a known allergy to SAGE-217 and its major excipient HPβCD.   
13. Subject has exposure to another investigational medication or device within the prior 
30 days. 
14. Subject has a history of suicidal behavior within 2 years or answers “YES” to questions 
3, 4, or 5 on the C-SSRS at the Screening Visit or on Day -1 or is currently at risk of 
suicide in the opinion of the Investigator. 
15. Subject has donated one or more units (1 unit = 450 mL) of blood or acute loss of an 
equivalent amount of blood within 60 days prior to dosing. 
16. Subject is unwilling or unable to comply with study procedures. 
17. Use of any known strong inhibitors and/or inducers of CYP3A4 within the 14 days or 
5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or St. John's Wort or products containing these within 30 days prior to receiving 
the first dose of study drug.   
8.3. 
Entrance Criteria for Part B 
The following entrance criteria will be applied prior to administration of blinded study drug in 
Part B; subjects who require dose adjustments on Days 5, 6, and 7 of Part A will not progress to 
Part B.   


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1. Subject must tolerate a maximum dose of ≥10 mg of SAGE-217 in Part A.   
2. Subject must have responded to SAGE-217, defined as a 30% reduction from baseline in 
TETRAS kinetic tremor combined score (ie, the sum of item 4c scores from both sides of 
the body) on Day 7.   
8.4. 
Subject Withdrawal Criteria 
If there is an adverse event or medical reason for the withdrawal, the subject should be followed 
medically until the condition has either resolved itself or is stable.  Details of the reason for 
withdrawal should be recorded in the subject’s case report form (CRF).   
Subjects who withdraw should, if possible, have a follow-up examination, including a physical 
examination, the appropriate investigations, vital signs, and clinical laboratory tests, as outlined 
for the Day 21 visit (Table 3).  All details of this follow-up examination should be recorded in 
the subject’s medical source documents.   
8.4.1. 
Study Drug Withdrawal 
Participation in the study is strictly voluntary.  Subjects are free to discontinue the study at any 
time without giving their reason(s).   
A subject must be withdrawn from the study treatment in the event of any of the following: 
• Withdrawal of the subject’s consent; 
• New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators and/Sponsor; 
• Occurrence of intolerable adverse events;  
• Occurrence of pregnancy;  
• Intake of nonpermitted concomitant medication; 
• Subject noncompliance;  
• Significant protocol deviation determined in consultation with the Medical Monitor. 
If a subject failed to attend scheduled assessments during the course of the study, the 
Investigators must determine the reasons and the circumstances as completely and accurately as 
possible and document this in the subject’s source documents.   
Subjects may be withdrawn from the study if there is concern for the subject’s safety or it is 
determined that the subject is no longer a qualified participant.  Any subject who is withdrawn 
from the study for any reason is to have the final visit assessments performed.   
Subjects who withdraw or are withdrawn from the study will be replaced only if they withdraw 
prior to dosing.  Subjects who are withdrawn from the study, fail to return or are no longer 
qualified will not be replaced.   


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8.4.2. 
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 adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons.  In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator. Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
participating subjects.   


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Number of Subjects 
Approximately 80 subjects with ET will be recruited into the study to yield at least 
60 randomized subjects for Part B.   
9.2. 
Treatment Assignment 
Study drug will be administered in the morning with food during Part A and in the morning and 
evening (every 12 hours) with food during Part B.  Food intake was standardized as specified by 
the Sponsor.   
9.2.1. 
Part A 
Subjects participating in Part A of the study will take study drug (SAGE-217) in an open-label 
manner.  All subjects will start on a 10 mg dose of study drug administered with food in the 
morning on Day 1.  Subjects will receive 20 mg with food on Day 2 and 30 mg with food daily 
on Days 3 to 7.  Dose adjustments will only be allowed any time the dose is not tolerated, 
assessed by occurrence of a severe adverse event judged by the investigator to be related to study 
drug (Section 9.3).  The dose tolerated for Days 5, 6, and 7 of the open-label dosing period will 
be determined to be the maximum dose for that subject.   
9.2.2. 
Part B 
Subjects participating in the double-blind, placebo-controlled, randomized withdrawal portion of 
the study (Part B) will be randomized to SAGE-217 morning dosing, SAGE-217 evening dosing, 
or placebo.  Subjects randomized to SAGE-217 will receive the maximum dose of SAGE-217 
from Part A of the study.  Following randomization, subjects will receive 7 days of study drug 
starting on Day 8.   
9.3. 
Dose Adjustment Criteria 
Dose adjustments will only be allowed during the open-label phase of the study (Part A).  If at 
any time the dose is not tolerated in Part A, assessed by occurrence of a severe adverse event 
judged by the investigator to be related to study drug, the dose on the next day will be reduced to 
the next lowest dose and continued for the remainder of the open-label dosing period (ie, subjects 
who are unable to tolerate the 30 mg dose will receive a lower dose of 20 mg, and subjects who 
are unable to tolerate 20 mg will be given a 10 mg dose).  The dose tolerated for Days 5, 6, and 7 
of the open-label dosing period will be determined to be the maximum dose for that subject.  
Subjects who require dose adjustments on Days 5, 6, and 7 of Part A will not progress to Part B.   


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9.4. 
Prior/Concomitant Medications and Restrictions 
9.4.1. 
Prior/Concomitant Medications 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 9.4.2.   
Record the name, start date (if known), indication for use and whether ongoing or stopped of 
medications/treatments taken within 2 weeks prior to study entry as well as any medications 
taken during the study.   
The charts of all study participants will be reviewed for new concomitant medications through 
discharge from the unit.  Chart reviews will include examination of nursing and physician 
progress notes, vital signs, and medication records in order to identify adverse events that may be 
associated with new concomitant medications.  New concomitant medications, ongoing 
concomitant medications with a change in dose and medical procedures ordered (eg, laboratory 
assessments, computed tomography or magnetic resonance imaging scans) will be reviewed to 
determine if they are associated with an adverse event not previously identified.   
9.4.2. 
Prohibited Medications 
The drug classes listed in Appendix 1 are not permitted in the 14 days prior to the admission visit 
and for the duration of the study (up to the Day 21 visit).  The list provides non-exhaustive 
examples of each drug class.   
Subjects are not permitted to use alcohol, caffeine, or nicotine within 3 days prior to Admission 
visit through the Day 21 visit.   
9.5. 
Treatment Compliance 
Investigational product will be prepared by the site pharmacist.  The Investigator(s) or designee 
will record the time and dose of study drug administration in the source documents.  Any reasons 
for non-compliance will also be documented, including: 
• Missed visits;  
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible.   


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose which is further diluted with Sterile 
Water for Injection to achieve the selected dosages.  The 6 mg/mL stock SAGE-217 Oral 
Solution will be compounded from SAGE-217 Drug Substance Powder in the Bottle and 
Excipient (s) in the Bottle (manufactured under clinical Good Manufacturing Practice [GMP] 
conditions at 
) and further admixed at the clinical site in preparation for dosing.  
Placebo will be matched to SAGE-217 study drug.  Detailed instructions for study drug 
preparation will be provided in the Pharmacy Manual.   
10.2. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured by 
 and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual.  The batch formula for a 125 mL solution of the 6 mg/mL 
stock solution is shown in Table 5.   
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
Ingredient 
Compendia Specification Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD (Kleptose®) 
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.029 
3.569 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations:  EP = European Pharmacopeia; HPβCD = hydroxylpropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
10.3. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation.  Study drug will be provided to the site as powder 
in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy at a volume of 
125 mL of a 6 mg/mL stock solution and then further diluted to approximately 40 mL at the 
identified doses.  Study drug labels with all required information and conforming to all 
applicable Code of Federal Regulations and GMP/GCP guidelines will be prepared by the 
clinical research organization.   
10.4. 
Study Drug Storage 
Upon receipt of study drug (SAGE-217 and placebo), the Investigator or designee will inspect 
the medication and complete and return the acknowledgment of receipt form enclosed with the 
parcel.  A copy of the signed receipt will be kept in the study files.  


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The study drug must be carefully stored at the temperature specified in the Pharmacy Manual 
(eg, clinical dosing solutions stored at approximately 2 to 8°C for 10 days or room temperature 
for up to 24 hours after preparation), safely and separately from other drugs.  The study drug 
may not be used for any purpose other than the present study.  After the study is completed, all 
unused study drug must be retained, returned as directed, or destroyed on site per the Sponsor’s 
instructions.   
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies.  An accurate, timely record of 
the disposition of all clinical supplies must be maintained.  The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed; 
• The date(s) and quantity of the drug dispensed to the subject; and 
• The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
A copy of the inventory record and a record of any clinical supplies that have been destroyed 
must be documented.  This documentation must include at least the information below or as 
agreed with the Sponsor: 
• The number of prepared units; 
• The number of administered units; 
• The number of unused units; 
• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 
10.5. 
Administration and Study Drug Accountability 
Doses will be prepared as an approximate 40 mL oral solution to be swallowed all at once, 
followed by approximately 200 mL of water which has been used to rinse the dosing bottle.  The 
start time of swallowing the approximately 40 mL oral solution is time zero for all assessments.  
Subjects may have assistance from the clinic staff when taking the study drug.   
10.5.1. 
Study Drug Administration 
While confined in the clinical unit (Day -1 through Day 3), subjects in Part A will receive a 
10 mg dose of study drug administered in the morning on Day 1, 20 mg on Day 2, and 30 mg on 
Day 3.   
While confined in the clinical unit in Part B (Day 7 through Day 10), subjects will receive 
randomized study drug in the morning and in the evening on Days 8, 9, and 10.   
For non-confinement days (Days 4 through 6 [Part A] and Days 11 through 14 [Part B]), dosing 
will be done at the clinical site or, if suitable arrangements can be made, via home administration 


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where local regulations allow.  Home administration of study drug will be performed according 
to a site-specific plan by a healthcare professional trained on the protocol and delivery of the 
study drug.   
10.5.2. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol.   
The Investigator or designee must maintain a record of all study drug received, used, and 
discarded.  It must be clear from the records which subject received which dose of active or 
placebo treatment.   
The Sponsor will be permitted access to the study supplies at any time within usual business 
hours and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation.  Only unblinded personnel will be able to access the study drug and 
accountability documentation from first dosing through database hard lock.   
10.6. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding, subsequent admixture, administration of test article, and for which subject the 
study drug was intended (ie, record subject initials and birth date or other unique identifier).   
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions; disposition of study drug will be 
documented.   


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11. 
ASSESSMENT OF EFFICACY 
Efficacy assessments include evaluation of subject symptom response by a measurement of 
tremor amplitude, TETRAS upper limb subscale, and TETRAS Performance Subscale (items 4, 
6, 7, and 8).  Quality-of-life assessments include TETRAS ADL, QUEST, and video recording 
of subjects performing three everyday tasks.  Physiological activity (ie, sympathetic nervous 
system tone as measured by electrodermal activity, skin temperature monitoring, and heart rate 
monitoring) will be assessed by the Empatica Wristband E4.   
11.1. 
Measurements of Tremor Amplitude 
In order to measure essential tremor amplitude, subjects will wear a wireless ring motion sensor.  
The motion sensor measures linear acceleration and angular velocity (the Kinesia score).  
Amplitudes from the motion sensor data are collected for three upper limb maneuvers (postural 
tremor, wing beating, kinetic tremor) on each side of the body, for a total of six amplitude 
measures per assessment.  Data are transmitted from the sensor to a computer using Bluetooth 
technology.  Information from the motion sensor data correlates to symptoms of tremor. The 
Kinesia score ranges from 0 to 4 in 0.5 step increments.  Higher scores indicate more tremors.  
The accelerometer assessment is completed in conjunction with the TETRAS Performance 
Subscale Item 4.   
In Part A, Kinesia will be performed predose on Day -1 (Admission; three assessments separated 
by at least 30 minutes) and predose and 2, 12, and 14 hours postdose (three assessments 
separated by at least 30 minutes) on Days 1, 2, and 7.  In Part B, Kinesia will be performed 
before morning dose, after morning dose (2 hours post morning dose), before evening dose 
(12 hours post morning dose), and after evening dose (14 hours post morning dose) (three 
assessments separated by at least 30 minutes) on Days 8, 9, and 14, and on Day 21.   
11.2. 
TRG Essential Tremor Rating Assessment Scale (TETRAS) 
Performance Scale 
Item #4 (upper limb tremor) of the TETRAS Performance Subscale will be completed using both 
the accelerometer and clinician assessment.  Testing should be completed within ±10 minutes of 
the planned questionnaire time points.  All three tests in the upper limb tremor series of 
assessments (Item 4) will be completed for both arms, first for the RIGHT arm and then for the 
LEFT.  Predose assessments can be done any time within 2 hours prior to the start of 
administration of solution.  The Day 21 follow-up visit assessments can be done at any time 
during the visit.   
Subjects will complete the TETRAS Performance Subscale, Item #4 (upper limb tremor) while 
wearing the accelerometer.  Simultaneous clinician assessment of item #4 will occur.  The 
accelerometer assessment is completed in conjunction with the TETRAS Performance Subscale 
at the same time points during the study.   
In Part A, the TETRAS upper limb subscale will be performed at Screening, predose on Day -1 
(Admission; three assessments separated by at least 30 minutes), and predose and 2, 12, and 
14 hours postdose (three assessments separated by at least 30 minutes) on Days 1, 2, and 7.  The 


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TETRAS (all ADL and Performance Subscale [Items 4, 6, 7, and 8]) will be performed on 
Day -1 (Admission) and on Day 7.   
In Part B, the TETRAS upper limb subscale will be before morning dose, after morning dose 
(2 hours post morning dose), before evening dose (12 hours post morning dose), and after 
evening dose (14 hours post morning dose) (three assessments separated by at least 30 minutes) 
on Days 8, 9, and 14, and on Day 21.  The TETRAS (all ADL and Performance Subscale [Items 
4, 6, 7, and 8]) will be performed on Day 14 and Day 21.   
Note that the bilateral TETRAS score for the test conducted during Screening will be used to 
determine eligibility and must be ≥2 on each side (left and right) for kinetic tremor and ≥2 on 
each side (left and right) for either wing beating or forward outstretched postural tremor.  A copy 
of the TETRAS is provided in Appendix 2.   
11.3. 
Empatica Wristband E4 
Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring) will be assessed by the 
Empatica Wristband E4.  The Empatica Wristband E4 is a wearable motion device that captures 
motion-based activity and sympathetic nervous system arousal, even when the wearer is not 
moving.  The Empatica Wristband E4 will be worn during the Confinement Periods and on 
Day 14.  Data from the Empatica Wristband E4 will not be presented in the study report; instead, 
they will be part of a separate report.   
11.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST) 
The QUEST is a brief, 30-item, ET-specific QOL scale in which subjects rate the extent to which 
tremor impacts a function or state, tremor severity in various body parts, perceived health, and 
overall QOL (Tröster 2005).  The QUEST will be administered predose on Day -1 (Admission), 
Day 7, and on Day 14.  A copy of the QUEST is provided in Appendix 3.   
11.5. 
Video Recording 
Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, 
and one additional task that the subject experiences difficulty with on a daily basis) will be taken 
on Day -1 (Admission) and predose on Day 7 in Part A and on Day 14 and Day 21 in Part B.   


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
In Part A, plasma samples for PK analysis will be collected predose and 0.25, 0.5, 1, 2, 4, 8, 12, 
and 24 hours postdose on Day 1 and predose on Days 2, 3, 4, 5, 6, and 7.  In Part B, plasma 
samples for PK analysis will be collected predose and 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours 
postdose on Day 8 and predose on Days 9, 10, 11, 12, 13, and 14.  The time of study drug 
administration is time zero and all post-dosing sampling times are relative to this time.  The 
Investigator or designee will arrange to have the plasma samples processed, stored, and 
transported as directed for bioanalysis.   
An additional PK sample may be collected at any time if clinically indicated and at the discretion 
of the Investigator (eg, for unusual or severe adverse events).   
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time.  The date and actual time that the blood sample was taken will be 
recorded on the CRF or electronically with a bar code or other method.   
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70°C to -80°C until analyzed.  
They should be packed as directed to avoid breakage during transit and with sufficient dry ice to 
prevent thawing for at least 72 hours.  A specimen-identification form must be completed and 
sent to the laboratory with each set of samples.  The clinical site will arrange to have the plasma 
samples transported as directed for bioanalysis as detailed in the PK instructions.   
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of SAGE-217 will be performed utilizing a 
validated liquid chromatography-tandem mass spectrometry method at a qualified laboratory.   
 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety and Tolerability Parameters 
Safety and tolerability of study drug will be evaluated by vital signs measurements, clinical 
laboratory measures, physical examination, ECGs, concomitant medication usage, C-SSRS, SSS, 
MOAA/S scores, and adverse event reporting.  The Bond-Lader Mood Rating Scale and a 
DEQ-5 will be used to assess mood and perception of drug effects, respectively.   
13.1.1. 
Demographic/Medical History 
Age, gender, race, and ethnic origin will be recorded at the Screening visit.  A full medical 
history including medication history will be recorded at the Screening visit.   
13.1.2. 
Vital Signs 
Vital signs comprise supine (supine for at least 5 minutes prior to the measurement) and standing 
systolic and diastolic blood pressure and heart rate, respiratory rate and temperature.   
In Part A, vital signs and pulse oximetry will be performed at Screening (vital signs only) and 
Day -1 (Admission), predose and at 1, 2, 3, 4, 6, 8, 12, 14, 16, and 24 hours postdose on Days 1, 
2, and 3, predose only on Days 4, 5, 6, and 7.  In Part B, vital signs and pulse oximetry will be 
performed predose and at 1, 2, 3, 4, 6, 8, 12, 14, 16, and 24 hours postdose on Days 8, 9, and 10, 
predose only on Days 11, 12, 13, and 14, and on Day 21.   
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visit.   
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening visit.   
13.1.5. 
Electrocardiogram (ECG) 
A supine 12-lead ECG will be performed at the times specified below and the standard intervals 
recorded as well as any abnormalities.   
In Part A, the 12-lead ECG will be assessed at Screening, predose on Day 1, at 1, 12, and 
24 hours postdose on Days 1, 2, 3, and 7.  In Part B, the 12-lead ECG will be assessed at 1, 12, 
and 24 hours postdose on Days 8, 9, and 10, on Day 14, and on Day 21.   
All time points are relative to the time of dosing.   
13.1.6. 
Laboratory Assessments 
In Part A, blood and urine samples will be collected for hematology, serum chemistry, and 
urinalysis at the Screening visit, on Day -1 (Admission), Day 1, and predose on Day 2.  In 
Part B, blood and urine samples will be collected predose on Day 8, Day 9, and on Day 21.   


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Serum and urine samples for pregnancy tests (females only) will also be collected.  These 
assessments should be performed in accordance with the Schedule of Events (Table 2 and 
Table 3) and as outlined individually below.   
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS); or abnormal, clinically significant 
(CS).  Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the medical monitor.  Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to 
Section 13.2.1, and recorded in the eCRF.   
13.1.6.1. Hematology 
Hematology tests will include complete blood count, including red blood cells, white blood cells 
with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets.  The coagulation panel 
will include activated partial thromboplastin time, prothrombin time, and international 
normalized ratio.   
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes, renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide, liver function tests, including total 
bilirubin, AST, and ALT, total protein, and albumin.   
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity.   
13.1.6.4. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
the study.   
13.1.6.5. Pregnancy Test 
Females of child-bearing potential will be tested for pregnancy by serum pregnancy test at the 
Screening visit and by urine pregnancy test on Day -1 (Admission), and at the follow-up visit on 
Day 28 in Part B.   
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011).  This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit.  The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).   


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If in the opinion of the Investigator, the subject is showing any suicidal tendency, no further 
study drug will be administered and the subject will be referred to a psychologist or psychiatrist 
for further evaluation.  This information will be tracked.   
The “Baseline/Screening” C-SSRS form will be completed on Day -1 (Admission) (lifetime 
history and past 24 months).  In Part A, the “Since Last Visit” C-SSRS form will be completed 
12 hours postdose on Day 1, predose on Day 4, and on Days 5, 6, and 7.  In Part B, the “Since 
Last Visit” C-SSRS form will be completed on Days 8, 11, 12, 13, and 14, on Day 21, and on 
Day 28.  The C-SSRS is provided in Appendix 4.   
13.1.8. 
Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling.  Degrees 
of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of ‘1’ indicates 
the subject is ‘feeling active, vital, alert, or wide awake’ and the highest score of ‘7’ indicates the 
subject is ‘no longer fighting sleep, sleep onset soon; having dream-like thoughts’.   
In Part A, the SSS will be administered predose and 1, 2, 3, 4, 6, 8, 12, 14, 16, and 24 hours 
postdose on Days 1, 2, and 3, and predose only on Days 4, 5, 6, and 7.  In Part B, the SSS will be 
administered predose and 1, 2, 3, 4, 6, 8, 12, 14, 16, and 24 hours postdose on Days 8, 9, and 10, 
predose only on Days 11, 12, 13, and 14, and on Day 21.  All time points are relative to the time 
of dosing.  The SSS is provided in Appendix 5.  The SSS should be performed prior to the 
MOAA/S score. 
13.1.9. 
Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) 
The MOAA/S allows exploration of deeper sedation states than the SSS.  If a MOAA/S score of 
3 or less was observed, the score was to be confirmed by waiting approximately 10 minutes and 
re-administering the MOAA/S assessment.  In Part A, the MOAA/S assessment should be 
conducted after other assessments that are scheduled at the same time point.  In Part A, the 
MOAA/S will be performed predose and 1, 2, 3, 4, 6, 8, 12, 14, 16, and 24 hours postdose on 
Days 1, 2, and 3, predose only on Days 4, 5, 6, and 7.  In Part B, the MOAA/S will be performed 
predose and 1, 2, 3, 4, 6, 8, 12, 14, 16, and 24 hours postdose on Days 8, 9, and 10, predose only 
on Days 11, 12, 13, and 14, and on Day 21.  The MOAA/S is provided in Appendix 6.   
13.1.10. 
Bond-Lader VAS Mood Scale 
Mood will be assessed using the Bond-Lader Mood Rating Scale.  This is a 16-part self-
administered questionnaire that employs a 100-mm VAS to explore different aspects of self-
reported mood.  In Part A, the mood scale will be administered predose on Days 1, 2, and 7.  In 
Part B, the mood scale will be administered predose on Days 8, 9, and 14 and on Day 21.  The 
Bond-Lader Mood Rating Scale is provided in Appendix 7.   
13.1.11. 
Drug Effects Questionnaire (DEQ-5) 
A DEQ-5 will be administered as follows: 
1. Do you FEEL a drug effect right now? 
2. Are you HIGH right now? 
3. Do you DISLIKE any of the effects that you are feeling right now? 


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4. Do you LIKE any of the effects that you are feeling right now? 
5. Would you like MORE of the drug you took, right now? 
The answers are recorded on a 100-mm VAS, with the answer for each being “Not at all” and 
“Extremely” at the extremes.  There will be options to record “Not applicable” for questions 3 
and 4 if no drug effects are felt and for question 5 prior to administration of study medication.  
The DEQ-5 will be performed 2 hours postdose on Days 1 and 7 in Part A and 2 hours postdose 
on Days 8 and 14 in Part B.  The DEQ-5 is provided in Appendix 8.   
13.2. 
Adverse and Serious Adverse Events 
Adverse events will be collected after the ICF has been signed.  Medical conditions that occur 
after the ICF has been signed will be captured on the adverse event eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (version 18.1 or higher).  
13.2.1. 
Definition of Adverse Events 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered. 
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug.   
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 


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All serious adverse events that occur after any subject has been enrolled, whether or not they are 
related to the study, must be recorded on forms provided by Sage Therapeutics or designee for 
the duration of the study. 
13.2.1.4. Recording Sedation as an Adverse Event 
Sedation will be assessed using protocol-specified rating scales.  In order to standardize the 
reporting of sedation as adverse events, Investigators need not record sedation as an adverse 
event unless there is a score of >5 on the SSS and/or a score of ≤2 on the MOAA/S.  
Consideration should be given to the most appropriate term to describe the sedation 
characteristics.   
13.2.2. 
Pregnancy 
Any pregnancy occurring during this study will be reported within 24 hours of notification of the 
Investigator.  The Investigator will promptly notify the Medical Monitor and withdraw the 
subject from the study.  The Investigator should request permission to contact the subject, the 
subject’s spouse/partner (if the subject is male and his spouse/partner becomes pregnant) or the 
obstetrician for information about the outcome of the pregnancy, and in the case of a live birth, 
about any congenital abnormalities.  If a congenital abnormality is reported, then it should be 
recorded in the source documents and reported as a serious adverse event.   
13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, possibly related or probably related).  
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product.  If no valid reason 
exists for suggesting a relationship, then the adverse event should be classified as “unrelated.”  If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the adverse event, then the 
adverse event should be considered “related.”   
Not 
Related: 
No relationship between the experience and the administration of study drug; related to other 
etiologies such as concomitant medications or subject’s clinical state. 
Possibly 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug and 
follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of therapy 
administered to the subject, but this is not known for sure. 
Probably 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug and 
follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s clinical 
state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered to be related 
to the investigational product for the purposes of expedited regulatory reporting.   


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13.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject 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.  Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event or lead to discontinuation of administration of 
study drug.   
Information about adverse events will be collected from the signing of the ICF until the final 
visit of the study for that subject.  Adverse events that occur after the first administration of study 
drug will be denoted TEAEs.   
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
no expectation of future change.   
The adverse event term should be reported in standard medical terminology when possible.  For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), intensity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study.   
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
13.5. 
Reporting Serious Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until 14 days following the last dose of study drug.  Any serious adverse events considered 
possibly or probably related to the investigational product and discovered by the Investigator at 
any time after the study should be reported.  All serious adverse events must be reported to the 
Sponsor or Sponsor’s designee immediately by phone and in writing within 24 hours of the first 
awareness of the event.  The Investigator must complete, sign and date the serious adverse event 
pages, verify the accuracy of the information recorded on the serious adverse event pages with 
the corresponding source documents, and send a copy to Sage Therapeutics or designee.   
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the CRF and/or study file.   
Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
certain events.  It is the Principal Investigator’s responsibility to notify the IRB of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements.  Investigators 
will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) 
that occur during the clinical study.  Each site is responsible for notifying its IRB of these 
additional serious adverse events.   


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13.6. 
Emergency Identification of Study Drug (Part B) 
Part B is a double-blind study.  The pharmacist responsible for preparing the solutions will be 
unblinded and will retain an official paper copy of the randomization schedule. 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received.  Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact the Sponsor prior to unblinding the 
study treatment administered to a subject.  Any request from the Investigator about the treatment 
administered to study subjects must be discussed with the Sponsor.  If the unblinding occurs 
without the Sponsor’s knowledge, the Investigator must notify the Sponsor as soon as possible 
and no later than the next business morning.  All circumstances surrounding a premature 
unblinding must be clearly documented in the source records.  Unless a subject is at immediate 
risk, any request for the unblinding of individual subjects must be made in writing to the Sponsor 
and approved by the appropriate Sponsor personnel, according to standard operating procedures.  
The blinding of the study will be broken after the database has been locked.  Electronic copies of 
the randomization code will be made available to the laboratory performing the bioanalytical 
analyses in order to allow for limited analysis of samples from subjects receiving placebo.   
In all cases where the study drug allocation for a subject is unblinded, pertinent information must 
be documented in the subject’s records and on the eCRF.  If the subject or study center personnel 
(other than pharmacist) have been unblinded, the subject will be terminated from the study.   


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14. 
STATISTICAL METHODS AND CONSIDERATIONS 
14.1. 
Data Analysis Sets 
The safety population is defined as all subjects who are administered study drug.   
The efficacy population will consist of all subjects in the safety population who complete at least 
one dose in Part B and have at least one post-randomization efficacy evaluation.   
The evaluable population will consist of all randomized subjects with at least one post-
randomization Kinesia assessment.   
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations.   
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data.  All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available.  No imputation process will be 
used to estimate missing data.  No sensitivity analysis of missing data will be performed.   
14.3. 
Demographics and Baseline Characteristics 
Demographics, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized.   
Categorical summaries, such as race and ethnicity, will be summarized by frequency and 
percentage.  Continuous summaries, such as age, height, weight, BMI, and baseline vital signs, 
will be summarized using descriptive statistics.   
Hepatitis, HIV, drug, and pregnancy screening results will be listed, but not summarized as they 
are considered part of the inclusion/exclusion criteria.   
Medical history will be listed by subject.   
14.4. 
Primary Efficacy Endpoint 
The change from randomization (Day 8) in the accelerometer-based Kinesia kinetic tremor 
combined score (ie, the sum of item 4c scores from both sides of the body) at Day 14 will be 
summarized by treatment group in Part B.   
14.5. 
Secondary Efficacy Endpoints 
The change from randomization (Day 8) in the accelerometer-based Kinesia upper limb total and 
individual item scores, TETRAS total and individual upper limb item scores, and TETRAS 
Performance Subscale scores at Day 14 will be summarized by treatment group in Part B.   
14.6. 
Exploratory Efficacy Endpoints 
The change from randomization (Day 8) in TETRAS ADL scores at Day 14 will be summarized 
by treatment group in Part B.   


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Empatica Wristband E4 Tremor oscillation and QUEST data will be listed by subject, study day, 
and time point.   
A summary of clinical ratings of video recordings will be presented by group in Part B.   
14.7. 
Safety and Tolerability Analyses 
Data from vital signs, clinical laboratory measures, ECG, C-SSRS, and MOAA/S will be 
summarized using descriptive statistics by group and time point, where applicable.  Continuous 
endpoints will be summarized with n, mean, standard deviation, median, minimum, and 
maximum.  In addition, change from baseline values will be calculated at each time point and 
will be summarized using descriptive statistics.  Out-of-range safety endpoints may be 
categorized as low or high, where applicable.  For all categorical endpoints, summaries will 
include counts and percentages.   
14.7.1. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system (version 18.1 or higher).  The 
analysis of adverse events will be based on the concept of TEAEs.  A TEAE is defined as an 
adverse event with onset after the start of open-label study drug, or any worsening of a pre-
existing medical condition/adverse event with onset after the start of open-label study drug and 
until 7 days after the last dose.  The incidence of TEAEs will be summarized overall and by 
MedDRA System Organ Class, preferred term, and dose group.  Incidences will be presented in 
order of decreasing frequency.  In addition, summaries will be provided by maximum severity 
and relationship to study drug (see Section 13.3).   
TEAEs leading to discontinuation and serious adverse events (see Section 13.2.1.3 for definition) 
with onset after the first dose of open-label study drug will also be summarized. 
All adverse events and serious adverse events (including those with onset or worsening before 
the start of open-label study drug) through the Day 28 follow-up visit will be listed.   
14.7.2. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection.  Mean changes from 
randomization in vital signs will be evaluated by time point.   
14.7.3. 
Physical Examinations 
Screening physical examination results will be listed by subject.  Any clinically significant 
physical examination will be recorded in medical history.   
14.7.4. 
12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QTcF.  Any clinically significant abnormalities or changes in ECGs should be listed as an 
adverse event.  Electrocardiogram findings will be listed by subject and visit.   
14.7.5. 
Clinical Laboratory Evaluations 
Clinical laboratory results will be listed by subject and timing of collection.  Mean changes from 
baseline and randomization in clinical laboratory measures will be evaluated.   


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14.7.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS will be listed for all subjects.  Listings will include 
behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the C-SSRS.   
14.7.7. 
Stanford Sleepiness Scale (SSS) 
Sedation data collected on the SSS will be listed for all subjects.  Changes in score over time will 
be represented graphically, and change from Day 1 will be measured. 
14.7.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) 
Sedation data collected on the MOAA/S will be listed for all subjects.  Changes in score over 
time will be represented graphically, and change from Day 1 will be measured. 
14.7.9. 
Bond-Lader VAS Mood Scale 
Mood data collected on the Bond-Lader VAS mood scale will be listed by subject, study day, 
and time point.  The scores and change from Day 1 will be summarized by study day and time 
point.   
14.7.10. 
Drug Effects Questionnaire (DEQ-5) 
Results from DEQ-5 will be listed by subject, study day, and time point.  The result for each 
question and change from Day 1 will be summarized by study day and time point.  
14.7.11. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization (WHO)-Drug dictionary September 2015, or later.   
Medications will be presented according to whether they are being taken prior to and/or during 
the study (concomitant).  Prior medications are defined as those taken during the 4 weeks prior to 
the date of the first dose of open-label study drug.  Concomitant medications are defined as those 
with a start date on or after the first dose of open-label study drug, or those with a start date 
before the first dose of open-label study drug that are ongoing or with a stop date on or after the 
first dose of open-label study drug.  If medication dates are incomplete and it is not clear whether 
the medication was concomitant, it will be assumed to be concomitant.   
Concomitant medications will be assigned to the part in which they are being taken.  If a 
concomitant medication assigned to a Part A continues to be taken through Part B, then the 
medication will be assigned to both parts of the study as appropriate.  If the start and stop dates 
of the concomitant medications do not clearly define the part during which a medication was 
taken, it will be assumed to be taken in both parts.  Details of prior and concomitant medications 
will be listed by study part, subject, start date, and verbatim term.   
14.8. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics.  Time to 
reach maximum concentration (tmax) will be summarized using n, mean, standard deviation, 
median, minimum, and maximum.  All other PK parameters will be summarized using n, 
geometric mean, coefficient of variation, median, minimum, and maximum and listed by subject.   


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Wherever necessary and appropriate, PK parameters will be dose-adjusted to account for 
individual differences in dose.   
Pharmacokinetic and pharmacodynamic modelling assessment of the relationship between 
plasma exposure of SAGE-217 and change from baseline in accelerometer-based Kinesia scores 
may be assessed.   
14.9. 
Determination of Sample Size 
Up to 80 subjects will be enrolled in Part A to yield at least 60 randomized subjects for Part B.  
A total sample size of 51 evaluable subjects (ie, 17 per group) will have 80% power to detect a 
difference in means of 3.0 on the primary endpoint assuming that the common standard deviation 
is 3.0 using a 2-group t-test with a 0.05 two-sided significance level.  Assuming a 15% non-
evaluability rate, 20 subjects per group will be randomized.  The number of subjects in each 
treatment group is also thought to be sufficient to assess preliminary safety and tolerability 
following multiple doses of SAGE-217 Oral Solution. 
14.10. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
statistical analysis plan.  


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Sage 
Therapeutics or designee will visit the investigational study site to:   
• Determine the adequacy of the facilities; and 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives.  This will be documented in a Clinical Study Agreement between 
Sage Therapeutics and the Investigator.   
During the study, a monitor from Sage Therapeutics or designee 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 CRFs, and that investigational product accountability 
checks are being performed; 
• Perform source data verification. This includes a comparison of the data in the CRFs 
with the subject’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 
subject (eg, clinic charts); 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm adverse events and serious adverse events have been properly documented 
on CRFs and confirm any serious adverse events have been forwarded to Sage 
Therapeutics or designee and those serious adverse events that met criteria for 
reporting have been forwarded to the IRB.   
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification.  The purpose of a Sage Therapeutics or designee audit or 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 guidelines of the International Council on 
Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency about an inspection.   


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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study, including the subject consent form and 
recruitment materials, must be maintained by the Investigator and made available for inspection.   


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
CRFs.   
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements.   
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate.  The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study.   
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  Sage Therapeutics or designee will provide this information to the Principal 
Investigator.   
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines.   
17.2. 
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 the most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements.   
17.3. 
Written Informed Consent 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study.  Subjects must also 
be notified that they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided.   
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures.   
The Principal Investigator(s) must maintain the original, signed ICF.  A copy of the signed ICF 
must be given to the subject.   
 


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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan.   
Electronic CRFs will be completed for each study subject.  It is the Investigator’s responsibility 
to ensure the accuracy, completeness, and timeliness of the data reported in the subject’s eCRF.  
Source documentation supporting the eCRF data should indicate the subject’s participation in the 
study and should document the dates and details of study procedures, adverse events, and subject 
status.   
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study.  For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct.   
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or, if not approved, 2 years following the 
discontinuance of the test article for investigation.  If it becomes necessary for Sage Therapeutics 
or the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records.   
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports and communications will identify the 
subject by the assigned subject number.  The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process.  The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations.   
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used.   


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All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information.  The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor.  It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study.  The information obtained from the clinical study will be used 
towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required.   


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19. 
PUBLICATION POLICY 
All information concerning SAGE-217 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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20. 
LIST OF REFERENCES 
Axelrad JE, Louis ED, Honig LS, et al. Reduced Purkinje cell number in essential tremor: A 
postmortem study. Arch Neurol. 2008;65(1):101–7. 
Belelli D, Casula A, Ling A, Lambert JJ.  The influence of subunit composition on the 
interaction of neurosteroids with GABA(A) receptors. Neuropharmacology. 2002 
Sep;43(4):651-61. 
Benito-Leon J, Louis ED. Clinical update: diagnosis and treatment of essential tremor. Lancet. 
2007;369(9568):1152-4. 
Boecker H, Kleinschmidt A, Requardt M, Hänicke W, Merboldt KD, Frahm J. Functional 
cooperativity of human cortical motor areas during self-paced simple finger movements. A high 
resolution MRI study. Brain. 1994;117(Pt 6):1231-9. 
Bucher SF, Seelos KC, Dodel RC, et al. Activation mapping in essential tremor with functional 
magnetic resonance imaging. Ann Neurol. 1997;41:32-40. 
Cavanagh JB, Holton JL, Nolan CC, Ray DE, Naik JT, Mantle PG. The effects of the 
tremorgenic mycotoxin penitrem A on the rat cerebellum. Vet Pathol. 1998;35:53–63. 
Deuschl G, Bain P, Brin M. Adhoc-Scientific-Committee. Consensus Statement of the 
Movement Disorder Society on Tremor. Mov Disord. 1998;13(suppl 3):2-23. 
Deuschl G, Elble R. Essential tremor—neurodegenerative or nondegenerative disease towards a 
working definition of ET. Mov Disord. 2009;24(14):2033–41. 
Deuschl G, Raethjen J, Hellriegel H, et al. Treatment of patients with essential tremor. Lancet 
Neurol. 2011;10:148–61. 
Elble RJ, Deuschl G. An update on essential tremor. Curr Neurol Neurosci Rep. 2009;9:273–7. 
Esmaeili A, Lynch JW, Sah P.  GABAA receptors containing gamma1 subunits contribute to 
inhibitory transmission in the central amygdala. J Neurophysiol. 2009;101(1):341-9.  
Gironell A, Kulisevsky J, Barbanoj M, et al. A randomized placebo controlled comparative trial 
of gabapentin and propranolol in essential tremor. Arch Neurol. 1999;56:475–80. 
Gorman WP, Cooper R, Pocock P, et al. A comparison of primidone, propranolol, and placebo in 
essential tremor, using quantitative analysis. J Neurol Neurosurg Psychiatry. 1986;49:64–8. 
Habib-ur-Rehman. Diagnosis and management of tremor. Arch Intern Med. 
2000;160(16):2438-44. 
Kralic JE, Criswell HE, Osterman JL, et al. Genetic essential tremor in gamma-aminobutyric 
acid A receptor alpha1 subunit knockout mice. J Clin Invest. 2005;115:774–9. 
Louis ED, Faust PL, Vonsattel JP, et al. Neuropathological changes in essential tremor: 33 cases 
compared with 21 controls. Brain. 2007;130:3297–307. 
Louis ED, Vonsattel JPG. The emerging neuropathology of essential tremor. Mov Disord. 
2008;23(2):174-82. 


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Louis ED. Essential tremors: a family of neurodegenerative disorders? Arch Neurol. 
2009;66:1202–8. 
Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on 
the worldwide prevalence of essential tremor. Mov Disord. 2010;25:534–41. 
Louis ED. Treatment of essential tremor: are there issues we are overlooking? Front Neurol. 
2012;2:91. 
Málly J, Baranyi M, Vizi ES. Change in the concentrations of amino acids in CSF and serum of 
patients with essential tremor. J Neural Transm. 1996;103:555-60. 
McAuley JH, Marsden CD. Physiological and pathological tremors and rhythmic central motor 
control. Brain. 2000;123 (Pt 8):1545-67. 
Miwa H. Rodent models of tremor. Cerebellum. 2007;6:66-72. 
O'Brien MD, Upton AR, Toseland PA. Benign familial tremor treated with primidone. Br Med J 
(Clin Res Ed). 1981;82(6259):178-80. 
Pahapill PA, Levy R, Dostrovsky JO, et al. Tremor arrest with thalamic microinjections of 
muscimol in patients with essential tremor. Ann Neurol. 1999;46(2):249-52. 
Pahwa R, Lyons KE. Essential tremor: differential diagnosis and current therapy. Am J Med. 
2003;115(2):134-42. 
Paris-Robidas S, Brochu E, Sintes M, et al. Defective dentate nucleus GABA receptors in 
essential tremor. Brain. 2012;135:105-16. 
Pinto AD, Lang AE, Chen R. The cerebellothalamocortical pathway in essential tremor. 
Neurology. 2003;60(12):1985-7. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 
Pritchett DB, Sontheimer H, Shivers BD, et al.  Importance of a novel GABAA receptor subunit 
for benzodiazepine pharmacology.  Nature. 1989;338(6216):582-5. 
Rajput AH, Rajput A. Medical Treatment of Essential Tremor. J Cent Nerv Syst Dis. 
2014;6:29-39. eCollection 2014. 
Schmouth JF, Dion PA, Rouleau GA. Genetics of essential tremor: from phenotype to genes, 
insights from both human and mouse studies. Prog Neurobiol. 2014 Aug-Sep;119-120:1-19.  
Schnitzler A, Munks C, Butz M, et al. Synchronized brain network associated with essential 
tremor as revealed by magnetoencephalography Mov Disord. 2009;24:1629-35. 
Shill HA, Adler CH, Sabbagh MN, et al. Pathologic findings in prospectively ascertained 
essential tremor subjects. Neurology. 2008;70:1452-5.   
Tröster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of life in Essential Tremor 
Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord. 2005 
Sep;11(6):367-73. 


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Wills AJ, Thompson PD, Findley LJ, et al. A positron emission tomography study of primary 
orthostatic tremor. Neurol. 1996;46(3):747-52. 
Zappia M, Albanese A, Bruno E, et al. Treatment of essential tremor: a systematic review of 
evidence and recommendations from the Italian Movement Disorders Association. J Neurol. 
2013;260:714–40. 


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21. 
APPENDICES 
Copies of scales and questionnaires included in Appendix 2 through Appendix 8 are for 
reference only; the rating scales and questionnaires reproduced in the eCRFs are to be used for 
actual subject assessment per the Schedule of Events.   
 


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APPENDIX 1. TREMOROGENIC DRUGS 
The following drug classes are not permitted in the 14 days prior to the admission visit and for 
the duration of the study (up to the Day 21 visit).  The list below gives a non-exhaustive list of 
examples of each drug class. 
Anti-arrhythmics 
 
amiodarone, procainamide 
Antiepileptic drugs 
 
valproic acid, carbamazepine 
Antipsychotic agents 
 
haloperidol, trifluoperazine 
Antimanic agents/mood stabilizer 
 
lithium at toxic levels 
Antivirals 
 
acyclovir, vidarabine 
Beta adrenergic agonists 
 
albuterol, terbutaline 
Calcium Channel blockers 
 
verapamil 
CNS stimulants 
 
methylphenidate, amphetamines, cocaine 
Corticosteroids (local injection topical, or inhalation allowed) 
 
cortisone, hydrocortisone, prednisone 
Cytotoxic agents 
 
cytarabine 
Hormones 
 
calcitonin, levothyroxine 
Immunomodulatory 
 
thalidomide 
Immunosuppressants 
 
cyclosporine, tacrolimus 
Monoamine depleting agents 
 
tetrabenazine 
Oral hypoglycemic agents 
 
metformin, glyburide, glipizide, tolbutamide, pioglitazone, rosiglitazone, acarbose, miglitol 
Prokinetics 
 
metoclopramide 
Tricyclic antidepressants 
 
amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, 
nortriptyline, protriptyline 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
 
fluoxetine 
Statins 
 
atorvastatin 


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Sympathomimetics 
 
epinephrine, pseudoephedrine 
Weight loss medication 
 
tiratricol 
Xanthine derivatives 
 
theophylline  
 


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APPENDIX 2. TRG ESSENTIAL TREMOR RATING ASSESSMENT 
SCALE (TETRAS) 
 


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Appendix 3. 
QUALITY OF LIFE IN ESSENTIAL TREMOR 
QUESTIONNAIRE (QUEST) 
 


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APPENDIX 4. COLUMBIA – SUICIDE SEVERITY RATING SCALE 
(C-SSRS) 
 
 


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APPENDIX 5. STANFORD SLEEPINESS SCALE (SSS) 
 
 


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APPENDIX 6. MODIFIED OBSERVER'S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) 
 
 


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APPENDIX 7. BOND-LADER VAS (MOOD RATING SCALE) 
 


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APPENDIX 8. DRUG EFFECTS QUESTIONNAIRE (DEQ-5) 
 

SAP_000.pdf: 
Clinical Study Report 
217-ETD-201
16.1 Study Information 
9.
DOCUMENTATION OF STATISTICAL METHODS
Statistical Analysis Plan 
•
Statistical Analysis Plan Parts A and B V2.0 02Oct2017
o
The Statistical Analysis Plan for Parts A and B underwent one revision and V2.0
is provided.
•
Statistical Analysis Plan Part C V1.0 14Dec2017


Sage Therapeutics, Inc 
Statistical Analysis Plan 
Methods 
Protocol 217-ETD-201/NCT02978781
Part A and Part B  
 A PHASE 2A, DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED 
WITHDRAWAL STUDY EVALUATING THE EFFICACY, SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS OF SAGE-217 IN THE 
TREATMENT OF SUBJECTS WITH ESSENTIAL TREMOR (ET) 
Author of SAP: 
, MStat 
Version: Version 2.0 
Date of SAP: 02 OCT 2017 
Sponsor 
Sage Therapeutics, Inc 
215 First Street 
Cambridge, Massachusetts 02142 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent of 
Sage Therapeutics Incorporated is strictly prohibited except to the extent required under applicable laws or regulations. 
Persons to whom the information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them.




Statistical Analysis Plan Methods 02 OCT 2017 Version 2.0 
Page 3 of 30 
Protocol Number: 217-ETD-201(Part A and Part B) 
 
Sage Therapeutics, Inc 
Confidential Information 
 
1 
TABLE OF CONTENTS 
Signature Page and Approvals .................................................................................................... 2 
1 
Table of Contents ................................................................................................................... 3 
2 
List of Abbreviations ............................................................................................................. 5 
3 
Introduction............................................................................................................................ 6 
4 
Study Objectives .................................................................................................................... 6 
4.1 
Primary Objective ............................................................................................................. 6 
4.2 
Secondary Objectives ....................................................................................................... 6 
4.3 
Other Objectives ............................................................................................................... 7 
5 
Study Endpoints ..................................................................................................................... 7 
5.1 
Efficacy Endpoints ........................................................................................................... 7 
5.1.1 
Primary Efficacy Endpoint ....................................................................................... 7 
5.1.2 
Secondary Efficacy Endpoints .................................................................................. 7 
5.1.3 
Other Efficacy Endpoints ......................................................................................... 8 
5.2 
Safety Endpoints ............................................................................................................... 8 
5.3 
Other Endpoints ................................................................................................................ 8 
6 
Study Design ........................................................................................................................... 8 
6.1 
Overall Design .................................................................................................................. 8 
6.2 
Sample Size and Power .................................................................................................... 9 
6.3 
Randomization .................................................................................................................. 9 
6.4 
Blinding and Unblinding ................................................................................................ 10 
7 
Modifications ........................................................................................................................ 10 
7.1 
Modifications to the Approved Clinical Study Protocol ................................................ 10 
7.2 
Modifications to the Approved Statistical Analysis Plan ............................................... 10 
7.3 
Modifications to the Approved DMC Charter ................................................................ 11 
8 
Analysis Populations ............................................................................................................ 11 
8.1 
Efficacy Population ........................................................................................................ 11 
8.2 
Safety Population ............................................................................................................ 11 
8.3 
PK Population ................................................................................................................. 11 
9 
Statistical Analysis ............................................................................................................... 11 
9.1 
General Considerations .................................................................................................. 11 
9.2 
Background Characteristics ............................................................................................ 13 
9.2.1 
Subject Disposition ................................................................................................. 13 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 13 
9.2.3 
Prior and Concomitant Medications ....................................................................... 14 
9.2.4 
Study Drug Exposure.............................................................................................. 14 
9.2.5 
Study Drug Compliance ......................................................................................... 14 
9.3 
Efficacy Analysis ............................................................................................................ 14 
9.3.1 
Analysis of Primary Efficacy Variable ................................................................... 15 
9.3.1.1 
Description of Primary Efficacy Variable........................................................ 15 
9.3.1.2 
Visit Windows for the Primary Endpoint ........................................................ 15 
9.3.1.3 
Primary Analysis .............................................................................................. 15 
9.3.1.4 
Supportive Analyses ........................................................................................ 15 
9.3.1.5 
Multiplicity Adjustment ................................................................................... 16 


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9.3.1.6 
Sensitivity Analysis .......................................................................................... 16 
9.3.1.7 
Subgroup Analyses .......................................................................................... 16 
9.3.2 
Analysis of Secondary Efficacy Variables ............................................................. 16 
9.3.2.1 
Kinesia Upper Limb Scores ............................................................................. 16 
9.3.2.2 
TETRAS Upper Limb Scores .......................................................................... 16 
9.3.2.3 
TETRAS Performance Subscale (Items 6, 7, and 8) Scores ............................ 17 
9.3.3 
Analysis of Exploratory Efficacy Variables ........................................................... 17 
9.3.3.1 
TETRAS ADL ................................................................................................. 17 
9.3.3.2 
QUEST ............................................................................................................. 18 
9.4 
Safety Analysis ............................................................................................................... 18 
9.4.1 
Adverse Events ....................................................................................................... 19 
9.4.2 
Clinical Laboratory ................................................................................................. 20 
9.4.3 
Electrocardiogram .................................................................................................. 20 
9.4.4 
Vital Signs .............................................................................................................. 21 
9.4.5 
Physical Examination ............................................................................................. 21 
9.4.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) .............................................. 21 
9.4.7 
Stanford Sleepiness Scale (SSS)............................................................................. 21 
9.4.8 
Bond-Lader Visual Analogue Scale (VAS)............................................................ 21 
9.4.9 
Drug Effects Questionnaire (DEQ-5) ..................................................................... 22 
9.5 
Pharmacokinetic Analysis .............................................................................................. 23 
10 Summary of Interim Analyses ............................................................................................ 23 
11 References ............................................................................................................................. 23 
12 List of Appendices................................................................................................................ 25 
12.1 Appendix A: Schedule of Assessments .......................................................................... 25 
12.1.1 
Part A (Open-Label) ............................................................................................... 25 
12.1.2 
Part B (Randomized Withdrawal) .......................................................................... 28 
 
 


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2 
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION OR DESCRIPTION 
ADL 
activities of daily living 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BLQ 
below the limit of quantification 
%CV 
percent coefficient of variation 
CI 
confidence interval 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DEQ-5 
Drug Effects Questionnaire 
CSR 
clinical study report 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
essential tremor 
FCS 
full conditional specification 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
LLOQ 
lower limit of quantitation 
LS 
least-squares 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PT 
preferred term 
QoL 
quality of life 
QTcF 
QT-interval for ECG corrected for heart rate (Fridericia) 
QUEST 
Quality of Life in Essential Tremor Questionnaire  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
System Organ Class 
SSS 
Stanford Sleepiness Scale 
TEAE 
treatment emergent adverse event 
TETRAS 
TRG Essential Tremor Rating Assessment Scale  
ULOQ 
upper limit of quantitation 
VAS 
visual analogue scale 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 


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3 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis of the study and is based on the approved 
clinical study protocol, dated September 5, 2017, Version 5.0, incorporating Amendment 4for Study 
217-ETD-201. Part A and Part B of this study are analyzed according to this SAP. Part C will be analyzed 
according to a separate SAP.  
This SAP addresses the safety, efficacy, and pharmacokinetics (PK) objectives of the study and describes 
the planned safety, efficacy, and PK statistical analyses and data presentations. 
The statistical plan described hereafter is an a priori plan and will be submitted to file before any analysis 
of data pertaining to Sage Study 217-ETD-201 (Part A and Part B) is performed. The SAP is to be 
finalized and approved before database lock. 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and graphical 
representations will be performed primarily using SAS (release 9.3 or higher) for Windows.  
Pharmacokinetic parameter estimation will be performed using Phoenix WinNonlin® software (Version 
6.4 or later; Pharsight, Cary, NC) on individual plasma concentration-time data. 
The reader of this SAP is encouraged to also read the clinical protocol, and other identified documents, 
for details on the planned conduct of this study. Operational aspects related to collection and timing of 
planned clinical assessments are not repeated in this SAP unless relevant to the planned analysis. 
There are 2 SAGE-217 formulations given in this study: subjects who consent before the approval of 
Protocol Version 4.0 (Amendment 3) by the Institutional Review Board (IRB) will receive the oral 
solution formulation for the duration of the study; subjects who consent after Protocol Version 4.0 
(Amendment 3) is approved by the IRB will receive the capsule formulation for the duration of the study. 
Due to the small number of subjects enrolled under Protocol Version 3.0 (Amendment 2) or earlier data 
collected for these subjects dosed with oral solution will only be listed, except where indicated otherwise.   
All objectives and analyses described herein therefore are with respect to subjects enrolled under Protocol 
Version 4.0 (Amendment 3) or later.  It is anticipated that all the subjects enrolled in Part B are after 
Protocol Version 4.0 and will be dosed with capsules only. 
4 
STUDY OBJECTIVES  
4.1 
Primary Objective 
The primary objective of this study (Part A and Part B) is to compare the effect of 7 days of 
administration of SAGE-217 Capsules to placebo on the change in tremor severity, as measured by the 
change from randomization (Day 8) in the accelerometer-based Kinesia kinetic tremor combined score 
(ie, the sum of Kinesia kinetic tremor scores across both sides of the body) at Day 14. 
4.2 
Secondary Objectives  
The secondary objectives of this study are to compare the effect of 7 days of administration of SAGE-217 
Capsules to placebo on the following endpoints: 
• 
Tremor severity as assessed by the change from randomization (Day 8) in the Kinesia upper limb 
total score (ie, the sum of accelerometer-based Kinesia forward outstretched postural tremor, 
lateral “wing beating” postural tremor, and kinetic tremor item scores from both sides of the 
body) and individual item scores at Day 14; 
• 
Tremor severity as measured by the change from randomization (Day 8) in TRG Essential 
Tremor Rating Assessment Scale (TETRAS) upper limb total score (ie, the sum of TETRAS 
Performance Subscale item 4 scores [4a, 4b, and 4c] from both sides of the body) and individual 
TETRAS Performance Subscale upper limb item scores at Day 14; 


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• 
Tremor severity as assessed by the change from randomization (Day 8) in other TETRAS 
Performance Subscale scores at Day 14; 
• 
Safety and tolerability as assessed by vital signs measurements, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Severity 
Rating Scale (C-SSRS), and adverse event (AE) reporting; 
• 
Sleepiness as assessed by the Stanford Sleepiness Scale (SSS) score; 
• 
Mood as assessed by the Bond-Lader visual analogue score (VAS) Mood Scale; and 
• 
How the subject feels after taking the study drug as assessed by Drug Effects Questionnaire 
(DEQ-5) ratings. 
The above objectives, with the exception of safety as assessed by AEs, will only be listed for SAGE-217 
Oral Solution since sufficient data will not be available for any further analysis. 
In addition, the PK objective of this study is to assess the PK profile of SAGE-217 in plasma samples 
following administration of SAGE-217 Capsules.  Pharmacokinetic data for subjects treated with SAGE-
217 Oral Solution will be listed only. 
4.3 
Other Objectives 
The other objectives of the study are to compare the effect of 7 days of administration of SAGE-217 
Capsules to placebo on: 
• 
Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring), as assessed by the Empatica 
Wristband E4. Tremor oscillation, as assessed by multidimensional accelerometer measurements 
(ie, raw accelerometer values) using the Empatica Wristband E4. 
• 
Quality of life (QoL), as assessed by TETRAS activities of daily living (ADL), Quality of Life in 
Essential Tremor Questionnaire (QUEST), and video recording assessment of subjects 
performing three everyday tasks (drinking a glass of water, fastening a button, and one additional 
task that the subject experiences difficulty with on a daily basis). 
In addition, PK and pharmacodynamic (PD) modelling assessment of the relationship between plasma 
exposure of SAGE-217 and change from baseline in Kinesia scores may be assessed. 
The above objectives will only be listed for SAGE-217 Oral Solution since sufficient data will not be 
available for any further analysis. 
5 
STUDY ENDPOINTS 
5.1 
Efficacy Endpoints 
The following efficacy endpoints are planned to be assessed only in subjects taking the capsules.  
5.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the change from randomization (Day 8) in the 
accelerometer-based Kinesia kinetic tremor combined score (ie, the sum of Kinesia kinetic tremor scores 
from both sides of the body) at Day 14. 
5.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study include the following: 
• 
Change from randomization (Day 8) in the Kinesia upper limb total score and individual item 
scores at Day 14 and all other time points; 


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• 
Change from randomization (Day 8) in TETRAS kinetic tremor score, TETRAS Performance 
Subscale upper limb total score, and individual TETRAS Performance Subscale upper limb item 
scores at Day 14 and all other time points; and 
• 
Change from baseline in other TETRAS Performance Subscale scores measured at Day 14 and all 
other time points. 
5.1.3 
Other Efficacy Endpoints 
The other efficacy endpoints of this study include the following:  
• 
Change from baseline in TETRAS ADL and QUEST scores at Day 14. 
5.2 
 Safety Endpoints 
The safety endpoints of this study for subjects taking capsules (except where specified otherwise) include 
the following: 
• 
Frequency and severity of AEs (including subjects on oral solution for Part A); 
• 
Safety and tolerability as assessed by changes from baseline in vital signs measurements, clinical 
laboratory data, ECG parameters, and incidences of suicidal ideation using the C-SSRS; 
• 
Change from baseline in sleepiness as assessed by the SSS scores; 
• 
Change from baseline in mood as assessed by the Bond-Lader VAS Mood Scale; and 
• 
DEQ-5 ratings. 
5.3 
Other Endpoints 
The PK endpoints include plasma concentrations of SAGE-217 and metabolites for subjects taking 
capsules as follows: 
• 
Mean plasma concentrations and parameters (area under the concentration-time curve from time 0 
to last time point [AUC0-t], area under the concentration-time curve from time 0 to infinity 
[AUC0-∞], maximum plasma concentration [Cmax], time to reach maximum concentration [tmax], 
and terminal half-life [t1/2], as appropriate) of SAGE-217 and possible metabolites. 
6 
STUDY DESIGN  
6.1 
Overall Design  
This study is a 3-part, multicenter, Phase 2a study to evaluate the efficacy, safety, tolerability, and PK of 
SAGE-217 in approximately 60 adult subjects with essential tremor (ET).  Subjects who consent before 
the approval of Protocol Version 4.0 (Amendment 3) by the IRB will receive the oral solution formulation 
for the duration of the study; subjects who consent after Protocol Version 4.0 (Amendment 3) is approved 
by the IRB will receive the capsule formulation for the duration of the study. 
Part A of the study is an open-label design with morning dosing for 7 days. Part B of the study is a 
double-blind, placebo-controlled, randomized withdrawal design. Subjects will be exposed to study drug 
(SAGE-217 or placebo) for up to 14 days and will be followed for an additional 14 days after the 
administration of the last dose. Part C of the study is an open-label design with evening dosing (and 
morning and evening dosing beginning on Day 4) for up to 14 days.  
During the Screening Period (Day -28 to Day -1), after signing the informed consent form (ICF), subjects 
will be assessed for study eligibility and the severity of each subject’s ET will be evaluated using 
TETRAS. Eligible subjects will return to the clinical study unit on Day -1.  


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The study will be conducted in 3 parts; however, only Part A and Part B will be discussed in this SAP 
(Part C will be discussed in a separate SAP):  
• 
Part A: Beginning on Day 1, all subjects will receive open-label SAGE-217 in the morning with 
food for 7 days. Subjects will receive SAGE-217 10 mg on Day 1, SAGE-217 20 mg on Day 2, 
and SAGE-217 30 mg from Day 3 to Day 7, with dose adjustments for severe AEs judged by the 
Investigator to be related to study drug.  
• 
Part B: In order to qualify for Part B of the study, a subject must tolerate a dose of ≥10 mg of 
SAGE-217, and the subject must have responded to SAGE-217, defined as a 30% reduction from 
baseline in TETRAS kinetic tremor (item 4c) combined score predose on Day 8. Eligible subjects 
will be randomized in a 1:1 fashion to receive SAGE-217 or placebo for 7 days beginning on Day 
8. All doses of study drug will be administered with food. Subjects randomized to SAGE-217 or 
placebo will receive their maximum (tolerated) dose as determined in Part A in the morning with 
food.   
Dose adjustments will only be allowed during Part A of the study. A dose will be considered not tolerated 
if the subject experiences a severe AE considered to be related to the study drug by the Investigator. If a 
dose is not tolerated, the dose on the next day will be reduced to the next lowest dose and continued for 
the remainder of the open-label dosing period (ie, subjects who are unable to tolerate SAGE-217 30 mg 
will receive SAGE-217 20 mg and subjects who are unable to tolerate SAGE-217 20 mg will receive 
SAGE-217 10 mg). The dose tolerated on Days 5, 6, and 7 of Part A will be considered the maximum 
dose for that subject. Subjects who require dose adjustments on Days 5, 6, or 7 of Part A will not progress 
to Part B.  
Assessments will be performed periodically during the study as outlined in the Schedule of Events for 
Part A and Part B (Sections 12.1.1 and 12.1.2, respectively). 
6.2 
Sample Size and Power 
Approximately 60 subjects will be enrolled in Part A to yield at least 40 randomized subjects for Part B. 
A total sample size of 34 evaluable subjects (ie, 17 per group) will have 80% power to detect a difference 
in means of 3.0 on the primary endpoint assuming that the common standard deviation is 3.0 using a 
2-sample t-test with a 0.05 two-sided significance level. Assuming a 15% non-evaluability rate, 20 
subjects per group will be randomly assigned to treatment. The number of subjects in each treatment 
group is also thought to be sufficient to assess preliminary safety and tolerability following multiple doses 
of SAGE-217. 
6.3 
Randomization 
Part A is open-label with no control group; therefore, there will be no randomization or blinding. Once it 
has been determined that a subject meets eligibility criteria, the subject will be sequentially assigned a 
subject number. Subject identification numbers will consist of the site number (eg, “01”) followed by 
subject number with leading zeroes (eg, “001”; the subject identification number would then be 
“01-001”). 
Part B of the study is a double-blind, placebo-controlled, randomized withdrawal design. Subjects who 
tolerate a dose of ≥10 mg of SAGE-217 in Part A and respond to SAGE-217, defined as a 30% reduction 
from baseline in TETRAS kinetic tremor combined score predose on Day 8, will be randomly assigned in 
a 1:1 fashion to receive SAGE-217 or placebo according to a computer-generated randomization 
schedule. Once it has been determined that a subject meets eligibility criteria for randomization, the 
subject will be sequentially assigned a randomization number from the randomization schedule provided 
to the unblinded pharmacist. Randomization numbers will consist of a 4-digit number starting with 1001. 
Subject randomization (including subject identifier, randomization number, and treatment assigned) will 
be provided in a listing. 


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6.4 
Blinding and Unblinding 
Subjects, clinicians, and the study team will be blinded to treatment allocation. The pharmacist, who will 
prepare the study drug according to the randomization schedule, will be unblinded. 
The randomization schedule will be generated prior to the start of the study. The randomization schedule 
will be generated using SAS® Software (release 9.3 or higher). Only the clinic pharmacist, who is 
responsible for preparing the study drug for administration, will be given a copy of the randomization 
schedule. In the event of a medical emergency, the pharmacist may reveal actual study drug contents to 
the investigator, who should also alert Sage of the emergency. In all cases where the study drug allocation 
for a subject is unblinded, pertinent information (including the reason for unblinding) must be 
documented in the subject’s records and on the electronic case report form (eCRF). If the subject or study 
center personnel (other than pharmacist) have been unblinded, the subject will be terminated from the 
study.  
Subjects randomized to SAGE-217 will receive their maximum dose as determined in Part A in the 
morning with food. Subjects randomized to the placebo arm will represent randomized withdrawal 
(withdrawal from SAGE-217 treatment they received in Part A). 
7 
MODIFICATIONS  
7.1 
Modifications to the Approved Clinical Study Protocol 
The following changes from the clinical study protocol (version 5.0, dated September 5, 2017) have been 
made in the SAP: 
The protocol describes an evaluable population consisting of all randomized subjects with at least 1 post-
baseline Kinesia assessment. This analysis set has been removed in the SAP as the evaluable population is 
expected to be similar to the efficacy population (see Section 8.1). Therefore, the Evaluable Population as 
defined in the protocol will not be used for efficacy analysis. 
The protocol also mentions that center will be included in the mixed effects repeated measures model of 
the primary endpoint and key secondary endpoints. Center has been removed from the model in the SAP 
(see Section 9.3.1.3) as the number of subjects per center are likely to be small and could lead to model 
convergence issues. 
The protocol specifies that change from baseline in TETRAS ADL and QUEST scores at Day 14 are 
exploratory endpoints; however, as per Sponsor request, these are going to be analyzed as other endpoints 
instead of exploratory. 
The protocol specifies the addition of a Part C; Part C will be analyzed in a separate SAP. 
7.2 
Modifications to the Approved Statistical Analysis Plan 
The following changes have been made to the SAP Version 1.0 (28 March 2017) as a result of Protocol 
Version 4.0 (Amendment 3): 
- 
Change of title and version of protocol that the SAP is based upon; 
- 
Change of Sage Therapeutics statistical signatory; 
- 
All endpoints and analyses changed to be based on subjects on the capsules instead of oral 
solution; 
- 
Clarification of analysis populations to indicate if based on oral solution or capsule; 
- 
Minor formatting/administrative changes. 
The following changes have been made to the SAP Version 1.0 (28 March 2017) as a result of Protocol 
Version 5.0 (Amendment 4): 


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- 
Addition of text referencing Part C, although Part C is not described herein. 
7.3 
Modifications to the Approved DMC Charter 
Not applicable. 
8 
ANALYSIS POPULATIONS 
Subjects included in the below analysis populations (and reason for exclusion, if applicable) will be 
provided in a listing. 
8.1 
Efficacy Population 
The Efficacy Population (Part A; Capsule) will consist of all subjects who complete at least one dose of 
the capsule formulation in Part A and have at least one postdose efficacy evaluation. The Efficacy 
Population (Part A; Capsule) will be used to analyze all Part A-Capsule efficacy data.  
The Efficacy Population (Part B; Capsule) will consist of all subjects who complete at least one dose of 
the capsule formulation in Part B and have at least one post-randomization efficacy evaluation. The 
Efficacy Population (Part B; Capsule) will be used to analyze all other efficacy data. 
No efficacy populations will be defined for the Oral Solution. 
8.2 
Safety Population 
The Safety Population (Part A; Both Formulations) will consist of all subjects who are administered open-
label study drug of either the oral solution or capsule formulation. The Safety Population (Part A; 
Capsule) will consist of all subjects who are administered open-label study drug of the capsule 
formulation. The Safety Population (Part B; Capsule) will consist of all subjects who are administered 
double-blind study drug of the capsule formulation. These populations will be used to provide descriptive 
summaries of safety in each respective part. Summaries of safety that are not part-specific will be based 
on Safety Population (Part A; Capsule). Summaries of safety that include both formulations will be based 
on Safety Population (Part A; Both Formulations). 
8.3 
PK Population 
The PK Population (Part A; Both Formulations) will consist of all subjects in the Safety Population (Part 
A; Both Formulations) with a sufficient number of plasma samples with quantifiable concentration of 
SAGE-217 in Part A. The PK Population (Part A; Capsule) will consist of all subjects in the Safety 
Population (Part A; Capsule) with a sufficient number of plasma samples with quantifiable concentration 
of SAGE-217 in Part A. The PK Population (Part B; Capsule) will consist of all subjects in the Safety 
Population (Part B; Capsule) with a sufficient number of plasma samples with quantifiable concentration 
of SAGE-217 in Part B. The PK Population will be used to summarize PK data in each respective study 
part. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
Continuous (quantitative) variable summaries will include the number of subjects (n) with non-missing 
values, mean, standard deviation (SD), median, minimum, and maximum. 
Categorical (qualitative) variables will be summarized using the number and proportion of each possible 
value. In general, the denominator for the percentage calculation will be based upon the total number of 
subjects in the study population for the treatment group. 
The minimum and maximum will be reported with the same degree of precision (ie, the same number of 
decimal places) as the observed data. Measures of location (mean and median) will be reported to 1 
degree of precision more than the observed data and measures of spread (standard deviation) will be 
reported to 2 degrees of precision more than the observed data. 


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Percentages will be presented to 1 decimal place unless otherwise specified. Assessments done on 
unscheduled visits will not be summarized but will be listed.  
Treatment group (ie, randomized treatment for efficacy summaries, treatment received otherwise) is 
defined as SAGE-217 or Placebo. Tolerated dose is defined as SAGE-217 10 mg, SAGE-217 20 mg, or 
SAGE-217 30 mg (Section 6.1).  
Data from subjects taking the oral solution will be primarily presented in the data listings; however, 
subject disposition, demographics, and AE data for Part A will be summarized by formulation (oral 
solution and capsule).  Otherwise, all background summaries will be presented by treatment group and 
overall subjects, unless otherwise specified. All safety summaries will be presented by overall subjects for 
Part A and treatment group for Part B. All efficacy summaries will be presented by overall subjects for 
Part A and treatment group for Part B. Pharmacokinetic data will be presented by overall subjects for Part 
A and tolerated dose for active treatment only for Part B. 
All final, planned analyses identified in the protocol and in this SAP will be performed after all relevant 
study data have been processed and integrated into the analysis database, analysis populations have been 
finalized, and the database has been locked. Any post-hoc, exploratory analysis performed to support 
planned study analyses, which were not identified in this SAP, will be documented and reported in 
Section 9.8 of the CSR. Any results from these unplanned analyses (post-hoc), including analyses based 
on data collected but not analyzed (Section 7.1), will also be clearly identified in the text of the CSR. 
All collected data will be presented in listings and will be sorted by subject.  
If partial dates occur, the convention for replacing missing dates for the purposes of calculating derived 
variables is as follows: 
For partial AE and medication start dates: 
• 
If the year is unknown, then do not impute the date but assign a missing value. 
• 
If the year is known, but the month or month and day is unknown, then: 
o If the year matches the year of first dose date, then impute as the month and day of the 
first dose date. 
o Otherwise, assign 01 January 
• 
If the year and month are known, but the day is unknown, then: 
o If the month and year match the month and year of the first dose date, then impute as the 
day of the first dose date. 
o Otherwise, assign 01 
For partial AE and medication end dates: 
• 
If the year is unknown, then do not impute the date but assign as missing value. 
• 
If the year is known, but the month or month and day is unknown, then: 
o If the year matches the year of the last date of the study (date of last contact if subject lost 
to follow-up; date of completion or early termination otherwise), then impute as the 
month and day of the last date of the study. 
o Otherwise, assign 31 December. 
• 
If the year and month are known, but the day is unknown, then: 
o If the month and year match the month and year of the last date of the study, then impute 
as the day of the last date of the study. 


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o Otherwise, assign the last day of the month. 
No missing data will be imputed unless otherwise specified. 
In general, for quantitative safety laboratory values reported as ‘<X’ or ‘≤X’, the lower limit of 
quantitation (LLOQ) will be used for analysis (ie, a value of X will be used in the analysis for lab values 
reported as ‘<X’ or ‘≤X’). Similarly, for safety quantitative laboratory values reported as ‘>X’ or ‘≥X’, 
the upper limit of quantitation (ULOQ) will be used for analysis (ie, a value of X will be used in the 
analysis for lab values reported as ‘>X’ or ‘≥X’). 
For analysis purposes, repeat laboratory rest results will not be used unless the original laboratory value is 
missing or indicated as invalid, in which case the first non-missing repeat laboratory value will be used 
for data analysis. 
The last observation recorded before receiving the first dose of study drug on Day 1 in Part A will be used 
as the baseline observation for all calculations of change from baseline. The last observation recorded 
before receiving the first dose of study drug before randomization on Day 8 in Part B will be used as the 
randomization observation for all calculations of change from randomization.   
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
All subjects who sign the ICF will be accounted for in this study.  
Subject disposition will be summarized separately for each study part, as follows: 
• 
For Part A, the number of subjects enrolled (ie, signed informed consent); treated; completed Part 
A; withdrew from Part A (including reason for withdrawal); and included in each Part A analysis 
population will be summarized by overall subjects within formulation.  
• 
For Part B, the number and percentage of subjects who were randomized; treated; completed 
Part B; withdrew from Part B (including reason for withdrawal); and included in each Part B 
analysis population will be summarized by treatment group and overall subjects. 
• 
Additionally, the previous Part B summary will be repeated by tolerated dose within treatment 
group. 
All disposition information will be included in a listing. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics, such as age, gender, child-bearing potential, race, and ethnicity, and baseline 
characteristics such as height, weight, body mass index (BMI), and time (years) since ET diagnosis (from 
date of ICF), will be summarized by overall subjects within formulation in Part A and treatment group in 
Part B.  
Categorical summaries, such as gender, childbearing potential, race, and ethnicity, will be summarized 
using frequency and percentage. Subjects who marked more than one race will be summarized in a “More 
than One Race” category. Continuous summaries, such as age, height, weight, BMI, and time since ET 
diagnosis, will be summarized using mean, standard deviation (SD), median, minimum, and maximum. 
The demographic and baseline characteristics table will be generated for subjects in the Safety 
Population.  
Hepatitis, human immunodeficiency virus (HIV), pregnancy, alcohol, cotinine, caffeine, and drug 
screening results will be listed, but not summarized as they are considered part of the inclusion/exclusion 
criteria. 
Medical history, coded using Medical Dictionary for Regulatory Activities (MedDRA) (version 18.1 or 
higher), will be listed. 


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9.2.3 
Prior and Concomitant Medications 
Concomitant medications will be coded using World Health Organization Drug Dictionary Enhanced 
(WHO-DDE) (Version September 1, 2015 or later). 
Frequencies and percentages of medications used in the study will be summarized as follows: 
• 
Prior medication: medication taken before the date of first dose of open-label study drug 
(including medications with a missing start date but a non-missing end date in this time period). 
• 
Concomitant medication: a medication with a start date on or after the first dose of open-label 
study drug (even if end date is missing) and on or before the last dose of study drug, or 
medications with a start date before the first dose of open-label study drug that are ongoing or 
with a stop date on or after the first dose of open-label study drug, will be considered 
concomitant. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Concomitant medications will be assigned to the study part in which they are being taken. A concomitant 
medication with a start date before the first dose of double-blind study drug will be assigned to Part A 
(including medications with missing start dates with either a missing end date or an end date before first 
dose of double-blind study drug). A concomitant medication with a start date on or after the first dose of 
double-blind study drug will be assigned to Part B. If a concomitant medication assigned to Part A 
continues to be taken through Part B, then the medication will be assigned to both parts of the study as 
appropriate. If the start and stop dates of the concomitant medications do not clearly define the part during 
which a medication was taken, it will be assumed to be taken in both parts. Details of prior and 
concomitant medications will be listed by study part, subject, start date, and verbatim term. All 
medications will be summarized by Anatomic Therapeutic Chemical (ATC) class and preferred term 
(PT). Furthermore, prior medications will be summarized by overall subjects; and concomitant 
medications will be summarized by overall subjects (Part A) and treatment group (Part B) for subjects 
taking capsules. Subjects will be counted once per ATC and PT in each study part. 
Medication summaries will be based on the Safety Populations.  
9.2.4 
Study Drug Exposure  
Study drug dosing information will be listed. 
9.2.5 
Study Drug Compliance 
Study drug noncompliance such as missing visits, interruptions in the schedule of administration, and 
nonpermitted medications will be listed in the protocol deviations listing. 
9.3 
Efficacy Analysis  
The primary efficacy variable for this study is change from randomization in accelerometer-based Kinesia 
kinetic tremor combined score in Part B; change from baseline for Part A will also be evaluated.  
The secondary efficacy variables for this study include change from baseline (Part A) and change from 
randomization (Part B) in:  
• 
Kinesia upper limb total and individual item scores 
• 
TETRAS total and individual upper limb item scores 
• 
TETRAS Performance Subscale scores 
The other efficacy variables for this study include change from baseline (Part A) and change from 
randomization (Part B) in:  
• 
TETRAS ADL scores 


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• 
QUEST scores 
All efficacy analyses will be conducted on the Efficacy Population, only for subjects taking capsules. 
9.3.1 
Analysis of Primary Efficacy Variable 
9.3.1.1 
Description of Primary Efficacy Variable 
The primary outcome measure is the change from randomization in accelerometer-based Kinesia kinetic 
tremor combined score, based on the Day 14, predose measurement. 
In order to measure essential tremor amplitude, subjects will wear a wireless ring motion sensor (ie, 
Kinesia). The motion sensor uses three orthogonal accelerometers and three orthogonal gyroscopes to 
monitor three-dimensional motion. Data are then transmitted from the sensor to a computer using 
Bluetooth technology. These measures of three-dimensional motion for each maneuver are then converted 
to Kinesia scores, which have been shown to correlate with corresponding clinician-rated TETRAS scores 
(ie, forward outstretched postural tremor, lateral “wing beating” postural tremor, and kinetic tremor on 
both sides of the body) (Giovanni, Giuffrida, Adam, Davidson, & Jankovic, 2010). Each Kinesia score 
ranges from 0 to 4; higher scores indicate more severe tremor. The Kinesia assessment is completed in 
conjunction with the TETRAS Performance Subscale Item 4 assessment.  
In Part A, Kinesia will be performed on Day -1 (three assessments separated by at least 30 minutes); a 
single assessment will be performed predose and 2 and 8 hours postdose on Days 1, 2, 3, and 7. In Part B, 
a single Kinesia reading will be performed predose and 2 and 8 hours postdose on Days 8, 9, and 14, and 
any time during the visit on Day 21.  
9.3.1.2 
Visit Windows for the Primary Endpoint 
For efficacy analyses, unscheduled measurements will only be included if a scheduled measurement is not 
available and the unscheduled measurement falls on the same study day. Due to the short duration of this 
study, this is not anticipated to occur. 
9.3.1.3 
Primary Analysis 
The difference between treatment groups in change from randomization to post-randomization in Kinesia 
kinetic tremor combined score from Part B will be evaluated by a mixed model for repeated measures 
(MMRM) with change from randomization of the Kinesia kinetic tremor combined scores as the 
dependent variable, and treatment group, study visit, and treatment group by study visit interaction as 
fixed effects, and the randomization (Day 8 predose) value as a covariate. An unstructured covariance 
matrix will be used to model the within-subject correlation. The Kenward-Roger approximation will be 
used to estimate denominator degrees of freedom.  
In case of convergence issues, other covariance structures will be used including (but not limited to) 
autoregressive (AR (1)), compound symmetry (CS), and variance components (VC) with each model fit 
to find the covariance structure with the best fit. The fit statistics will be compared for all covariance 
structures; the structure with the smallest Akaike information criterion will be retained as the preferred 
model. 
In comparing the visit value to randomization, least-squares (LS) mean change from randomization will 
be presented along with associated 95% CI and P values. In comparing treatments (SAGE-217 minus 
placebo), LS mean differences in change from randomization will be presented along with associated 
95% CI and pairwise treatment P values.  
9.3.1.4 
Supportive Analyses 
For all subjects, observed values and change from baseline in Kinesia kinetic tremor combined score will 
be summarized for all Part A time points by overall subjects. For subjects entering Part B, observed 
values and change from baseline (Part A time points) / change from randomization (Part B time points) in 


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Kinesia kinetic tremor combined score will be summarized for all time points by treatment group.  For 
Part B, additional summaries may be performed by tolerated dose.   
9.3.1.5 
Multiplicity Adjustment 
Not applicable. 
9.3.1.6 
Sensitivity Analysis  
Not applicable. 
9.3.1.7 
Subgroup Analyses 
Not applicable. 
9.3.2 
Analysis of Secondary Efficacy Variables 
9.3.2.1 
Kinesia Upper Limb Scores 
Description of Kinesia Upper Limb Scores 
The accelerometer-based Kinesia upper limb total score is the sum of Kinesia scores (ie, forward 
outstretched postural tremor, lateral “wing beating” postural tremor, and kinetic tremor) from both sides 
of the body. The upper limb individual item question score for each side of the body ranges from 0 to 4, 
with higher scores indicating more tremors/greater tremor amplitude. 
Analysis of Kinesia Upper Limb Scores 
For all subjects, observed values and change from baseline in Kinesia upper limb individual item and total 
scores will be summarized for all Part A time points by overall subjects. For subjects entering Part B, 
observed values and change from baseline (Part A time points) / randomization (Part B time points) in the 
Kinesia upper limb individual item and total scores will be summarized by treatment group. 
The difference between treatment groups will be analyzed using the MMRM model as described for the 
primary analysis (Section 9.3.1.3) for post-randomization time points only. 
9.3.2.2 
TETRAS Upper Limb Scores  
Description of TETRAS Upper Limb Scores  
Items 4a (forward outstretched postural tremor), 4b (lateral “wing beating” postural tremor), and 4c 
(kinetic tremor), assessed on both sides of the body, comprise the TETRAS Performance Subscale upper 
limb scores. The TETRAS kinetic tremor combined score is the sum of the item 4c scores from both sides 
of the body. The TETRAS Performance Subscale upper limb total score is the sum of all item 4 scores 
from both sides of the body (Elble, Comella, & al, 2012).  
In Part A, TETRAS Performance Subscale upper limb scores will be assessed at Screening and on Day -1 
(three assessments separated by at least 30 minutes); a single assessment will be performed predose and 2, 
3, and 8 hours postdose on Days 1, 2, 3, and 7. In Part B, TETRAS Performance Subscale upper limb 
scores will be assessed at predose and 2, 3, and 8 hours postdose on Days 8, 9, and 14, and any time 
during the visit on Day 21.  


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Analysis of TETRAS Upper Limb Scores 
For all subjects, observed values and change from baseline in TETRAS kinetic tremor combined score, 
upper limb individual item scores, and upper limb total score will be summarized for all Part A time 
points by overall subjects. For subjects entering Part B, observed values and change from baseline (Part A 
time points) / randomization (Part B time points) in TETRAS kinetic tremor combined score, upper limb 
individual item scores, and upper limb total scores will be summarized by treatment group. 
The difference between treatment groups will be analyzed using the MMRM model as described for the 
primary analysis (Section 9.3.1.3) for post-randomization time points only.  
9.3.2.3 
TETRAS Performance Subscale (Items 6, 7, and 8) Scores 
Description of TETRAS Performance Subscale (Items 6, 7, and 8) Scores 
The TETRAS Performance Subscale score includes the following 9 items: head tremor, face (including 
jaw) tremor, voice tremor, upper limb tremor, lower limb tremor, Archimedes spirals, handwriting, dot 
approximation task, and standing tremor (Elble, Comella, & al, 2012). However, only Archimedes spirals 
(item 6), handwriting (item 7), and dot approximation task (item 8) assessments, in addition to upper limb 
tremor as described above, were performed for this study. 
In Part A, TETRAS Performance Subscale items 6, 7, and 8 will be assessed on Day -1 and predose on 
Day 7. In Part B, TETRAS Performance Subscale items 6, 7, and 8 will be assessed at predose on Day 14 
and any time during the visit on Day 21. 
Analysis of TETRAS Performance Subscale (Items 6, 7, and 8) Scores 
For all subjects, observed values and change from baseline in TETRAS Performance Subscale scores will 
be summarized for all Part A time points by overall subjects. For subjects entering Part B, observed 
values and change from baseline in TETRAS Performance Subscale scores will be summarized by 
treatment group. 
The difference between treatment groups will be analyzed using the MMRM model as described for the 
primary analysis (Section 9.3.1.4 & 9.3.1.3) for all post-baseline time points.  
9.3.3 
Analysis of Exploratory Efficacy Variables 
9.3.3.1 
TETRAS ADL  
Description of TETRAS ADL  
The QoL as assessed by the TETRAS ADL Subscale includes the following 12 items: speaking; feeding 
with a spoon; drinking from a glass; hygiene; dressing; pouring; carrying food trays, plates, or similar 
items; using keys; writing; working; overall disability with the most affected task; and social impact 
(Elble, Comella, & al, 2012). Each individual item question score ranges from 0 to 4, where higher scores 
indicate worse QoL. The total score is derived as the sum of all of the individual items scores, with a 
maximum total score of 48. If one of the individual item scores is missing, the total score will be set to 
missing. 
In Part A, the TETRAS ADL Subscale will be assessed on Day -1 and predose on Day 7. In Part B, the 
TETRAS ADL Subscale will be assessed at predose on Day 14 and any time during the visit on Day 21. 
Analysis of TETRAS ADL 
For all subjects, observed values and change from baseline in TETRAS ADL scores will be summarized 
for each item score and total score for all Part A time points by overall subjects. For subjects entering 
Part B, observed values and change from baseline in TETRAS ADL scores will be summarized for each 
item score and total score for all time points by treatment group. 


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9.3.3.2 
QUEST  
Description of QUEST  
The QUEST is a brief, ET-specific QoL scale in which subjects rate the extent to which tremor impacts a 
function or state (30 questions), waking hours with tremor in any part, tremor self-assessment rating 
tremor severity in various body parts (head, voice, right arm/hand, left arm/hand, right leg/foot, and left 
leg/foot), health status, and overall QoL, along with 4 questions gathering general information describing 
work status and issues occurring in the past month (tremor interference with sexual satisfaction, side 
effects from tremor medication, and satisfaction of tremor control achieved by medication) (Tröster, 
Pahwa, Fields, Tanner, & Lyons, 2005). The extent to which tremor impacts a function or state is rated as 
never/no, rarely, sometimes, frequently, always/yes, and not applicable. Tremor severity is rated as none, 
mild, moderate, marked, or severe. Perceived health and overall QoL are rated on a scale of 0 to 100 in 5-
point increments, where 0=very poor health and 100=excellent/perfect health. 
For the 30-question component of the QUEST, the questions will be scored in 5 dimensions: 
Communication (questions 1-3); Work and Finances (questions 4-9); Hobbies and Leisure (questions 
10-12); Physical (questions 13-21); and Psychosocial (questions 22-30).  
The dimension scoring algorithm is as follows: 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑒𝑒=
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑓𝑓𝑓𝑓𝑓𝑓 𝑒𝑒𝑒𝑒𝑒𝑒ℎ 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 (# 𝑜𝑜𝑜𝑜 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞 ×  4)𝑓𝑓𝑓𝑓𝑓𝑓 𝑒𝑒𝑒𝑒𝑒𝑒ℎ 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 
The point values assigned to each question are as follows: 0 = “Never/No”; 1 = “Rarely”; 2 = 
“Sometimes”; 3 = “Frequently”; 4 = “Always/Yes”; blank = Not Applicable (question is not counted 
toward applicable points or questions) (Movement Disorders Society Rating Scales, n.d.). 
In Part A, QUEST will be assessed on Day -1 and Day 7. In Part B, QUEST will be assessed on Day 14. 
Analysis of QUEST 
For all subjects, observed values and change from baseline in QUEST scores will be summarized for each 
dimension score for all Part A time points by overall subjects. For subjects entering Part B, observed 
values and change from baseline in QUEST scores will be summarized for each dimension score for all 
time points by treatment group.  
9.4 
Safety Analysis 
Safety will be evaluated through incidence and severity of AEs, as well as observed values and changes 
from baseline in vital signs, clinical laboratory measures (including shifts from baseline), ECG 
parameters, suicidal ideation using the C-SSRS, and the SSS. Safety summaries will be presented for 
subjects taking the capsule formulation, unless otherwise specified. 
For Part A, safety endpoints will be summarized by overall subjects, unless otherwise specified (eg, by 
the type of formulation). For Part B, safety endpoints will be summarized by treatment group (ie, 
SAGE-217 or placebo). All safety data will be presented in individual subject data listings. Safety 
analysis will be conducted for the Safety Population. 
Safety 
Evaluation 
Incidence  
Raw 
Value 
Change 
from 
Baseline 
Abnormality/
Clinical 
Significance 
AEs 
X 
 
 
 
CMs 
X 
 
 
 


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Safety 
Evaluation 
Incidence  
Raw 
Value 
Change 
from 
Baseline 
Abnormality/
Clinical 
Significance 
Labs 
 
X 
X  
* 
ECG 
 
X 
X 
* 
Vital Signs 
 
X 
X  
 
C-SSRS 
 
X 
X 
 
SSS 
 
X 
X 
 
VAS 
 
X 
X 
 
DEQ-5 
 
X 
X 
 
X = Safety Assessment will be summarized in tables 
* = Safety Assessment will be summarized in individual subject 
data listings 
9.4.1 
Adverse Events  
Adverse events (AEs) will be coded using the MedDRA coding system (version 19.1 or higher). The 
analysis of AEs will be based on the concept of treatment-emergent AEs (TEAEs). A TEAE for Part A is 
defined as an AE with onset after the start of open-label study drug, or any worsening of a pre-existing 
medical condition/AE with onset after the start of open-label study drug and until 14 days after the last 
dose or start of double-blind study drug, whichever is earlier. A TEAE for Part B is defined as an AE with 
onset after the start of double-blind study drug, or any worsening of a pre-existing medical condition/AE 
with onset after the start of double-blind study drug and until 14 days after the last dose. Any TEAEs 
occurring in the follow-up period after last dose of study drug will be summarized based on the last dose 
of study drug taken. 
Adverse events will be assigned to the study part in which they first occur. An AE with a start date before 
the first dose of double-blind study drug will be assigned to Part A (including AE with missing start dates 
with either a missing end date or an end date before first dose of double-blind study drug). An AE with a 
start date on or after the first dose of double-blind study drug will be assigned to Part B. If the start and 
stop dates of the AE do not clearly define the part during which an AE first occurred, it will be assumed 
to be occurring in both parts. 
A summary of the number and percentage of subjects with TEAEs will be provided separately for each 
study part. The summary for Part A will present data from subjects on both formulations, by overall 
subjects within formulation. The summary for Part B will be presented by treatment group. Frequencies 
and percentages of the following will be included: 
• 
Any TEAE 
• 
Severe TEAEs 
• 
Possibly or Probably Related TEAEs 
• 
TEAEs Leading to Discontinuation 


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• 
TEAEs Leading to Death 
• 
Serious AEs (SAEs)  
In Part A, the incidence of TEAEs will be summarized by the following, for overall subjects: 
• 
SOC and PT (including subjects on both formulations) 
• 
PT 
• 
Dose, Day, and PT 
• 
SOC, PT, and Maximum Severity 
• 
SOC, PT, and Relationship to Study Drug 
In Part B, the incidence of TEAEs will be summarized by the following, for subjects entering Part B: 
• 
Treatment group, SOC, and PT 
• 
Treatment group and PT 
• 
Treatment group, Dose, Day, and PT 
• 
Treatment group, SOC, PT, and Maximum Severity 
• 
Treatment group, SOC, PT, and Relationship to Study Drug 
Incidences will be presented by descending frequency of SOC (where applicable), then in order of 
decreasing frequency of PT (within SOC, if applicable; first for SAGE-217 then placebo), and then 
alphabetically within PT where the incidence is the same. The presentation of TEAEs by dose, day, and 
PT will include counts of TEAEs that started on that particular day. For Part A, the dose of the TEAE will 
correspond to the dose the subject was on at the start of the TEAE. For Part B, the dose of the TEAE will 
correspond to either tolerated dose (subjects receiving SAGE-217) or placebo (subjects receiving 
placebo). 
All AEs, SAEs (including those with onset or worsening before the start of open-label study drug), AEs 
leading to discontinuation, and AEs leading to death through the Day 28 visit will be listed in separate 
tables. 
9.4.2 
Clinical Laboratory 
All summaries of laboratory values will be presented using SI units. Continuous hematology, chemistry, 
and urinalysis results will be listed by subject and timing of collection. Observed values and change from 
baseline at each time point in Part A will be summarized by overall subjects taking the capsule 
formulation. For subjects entering Part B, observed values and change from baseline at each time point 
will be summarized by treatment group. Shifts from baseline will also be summarized by overall subjects 
(Part A) and treatment group (Part B). Clinically significant abnormal findings will be reported as AEs.  
9.4.3 
Electrocardiogram 
The following 12-ECG parameters will be listed for each subject: heart rate, PR interval, QRS duration, 
QT interval, and QTcF interval (derived as QT interval / (RR interval)1/3). Any clinically significant 
abnormalities or changes in ECGs should be listed as an AE. Observed values and change from baseline 
at each time point in Part A will be summarized by overall subjects for Part A taking the capsule 
formulation. 12-ECG data for subjects taking oral solution will be listed only. For subjects entering 
Part B, observed values and change from baseline at each time point will be summarized by treatment 
group. Additionally, the number and percentage of subjects with a QTcF value meeting various clinical 
significance criteria (raw QTcF >450 msec, >480 msec, and >500 msec; change from baseline QTcF >30 


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msec and >60 msec) will be summarized separately for each study part: by overall subjects for Part A and 
by treatment group for Part B. 
9.4.4 
Vital Signs 
Vital sign results (body temperature, heart rate, respiratory rate, supine and standing diastolic blood 
pressure, supine and standing systolic blood pressure, and pulse oximetry) will be listed by subject and 
timing of collection. Observed values and change from baseline at each time point in Part A will be 
summarized by overall subjects taking the capsule formulation. Vital sign data for subjects taking oral 
solution will be listed only. For subjects entering Part B, observed values and change from baseline at 
each time point will be summarized by treatment group. 
9.4.5 
Physical Examination  
Screening physical examination results for Part A that are clinically significant will be listed in the 
medical history listing. Post-screening physical examination results for that are clinically significant will 
be listed in the AE listing. A listing will be provided containing information on when physical 
examination occurred and reason it was not done if applicable. 
9.4.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner, Brown, Stanley, & al, 2011). 
This scale consists of a baseline evaluation that assesses the lifetime experience of the subject with 
suicidal ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes “yes” or “no” responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most 
severe).  
Suicidality data collected on the C-SSRS will be listed for all subjects. Tables will include results from 
the Suicidal Ideation and Suicidal Behavior sections of the C-SSRS. Frequencies and percents of subjects 
with a response of “Yes” at any point on the Suicidal Ideation and Suicidal Behavior items will be 
summarized by overall subjects for Part A taking the capsule formulation. All C-SSRS data for subjects 
taking oral solution will be listed only, and by treatment group for Part B. Both baseline (“pre-treatment”) 
and post-baseline (“post-treatment”) results will be presented.  
9.4.7 
Stanford Sleepiness Scale (SSS) 
The SSS is a subject-rated scale designed to quickly assess how alert a subject is feeling (Hoddes, 
Dement, & Zarcone, 1972). Degrees of sleepiness and alertness are rated on a scale of 1 to 7, where the 
lowest score of 1 indicates the subject is “feeling active, vital, alert, or wide awake” and the highest score 
of 7 indicates the subject is “no longer fighting sleep, sleep onset soon; having dream-like thoughts”.  
Sedation data collected on the SSS will be listed for all subjects. Mean total score over time will be 
represented graphically by overall subjects in Part A (taking the capsule formulation) and by treatment 
group in Part B. All SSS data for subjects taking oral solution will be listed only. Observed values and 
change from baseline at each time point in Part A will be summarized by overall subjects. For subjects 
entering Part B, observed values and change from baseline at each time point will be summarized by 
treatment group. 
9.4.8 
Bond-Lader Visual Analogue Scale (VAS) 
Mood will be assessed using the Bond-Lader VAS Mood Scale. This is a 16-part self-administered 
questionnaire that employs a 100-mm VAS to explore different aspects of self-reported mood (Bond & 
Lader, 1974). The 16 different mood ranges include:  
1. 0 = “Alert” to 100 = “Drowsy”;  
2. 0 = “Calm” to 100 = “Excited”;  


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3. 0 = “Strong” to 100 = “Feeble”;  
4. 0 = “Muzzy” to 100 = “Clear-headed”;  
5. 0 = “Well-coordinated” to 100 = “Clumsy”;  
6. 0 = “Lethargic” to 100 = “Energetic”;  
7. 0 = “Contented” to 100 = “Discontented”;  
8. 0 = “Troubled” to 100 = “Tranquil”;  
9. 0 = “Mentally slow” to 100 = “Quick-witted”;  
10. 0 = “Tense” to 100 = “Relaxed”;  
11. 0 = “Attentive” to 100 = “Dreamy”;  
12. 0 = “Incompetent” to 100 = “Proficient”;  
13. 0 = “Happy” to 100 = “Sad”;  
14. 0 = “Antagonistic” to 100 = “Amicable”;  
15. 0 = “Interested” to 100 = “Bored”; and  
16. 0 = “Withdrawn” to 100 = “Gregarious”. 
In order to directly compare VAS results across the 16 items, items 4, 6, 8, 9, 10, 12, 14, and 16 will be 
reverse-scored by subtracting the scores from 100. In order to normalize the results, the scores will be 
converted to loge (after setting any scores of 0 to 1), with a resulting range of 0 to 4.605. Based on the 
factor loadings from Table 4 of the Bond and Lader article, the following equations will be used to 
compute the 3 factor scores: 
• 
Alertness = 0.827X1 + 0.618X3 + 0.755X4 + 0.642X5 + 0.776X6 + 0.635X9 + 0.792X11 + 0.593X12 
+ 0.614X15; 
• 
Contentedness = 0.677X7 + 0.697X8 + 0.823X13 + 0.738X14 + 0.594X16; and 
• 
Calmness = 0.845X2 + 0.677X10, 
where Xi represents a subject’s item score after normalization, and i represents the item number from 
the entire scale (in order from 1-16). 
Bond-Lader VAS results will be listed for all subjects. Observed values and change from baseline at each 
time point in Part A will be summarized by parameter (including the 3 factor scores) and overall subjects 
taking the capsule formulation. All Bond-Lader VAS data for subjects taking oral solution will be listed 
only. Observed values and change from baseline at each time point in Part B will be summarized by 
parameter (including the 3 factor scores) and treatment group. 
9.4.9 
Drug Effects Questionnaire (DEQ-5) 
The DEQ-5 will be administered as follows: 
1. Do you FEEL a drug effect right now? 
2. Are you HIGH right now? 
3. Do you DISLIKE any of the effects that you are feeling right now?  
4. Do you LIKE any of the effects that you are feeling right now?  
5. Would you like MORE of the drug you took, right now?  
The answers are recorded on a 100-mm VAS, with the answer for each being “Not at all” and 
“Extremely” at the extremes. There will be options to record “Not applicable” for questions 3 and 4 if no 
drug effects are felt and for question 5 prior to administration of study medication.  
The DEQ-5 results will be listed for all subjects. Since no baseline (before first dose of open-label study 
drug) values were recorded, only raw values at each time point will be summarized by parameter and 


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overall subjects for Part A taking the capsule formulation, and by parameter and treatment group for Part 
B. All DEQ-5 data for subjects taking oral solution will be listed only. 
9.5 
Pharmacokinetic Analysis 
For plasma concentration data, all values below the limit of quantification (BLQ) will be set to 0 for 
summary statistics and graphs. Individual plasma concentrations of SAGE-217 will be summarized at 
each time point using descriptive statistics, including number of subjects, mean, SD, median, maximum, 
minimum, percent coefficient of variation (%CV), and geometric mean. Part A data will be summarized 
by overall subjects, and Part B data will be summarized by tolerated dose for subjects who received 
SAGE-217. Individual concentration plots and mean data graphs will be produced for the intensive PK 
sampling (Days 1 and 7 for Part A and Day 8, predose through Day 14, predose [ie, trough 
concentrations] for Part B). All graphs will be presented using both linear and semi-logarithmic scales. 
The above descriptive summary will be performed for the PK population.  
All SAGE-217 plasma concentrations for both formulations will be presented in a by-subject listing.  
Pharmacokinetic parameter estimation will be performed using Phoenix WinNonlin® software (Version 
6.4 or later; Pharsight, Cary, NC) on individual plasma concentration-time data. For the PK parameter 
calculation, BLQ plasma concentrations occurring before tmax will be set to 0, with the exception of a 
BLQ value occurring between two measurable concentrations, in which case it will be set to missing. 
BLQ plasma concentrations occurring after tmax will be set to missing. Pharmacokinetic parameter 
estimates and summaries will be completed for subjects in the PK population having sufficient 
measurable concentrations to define the profile.  
Pharmacokinetic parameter estimates for Part A as based on Day 1 and Day 7 intensive sampling, 
including Cmax, tmax, λZ, AUC0-t, AUC0-∞, and t1/2, where appropriate and as data permit, and for Part B, 
including Cmin, will be summarized using descriptive statistics, including arithmetic and geometric means, 
SD, %CV, median, minimum, and maximum. Part A data will be summarized by overall subjects, and 
Part B data will be summarized by tolerated dose within active treatment group. As tmax is a categorical 
variable, only the median and the range will be reported.  
Wherever necessary and appropriate, PK parameters may be dose-adjusted to account for individual 
differences in dose. 
A graph comparing change from baseline (Part A) at Day 7 in accelerometer-based Kinesia combined and 
upper limb total scores and time-matched PK concentrations over time (ie, 0, 2, and 8 hours postdose) 
may be produced for overall subjects in the PK Population. 
All PK summaries will only include subjects on the capsule formulation. 
10 SUMMARY OF INTERIM ANALYSES 
Not applicable. 
11 REFERENCES 
Bond, A., & Lader, M. (1974). The use of analogue scales in rating subjective feelings. Br. J. 
med. Psychol., 47, 211-218. 
Elble, R., Comella, C., & al. (2012). Reliability of a new scale for essential tremor. Mov Disord, 
27(12):1587-1569. 
Giovanni, M., Giuffrida, J., Adam, O., Davidson, A., & Jankovic, J. (2010). Correlation between 
Kinesia system assessments and clinical tremor scores in patients with essential tremor. 
Mov Disord, 25(12):1938-43. 


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Hoddes, E., Dement, W., & Zarcone, V. (1972). The development and use of the Stanford 
Sleepiness Scale (SSS). Psychophysiology, 9:150. 
Movement Disorders Society Rating Scales. (n.d.). Retrieved from 
http://www.movementdisorders.org/MDS-Files1/PDFs/Rating-
Scales/QUESTScoreSheet.pdf. 
Posner, K., Brown, G., Stanley, B., & al. (2011). The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry, 168(12):1266-77. 
Tröster, A., Pahwa, R., Fields, J., Tanner, C., & Lyons, K. (2005). Quality of life in Essential 
Tremor Questionnaire (QUEST): development and initial validation. Parkinsonism Relat 
Disord., 11(6):367-73. 


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12 LIST OF APPENDICES 
12.1 Appendix A: Schedule of Assessments 
12.1.1 Part A (Open-Label) 
Visit Days 
Screening 
(Day -28 to Day -1) 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Body weight/height 
X 
 
 
 
 
 
 
 
 
Drug/alcohol screen a 
X 
X 
 
 
 
 
 
 
 
Complete blood count/ 
serum chemistry b 
X 
X 
X 
X 
 
 
 
 
 
Pregnancy test  
X 
(serum) 
X 
(urine) 
 
 
 
 
 
 
 
Urinalysis b  
X 
X 
X 
X 
 
 
 
 
 
Hepatitis & HIV screen 
X 
 
 
 
 
 
 
 
 
Exploratory biochemistry sample c 
O 
 
 
 
O 
 
 
 
O 
Genetic sample d 
O 
 
 
 
 
 
 
 
 
Vital signs e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetry e 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG f 
X 
 
X 
X 
X 
X 
 
 
X 
C-SSRS g 
X 
X 
X 
 
 
X 
X 
X 
X 
SSS h 
 
 
X 
X 
X 
X 
X 
X 
X 


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Visit Days 
Screening 
(Day -28 to Day -1) 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Bond-Lader-VAS i 
 
 
X 
X 
 
 
 
 
X 
DEQ-5 j 
 
 
X 
 
 
 
 
 
X 
Kinesia (accelerometer) k 
 
X 
X 
X 
X 
 
 
 
X 
TETRAS upper limb items k 
X 
X 
X 
X 
X 
 
 
 
X 
TETRAS (ADL Subscale and items 
4, 6, 7, and 8 of Performance 
Subscale) l 
 
X 
 
 
 
 
 
 
X 
Empatica Wristband E4 m 
 
X 
X 
X 
X 
 
 
 
X 
QUEST 
 
X 
 
 
 
 
 
 
X 
Plasma PK samples n 
 
 
X 
X 
X 
X 
X 
X 
X 
Administer study drug o 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
Prior/concomitant medications p 
X 
Videos q 
 
X 
 
 
 
 
 
 
X 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram; HIV 
= human immunodeficiency virus; O = optional; PK = pharmacokinetic; QUEST = Quality of Life in Essential Tremor Questionnaire; SSS = Stanford 
Sleepiness Scale; TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue score 
a A urine sample for assessment of selected drugs (sedative/hypnotics [eg, opioids], cotinine, and caffeine) and a breath sample for alcohol screen will be 
collected at screening and Day -1. 
b Screening and safety laboratory tests will be performed at screening, Day -1, predose on Day 1, and predose on Day 2. 
c An optional blood sample for exploratory biochemistry, where consent is given. 
d An optional genetic sample for biomarker testing, where consent is given. 
e Vital signs (heart rate, respiratory rate, temperature, and supine [for at least 5 minutes prior to the measurement] and standing [for at least 2 to 3 minutes] 
systolic and diastolic blood pressure) and pulse oximetry will be performed at screening (vital signs only) and Day -1, predose and at 1, 2, 3, 4, 6, and 8 
hours postdose on Days 1, 2, 3, and 4, and predose on Days 5, 6, and 7.  Vital signs and pulse oximetry assessments will be performed within ±10 minutes 
of the scheduled times. 
f 12-lead ECGs will be performed at screening, predose, and at 1 and 8 hours (±10 minutes) postdose on Days 1, 2, 3, 4, and 7. 
g The C-SSRS will be performed at screening, on Day -1, 8 hours (±1 hour) postdose on Day 1, predose on Day 4, and on Days 5, 6, and 7.  
Baseline/Screening version of C-SSRS should be used on day of screening and Since Last Visit version should be used on all subsequent time points. 


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h The SSS will be performed predose and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 1, 2, 3, and 4, and predose only on Days 5, 6, and 7.  The SSS is to be 
performed within ±10 minutes of the scheduled times. 
i The Bond-Lader VAS will be performed predose and 2 hours (±10 minutes) postdose on Days 1, 2, and 7. 
j The DEQ-5 will be performed 2 hours (±10 minutes) postdose on Days 1 and 7. 
k Kinesia and TETRAS upper limb items will be performed at screening (TETRAS upper limb items only), on Day -1 (three assessments separated by at 
least 30 minutes); single assessments will be performed predose and 2 and 8 hours (±30 minutes) postdose on Days 1, 2, 3, and 7.  In addition, the 
TETRAS upper limb items will be performed, while wearing the Empatica Wristband E4, on Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3, 
and 7. All three maneuvers in the upper limb assessments (items 4a, 4b, and 4c) will be completed for both arms, first for the RIGHT arm and then for the 
LEFT. 
l TETRAS (ADL Subscale and items 4, 6, 7, and 8 of Performance Subscale) will be performed on Day -1 and predose (±30 minutes) on Day 7. 
m The Empatica Wristband E4 will be worn during the study visits while in clinic on Days -1, 1, 2, 3, and 7.  With the exception of during the TETRAS 
upper limb assessments, the Empatica Wristband E4 will be worn on the wrist that, of the two arms, exhibits more severe tremor symptoms.  During the 
TETRAS upper limb assessments on Day -1 and 3 hours (±30 minutes) postdose on Days 1, 2, 3, and 7, the Empatica Wristband E4 will be worn on the 
wrist corresponding to the side of the body being assessed. 
n Plasma pharmacokinetic samples will be taken predose (±5 minutes) and 0.25, 0.5, 1, 2, 4, and 8 hours postdose on Days 1 and 7 and predose on Days 2, 3, 
4, 5, and 6. 
o Study drug will be administered in the morning with food. 
p To include those taken within 2 weeks prior to informed consent and throughout the study. 
q Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences 
difficulty with on a daily basis) will be taken on Day -1and predose on Day 7. 
 
 
 
 
 


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12.1.2 Part B (Randomized Withdrawal) 
Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21±1 day a 
(Early 
Termination 
Visit) 
End of Study 
Day 28±1 day 
Randomization 
X 
 
 
 
 
 
 
 
 
Complete blood count/ 
serum chemistry b 
X 
X 
 
 
 
 
 
X 
 
Pregnancy test c 
X 
(urine) 
 
 
 
 
 
 
 
X 
(urine) 
Urinalysis b 
X 
X 
 
 
 
 
 
X 
 
Vital signs d 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pulse oximetry d 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG e 
X 
X 
X 
 
 
 
X 
X 
 
C-SSRS f 
X 
 
 
X 
X 
X 
X 
X 
X 
SSS g 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bond-Lader-VAS h 
X 
X 
 
 
 
 
X 
X 
 
DEQ-5 i 
X 
 
 
 
 
 
X 
 
 
Kinesia (accelerometer) j 
X 
X 
 
 
 
 
X 
X 
 
TETRAS upper limb items j 
X 
X 
 
 
 
 
X 
X 
 
TETRAS (ADL Subscale and items 
4, 6, 7, and 8 of Performance 
Subscale) k 
 
 
 
 
 
 
X 
X 
 
Empatica Wristband E4 l 
X 
X 
 
 
 
 
X 
X 
 
QUEST 
 
 
 
 
 
 
X 
 
 
Plasma PK samples m 
X 
X 
X 
X 
X 
X 
X 
 
 


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Visit Days 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Follow-up  
Day 21±1 day a 
(Early 
Termination 
Visit) 
End of Study 
Day 28±1 day 
Administer study drug n 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events 
X 
Concomitant medications o 
X 
Videos p 
 
 
 
 
 
 
X 
X 
 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram;  
HIV = human immunodeficiency virus; PK = pharmacokinetic; QUEST = Quality of Life in Essential Tremor Questionnaire; SSS = Stanford Sleepiness 
Scale; TETRAS = TRG Essential Tremor Rating Assessment Scale; VAS = visual analogue score 
a In addition to subjects who complete Part B, subjects who receive at least one dose of study drug and do not complete Part B will have a visit 1 week 
following the last dose of study drug to assess safety measures. 
b Safety laboratory tests will be performed predose on Day 8 and Day 9 and anytime during the visit on Day 21. 
c To be performed predose on Day 8 and anytime during the visit on Day 28. 
d Vital signs (heart rate, respiratory rate, temperature, and supine [for at least 5 minutes prior to the measurement] and standing [for at least 2 to 3 minutes] 
systolic and diastolic blood pressure) and pulse oximetry will be performed predose on Day 8 and at 1, 2, 3, 4, 6, and 8 hours postdose on Days 8, 9, and 
10, predose on Days 11, 12, 13, and 14, and anytime during the visit on Day 21.  Vital signs and pulse oximetry assessments will be performed within ±10 
minutes of the scheduled times. 
e 12-lead ECGs will be performed at 1 and 8 hours (±10 minutes) postdose on Days 8, 9, 10, and 14, and anytime during the visit on Day 21. 
f The C-SSRS (Since Last Visit version) will be performed 8 hours (±1 hour) postdose on Days 8, 11, 12, 13 and 14 and anytime during the visits on 
Days 21 and 28. 
g The SSS will be performed predose and 1, 2, 4, 6, and 8 hours postdose on Days 8, 9, 10, 11, 12, 13, and 14, and anytime during the visit on Day 21.  The 
SSS is to be performed within ±10 minutes of the scheduled times. 
h The Bond-Lader VAS will be performed predose and 2 hours (±10 minutes) postdose on Days 8, 9, and 14 and anytime during the visit on Day 21. 
i The DEQ-5 will be performed 2 hours (±10 minutes) postdose on Days 8 and 14. 
j Kinesia and TETRAS upper limb items will be performed predose, 2 and 8 hours (±30 minutes) postdose on Days 8, 9, and 14, and anytime during the 
visit on Day 21.  In addition, the TETRAS upper limb items will be performed, while wearing the Empatica Wristband E4, 3 hours (±30 minutes) postdose 
on Days 8, 9, and 14, and anytime during the visit on Day 21.  All three maneuvers in the upper limb assessments (items 4a, 4b, and 4c) will be completed 
for both arms, first for the RIGHT arm and then for the LEFT. 
k TETRAS ADL Subscale and items 4, 6, 7, and 8 of Performance Subscale will be performed predose (±30 minutes) on Day 14 and anytime during the visit 
on Day 21. 
l The Empatica Wristband E4 will be worn during the study visits while in clinic on Days 8, 9, 14, and 21.  With the exception of during the TETRAS upper 
limb assessments, the Empatica Wristband E4 will be worn on the wrist that, of the two arms, exhibits more severe tremor symptoms.  During the 


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TETRAS upper limb assessments 3 hours (±30 minutes) postdose on Days 8, 9, and 14 and anytime during the visit on Day 21, the Empatica Wristband E4 
will be worn on the wrist corresponding to the side of the body being assessed. 
m Plasma pharmacokinetic samples will be taken predose (±5 minutes) on Days 8, 9, 10, 11, 12, 13, and 14. 
n Study drug will be administered in the morning with food. 
o To include those taken throughout the study. 
p Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences 
difficulty with on a daily basis) will be taken predose on Day 14 and anytime during the visit on Day 21. 
  


 
 
Sage Therapeutics, Inc 
Statistical Analysis Plan 
Methods 
Protocol 217-ETD-201 
Part C  
 A PHASE 2A, DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED 
WITHDRAWAL STUDY EVALUATING THE EFFICACY, SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS OF SAGE-217 IN THE 
TREATMENT OF SUBJECTS WITH ESSENTIAL TREMOR (ET) 
Author of SAP: 
, MStat 
Version: Version 1.0 
Date of SAP: 14 DEC 2017 
 
Sponsor 
Sage Therapeutics, Inc 
215 First Street 
Cambridge, Massachusetts 02142 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent of 
Sage Therapeutics Incorporated is strictly prohibited except to the extent required under applicable laws or regulations. 
Persons to whom the information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them.




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1 
TABLE OF CONTENTS 
Signature Page and Approvals .................................................................................................... 2 
1 
Table of Contents ................................................................................................................... 3 
2 
List of Abbreviations ............................................................................................................. 5 
3 
Introduction............................................................................................................................ 6 
4 
Study Objectives .................................................................................................................... 6 
4.1 
Primary Objective ............................................................................................................. 6 
4.2 
Secondary Objectives ....................................................................................................... 6 
4.3 
Safety Objectives .............................................................................................................. 6 
4.4 
Exploratory Objectives ..................................................................................................... 7 
5 
Study Endpoints ..................................................................................................................... 7 
5.1 
Efficacy Endpoints ........................................................................................................... 7 
5.1.1 
Primary Efficacy Endpoint ....................................................................................... 7 
5.1.2 
Secondary Efficacy Endpoints .................................................................................. 7 
5.1.3 
Exploratory Efficacy Endpoints ............................................................................... 7 
5.2 
Safety Endpoints ............................................................................................................... 7 
5.3 
Other Endpoints ................................................................................................................ 8 
6 
Study Design ........................................................................................................................... 8 
6.1 
Overall Design .................................................................................................................. 8 
6.2 
Sample Size and Power .................................................................................................... 9 
6.3 
Randomization .................................................................................................................. 9 
6.4 
Blinding and Unblinding .................................................................................................. 9 
7 
Modifications .......................................................................................................................... 9 
7.1 
Modifications to the Approved Clinical Study Protocol .................................................. 9 
7.2 
Modifications to the Approved Statistical Analysis Plan ................................................. 9 
7.3 
Modifications to the Approved DMC Charter .................................................................. 9 
8 
Analysis Populations .............................................................................................................. 9 
8.1 
Efficacy Population .......................................................................................................... 9 
8.2 
Safety Population .............................................................................................................. 9 
8.3 
PK Population ................................................................................................................... 9 
9 
Statistical Analysis ............................................................................................................... 10 
9.1 
General Considerations .................................................................................................. 10 
9.2 
Background Characteristics ............................................................................................ 11 
9.2.1 
Subject Disposition ................................................................................................. 11 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 11 
9.2.3 
Prior and Concomitant Medications ....................................................................... 12 
9.2.4 
Study Drug Exposure and Compliance .................................................................. 12 
9.3 
Efficacy Analysis ............................................................................................................ 13 
9.3.1 
Analysis of Primary Efficacy Variable ................................................................... 13 
9.3.1.1 
Description of Primary Efficacy Variable........................................................ 13 
9.3.1.2 
Visit Windows for the Primary Endpoint ........................................................ 13 
9.3.1.3 
Primary Analysis .............................................................................................. 14 
9.3.1.4 
Supportive Analyses ........................................................................................ 14 
9.3.1.5 
Multiplicity Adjustment ................................................................................... 14 


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9.3.1.6 
Sensitivity Analysis .......................................................................................... 14 
9.3.1.7 
Subgroup Analyses .......................................................................................... 14 
9.3.2 
Analysis of Secondary Efficacy Variables ............................................................. 14 
9.3.2.1 
Kinesia Upper Limb Individual Scores ............................................................ 14 
9.3.2.2 
TETRAS Upper Limb Individual and Total Scores ......................................... 14 
9.3.2.3 
TETRAS Performance Subscale Individual and Total Scores ......................... 15 
9.3.3 
Analysis of Exploratory Efficacy Variables ........................................................... 15 
9.3.3.1 
TETRAS ADL ................................................................................................. 15 
9.3.3.2 
QUEST ............................................................................................................. 16 
9.4 
Safety Analysis ............................................................................................................... 16 
9.4.1 
Adverse Events ....................................................................................................... 17 
9.4.2 
Clinical Laboratory ................................................................................................. 18 
9.4.3 
Electrocardiogram .................................................................................................. 18 
9.4.4 
Vital Signs .............................................................................................................. 18 
9.4.5 
Physical Examination ............................................................................................. 18 
9.4.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) .............................................. 18 
9.4.7 
Bond-Lader Visual Analogue Scale (VAS)............................................................ 19 
9.4.8 
Drug Effects Questionnaire (DEQ-5) ..................................................................... 19 
9.5 
Pharmacokinetic Analysis .............................................................................................. 20 
10 Summary of Interim Analyses ............................................................................................ 20 
11 References ............................................................................................................................. 20 
12 List of Appendices................................................................................................................ 21 
12.1 Appendix A: Schedule of Assessments .......................................................................... 21 
12.1.1 
Part C (Open-Label) ............................................................................................... 21 
 
 


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2 
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION OR DESCRIPTION 
ADL 
activities of daily living 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BLQ 
below the limit of quantification 
%CV 
percent coefficient of variation 
CI 
confidence interval 
CM 
concomitant medications 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DEQ-5 
Drug Effects Questionnaire 
CSR 
clinical study report 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
essential tremor 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
LLOQ 
lower limit of quantitation 
LS 
least-squares 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PT 
preferred term 
QoL 
quality of life 
QTcF 
QT-interval for ECG corrected for heart rate (Fridericia) 
QUEST 
Quality of Life in Essential Tremor Questionnaire  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
System Organ Class 
TEAE 
treatment emergent adverse event 
TETRAS 
TRG Essential Tremor Rating Assessment Scale  
ULOQ 
upper limit of quantitation 
VAS 
visual analogue scale 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 


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3 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis of the study and is based on the approved 
clinical study protocol, dated September 5, 2017, Version 5.0, incorporating Amendment 4 for Study 
217-ETD-201. Part A and Part B of this study were analyzed in a separate SAP. Part C will be analyzed 
according to this SAP.  
This SAP addresses the safety, efficacy, and pharmacokinetics (PK) objectives of the study and describes 
the planned safety, efficacy, and PK statistical analyses and data presentations. 
The statistical plan described hereafter is an a priori plan and will be submitted to file before any analysis 
of data pertaining to Sage Study 217-ETD-201 (Part C) is performed. The SAP is to be finalized and 
approved before database lock. 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and graphical 
representations will be performed primarily using SAS (release 9.3 or higher) for Windows.  
Pharmacokinetic parameter estimation will be performed using population PK methods.  
The reader of this SAP is encouraged to also read the clinical protocol, and other identified documents, 
for details on the planned conduct of this study. Operational aspects related to collection and timing of 
planned clinical assessments are not repeated in this SAP unless relevant to the planned analysis. 
4 
STUDY OBJECTIVES  
4.1 
Primary Objective 
The primary objective of this study (Part C) is to assess the effect of 14 days administration of SAGE-217 
Capsules on tremor severity, as measured by the change from baseline (Day 1) in the accelerometer-based 
Kinesia upper limb tremor combined score (ie, the sum of accelerometer-based Kinesia forward 
outstretched postural tremor, lateral "wing beating" postural tremor, and kinetic tremor item scores from 
both sides of the body) at Day 15. 
4.2 
Secondary Objectives  
The secondary objectives of this study are to assess the effect of 14 days of administration of SAGE-217 
Capsules on the following endpoints: 
• 
Tremor severity, as assessed by the change from baseline (Day 1) in the Kinesia upper limb 
individual item scores at Day 15; 
• 
Tremor severity, as measured by the change from baseline (Day 1) in the TETRAS upper limb 
total score (ie, the sum of TETRAS Performance Subscale item 4 scores [4a, 4b, and 4c] from 
both sides of the body) and individual TETRAS Performance Subscale upper limb item scores at 
Day 15; 
• 
Tremor severity, as assessed by the change from baseline (Day 1) in the total TETRAS 
Performance subscale score and other TETRAS Performance Subscale scores measured at Day 
15; 
4.3 
Safety Objectives 
• 
Safety and tolerability as assessed by vital signs measurements, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Severity 
Rating Scale (C-SSRS), and adverse event (AE) reporting; 
• 
Mood as assessed by the Bond-Lader visual analogue score (VAS) Mood Scale; and 
• 
How the subject feels after taking the study drug as assessed by Drug Effects Questionnaire 
(DEQ-5) ratings. 


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In addition, the PK objective of this study is to assess the PK profile of SAGE-217 in plasma samples 
following administration of SAGE-217 Capsules.   
4.4 
Exploratory Objectives 
The exploratory objectives of the study are to compare the effect of 14 days of administration of SAGE-
217 Capsules on: 
• 
Physiological activity (ie, sympathetic nervous system tone as measured by electrodermal 
activity, skin temperature monitoring, and heart rate monitoring), as assessed by the Empatica 
Wristband E4. Tremor oscillation, as assessed by multidimensional accelerometer measurements 
(ie, raw accelerometer values) using the Empatica E4 Wristband. 
• 
Quality of life (QoL), as assessed by TETRAS activities of daily living (ADL), Quality of Life in 
Essential Tremor Questionnaire (QUEST), and video recording assessment of subjects 
performing three everyday tasks (drinking a glass of water, fastening a button, and one additional 
task that the subject experiences difficulty with on a daily basis). 
In addition, PK and pharmacodynamic (PD) modelling assessment of the relationship between plasma 
exposure of SAGE-217 and change from baseline in Kinesia scores may be assessed. 
5 
STUDY ENDPOINTS 
5.1 
Efficacy Endpoints 
5.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the change from baseline (Day 1) in the 
accelerometer-based Kinesia upper limb tremor combined score (ie, the sum of accelerometer-based 
Kinesia forward outstretched postural tremor, lateral "wing beating" postural tremor, and kinetic tremor 
item scores from both sides of the body) at Day 15. 
5.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study include the following: 
• 
Change from baseline in the Kinesia upper limb individual item scores at Day 15 and all other 
time points; 
• 
Change from baseline in TETRAS Performance Subscale upper limb total score (ie, the sum of 
TETRAS Performance Subscale item 4 scores [4a, 4b, and 4c] from both sides of the body) and 
individual TETRAS Performance Subscale upper limb item scores at Day 15 and all other time 
points; and 
• 
Change from baseline in other TETRAS Performance Subscale scores measured at Day 15 and all 
other time points. 
5.1.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints of this study include the following:  
• 
Change from baseline in TETRAS ADL and QUEST scores at Day 15. 
5.2 
 Safety Endpoints 
The safety endpoints of this study include the following: 
• 
Frequency and severity of AEs; 
• 
Safety and tolerability as assessed by changes from baseline in vital signs measurements, clinical 
laboratory data, ECG parameters, and incidences of suicidal ideation using the C-SSRS; 


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• 
Change from baseline in mood as assessed by the Bond-Lader VAS Mood Scale; and 
• 
DEQ-5 ratings. 
5.3 
Other Endpoints 
The PK endpoints include plasma concentrations of SAGE-217 and metabolites for subjects taking 
capsules as follows: 
• 
Mean plasma concentrations and parameters (area under the concentration-time curve from time 0 
to last time point [AUC0-t], area under the concentration-time curve from time 0 to infinity 
[AUC0-∞], maximum plasma concentration [Cmax], time to reach maximum concentration [tmax], 
and terminal half-life [t1/2], as appropriate) of SAGE-217 and possible metabolites. 
6 
STUDY DESIGN  
6.1 
Overall Design  
This study is a 3-part, multicenter, Phase 2a study to evaluate the efficacy, safety, tolerability, and PK of 
SAGE-217 in adult subjects with essential tremor (ET). Subjects who consent before the approval of 
Protocol Version 4.0 (Amendment 3) by the IRB will receive the oral solution formulation for the 
duration of the study; subjects who consent after Protocol Version 4.0 (Amendment 3) is approved by the 
IRB will receive the capsule formulation for the duration of the study. Part A of the study was an 
open-label design with morning dosing for 7 days. Part B of the study was a double-blind, 
placebo-controlled, randomized withdrawal design. Subjects were exposed to study drug (SAGE-217 or 
placebo) for up to 14 days and were followed for an additional 14 days after the administration of the last 
dose. Part C of the study is an open-label design with evening dosing (and morning and evening dosing 
beginning on Day 4) for up to 14 days. All subjects in Part C will receive the capsule formulation. 
During the Screening Period (Day -28 to Day -1), after signing the informed consent form (ICF), subjects 
will be assessed for study eligibility and the severity of each subject’s ET will be evaluated using 
TETRAS. Eligible subjects will return to the clinical study unit on Day -1.  
The study will be conducted in 3 parts; however, only Part C will be discussed in this SAP (Part A and 
Part B were discussed in a separate SAP):  
• 
Part C: All eligible subjects will start on a 10 mg dose of study drug administered with food in 
the evening on Day 1, 20 mg with food in the evening on Day 2, and 30 mg with food in the 
evening on Day 3.  Beginning on Day 4 and continuing through Day 14, subjects will receive a 
40 mg total daily dose (administered as 10 mg with food in the morning and 30 mg with food in 
the evening).  Study drug will be self-administered by subjects on an outpatient basis for the 
entire 14-day Treatment Period.   
Dose adjustments will be allowed during Part C of the study. A dose will be considered not tolerated if 
the subject experiences a severe AE or a moderate AE of special interest (sedation, somnolence, 
dizziness, euphoric mood, confusion, drowsiness, inebriation (feeling drunk), or fatigue) judged by the 
investigator to be related to study drug. If a dose is not tolerated, the dose on the next day will be reduced 
to the next lowest dose and continued for the remainder of the treatment period. Subjects who cannot 
tolerate the 20 mg dose on Day 2 will be discontinued. Subjects who do not tolerate 30 mg on Day 3 will 
receive 20 mg for the remainder of the treatment period (10 mg in the morning and 10 mg in the evening). 
Subjects who do not tolerate 40 mg on Day 4 or any time thereafter will receive 30 mg for the remainder 
of the treatment period (10 mg in the morning and 20 mg in the evening).  
Assessments will be performed periodically during the study as outlined in the Schedule of Events for 
Part C (Section 12.1.1). 


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6.2 
Sample Size and Power 
For Part C, approximately 15 subjects will be enrolled to ensure at least 10 subjects complete the study 
(through Day 15).  The sample size for Part C was selected based on clinical and not statistical 
considerations. 
6.3 
Randomization 
Part C is open-label with no control group; therefore, there will be no randomization. Once it has been 
determined that a subject meets eligibility criteria, the subject will be sequentially assigned a subject 
number. Subject identification numbers will consist of the site number (eg, “01”) followed by subject 
number with leading zeroes (eg, “001”; the subject identification number would then be “01-001”). 
6.4 
Blinding and Unblinding 
Part C is an open-label study with no control group; therefore, there will be no blinding. 
7 
MODIFICATIONS  
7.1 
Modifications to the Approved Clinical Study Protocol 
The following changes from the clinical study protocol (version 5.0, dated September 5, 2017) have been 
made in the SAP: 
• 
The protocol describes Part A and Part B; these were analyzed according to a separate SAP. 
• 
This SAP includes safety objectives for assessing mood and how the subject feels after taking the 
study drug which are not explicitly outlined in the protocol, although the endpoints used to assess 
the objectives (Bond-Lader VAS Mood Scale and DEQ-5, respectively) are described in the 
protocol.  
7.2 
Modifications to the Approved Statistical Analysis Plan 
This is the first version of the SAP. 
7.3 
Modifications to the Approved DMC Charter 
Not applicable. 
8 
ANALYSIS POPULATIONS 
Subjects included in the below analysis populations (and reason for exclusion, if applicable) will be 
provided in a listing. 
8.1 
Efficacy Population 
The Efficacy Population (Part C; Capsule) will consist of all subjects who complete at least one dose of 
study drug in Part C and have at least one postdose efficacy evaluation. The Efficacy Population (Part C; 
Capsule) will be used to analyze all Part C-Capsule efficacy data.  
8.2 
Safety Population 
The Safety Population (Part C; Capsule) will consist of all subjects who are administered at least one dose 
of study drug. This population will be used to provide descriptive summaries of safety. 
8.3 
PK Population 
The PK Population (Part C; Capsule) will consist of all subjects in the Safety Population (Part C; 
Capsule) with at least one sample with quantifiable plasma concentration of SAGE-217 in Part C. This 
population will be used to summarize PK data. 


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9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
Continuous (quantitative) variable summaries will include the number of subjects (n) with non-missing 
values, mean, standard deviation (SD), median, minimum, and maximum. 
Categorical (qualitative) variables will be summarized using the number and proportion of each possible 
value. In general, the denominator for the percentage calculation will be based upon the total number of 
subjects in the study population for the treatment group. 
The minimum and maximum will be reported with the same degree of precision (ie, the same number of 
decimal places) as the observed data. Measures of location (mean and median) will be reported to 1 
degree of precision more than the observed data and measures of spread (standard deviation) will be 
reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place unless otherwise specified. Assessments done on 
unscheduled visits will not be summarized but will be listed.  
Treatment group is defined as SAGE-217. For any outputs showing tolerated dose, tolerated dose is 
defined as SAGE-217 20 mg, SAGE-217 30 mg, or SAGE-217 40 mg (Section 6.1).  
The last observation recorded before receiving the first dose of study drug on Day 1 in Part C will be used 
as the baseline observation for all calculations of change from baseline.   
All summaries will be presented by overall subjects, unless otherwise specified. 
All final, planned analyses identified in the protocol and in this SAP will be performed after all relevant 
study data have been processed and integrated into the analysis database, analysis populations have been 
finalized, and the database has been locked. Any post-hoc analyses performed to support planned study 
analyses in the clinical study report (CSR), which were not identified in this SAP, will be documented in 
Section 9.8 of the CSR as a change in the conduct of the study or planned analyses.  
All collected data will be presented in listings and will be sorted by subject.  
If partial dates occur, the convention for replacing missing dates for the purposes of calculating derived 
variables is as follows: 
For partial AE and medication start dates: 
• 
If the year is unknown, then do not impute the date but assign a missing value. 
• 
If the year is known, but the month or month and day is unknown, then: 
o If the year matches the year of first dose date and the end date (if present) is after first 
dose date, then impute as the month and day of the first dose date. 
o Otherwise, assign 01 January 
• 
If the year and month are known, but the day is unknown, then: 
o If the month and year match the month and year of the first dose date, then impute as the 
day of the first dose date. 
o Otherwise, assign 01 
For partial AE and medication end dates: 
• 
If the year is unknown, then do not impute the date but assign as missing value. 
• 
If the year is known, but the month or month and day is unknown, then: 


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o If the year matches the year of the last date of the study (date of last contact if subject lost 
to follow-up; date of completion or early termination otherwise), then impute as the 
month and day of the last date of the study. 
o Otherwise, assign 31 December. 
• 
If the year and month are known, but the day is unknown, then: 
o If the month and year match the month and year of the last date of the study, then impute 
as the day of the last date of the study. 
o Otherwise, assign the last day of the month. 
No missing data will be imputed unless otherwise specified. 
In general, for quantitative safety laboratory values reported as ‘<X’ or ‘≤X’, the lower limit of 
quantitation (LLOQ) will be used for analysis (ie, a value of X will be used in the analysis for lab values 
reported as ‘<X’ or ‘≤X’). Similarly, for safety quantitative laboratory values reported as ‘>X’ or ‘≥X’, 
the upper limit of quantitation (ULOQ) will be used for analysis (ie, a value of X will be used in the 
analysis for lab values reported as ‘>X’ or ‘≥X’). 
For analysis purposes, repeat laboratory results will not be used unless the original laboratory value is 
missing or indicated as invalid, in which case the first non-missing repeat laboratory value will be used 
for data analysis. 
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
All subjects who sign the ICF will be accounted for in this study.  
Subject disposition will be summarized as follows: 
• 
The number of subjects enrolled (ie, signed informed consent); treated; completed Part C; 
withdrew from Part C (including reason for withdrawal); and included in each Part C analysis 
population will be summarized by overall subjects; and  
• 
The number and percentage of subjects enrolled; treated; completed Part C; withdrew from Part C 
(including reason for withdrawal); and included in each Part C analysis population will be 
summarized by tolerated dose. 
All disposition information will be included in a listing. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics, such as age, gender, child-bearing potential, race, and ethnicity, and baseline 
characteristics such as height, weight, body mass index (BMI), and time (years) since ET diagnosis (from 
date of ICF; a missing ET diagnosis month will be imputed as January, and the missing day will be 
imputed as 01), will be summarized by overall subjects.  
Categorical summaries, such as gender, childbearing potential, race, and ethnicity, will be summarized 
using frequency and percentage. Subjects who marked more than one race will be summarized in a “More 
than One Race” category. Continuous summaries, such as age, height, weight, BMI, and time since ET 
diagnosis, will be summarized using mean, standard deviation (SD), median, minimum, and maximum. 
The demographic and baseline characteristics table will be generated for subjects in the Safety 
Population.  
Hepatitis, human immunodeficiency virus (HIV), pregnancy, alcohol, cotinine, caffeine, and drug 
screening results will be listed, but not summarized as they are considered part of the inclusion/exclusion 
criteria. 


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Medical history, coded using Medical Dictionary for Regulatory Activities (MedDRA) (version 19.1 or 
higher), will be listed. 
9.2.3 
Prior and Concomitant Medications 
Concomitant medications (CM) will be coded using World Health Organization Drug Dictionary 
Enhanced (WHO-DDE) (Version September 1, 2015 or later). 
Frequencies and percentages of medications used in the study will be summarized as follows: 
• 
Prior medication: medication taken before the date of first dose of open-label study drug 
(including medications with a missing start date but a non-missing end date in this time period). 
• 
Concomitant medication: a medication with a start date on or after the first dose of open-label 
study drug (even if end date is missing) and on or before the last dose of study drug, or 
medications with a start date before the first dose of open-label study drug that are ongoing or 
with a stop date on or after the first dose of open-label study drug, will be considered 
concomitant. 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 subject, start date, and verbatim term. All 
medications will be summarized by Anatomic Therapeutic Chemical (ATC) class Level 3 and preferred 
term (PT). Furthermore, both prior and concomitant medications will be summarized by overall subjects. 
Subjects will be counted once per ATC and PT. 
Medication summaries will be based on the Safety Population.  
9.2.4 
Study Drug Exposure and Compliance 
For all of the below formulas, i = individual subject for the entire treatment period (unless otherwise 
specified). 
• 
Total drug exposure in mg will be calculated as: 
෍𝐴𝐴𝑆𝑆𝑇𝑇𝑞𝑞𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝐷𝐷
𝑖𝑖
 (𝐷𝐷𝑚𝑚) 
• 
Average daily dose (Days 4-14) in mg/day will be calculated as: 
∑𝐴𝐴𝑆𝑆𝑇𝑇𝑞𝑞𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝐷𝐷
𝑖𝑖
 (𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 4 −14) (𝐷𝐷𝑚𝑚)
∑𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑆𝑆𝑆𝑆𝑆𝑆𝑑𝑑𝑆𝑆 𝐷𝐷𝑆𝑆𝐷𝐷𝐷𝐷 (𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 4 −14)
𝑖𝑖
 
Days 1-3 are excluded since they are dose escalation days.  
• 
Total days of exposure will be calculated as: 
෍𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑆𝑆𝑆𝑆𝑆𝑆𝑑𝑑𝑆𝑆 𝐷𝐷𝑆𝑆𝐷𝐷𝐷𝐷
𝑖𝑖
 
• 
Study drug compliance will be calculated as: 
∑𝐴𝐴𝑆𝑆𝑇𝑇𝑞𝑞𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝐷𝐷
𝑖𝑖
 (𝐷𝐷𝑚𝑚)
∑𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 (𝐷𝐷𝑚𝑚)
𝑖𝑖
× 100 
where planned doses  are summed up to the point of discontinuation (eg, if a subject discontinues 
early, only planned doses up to that discontinuation day are counted in the denominator). 
Total drug exposure (mg), average total daily dose (mg/day) (starting at Day 4), total days of exposure, 
and compliance (%) will be summarized descriptively by overall subjects. Additionally, number of 
subjects at each tolerated total daily dose (ie, the sum of the final morning and evening doses received by 


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each subject during Days 4-14) will be summarized. If a subject discontinued after a morning dose (ie, did 
not receive an evening dose), the previous daily’s total daily dose will be considered as the tolerated total 
daily dose. If a subject only received evening doses, the final evening dose received will be considered as 
the tolerated total daily dose. 
Study drug dosing and compliance information (including details of unplanned dose adjustments) will be 
listed. Any other study drug noncompliance such as missing visits, interruptions in the schedule of 
administration, and nonpermitted medications will be listed in the protocol deviations listing. 
9.3 
Efficacy Analysis  
The primary efficacy variable for this study (Part C) is change from baseline in accelerometer-based 
Kinesia upper limb tremor combined score.  
The secondary efficacy variables for this study (Part C) include change from baseline in:  
• 
Kinesia upper limb individual item scores 
• 
TETRAS Performance subscale total and individual upper limb item scores 
• 
Other TETRAS Performance Subscale scores  
The other efficacy variables for this study (Part C) include change from baseline in:  
• 
TETRAS ADL scores 
• 
QUEST scores 
All efficacy analyses will be conducted on the Efficacy Population. 
9.3.1 
Analysis of Primary Efficacy Variable 
9.3.1.1 
Description of Primary Efficacy Variable 
The primary outcome measure is the change from baseline in the accelerometer-based Kinesia upper limb 
tremor combined score (ie, the sum of accelerometer-based Kinesia forward outstretched postural tremor, 
lateral "wing beating" postural tremor, and kinetic tremor item scores from both sides of the body), based 
on the Day 15 measurement.  
In order to measure essential tremor amplitude, subjects will wear a wireless ring motion sensor (ie, 
Kinesia). The motion sensor uses three orthogonal accelerometers and three orthogonal gyroscopes to 
monitor three-dimensional motion. Data are then transmitted from the sensor to a computer using 
Bluetooth technology. These measures of three-dimensional motion for each maneuver are then converted 
to Kinesia scores, which have been shown to correlate with corresponding clinician-rated TETRAS scores 
(ie, forward outstretched postural tremor, lateral “wing beating” postural tremor, and kinetic tremor on 
both sides of the body) (Giovanni, Giuffrida, Adam, Davidson, & Jankovic, 2010). Each Kinesia score 
ranges from 0 to 4; higher scores indicate more severe tremor. The Kinesia assessment is completed in 
conjunction with the TETRAS Performance Subscale Item 4 assessment.  
In Part C, Kinesia will be performed at pre-PM dose on Days 1 and 8; on Day 15; and at follow-up on 
Day 21.  
9.3.1.2 
Visit Windows for the Primary Endpoint 
For efficacy analyses, unscheduled measurements will only be included if a scheduled measurement is not 
available and the unscheduled measurement falls on the same study day. Due to the short duration of this 
study, this is not anticipated to occur. 


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9.3.1.3 
Primary Analysis 
The difference in change from baseline to post-baseline in Kinesia upper limb tremor combined score will 
be evaluated by a mixed model for repeated measures (MMRM) with change from baseline of the Kinesia 
upper limb tremor combined scores as the dependent variable, study visit as fixed effect, and the baseline 
value as a covariate. An unstructured covariance matrix will be used to model the within-subject 
correlation. The Kenward-Roger approximation will be used to estimate denominator degrees of freedom.  
In case of convergence issues, other covariance structures will be used including (but not limited to) 
autoregressive (AR (1)), compound symmetry (CS), and variance components (VC) with each model fit 
to find the covariance structure with the best fit. The fit statistics will be compared for all covariance 
structures; the structure with the smallest Akaike information criterion will be retained as the preferred 
model. 
In comparing the visit value to baseline, least-squares (LS) mean change from baseline will be presented 
along with associated 95% CI and P values. Since the sample size was not based upon statistical 
considerations, all P values are considered nominal. 
9.3.1.4 
Supportive Analyses 
Observed values, change from baseline, and percent change from baseline in Kinesia upper limb tremor 
combined score will be summarized for all time points for overall subjects.   
9.3.1.5 
Multiplicity Adjustment 
Not applicable. 
9.3.1.6 
Sensitivity Analysis  
Not applicable. 
9.3.1.7 
Subgroup Analyses 
Not applicable. 
9.3.2 
Analysis of Secondary Efficacy Variables 
9.3.2.1 
Kinesia Upper Limb Individual Scores 
Description of Kinesia Upper Limb Individual Scores 
The accelerometer-based Kinesia upper limb individual scores include the sum from both sides of the 
body in the following Kinesia areas: forward outstretched postural tremor, lateral “wing beating” postural 
tremor, and kinetic tremor. The upper limb individual item question score for each side of the body ranges 
from 0 to 4, with higher scores indicating more tremors/greater tremor amplitude. 
Analysis of Kinesia Upper Limb Individual Scores 
Observed values, change from baseline, and percent change from baseline in Kinesia upper limb 
individual item scores will be summarized for all time points by overall subjects. 
The change from baseline will be analyzed using the MMRM model as described for the primary analysis 
(Section 9.3.1.3) for post-baseline time points only. 
9.3.2.2 
TETRAS Upper Limb Individual and Total Scores  
Description of TETRAS Upper Limb Individual and Total Scores  
Items 4a (forward outstretched postural tremor), 4b (lateral “wing beating” postural tremor), and 4c 
(kinetic tremor), assessed on both sides of the body, comprise the TETRAS Performance Subscale upper 


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limb scores. The TETRAS Performance Subscale upper limb total score is the sum of all item 4 scores 
from both sides of the body (Elble, Comella, & al, 2012).  
In Part C, TETRAS Performance Subscale upper limb scores will be assessed at Screening and on Day -1; 
pre-PM dose on Days 1 and 8; on Day 15; and at follow-up on Day 21.  
Analysis of TETRAS Upper Limb Individual and Total Scores  
Observed values , change from baseline, and percent change from baseline in TETRAS upper limb 
individual item and total scores will be summarized for all time points by overall subjects.  
The change from baseline will be analyzed using the MMRM model as described for the primary analysis 
(Section 9.3.1.3) for post-baseline time points only.  
9.3.2.3 
TETRAS Performance Subscale Individual and Total Scores 
Description of TETRAS Performance Subscale Individual and Total Scores 
The TETRAS Performance Subscale score includes the following 9 items: head tremor, face (including 
jaw) tremor, voice tremor, upper limb tremor, lower limb tremor, Archimedes spirals, handwriting, dot 
approximation task, and standing tremor (Elble, Comella, & al, 2012). However, only Archimedes spirals 
(item 6), handwriting (item 7), and dot approximation task (item 8) assessments, in addition to upper limb 
tremor as described above, were performed for this study.  The TETRAS Performance Subscale total 
score is the sum of all item 4, 6, 7, and 8 scores from both sides of the body  
In Part C, TETRAS Performance Subscale items 6, 7, and 8 will be assessed at Screening and on Day -1; 
pre-PM dose on Days 1 and 8; on Day 15; and at follow-up on Day 21. 
Analysis of TETRAS Performance Subscale Individual and Total Scores 
Observed values, change from baseline, and percent change from baseline in TETRAS Performance 
Subscale individual item and total scores will be summarized for all time points by overall subjects.  
The change from baseline will be analyzed using the MMRM model as described for the primary analysis 
(Section 9.3.1.3) for all post-baseline time points.  
9.3.3 
Analysis of Exploratory Efficacy Variables 
9.3.3.1 
TETRAS ADL  
Description of TETRAS ADL  
The QoL as assessed by the TETRAS ADL Subscale includes the following 12 items: speaking; feeding 
with a spoon; drinking from a glass; hygiene; dressing; pouring; carrying food trays, plates, or similar 
items; using keys; writing; working; overall disability with the most affected task; and social impact 
(Elble, Comella, & al, 2012). Each individual item question score ranges from 0 to 4, where higher scores 
indicate worse QoL. The total score is derived as the sum of all of the individual items scores, with a 
maximum total score of 48. If one of the individual item scores is missing, the total score will be set to 
missing. 
In Part C, the TETRAS ADL Subscale will be assessed at pre-PM dose on Days 1 and 8; on Day 15; and 
follow-up on Day 21. 
Analysis of TETRAS ADL  
Observed values, change from baseline, and percent change from baseline in TETRAS ADL scores will 
be summarized for each item score and total score for all time points by overall subjects. 


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9.3.3.2 
QUEST  
Description of QUEST  
The QUEST is a brief, ET-specific QoL scale in which subjects rate the extent to which tremor impacts a 
function or state (30 questions), waking hours with tremor in any part, tremor self-assessment rating 
tremor severity in various body parts (head, voice, right arm/hand, left arm/hand, right leg/foot, and left 
leg/foot), health status, and overall QoL, along with 4 questions gathering general information describing 
work status and issues occurring in the past month (tremor interference with sexual satisfaction, side 
effects from tremor medication, and satisfaction of tremor control achieved by medication) (Tröster, 
Pahwa, Fields, Tanner, & Lyons, 2005). The extent to which tremor impacts a function or state is rated as 
never/no, rarely, sometimes, frequently, always/yes, and not applicable. Tremor severity is rated as none, 
mild, moderate, marked, or severe. Perceived health and overall QoL are rated on a scale of 0 to 100 in 5-
point increments, where 0=very poor health and 100=excellent/perfect health. 
For the 30-question component of the QUEST, the questions will be scored in 5 dimensions: 
Communication (questions 1-3); Work and Finances (questions 4-9); Hobbies and Leisure (questions 
10-12); Physical (questions 13-21); and Psychosocial (questions 22-30).  
The dimension scoring algorithm is as follows: 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆=
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑓𝑓𝑓𝑓𝑓𝑓 𝑒𝑒𝑒𝑒𝑒𝑒ℎ 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 (# 𝑜𝑜𝑜𝑜 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞 ×  4)𝑓𝑓𝑓𝑓𝑓𝑓 𝑒𝑒𝑒𝑒𝑒𝑒ℎ 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 
The point values assigned to each question are as follows: 0 = “Never/No”; 1 = “Rarely”; 2 = 
“Sometimes”; 3 = “Frequently”; 4 = “Always/Yes”; blank = Not Applicable (question is not counted 
toward applicable points or questions) (Movement Disorders Society Rating Scales, n.d.). 
In Part C, QUEST will be assessed on Days 1, 8, 15, and 21. 
Analysis of QUEST 
Observed values, change from baseline, and percent change from baseline in QUEST scores will be 
summarized for each dimension score for all time points by overall subjects.  
9.4 
Safety Analysis 
Safety will be evaluated through incidence and severity of AEs, as well as observed values and changes 
from baseline in vital signs, clinical laboratory measures (including shifts from baseline), ECG 
parameters, and suicidal ideation using the C-SSRS. 
For Part C, safety endpoints will be summarized by overall subjects, unless otherwise specified.  All 
safety data will be presented in individual subject data listings. Safety analysis will be conducted for the 
Safety Population. 
Safety 
Evaluation 
Incidence  
Raw 
Value 
Change 
from 
Baseline 
Abnormality/
Clinical 
Significance 
AEs 
X 
 
 
 
CMs 
X 
 
 
 
Labs 
 
X 
X  
* 
ECG 
 
X 
X 
* 


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Safety 
Evaluation 
Incidence  
Raw 
Value 
Change 
from 
Baseline 
Abnormality/
Clinical 
Significance 
Vital Signs 
 
X 
X  
 
C-SSRS 
X 
 
 
 
VAS 
 
X 
X 
 
DEQ-5 
 
X 
X 
 
X = Safety Assessment will be summarized in tables 
* = Safety Assessment will be presented in individual subject data 
listings 
9.4.1 
Adverse Events  
Adverse events (AEs) will be coded using the MedDRA coding system (version 19.1 or higher). The 
analysis of AEs will be based on the concept of treatment-emergent AEs (TEAEs). A TEAE for Part C is 
defined as an AE with onset after the start of open-label study drug, or any worsening of a pre-existing 
medical condition/AE with onset after the start of open-label study drug and until 14 days after the last 
dose. Any TEAEs occurring in the follow-up period after last dose of study drug will be summarized 
based on the last dose of study drug taken. 
A summary of the number and percentage of subjects with TEAEs will be provided for overall subjects. 
Frequencies and percentages of the following will be included: 
• 
Any TEAE 
• 
Maximum severity of TEAEs 
• 
Possibly or Probably Related TEAEs 
• 
TEAEs Leading to Discontinuation 
• 
TEAEs Leading to Death 
• 
Serious AEs (SAEs)  
In Part C, the incidence of TEAEs will be summarized by the following, for overall subjects: 
• 
SOC and PT 
• 
PT 
• 
Dose, Day, and PT 
• 
SOC, PT, and Maximum Severity 
• 
SOC, PT, and Relationship to Study Drug 
Incidences will be presented by descending frequency of SOC (where applicable), then in order of 
decreasing frequency of PT (within SOC, if applicable), and then alphabetically within PT where the 
incidence is the same. The presentation of TEAEs by dose, day, and PT will include counts of TEAEs that 
started on that particular day.  The dose of the TEAE will correspond to the dose the subject was on at the 
start of the TEAE. 


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All AEs, SAEs (including those with onset or worsening before the start of open-label study drug), AEs 
leading to discontinuation, and AEs leading to death through the Day 28 visit will be listed in separate 
tables. 
9.4.2 
Clinical Laboratory 
Screening and safety laboratory tests will be performed at screening, Day -1; pre-PM dose on Days 1 and 
8; on Day 15; and follow-up on Day 21 and Day 28. All summaries of laboratory values will be presented 
using SI units. Continuous hematology, chemistry, and urinalysis results will be listed by subject and 
timing of collection. Observed values and change from baseline at each time point in will be summarized 
by overall subjects.  Shifts from baseline will also be summarized by overall subjects. Clinically 
significant abnormal findings will be reported as AEs.  
9.4.3 
Electrocardiogram 
12-lead ECGs will be performed at screening, Day -1; pre-PM dose on Days 1 and 8; on Day 15; and 
follow-up on Day 21 and Day 28. The following 12-ECG parameters will be listed for each subject: heart 
rate, PR interval, QRS duration, QT interval, and QTcF interval (derived as QT interval / (RR 
interval)1/3). Any clinically significant abnormalities or changes in ECGs should be listed as an AE. 
Observed values and change from baseline at each time point will be summarized by overall subjects. 
Additionally, the number and percentage of subjects with a QTcF value meeting any of the following 
clinical significance criteria will be summarized separately by overall subjects: raw QTcF >450 msec, 
>480 msec, and >500 msec; change from baseline QTcF >30 msec and >60 msec. 
9.4.4 
Vital Signs 
Vital sign results (body temperature, heart rate, respiratory rate, supine and standing diastolic blood 
pressure, supine and standing systolic blood pressure, and pulse oximetry) will be performed at screening, 
Day -1; pre-PM dose on Days 1 and 8; on Day 15; and follow-up on Day 21 and Day 28 and will be listed 
by subject and timing of collection. Observed values and change from baseline at each time point will be 
summarized by overall subjects. 
9.4.5 
Physical Examination  
Screening physical examination results for Part C that are clinically significant will be listed in the 
medical history listing. Post-screening physical examination results that are clinically significant will be 
listed in the AE listing. A listing will be provided containing information on when physical examination 
occurred and reason it was not done if applicable. 
9.4.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner, Brown, Stanley, & al, 2011). 
This scale consists of a baseline evaluation that assesses the lifetime experience of the subject with 
suicidal ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes “yes” or “no” responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most 
severe).  
Suicidality data collected on the C-SSRS will be listed for all subjects. Tables will include results from 
the Suicidal Ideation and Suicidal Behavior sections of the C-SSRS. Frequencies and percentages of 
subjects with a response of “Yes” at any point on the Suicidal Ideation and Suicidal Behavior items will 
be summarized by overall subjects. Both baseline (“pre-treatment”) and post-baseline (“post-treatment”) 
results will be presented.  


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9.4.7 
Bond-Lader Visual Analogue Scale (VAS) 
Mood will be assessed using the Bond-Lader VAS Mood Scale at pre-PM dose on Days 1 and 8; on 
Day 15; and follow-up on Day 21. This is a 16-part self-administered questionnaire that employs a 100-
mm VAS to explore different aspects of self-reported mood (Bond & Lader, 1974). The 16 different 
mood ranges include:  
1. 0 = “Alert” to 100 = “Drowsy”;  
2. 0 = “Calm” to 100 = “Excited”;  
3. 0 = “Strong” to 100 = “Feeble”;  
4. 0 = “Muzzy” to 100 = “Clear-headed”;  
5. 0 = “Well-coordinated” to 100 = “Clumsy”;  
6. 0 = “Lethargic” to 100 = “Energetic”;  
7. 0 = “Contented” to 100 = “Discontented”;  
8. 0 = “Troubled” to 100 = “Tranquil”;  
9. 0 = “Mentally slow” to 100 = “Quick-witted”;  
10. 0 = “Tense” to 100 = “Relaxed”;  
11. 0 = “Attentive” to 100 = “Dreamy”;  
12. 0 = “Incompetent” to 100 = “Proficient”;  
13. 0 = “Happy” to 100 = “Sad”;  
14. 0 = “Antagonistic” to 100 = “Amicable”;  
15. 0 = “Interested” to 100 = “Bored”; and  
16. 0 = “Withdrawn” to 100 = “Gregarious”. 
In order to directly compare VAS results across the 16 items, items 4, 6, 8, 9, 10, 12, 14, and 16 will be 
reverse-scored by subtracting the scores from 100. In order to normalize the results, the scores will be 
converted to loge (after setting any scores of 0 to 1), with a resulting range of 0 to 4.605. Based on the 
factor loadings from Table 4 of the Bond and Lader article, the following equations will be used to 
compute the 3 factor scores: 
• 
Alertness = 0.827X1 + 0.618X3 + 0.755X4 + 0.642X5 + 0.776X6 + 0.635X9 + 0.792X11 + 0.593X12 
+ 0.614X15; 
• 
Contentedness = 0.677X7 + 0.697X8 + 0.823X13 + 0.738X14 + 0.594X16; and 
• 
Calmness = 0.845X2 + 0.677X10, 
where Xi represents a subject’s item score after normalization, and i represents the item number from 
the entire scale (in order from 1-16). 
Bond-Lader VAS results will be listed for all subjects. Observed values and change from baseline at each 
time point in will be summarized by parameter (including the 3 factor scores) and overall subjects. 
9.4.8 
Drug Effects Questionnaire (DEQ-5) 
The DEQ-5 will be administered at pre-PM dose on Day 8, on Day 15, and follow-up on Day 21, as 
follows: 
1. Do you FEEL a drug effect right now? 
2. Are you HIGH right now? 
3. Do you DISLIKE any of the effects that you are feeling right now?  
4. Do you LIKE any of the effects that you are feeling right now?  
5. Would you like MORE of the drug you took, right now?  


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The answers are recorded on a 100-mm VAS, with the answer for each being “Not at all” and 
“Extremely” at the extremes. There will be options to record “Not applicable” for questions 3 and 4 if no 
drug effects are felt and for question 5 prior to administration of study medication.  
The DEQ-5 results will be listed for all subjects. Since no baseline (before first dose of open-label study 
drug) values were recorded, only raw values at each time point will be summarized by parameter and 
overall subjects. 
9.5 
Pharmacokinetic Analysis 
Plasma pharmacokinetic samples will be taken pre-PM dose on Days 1 and 8, and on Day 15. For plasma 
concentration data, all values below the limit of quantification (BLQ) will be set to 0 for summary 
statistics and graphs. Individual plasma concentrations of SAGE-217 will be summarized at each time 
point using descriptive statistics, including number of subjects, mean, SD, median, maximum, minimum, 
percent coefficient of variation (%CV), and geometric mean. Pharmacokinetic parameters (eg, Cmax, 
AUC, Cmin) will be derived using population pharmacokinetic methods; the details of this analysis are 
outside the scope of this SAP and will be provided separately.  The population-derived PK parameters 
will be summarized by overall subjects. Individual concentration plots and mean data graphs will be 
produced for all time point. All graphs will be presented using both linear and semi-logarithmic scales. 
The above descriptive summary will be performed for the PK population.  
10 SUMMARY OF INTERIM ANALYSES 
Not applicable. 
11 REFERENCES 
Bond, A., & Lader, M. (1974). The use of analogue scales in rating subjective feelings. Br. J. 
med. Psychol., 47, 211-218. 
Elble, R., Comella, C., & al. (2012). Reliability of a new scale for essential tremor. Mov Disord, 
27(12):1587-1569. 
Giovanni, M., Giuffrida, J., Adam, O., Davidson, A., & Jankovic, J. (2010). Correlation between 
Kinesia system assessments and clinical tremor scores in patients with essential tremor. 
Mov Disord, 25(12):1938-43. 
Hoddes, E., Dement, W., & Zarcone, V. (1972). The development and use of the Stanford 
Sleepiness Scale (SSS). Psychophysiology, 9:150. 
Movement Disorders Society Rating Scales. (n.d.). Retrieved from 
http://www.movementdisorders.org/MDS-Files1/PDFs/Rating-
Scales/QUESTScoreSheet.pdf. 
Posner, K., Brown, G., Stanley, B., & al. (2011). The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry, 168(12):1266-77. 
Tröster, A., Pahwa, R., Fields, J., Tanner, C., & Lyons, K. (2005). Quality of life in Essential 
Tremor Questionnaire (QUEST): development and initial validation. Parkinsonism Relat 
Disord., 11(6):367-73. 


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12 LIST OF APPENDICES 
12.1 Appendix A: Schedule of Assessments 
12.1.1 Part C (Open-Label) 
Study Procedure 
Study Period / Visit Day 
Screening 
Treatment 
Follow-up 
Day -28 to Day -1 
Day -1 
Day 1 
Day 8 
Day 15 
Day 21±1 dayb 
(Early Termination 
Visit) 
End of Study 
Day 28±1 day 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
X 
X 
X 
Body weight/height 
X 
 
 
 
 
 
 
Drug/alcohol screenc 
X 
X 
 
X 
 
 
 
Complete blood count/ 
serum chemistryd 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test  
X 
(serum) 
X 
(urine) 
 
 
 
X 
(urine) 
X 
(urine) 
Urinalysisd 
X 
X 
X 
X 
X 
X 
X 
Hepatitis & HIV screen 
X 
 
 
 
 
 
 
Exploratory biochemistry samplee 
O 
 
 
O 
O 
O 
 
Genetic samplef 
O 
 
 
 
 
O 
 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 


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Study Procedure 
Study Period / Visit Day 
Screening 
Treatment 
Follow-up 
Day -28 to Day -1 
Day -1 
Day 1 
Day 8 
Day 15 
Day 21±1 dayb 
(Early Termination 
Visit) 
End of Study 
Day 28±1 day 
C-SSRSi 
X 
X 
X 
X 
X 
X 
X 
Bond-Lader-VASj 
 
 
X 
X 
X 
X 
 
DEQ-5k 
 
 
 
X 
X 
X 
 
Kinesia (accelerometer)l 
 
 
X 
X 
X 
X 
 
TETRAS Performance Subscalel 
X 
X 
X 
X 
X 
X 
 
TETRAS ADL Subscalem 
 
 
X 
X 
X 
X 
 
Empatica E4 Wristbandn 
 
X 
X 
X 
X 
 
 
QUEST 
 
 
X 
X 
X 
X 
 
Plasma PK sampleso 
 
 
X 
X 
X 
 
 
Dispense study drugp 
 
 
X 
X 
 
 
 
Adverse events/Serious adverse 
events 
X 
X 
Prior/concomitant medicationsq 
X 
X 
Videosr 
 
 
X 
X 
X 
X 
 
Treatment compliance calls 
 
 
X 
 
 
ADL = activities of daily living; C-SSRS = Columbia-Suicide Severity Rating Scale; DEQ-5 = Drug Effects Questionnaire; ECG = electrocardiogram; HIV 
= human immunodeficiency virus; O = optional; PK = pharmacokinetic; QUEST = Quality of Life in Essential Tremor Questionnaire; TETRAS = TRG 
Essential Tremor Rating Assessment Scale; VAS = visual analogue score. 
Note: Pre-dose assessments refer to the evening dose only. 
 
a An unscheduled visit may be needed if a dose adjustment is deemed necessary by the Investigator at any time during the treatment period in order for the 
adjusted dose to be dispensed. 
b In addition to subjects who complete Part C, subjects who receive at least one dose of study drug and do not complete Part C will have a visit 1 week 
following the last dose of study drug to assess safety measures. 


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c A urine sample for assessment of selected drugs (sedative/hypnotics [eg, opioids], cotinine, and caffeine) and a breath sample for alcohol screen will be 
collected at screening, Day -1 and Day 8. 
d Screening and safety laboratory tests will be performed at screening, Day -1, predose on Day 1, predose on Day 8, on Day 15, and follow-up on Day 21 
and Day 28. 
e An optional blood sample for exploratory biochemistry, where consent is given. 
f An optional genetic sample for biomarker testing, where consent is given. 
g Vital signs (heart rate, respiratory rate, temperature, and supine [for at least 5 minutes prior to the measurement] and standing [for at least 2 to 3 minutes] 
systolic and diastolic blood pressure) will be performed at screening, Day -1, predose on Day 1 and Day 8, on Day 15, and at follow-up on Day 21 and Day 
28.   
h 12-lead ECGs will be performed at screening, on Day -1, predose on Days 1 and 8, on Day 15, and follow-up on Days 21 and 28. 
i The C-SSRS will be performed at screening, on Day -1, predose on Days 1 and 8, on Day 15, and follow-up on Days 21 and 28.  Baseline/Screening 
version of C-SSRS should be used on day of screening and Since Last Visit version should be used on all subsequent time points. 
j The Bond-Lader VAS will be performed predose on Days 1 and 8, on Day 15, and follow-up on Day 21.  
k The DEQ-5 will be performed predose on Day 8, on Day 15, and follow-up on Day 21. 
l Kinesia and TETRAS Performance Subscale will be performed at screening and Day -1 (TETRAS Performance Subscale only), and predose on Days 1 
and 8, on Day 15, and follow-up on Day 21.  
m TETRAS ADL Subscale will be performed predose on Days 1 and 8, on Day 15, and follow-up on Day 21. 
n The Empatica E4 Wristband will be worn at all times (except while bathing) during three 5-day intervals: at the start of the Day -1 visit until the morning 
of Day 4, at the start of the Day 8 visit until the morning of Day 12, and at the start of the Day 15 visit until the morning of Day 19.  The Empatica E4 
Wristband will be worn on the wrist that, of the two arms, exhibits more severe tremor symptoms (i.e. tremor-dominant hand), as determined during 
screening. 
o Plasma pharmacokinetic samples will be taken predose on Days 1 and 8, and on Day 15. 
p Study drug will be dispensed at the scheduled clinic visits during the treatment period for outpatient administration daily with food (in the evening on Days 
1-3 and in the morning and in the evening on Days 4-14). 
q To include those taken within 2 weeks prior to informed consent and throughout the study. 
r Videos of subjects performing three everyday tasks (drinking a glass of water, fastening a button, and one additional task that the subject experiences 
difficulty with on a daily basis) will be taken predose on Day 1 and Day 8, on Day 15, and follow-up on Day 21. 
s A treatment compliance call will be made within approximately 60 minutes after the scheduled evening dose (between approximately 8:00PM and 9:00PM) 
on Days 1-14.