Clinical trial NCT05021978
Conditions: Essential Tremor
Keywords: Movement Disorder Benign Essential Tremor Familial Tremor Hereditary Essential Tremor Movement Disorder Agents Calcium Channels, T-type
Sponsor: Praxis Precision Medicines
Start date: 2020-03-03; Completion date: 2022-03-24
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 2-part clinical trial to evaluate the efficacy, safety, and tolerability of 40 and 120 mg oral PRAX-944 compared to placebo in the treatment of adults with essential tremor. Part A is designed to study the dose titration from 20 to 40 mg every morning (QAM) (ie, 2 weeks with 7 days at each dose level). Part B is designed to study the dose titration from 20 to up to 120 mg QAM with at least 14 days of dosing at the highest tolerated dose for each participant. Blood levels of PRAX-944 will also be measured throughout the trial and pharmacokinetics will be evaluated.

Detailed description:

Arms: arm 1: Once daily, oral dosing with 7 days of 20 mg and 7 days of 40 mg arm 2: Once daily, oral dosing with titration to 120 mg: 3 days of 20 mg, 4 days of 40 mg, 7 days of 60 mg, 7 days of 80 mg, 7 days of 100 mg, 28 days of 120 mg arm 3: Once daily, oral dosing with titration to 120 mg: 3 days of 20 mg, 4 days of 40 mg, 7 days of 60 mg, 7 days of 80 mg, 7 days of 100 mg, 14 days of 120 mg, 14 days placebo
Interventions: intervention 1: Part A: 20 and 40 mg PRAX-944 intervention 2: Part B: 120 mg PRAX-944 intervention 3: Part B: 120 mg PRAX-944 and Placebo
Intervention descriptions: intervention 1: Once daily oral treatment intervention 2: Once daily oral treatment with titration intervention 3: Once daily oral treatment with titration followed by placebo

Protocol documents:
Prot_000.pdf: 
CLINICAL TRIAL PROTOCOL 
PROTOCOL TITLE 
A Phase 2 Clinical Trial Evaluating the Efficacy, Safety, 
Tolerability, and Pharmacokinetics of PRAX-944 in Adults 
with Essential Tremor 
PROTOCOL NUMBER 
PRAX-944-221 
COMPOUND NUMBER 
PRAX-944 
CLINICAL TRIAL PHASE 
Phase 2 
SPONSOR NAME 
Praxis Precision Medicines Australia Pty Ltd 
SPONSOR ADDRESS 
727 Collins Street Docklands Vic 3008, Australia 
REGULATORY AGENCY 
IDENTIFIER NUMBER(S) 
N/A 
CURRENT VERSION DATE 
Version 6.0 – 11 August 2021 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and privileged to personnel directly 
involved in the conduct of the clinical trial. Any distribution, copying, or disclosure is strictly 
prohibited unless such disclosure is required by applicable laws and regulations. Persons to whom the 
information is disclosed must know that it is confidential.  
NCT Number-  NCT05021978
PR ~
S 
PRECISION MEDICINES 


Praxis Precision Medicines 
Protocol PRAX-944-221 , Version 6.0 
SIGNATURE PAGE FOR SPONSOR 
Protocol Title: A Phase 2 Clinical Trial Evaluating the Efficacy, Safety, Tolerability, and 
Pha1macokinetics of PRAX-944 in Adults with Essential Tremor 
Clinical Trial o: PRAX-944-221 
Current Version Date: Version 6.0 - 11 August 2021 
This clinical trial protocol was subject to critical review and has been approved by the 
appropriate protocol review committee of the Sponsor. The infmmation contained in this 
protocol is consistent with: 
• 
The cmrent risk-benefit evaluation of the study diug. 
• 
The ethical and scientific principles governing clinical reseaTch as set out in the 
Declaration of Helsinki, and the principles of the International Council for 
Ha1monisation (ICH), and local country regulations. 
The Investigator will be supplied with details of any significant or new findings, including 
adverse events (AEs), relating to treatment with the study diug. 
IIDocuSigned by: 
0 
Signer Name:-
1 
Signing Reason I approve this document 
Signing Time: 15-Aug-2021 I 21 :36:04 EDT 
15-Aug-2021 I 21:36:08 EDT 
.. 
-
I 
• 4A0B814E683880247E02 
MD, MS 
Date 
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INVESTIGATOR’S AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the Sponsor. I agree to conduct this clinical trial in 
accordance with the requirements of this protocol, and also to protect the rights, safety, privacy, 
and well-being of clinical trial participants in accordance with the following: 
•
The ethical principles that have their origin in the Declaration of Helsinki.
•
International Council for Harmonisation, E6 Good Clinical Practice: Consolidated
Guideline.
•
All applicable laws and regulations.
•
This document contains confidential information from the Sponsor, which may not be
disclosed to anyone other than clinical trial staff and members of the IRB/IEC.
Printed Name of Investigator 
Signature of Investigator 
Date 


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CONTACT INFORMATION IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Clinical Trial 
Name 
Address and Telephone Number 
Responsible Physician 
, MD, PhD 
One Broadway, 16th Floor 
Cambridge, MA 02142, USA 
Telephone: +1 617 504 3087 


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PROTOCOL SUMMARY TABLE 
DOCUMENT HISTORY 
DATE 
Version 1.0 
11 January 2019 
Version 2.0 
07 November 2019 
Version 3.0 
18 July 2020 
Version 4.0 
20 October 2020 
Version 5.0 
13 July 2021 
Version 6.0 
11 August 2021 


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TABLE OF CONTENTS 
SIGNATURE PAGE FOR SPONSOR ........................................................................................ 2 
INVESTIGATOR’S AGREEMENT ........................................................................................... 3 
CONTACT INFORMATION IN CASE OF EMERGENCY ....................................................... 4 
PROTOCOL SUMMARY TABLE ............................................................................................. 5 
TABLE OF CONTENTS ............................................................................................................ 6 
LIST OF TABLES .................................................................................................................... 10 
LIST OF FIGURES .................................................................................................................. 10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................. 11 
1. 
PROTOCOL SUMMARY ...................................................................................... 14 
1.1. 
Synopsis ................................................................................................................. 14 
1.2. 
Study Schema ......................................................................................................... 28 
1.3. 
Schedule of Activities ............................................................................................. 29 
2. 
INTRODUCTION .................................................................................................. 38 
2.1. 
Background and Clinical Trial Rationale ................................................................ 38 
2.2. 
Benefit/Risk Assessment ........................................................................................ 39 
2.3. 
Known Potential Benefits ....................................................................................... 39 
2.4. 
Known Potential Risks............................................................................................ 39 
3. 
OBJECTIVES AND ENDPOINTS ......................................................................... 41 
3.1. 
Part A ..................................................................................................................... 41 
3.2. 
Part B ..................................................................................................................... 42 
4. 
INVESTIGATIONAL PLAN ................................................................................. 45 
4.1. 
Overall Design ........................................................................................................ 45 
4.1.1. 
Screening/ Baseline Period ..................................................................................... 45 
4.1.2. 
Intervention Period ................................................................................................. 46 
4.1.3. 
Safety Follow-up Period ......................................................................................... 48 
4.1.4. 
Clinical Trial Duration ............................................................................................ 48 
4.2. 
Scientific Rationale for Clinical Trial Design .......................................................... 48 
4.3. 
Justification for Dose .............................................................................................. 48 
4.4. 
Clinical Trial Committees ....................................................................................... 49 
4.5. 
End of Clinical Trial Definition .............................................................................. 49 
5. 
POPULATION ....................................................................................................... 50 


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5.1. 
Number of Participants ........................................................................................... 50 
5.1.1. 
Part A ..................................................................................................................... 50 
5.1.2. 
Part B ..................................................................................................................... 50 
5.1.3. 
Participant Replacement ......................................................................................... 50 
5.2. 
Inclusion Criteria .................................................................................................... 50 
5.3. 
Exclusion Criteria ................................................................................................... 51 
5.4. 
Lifestyle Considerations ......................................................................................... 52 
5.4.1. 
Meals and Dietary Restrictions ............................................................................... 52 
5.4.2. 
Activity Restrictions ............................................................................................... 53 
5.4.3. 
Contraception ......................................................................................................... 53 
5.4.4. 
Sperm and Ova Donation ........................................................................................ 54 
5.5. 
Screen Failures ....................................................................................................... 54 
6. 
CLINICAL TRIAL INTERVENTION ................................................................... 55 
6.1. 
Study Drug(s) Administered ................................................................................... 55 
6.1.1. 
Part A ..................................................................................................................... 55 
6.1.2. 
Part B ..................................................................................................................... 55 
6.2. 
Preparation/Handling/Storage/Accountability ......................................................... 57 
6.3. 
Randomization and Blinding................................................................................... 57 
6.3.1. 
Breaking the Blind .................................................................................................. 57 
6.4. 
Study Drug Compliance .......................................................................................... 57 
6.5. 
Concomitant Therapy ............................................................................................. 58 
6.5.1. 
Prohibited Medications ........................................................................................... 58 
6.5.2. 
Permitted Medications ............................................................................................ 59 
6.6. 
Dose Modification .................................................................................................. 59 
6.7. 
Intervention After the End of the Clinical Trial ....................................................... 59 
7. 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL................................................................ 60 
7.1. 
Discontinuation of Study Drug ............................................................................... 60 
7.1.1. 
Temporary Discontinuation .................................................................................... 60 
7.1.2. 
Rechallenge ............................................................................................................ 60 
7.2. 
Participant Discontinuation/Withdrawal from the Clinical Trial .............................. 60 
7.3. 
Lost to Follow-Up .................................................................................................. 60 
8. 
CLINICAL TRIAL ASSESSMENTS AND PROCEDURES .................................. 62 


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8.1. 
Efficacy Assessments ............................................................................................. 62 
8.1.1. 
TETRAS ................................................................................................................ 62 
 
 
 
 
8.1.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST; Part B Only) .............. 65 
 
 
 
 
8.2. 
Safety Assessments................................................................................................. 65 
8.2.1. 
Physical Examinations ............................................................................................ 65 
8.2.2. 
Vital Sign Measurements ........................................................................................ 65 
8.2.3. 
Electrocardiograms ................................................................................................. 66 
8.2.4. 
Clinical Safety Laboratory Assessments ................................................................. 66 
8.2.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Measurements ......................... 67 
8.3. 
Pharmacokinetic Assessments................................................................................. 67 
8.4. 
Adverse and Serious Adverse Events ...................................................................... 67 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information ...................... 67 
8.4.2. 
Method of Detecting AEs and SAEs ....................................................................... 67 
8.4.3. 
Follow-up of AEs and SAEs ................................................................................... 68 
8.4.4. 
Regulatory Reporting Requirements for SAEs ........................................................ 68 
8.4.5. 
AEs of Special Interest ........................................................................................... 68 
8.4.6. 
Pregnancy ............................................................................................................... 68 
8.4.7. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs .......................................................................................................... 69 
8.5. 
Exploratory Biomarkers .......................................................................................... 69 
8.6. 
Treatment of Overdose ........................................................................................... 69 
8.7. 
Genetics.................................................................................................................. 69 
8.8. 
Health Economics/Medical Resource Utilization and Health Economics ................. 69 
9. 
STATISTICAL CONSIDERATIONS .................................................................... 70 
9.1. 
Sample Size Determination ..................................................................................... 70 
9.2. 
Populations for Analyses ........................................................................................ 70 
9.3. 
Statistical Analyses ................................................................................................. 70 
9.3.1. 
Efficacy Analyses ................................................................................................... 71 
9.3.2. 
Safety Analyses ...................................................................................................... 71 
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9.3.3. 
Pharmacokinetic Analyses ...................................................................................... 71 
9.3.4. 
Other Analyses ....................................................................................................... 71 
9.3.5. 
Interim Analyses ..................................................................................................... 72 
10. 
REGULATORY, ETHICAL, AND CLINICAL TRIAL OVERSIGHT 
CONSIDERATIONS .............................................................................................. 73 
10.1. 
Regulatory and Ethical Considerations.................................................................... 73 
10.2. 
Financial Disclosure ............................................................................................... 73 
10.3. 
Informed Consent Process ...................................................................................... 73 
10.4. 
Data Protection ....................................................................................................... 74 
10.5. 
Data Quality Assurance .......................................................................................... 74 
10.6. 
Source Documents .................................................................................................. 75 
10.7. 
Clinical Trial Files and Retention of Records .......................................................... 75 
10.8. 
Clinical Trial and Site Closure ................................................................................ 76 
10.9. 
Clinical Study Report ............................................................................................. 76 
10.10. 
Publication Policy ................................................................................................... 76 
11. 
REFERENCES ....................................................................................................... 77 
12. 
APPENDICES ........................................................................................................ 79 
APPENDIX 1. CLINICAL LABORATORY EVALUATIONS .............................................. 79 
APPENDIX 2. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ..................... 80 
APPENDIX 3. ACCEPTABLE BENZODIAZEPINES FOR CONCOMITANT USE ............ 84 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ............................................................................... 4 
Table 2:  
Schedule of Activities (SoA) – Part A ..................................................................... 30 
Table 3:  
Schedule of Activities (SoA) – Part B ..................................................................... 33 
Table 4: 
Study Drug Information .......................................................................................... 56 
LIST OF FIGURES 
Figure 1: 
Study Schema ......................................................................................................... 28 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
AUC0-tau 
area under the concentration vs time curve from the time of dosing through 
the dosing interval 
 
 
 
 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Ca2+ 
Calcium 
CBC 
complete blood count 
 
 
 
 
 
 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL/F 
apparent systemic clearance following oral administration 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CRF 
case report form 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EEG 
electroencephalogram 
ET 
essential tremor 
D
D• -
• --


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Abbreviation 
Definition 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
KDIGO 
Kidney Disease Improving Global Outcomes 
KIM-1 
kidney injury molecule-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
modified release 
NREM 
non-rapid eye movement 
P-gp 
P-glycoprotein 
 
 
PK 
pharmacokinetic 
PT 
preferred term 
QAM 
every morning 
QUEST 
Quality of Life in Essential Tremor Questionnaire 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCr 
serum creatinine 
SD 
standard deviation 
SoA 
Schedule of Activities 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
t½  
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TETRAS 
The Essential Tremor Rating Assessment Scale  
Tmax 
time to maximum observed concentration 
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Abbreviation 
Definition 
TRG 
Tremor Research Group 
ULN 
upper limit of normal 
Vd/F 
apparent volume of distribution after non-intravenous administration 
WBC 
white blood cell 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
This is a brief summary of the clinical trial. For complete details, refer to the body of the 
protocol. 
PROTOCOL TITLE 
A Phase 2 Clinical Trial Evaluating the Efficacy, Safety, Tolerability, and Pharmacokinetics of 
PRAX-944 in Adults with Essential Tremor 
RATIONALE 
Essential Tremor (ET) is one of the most common neurological disorders with a prevalence of 
nearly 1%. It is characterized by a 6 to 12 Hz postural and kinetic tremor. Tremor typically 
occurs in the hands, arms, head, and voice, and is less common in the face, legs, and trunk. ET, 
by definition, is not associated with other neurological signs, although a resting tremor and 
impairments in balance, particularly tandem gait, have been described. The diagnosis of ET is 
based on medical history and neurological exam as described in The International Parkinson and 
Movement Disorders Society Consensus Statement on the Classification of Tremors. 
There is a range in the severity of ET; some patients require no treatment, whereas others have 
severe disability with impairment in activities of daily living (ADLs) such as dressing and eating. 
Treatments for ET include pharmacological therapies, regional injection of botulinum toxin 
(off-label usage), and surgical therapies for those with severe disability. The most effective 
pharmacological therapies are propranolol and primidone. They have limited efficacy, with about 
50% of patients having a durable yet incomplete response. Dose-limiting side effects are 
common and include bradycardia for propranolol, and sedation and dizziness for primidone. 
Surgical therapies, including deep brain stimulation and ablation of the nucleus ventralis 
intermedius of the thalamus, are effective but they are reserved for medically refractory patients 
due to the risks associated with brain surgery. Many patients who are eligible for surgical 
therapies do not elect to have these procedures. Thus, there is a high unmet need for efficacious 
and well-tolerated pharmacological therapies for ET. 
While the genetics and pathophysiology of ET is not fully understood, it is thought to involve 
abnormal activity of cerebellar afferent and efferent pathways. This network consists of input 
from the inferior olive to the cerebellar cortex, and outflow through deep cerebellar nuclei to the 
ventral thalamus and cortex. Low voltage, T-type calcium (Ca2+)-channels in the inferior olive 
and thalamus may play a role in the pathogenesis and treatment of ET. The T-type Ca2+-channel 
family is comprised of 3 different isoforms: CaV3.1, CaV3.2, and CaV3.3. These channels are 
involved in generation of physiological and pathophysiological rhythms in the brain. In the 
harmaline rodent model of ET, synchronous neuronal discharges which are associated with T-
type Ca2+-channels are increased. The abnormal discharges were attenuated in mice lacking the 
gene that encodes for CaV3.1, and in wildtype mice, selective knockdown of CaV3.1 in the 
inferior olive by shRNA suppressed the harmaline-induced tremor. The non-selective Ca2+ 
channel blocker ethosuximide was found to suppress tremor in the harmaline model and in a 
genetic model of ET, in a dose-dependent fashion. 


Praxis Precision Medicines 
Protocol PRAX-944-221, Version 6.0 
PRAX-944 is an orally active, small molecule that belongs to the class of T-type Ca2+ -channel 
blockers. PRAX-944 blocks all 3 T-type Ca2+-channel subtypes with high potency and is 
therefore being studied for the treatment of ET. Different fo1mulations of PRAX-944 have been 
studied in 4 single and multiple ascending dose trials in healthy volunteers. The modified-release 
(MR)7 fo1mulation (80% of drug product released within 7 hours), which will be used in this 
trial, was well tolerated at doses of up to 120 mg per day when administered in a titration 
regunen. 
In a human electroencephalogram (EEG)/polysomnography clinical trial, PRAX-944 showed 
robust suppression of the sigma frequency band during non-rapid eye movement (NREM) sleep, 
a marker of sleep spindle activity, at the 20 mg, 40 mg, and 60 mg dose levels. Sleep spindles are 
prominent oscillations of 11 to 15 Hz observed in the human scalp EEG during NREM sleep that 
are mediated by activation of T-type Ca2+ channels in the thalamus. Thus, these data suggest that 
PRAX-944 blocks T-type Ca2+ channels in the central nervous system (CNS) at well tolerated 
doses. 
The aim of this development program is to evaluate whether oral administration of PRAX-944 
can provide therapeutic benefit to patients with ET. The study is divided into 2 parts: Pait A is 
designed to study the dose titration from 20 to 40 mg eve1y morning (QAM) (ie, 2 weeks with 7 
days at each dose level) and Pait B is designed to study the dose titration from 20 to up to 
120 mg QAM with at least 14 days of dosing at the highest tolerated dose for each pa1ticipant. 
OBJECTIVES AND ENDPOINTS 
Part A 
Objective 
Endpoint 
Primruy 
• To evaluate the efficacy of PRAX-944 on 
• Change from Baseline to Day 7 and Day 14 
upper limb tremor in pa1ticipants with ET 
in The Essential Tremor Rating Assessment 
Scale (TETRAS) upper limb score (bilateral 
sum of items 4a, 4b, and 4c) 
Seconda1y 
• To evaluate the efficacy of PRAX-944 on 
• Change from Baseline to Day 7 and Day 14 
other measures of tremor severity in 
in: 
pruticipants with ET 
0 
TETRAS Pe1fo1mance subscale total 
score 
0 
Accelerometer-based upper limb score 
(bilateral sum of items 4a, 4b, and 4c) 
0 
TETRAS Pe1fo1mance subscale 
individual item scores 
• To evaluate the safety and tolerability of 
• Incidence and seve1ity of adverse events 
PRAX-944 in pa1ticipants with ET 
(AEs) 
• Changes in vital sign measurements 
• Changes in clinical laborato1y results 
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Explorato1y 
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Protocol PRAX-944-221, Version 6.0 
Endpoint 
• 
Changes in electrocardiogram (ECG) 
parameters 
• 
Incidence of Columbia-Suicide Sevedty 
Rating Scale (C-SSRS) measured suicidal 
ideation or behavior 
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Part B 
Objective 
Primruy 
• 
To evaluate the safety and tolerability of 
PRAX-944 in pa1ticipants with ET 
Seconda1y 
• 
To evaluate the efficacy of PRAX-944 on 
upper limb tremor in pa1ticipants with ET 
• 
To evaluate the efficacy of PRAX-944 on 
other measures of tremor severity in 
pruticipants with ET 
• 
To evaluate the efficacy of PRAX-944 on 
measures of disease impact in pruticipants 
with ET 
Explorato1y 
Confidential 
Protocol PRAX-944-221, Version 6.0 
Endpoint 
• 
Incidence and seve1ity of AEs 
• 
Changes in vital sign measurements 
• 
Changes in clinical laborato1y results 
• 
Changes in ECG pru·ameters 
• 
Incidence of C-SSRS measured suicidal 
ideation or behavior 
• 
Change from Baseline to Day 42 in TETRAS 
Upper Limb score (bilateral sum of items 4a, 
4b, and 4c) 
• 
Change from Baseline to Day 7 and Day 21 
in TETRAS Upper Limb score (bilateral sum 
of items 4a, 4b, and 4c) 
• 
Change from Baseline to Day 7, Day 21, and 
Day 42 in the following: 
o 
TETRAS Pe1fo1mance subscale total 
score 
o 
Accelerometer-based upper limb score 
(bilateral sum of items 4a, 4b, and 4c) 
o 
TETRAS Pe1fo1mance individual item 
scores 
• 
Change from Baseline to Day 7, Day 21, and 
Day 42 in the following: 
o 
TETRAS ADL subscale score 
o 
Quality of Life in Essential Tremor 
Questionnaire (QUEST) total and 
subscale scores 
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Objective 
Endpoint 
OVERALL DESIGN 
This multi-center clinical trial will assess the efficacy, safety, tolerability, and PK of PRAX-944 
in participants aged 18 years of age or older who have had signs and symptoms consistent with 
ET for at least 3 years, with an onset before age 65. 
The clinical trial will be conducted in 2 parts (Part A and Part B). Both parts will consist of 
3 periods: Screening/Baseline, Intervention, and Safety Follow-up. 


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Part A of the clinical trial is open-label and will assess the safety and tolerability of PRAX-944, 
as well as the overall magnitude and pattern of change in ET severity. Daily dose levels will be 
titrated from 20 mg to 40 mg. 
Part B of the clinical trial consists of both an open-label titration phase and a randomized, 
double-blind, placebo-controlled withdrawal phase. Part B will assess the safety and tolerability 
of PRAX-944, as well as the overall magnitude and pattern of change in ET severity and the 
duration of that effect. Daily dose levels will be titrated from 20 mg to up to 120 mg during the 
open-label phase. In the randomized, double-blind, placebo-controlled withdrawal phase, 
participants will either be maintained on their final open-label dose or switched to placebo. 
Participants who received study drug in Part A are not eligible for Part B (see Exclusion 
Criterion #19). 
Screening/Baseline Period 
The Screening period for Part A and Part B will be up to 28 days (Day -28 to Day -1). Fourteen 
additional days (ie, 42 days total) will be allowed in the Screening period for participants who 
are discontinuing primidone. 
Prior to any procedures, participants will provide written informed consent to participate in the 
clinical trial. Key Screening assessments will include medical history, demographics, physical 
examination, drug screen, clinical laboratory evaluations and serum pregnancy for women of 
childbearing potential, 12-lead ECG, vital signs, C-SSRS, assessment of ET severity using the 
TETRAS Performance subscale (including a video for independent review of eligibility), and a 
review of concomitant medications. To be eligible, potential participants who are taking 
prohibited medications will need to successfully discontinue these medications for at least 5 half-
lives or 14 days prior (whichever is the longer period of time) before the first dose of study drug. 
For those participants requiring the 14 additional days in the Screening period to discontinue 
primidone, all or some of the Screening assessments may need to be repeated, pending approval 
by the Sponsor’s Medical Monitor. 
For participants in Part A, following confirmation of eligibility, including review by the Sponsor 
or designee, participants will complete Baseline assessments (Day 0). Day 0 (Baseline) activities 
may be combined with Day 1 activities, provided that Baseline activities are completed before 
dosing and that dosing occurs in the morning of Day 1. In addition, Baseline efficacy 
assessments should either be conducted on Day 0 or Day 1 pre-dose, but not both to avoid 
learning effects. 
For participants in Part B, TETRAS Upper Limb items will also be completed with 
accelerometry at Screening and via telehealth on Day -2 of the Screening period. The Screening 
telehealth visit is needed to ensure participants can complete the TETRAS Upper Limb 
assessment successfully via telehealth and to provide a pre-dose measure. Additional 
assessments added to Part B screening include TETRAS ADL and 
. Following 
confirmation of eligibility, including review by the Sponsor or designee, participants will 
complete Baseline assessments (Day 1). Some Baseline assessments (as indicated in Table 3) 
may be completed on Day -1. 
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Intervention Period 
Part A 
On Day 1, participants will receive a 20 mg dose of PRAX-944, administered in the morning. 
Participants will remain in a clinical setting under medical observation for approximately 
6 hours. TETRAS Performance assessments will be performed before dosing and 6 hours post-
dose. After the first dose, participants will continue QAM dosing at home after breakfast through 
Day 7. Participants will return to the clinic on Day 7 for efficacy testing at the 20 mg dose level. 
On Day 8, the dose will increase to 40 mg QAM after breakfast through Day 14 for efficacy 
testing at the 40 mg dose level. Participants will return to the clinic on Day 14 for efficacy 
testing at the 40 mg dose level. Participants who agree to optional additional PK sampling will 
remain overnight in the clinic on Day 1, Day 7, and Day 14. 
Key safety measures will include clinical laboratory evaluations, 12-lead ECG, C-SSRS, and 
vital signs (Table 2). Key efficacy assessments will include the TETRAS Performance subscale, 
(Table 2). Blood samples will be 
obtained for the determination of PRAX-944 plasma concentrations using a validated 
bioanalytical method and may also be used for exploratory method development and/or 
metabolite characterization. 
Part B 
Open-label Titration Phase 
On Day 1, participants will receive a 20 mg dose of PRAX-944 on an empty stomach (at least 1 
hour before breakfast). Participants will remain in a clinical setting under medical observation 
for approximately 6 hours. TETRAS Performance assessments will be performed before dosing 
and 6 hours (±2) post-dose. 
For dosing on Day 2 through Day 41, participants will be instructed to dose QAM at least 1 hour 
before breakfast at home. 
Participants will continue taking PRAX-944 20 mg QAM at home through Day 3. 
On Day 3, participants will receive a telephone call from site staff to inquire about AEs and 
concomitant medications, confirm dose escalation, and remind the participant about the number 
of study drug tablets to take on Day 4 through Day 7. 
On Day 4, participants will escalate to 40 mg QAM through Day 7, when they will return to the 
clinic for safety assessments and efficacy testing. On Day 8, participants should escalate to 
60 mg QAM through Day 14. 
On Day 14, participants will receive a telephone call from site staff to inquire about AEs and 
concomitant medications, confirm dose escalation, and remind the participant about the number 
of study drug tablets to take on Day 15 through Day 21. 
On Day 15, participants should escalate to 80 mg QAM through Day 21, when they will return to 
the clinic for safety assessments and efficacy testing. On Day 22, participants should escalate to 
100 mg QAM through Day 28. 


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On Day 28, participants will receive a telephone call from site staff to inquire about AEs and 
concomitant medications, confirm dose escalation, and remind the participant about the number 
of study drug tablets to take on Day 29 through Day 42. 
On Day 29, participants will escalate to 120 mg QAM through Day 42, when they will return to 
the clinic for safety assessments and efficacy testing. The dose on Day 42 will be taken in the 
clinic (see Double-blind Randomized Withdrawal Phase below). 
On Day 35, participants will receive a telephone call from site staff to inquire about AEs and 
concomitant medications. 
On Day 41, participants will complete a TETRAS Performance Upper Limb assessment via a 
telehealth visit. 
If at any point during the open-label titration phase a participant does not tolerate escalation and 
the Investigator returns the participant to a lower dose level, the participant will continue 
according to the schedule outlined above, but no further dose changes will be allowed. The 
Investigator should discuss the decision to continue at a lower dose level with the Sponsor and 
Medical Monitor. Participants can only change to a lower dose level once, and no dose changes 
may occur after Day 36. 
Double-blind Randomized Withdrawal Phase 
On Day 42, participants will complete the final clinic visit of the open-label titration phase. 
Participants will receive their dose of PRAX-944 in the clinic on an empty stomach (at least 1 
hour before breakfast). Participants will remain in a clinical setting under medical observation 
for approximately 6 hours. TETRAS Performance assessments will be performed before dosing 
and 6 hours (±2) post-dose. 
After Day 42, participants will either continue receiving PRAX-944 at their current dose or 
switch to placebo, depending on their randomization. Randomization in a 1:1 fashion may be 
completed at any time on Day 37 through 42. 
Safety Follow-up Period 
Part A 
The Safety Follow-up period will take place from Day 15 to Day 21. At the end of the Safety 
Follow-up period, participants will return to the clinic on Day 21 (±1 day) for the final clinical 
trial assessments (Table 2). 


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Part B 
The Safety Follow-up period will take place from Day 57 to Day 70. At the end of the Safety 
Follow-up period, participants will return to the clinic on Day 70 for the final clinical trial 
assessments (Table 3). 
Safety Monitoring 
The Sponsor will review ongoing safety data. The clinical trial may be stopped, or clinical trial 
enrollment suspended if: 
• The Sponsor, in consultation with the Principal Investigators, consider that the 
number and/or severity of AEs justify discontinuation of the clinical trial 
• The Sponsor makes a decision to do so 
Critical safety endpoints are listed in Section 8.2. AEs and concomitant medication and 
procedures use will be monitored from the time of informed consent to Day 21 (±1 day) in Part 
A and to Day 70 in Part B. At that time, participants will have completed the clinical trial. 
Renal function monitoring will be based on the KDIGO criteria for acute kidney injury (AKI) as 
outlined in Section 8.2.4.1. If a participant’s laboratory values exceed these thresholds, dosing of 
that participant will be stopped, and the laboratory tests repeated. 
NUMBER OF PARTICIPANTS 
Part A 
Up to 12 participants are planned to be administered PRAX-944. 
Part B 
Approximately 12 participants are planned to be administered PRAX-944 for the first 42 days 
followed by randomization (1:1) to 2 additional weeks on the highest tolerated dose of PRAX-
944 or placebo. Up to 12 additional participants may be enrolled at the discretion of the Sponsor 
to ensure inclusion of a broad range of tremor severity. 
Participant Replacement 
Participants who withdraw from either Part A or Part B prior to completion of the clinical trial 
may be replaced at the discretion of the Sponsor. No more than 6 participants in either part of the 
study will be replaced. 
DURATION OF CLINICAL TRIAL 
Participants will be part of the clinical trial for the following time intervals: 
Part A 
Screening/Baseline Period 
Up to 28 days (+14 days if on primidone) 
Intervention Period 
14 days 
Safety Follow-up Period 
7 days 


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Total Participation 
Up to 49 days (63 days if on primidone) 
Part B 
Screening/Baseline Period 
Up to 28 days (+14 days if on primidone) 
Safety Follow-up Period 
14 days 
Total Participation 
Up to 98 days (112 days if on primidone) 
INCLUSION/EXCLUSION CRITERIA 
Inclusion Criteria 
A participant must meet the following criteria at Screening and Baseline (unless otherwise 
specified) to be eligible to participate in this clinical trial: 
I 1. 
Male or non-pregnant, non-lactating female aged 18 years or older. 
I 2. 
Willing and able to understand and sign an informed consent document indicating 
that he/she understands the clinical trial purpose, the clinical trial procedures, and that 
he/she is willing to participate in the clinical trial and comply with the protocol. 
I 3. 
Body mass index (BMI) at Screening between 18 and 40 kg/m2, inclusive. 
I 4. 
Clinical diagnosis of ET consistent with Movement Disorders Society Criteria, a 
duration of ET of at least 3 years and with onset before the age of 65. 
I 5. 
Moderate to severe ET as defined by the following: 
a. A combined bilateral score of ≥10 on the TETRAS Upper Limb items 4 a, b, c. 
(UL tremor severity at Screening will be confirmed by central video review, for 
eligibility) 
OR 
b. A score of ≥2 on 2 or more of the following TETRAS activities of daily living 
(ADL) subscale items: (2) Feeding with a spoon, (3) Drinking from a glass, 
(5) Dressing, (6) Pouring, (9) Writing 
OR 
c. A score of ≥2 on 1 of the following TETRAS ADL subscale items: (2) Feeding 
with a spoon, (3) Drinking from a glass, (5) Dressing, (6) Pouring, or (9) Writing 
AND a score of ≥2 on both of the following TETRAS ADL subscale items: 
(10) Working and (12) Social Impact 
Note: ET severity at Baseline will be confirmed by the Investigator at the clinical 
trial site. 
I 6. 
Those currently receiving any medication for their ET must be willing and able to 
discontinue all but 1 tremor medication and be on a stable dose for at least 28 days. 


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I 7. 
Willing to comply with medically acceptable method of contraception as defined in 
Section 5.4.3. 
Exclusion Criteria 
A participant who meets any of the following criteria at Screening or Baseline (unless otherwise 
specified) will be excluded from this clinical trial: 
E 1. 
Known hypersensitivity to any component of the formulation of PRAX-944. 
E 2. 
Unwilling or unable to refrain from episodic use of medication(s)/substance(s) that 
might interfere with the evaluation of tremor during the trial. Stable use of 
medication(s)/substance(s) that might impact tremor, including beta-agonist 
bronchodilators, is allowed so long as the tremor is judged by the investigator to be 
primarily due to the participant's ET diagnosis. 
E 3. 
Trauma to the nervous system within 3 months preceding the onset of tremor. 
E 4. 
Clinical evidence of psychogenic tremor as ascertained by the Investigator. 
E 5. 
History of other medical, neurological or psychiatric condition that may explain or 
cause tremor, including but not limited to Parkinson's disease, dystonia, cerebellar 
disease, family history of Fragile X syndrome, traumatic brain injury, alcohol abuse 
or withdrawal, benzodiazepine abuse or withdrawal, multiple sclerosis, 
polyneuropathy, and endocrine states such as hyperthyroidism. 
E 6. 
Prior magnetic resonance-guided focused ultrasound or surgical intervention for ET 
such as deep brain stimulation or thalamotomy. 
E 7. 
Botulinum toxin injection for ET in the 6 months prior to Screening. 
E 8. 
Unwilling or unable to discontinue primidone. 
E 9. 
Unwilling or unable to refrain from alcohol 24 hours before and during clinical trial 
visits. Or regular use of alcohol that would preclude abstinence from alcohol in this 
period, in the judgement of the Investigator. 
E 10. Substance use disorder in the judgement of the Investigator 
E 11. Sporadic use of a benzodiazepine, sleep medication or anxiolytic, that in the 
judgement of the Investigator or Sponsor would confound the assessment of tremor. 
Stable use at a consistent dose not exceeding the equivalent of 2 mg/day of lorazepam 
(see Section 6.5.2) is allowed as long as tremor persists against the background of 
regular medication use. 
E 12. Use of prescription or non-prescription products and food known to be strong 
inhibitors or inducers of CYP3A4 or known to be a P-gp substrate (see Section 6.5.1) 
which cannot be discontinued at least 5 half-lives or 14 days prior (whichever is the 
longer period of time) to Baseline and withheld throughout the clinical trial, including 
primidone. 
E 13. The participant has any of the following at the Screening visit: a serum total bilirubin 
value >1.5×ULN; a serum alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) value >2×ULN. As an exception, participants that present 


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with elevated bilirubin in the absence of elevations in ALT or AST that fits the 
pattern of Gilbert’s syndrome may be enrolled after discussion with the medical 
monitor if their conjugated bilirubin is within the ULN. 
E 14. Criterion removed from protocol in Version 5.0. 
E 15. History of any suicide attempt within the past 2 years. 
E 16. History of structural heart disease (eg, congestive heart failure, depressed ejection 
fraction or left ventricular hypertrophy) or clinically significant cardiac arrhythmias 
(eg ventricular tachycardia) excluding sinus arrhythmia. 
E 17. History of cancer treated with chemotherapy 
E 18. Any other significant disease, disorder, laboratory abnormalities, or environmental 
factor that, in the opinion of the Investigator or Sponsor, may either put the 
participant at risk due to participation in the clinical trial, may influence or confound 
the result of the clinical trial, or affect the participant’s ability to participate in the 
clinical trial. 
E 19. Has previously received treatment with PRAX-944 in any clinical trial (including 
Part A of the current trial for participants enrolling in Part B) 
TEST PRODUCT, REFERENCE THERAPY, AND ADMINISTRATION 
20 mg PRAX-944 MR7 tablets or matching placebo will be administered orally and provided in 
pre-packaged containers to the participants. 
DOSE/ROUTE/REGIMEN 
Part A 
All participants will receive PRAX-944 orally, 20 mg QAM for 7 days and 40 mg QAM for 7 
days. 
Part B 
Open-label Titration 
The planned titration schedule for PRAX-944 is as follows: 
• 20 mg QAM for 3 days 
• 40 mg QAM for 4 days 
• 60 mg QAM for 7 days 
• 80 mg QAM for 7 days 
• 100 mg QAM for 7 days 
• 120 mg QAM for 14 days 


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SAMPLE SIZE 
The sample size of each part (up to 12 participants) is a convenience sample. The sample size 
was not selected according to any statistical power calculation. Instead, the sample size was 
determined according to feasibility and is thought to provide sufficient efficacy and safety data to 
inform the development of future controlled studies with PRAX-944 in participants with ET. 
Part B sample size may be increased to up to 24 participants to ensure inclusion of a broad range 
of tremor severity. In the open-label phases of the trial (Part A and Part B, open-label titration), a 
sample size of at least 10 participants would provide an 80% probability of observing at least 1 
AE with an underlying incidence of 15% or greater. In addition, 10 participants should also 
provide approximately 80% power to detect an effect size of 1.0 on the primary endpoint of 
change from Baseline in TETRAS Upper Limb score. 
STATISTICAL METHODS 
For all data displays, separate summaries will be generated for each part of the clinical trial. For 
the randomized portion of Part B, data will be summarized by the randomized continuation 
treatment. Safety, tolerability, PK, and efficacy variables will be summarized using descriptive 
statistics. Descriptive summaries for categorical variables will include counts and percentage. 
Descriptive summaries for continuous variables will include number of participants (n), mean, 
standard deviation (SD), median, minimum, and maximum. Where appropriate, 95% confidence 
intervals (CIs) may be reported. Summaries will be presented by time point, where appropriate. 
Unless specified otherwise, all data recorded will be listed by participant. 
Reported values and change from baseline values in TETRAS Upper Limb score, TETRAS 
Performance subscale total and individual scores,
The Enrolled Analysis set includes all participants who sign an informed consent form and are 
provided with an enrollment number. The Enrolled Analysis set will be used for all participant 
disposition analyses. 
The Safety Analysis set includes all participants who received at least 1 dose of study drug. 
Participants will be classified according to actual intervention received. The Safety Analysis set 
will be used for all demographic, baseline characteristics, prior/concomitant medication, study 
drug exposure, and safety analyses. 
The Full Analysis set includes all participants who took at least 1 dose of study drug and have a 
valid Baseline TETRAS assessment and at least 1 valid post-Baseline TETRAS assessment. The 
Full Analysis set will be used for the analysis of all efficacy data. 


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The PK Analysis Set includes all participants who received at least 1 dose of study drug and 
have at least 1 evaluable plasma concentration. The PK Analysis Set will be used for the analysis 
of plasma concentrations and PK parameters. 
Adverse event data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of participants experiencing any treatment-emergent 
AE (TEAE) will be summarized by system organ class (SOC) and preferred term (PT). In 
addition, TEAEs will be summarized similarly by maximum severity and maximum relationship 
to PRAX-944. Serious AEs (SAEs) and TEAEs leading to discontinuation of PRAX-944 will be 
listed. Reported values and change from Baseline values in vital signs, ECG parameters, and 
hematology and clinical chemistry laboratory parameters will be summarized by time point. 
For the C-SSRS, the number and percentage of participants with suicidal ideation or behavior 
events will be tabulated. 
For Part A, standard PK parameters will be estimated using noncompartmental methods based on 
the concentration-time data. These parameters will include, where possible, Cmax, Tmax, t1/2, 
AUC0-tau, CL/F and Vd/F. Part B, concentration-time data will be summarized. Exploratory 
analyses examining the relationship between PK and efficacy parameters may be performed for 
the PK Analysis Set. 


Praxis Precision Medicines 
Protocol PRAX-944-221, Version 6.0 
1.2. 
Study Schema 
Figure 1: Study Schema 
Part A (N=12): Open-label Study of 20 mg and 40 mg 
Day -28 to •1 
Screening 
DayO 
Baseline 
Day 1 
20 mgQAM 
study drug 
Day 7 
Last day of 
20mg 
QAM 
Daya 
40 mg 
QAM study 
drug 
Day 14 
Last day of 
40mgOAM 
Part B (N=12): Open-label Titration and 
Randomized Withdrawal Study of 120 mg 
Day 15 to 21 
Safety 
Follow-up 
Period 
1 :1 
Day -28 to -1 
Day 1-3 
Day4•7 
Day 8·14 
Day 15-21 
Day 22-28 
Day 29-42 
Randomization 
Screening 
PRAX-944 
PRAX-944 
PRAX-944 
40mg QAM 
60 mgQAM 
80mgQAM 
a1.1i1c 
Vh"4 
Oay21 
PRAX•944 
PRAX·944 
100mgQAM 
120mgQAM 
Ooy2S 
= Site conducted telehEellh al 
home TETRAS uppe, limb 
items assessment 
= Telephone checi\•in 
Note: This schema is intended to provide a visual reference to the basic study design. Key aspects of 
the study, including flexibility with dose level and visit schedule are not represented here - please refer to 
the text of the protocol and the SoA for these details. 
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1.3. 
Schedule of Activities 
The schedule of clinical trial activities for Part A is presented in Table 2. The schedule of clinical 
trial activities for Part B is presented in Table 3.


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Table 2:  
Schedule of Activities (SoA) – Part A 
Visit Days 
Day -28 to 
Day -1 
(Screening) 
Day 0* 
(Baseline)  
Day 1 
Day 7 (±1)  
Day 14 (±1) 
Day 21 (±1) 
End of 
Clinical 
Trial or 
Early 
Termination  
CLINICAL TRIAL ENTRY AND GENERAL ASSESSMENTS 
Informed Consent 
X 
 
 
 
 
 
Inclusion/ Exclusion 
X 
X 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Body Weight/ Height 
X 
 
 
 
 
 
Drug/ Alcohol Screen a 
X 
X 
 
 
 
 
Pregnancy test 
X (serum) 
X (urine) 
 
 
 
X (urine) 
SAFETY ASSESSMENTS 
Vital Signs b 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
 
  
  
X  
Clinical Laboratory Tests c 
X 
X 
 
X 
X 
X 
12-lead ECG d 
X 
X 
 
X 
X 
 
C-SSRS (Baseline/Screening) 
X 
 
 
 
 
 
C-SSRS (Since Last Visit) 
 
X 
 
X 
X 
X 
AE Monitoring 
X 
Concomitant Meds/ Procedures 
X 
EFFICACY ASSESSMENTS 
TETRAS Performance e 
X 
X 
X 
X 
X 
X 


Praxis Precision Medicines 
Visit Days 
TETRAS Video Recording r 
TETRAS Pe1fo1mance Upper Limb Items with 
Accelerometer g 
--
Blood Collection for Study Dmg Concentration 
(sparse sampling) h 
Blood Collection for Study Dmg Concentration 
(sedal sampling) i 
Day -28 to 
Day 0* 
Day-1 
(Baseline) 
Day 1 
(Screening) 
X 
X 
X 
X 
X 
PHARMACOKINETICS 
X 
0 
STUDY DRUG 
Protocol PRAX-944-221, Version 6.0 
Day 21 (±1) 
End of 
Clinical 
Day7 (±1) 
Day 14 (±1) 
Trial or 
Early 
Termination 
X 
X 
X 
X 
X 
X 
I 
I 
I 
I 
X 
X 
0 
0 
X 
AE=adverse event; 
C-SSRS=Colwnbia-Suicide Severity 
Rating Scale; ECG=e ectrocar rogram; O=ophona ; 
; TETRAS=T e Essential Tremor Rating Assessment Scale. 
* Day O (Baseline) activities may be combined with Day 1 activities, provided that Baseline activities are completed before dosing in the moming. Baseline 
testing of TETRAS Performance, TETRAS Video Recording, and TETRAS Performance Upper Limb Items with Accelerometer should all be done on the 
same day and can occw- on Day O or Day 1 pre-dose, but not both. 
• Urine sample for assessment of selected drugs and a breath sample for alcohol screen. 
b Vital signs (pulse rate, respiratory rate, temperatw-e, and blood pressw-e [ after the participant has been supine for at least 5 minutes and standing for at least 2 
minutes]). On Day 1, should be performed 2 and 6 how-s after dosing (±30 min). 
c Including CBC, clinical chemistry, coagulation factors, viral serology screen, exploratory mine biomarkers, w-inalysis and w-ine albumin. Coagulation factors 
and viral serology screen collected at Screening only. 
d Triplicate measmement will be taken at Screening only; for all other timepoints, single measw-ement is acceptable. 
e Screening, Day O and Day 21: completed anytime; Day 1, pre-dose (if not done on Day 0) and 6 (±2) how-s post-dose; Day 7 and Day 14, 6 (±2) how-s post-
dose. 
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Visit Days 
Day -28 to 
Day -1 
(Screening) 
Day 0* 
(Baseline)  
Day 1 
Day 7 (±1)  
Day 14 (±1) 
Day 21 (±1) 
End of 
Clinical 
Trial or 
Early 
Termination  
f The TETRAS Performance assessment will be captured on video for central reading. The local rater will rate the same TETRAS Performance assessment that 
is captured on video. The Screening video will be independently assessed for eligibility. 
g To be performed 2 consecutive times separated by at least 30 minutes, the first of the two accelerometer assessments should be completed immediately after 
the TETRAS Performance assessment. All 3 maneuvers in the upper limb item (sub-items 4a, 4b, and 4c) will be completed for both arms, first for the 
RIGHT arm and then for the LEFT.  
h Day 1: 0 (pre-dose); Day 1, 7 and 14; post-dose immediately after completion of the 2nd accelerometer-based upper limb assessment; When PK sampling 
timepoints coincide with the TETRAS Performance timepoints or accelerometer-based assessment timepoints the PK sample is to be obtained last. 
i Optional samples collected at sites that have capabilities to perform serial sample collection: Day 1, 7 and 14: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 
hours post-dose. All collection times up to 4 hours post-dose have a ±15 min window and a ±30 min window thereafter. 24-hour timepoint samples are to be 
taken prior to the AM dose. When PK sampling timepoints coincide with the TETRAS Performance timepoints or accelerometer-based assessment 
timepoints the PK sample is to be obtained last. 
j Administered in clinic on Day 1. All other days it should be taken in the morning, within 30 minutes after breakfast. On Day 1 participant should be observed 
in clinic for approximately 6 hours before discharge. Study drug is dispensed (20 mg QAM for Day 1 to Day 7; 40 mg QAM for Day 8 to Day 14). 


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Table 3:  
Schedule of Activities (SoA) – Part B 
Study Phase 
Screening 
 
Open-label Titration 
Visit Days 
(Visit Window) 
Day -28 to  
Day -1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Day 
14  
Day 
21 
Day 
28 
Day 
35 
Day 
41 
Day 
42 
 
Day 
-2 
(-2) 
CLINICAL TRIAL ENTRY AND GENERAL ASSESSMENTS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X* 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
Drug/Alcohol Screen a 
X 
 
X* 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
(serum) 
 
X (urine)* 
 
 
 
 
 
 
 
 
SAFETY ASSESSMENTS 
Vital Signs b 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Physical Examination 
X 
 
X* 
 
 
 
 
 
 
 
 
Clinical Laboratory 
Tests c 
X 
 
X* 
 
X 
 
X 
 
 
 
X 
12-lead ECG d 
X 
 
X* 
 
X 
 
X 
 
 
 
X 


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Study Phase 
Screening 
 
Open-label Titration 
Visit Days 
(Visit Window) 
Day -28 to  
Day -1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Day 
14  
Day 
21 
Day 
28 
Day 
35 
Day 
41 
Day 
42 
 
Day 
-2 
(-2) 
C-SSRS 
(Baseline/Screening) 
X 
 
 
 
 
 
 
 
 
 
 
C-SSRS (Since Last 
Visit) 
 
 
X* 
 
X 
 
X 
 
 
 
X 
Phone Call Check-in 
 
 
 
X 
 
X 
 
X 
X 
 
 
AE Monitoring 
X 
Concomitant Meds/ 
Procedures 
X 
EFFICACY ASSESMENTS 
TETRAS Performance e 
X 
 
X 
 
X 
 
X 
 
 
 
X 
TETRAS Video  
Recording f 
X 
 
X 
 
X 
 
X 
 
 
 
X 
TETRAS Performance 
Upper Limb Items with 
Accelerometer g 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Telehealth TETRAS 
Upper Limb Items 
Assessment 
 
X 
 
 
 
 
 
 
 
X 
 


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Study Phase 
Screening 
 
Open-label Titration 
Visit Days 
(Visit Window) 
Day -28 to  
Day -1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Day 
14  
Day 
21 
Day 
28 
Day 
35 
Day 
41 
Day 
42 
 
Day 
-2 
(-2) 
TETRAS ADLh 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUEST 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETICS 
Blood Collection for 
Study Drug 
Concentration i 
 
 
X 
 
X 
 
X 
 
 
 
X 
STUDY DRUG 
Randomization j 
 
 
 
 
 
 
 
 
 
 
X 
Study Drug Dispensing 
 
 
X 
 
X 
 
X 
 
 
 
X 
Study Drug 
Administration k 
 
 
X 
(open label) 
-
I 
I 
I 
I 
I 
-
I 
I 
I 
-
I 
I 
I 
-
I 
I 
I 
I 
I 
I 
• 
I 
I 
I 
I 
I 
I 


Praxis Precision Medicines 
Protocol PRAX-944-221, Version 6.0 
Study Phase 
Visit Days 
(Visit Window) 
Screening 
Day-28 to 
Day -1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Open-label Titration 
Day 
14 
Day 
21 
Day 
28 
Day 
35 
Day 
41 
CBC=complete blood count; 
-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; Meds=Medications; 
; PK=phannacokinetics; QAM=every moming; QUEST=Quality 
of Life in Essential Tremor Questionnaire; TETRAS=The Essential Tremor Rating Assessment Scale. 
* May be perfoimed on Day -1. 
• Urine sample for assessment of selected drngs and a breath sample for alcohol screen. 
b Vital signs include pulse rate, respiratory rate, temperature, and blood pressure. Blood pressure must be measured once after the participant has been supine 
for at least 5 minutes and once after the paiticipant has been standing for at least 2 minutes. On Day 1, vital signs should be measured pre-dose, 2 hours post-
dose (±30 min), and 6 hours post-dose (±30 min). 
c Including CBC, clinical chemistty, coagulation factors, viral serology screen, urinalysis, and urine albumin. Coagulation factors and viral serology screen 
collected at Screening only. 
d A triplicate measurement must be taken at Screening only; for all other timepoints, a single measurement is acceptable. 
e TETRAS can be completed anytime at Screening and Day 70. On other days, the following timing should be followed: 
Day 1: pre-dose and 6 (±2) hours after a 20 mg QAM dose 
Day 7: 6 (±2) hours after a 40 mg QAM dose 
Day 21: 6 (±2) hours after an 80 mg (or highest tolerated dose) QAM dose 
Day 42: pre-dose and 6 (±2) hours after a 120 mg (or highest tolerated dose) QAM dose 
Day 56: 6 (±2) hours post-dose 
f The TETRAS Performance assessment will be captured on video for central reading. The local rater must rate the same TETRAS Perfonnance assessment as 
that which is captured on video for central reading. The Screening video will also be independently assessed for eligibility. 
g Kinesia ONE assessments must be completed immediately after the TETRAS Perfoimance assessments (including both pre-dose and post-dose assessments 
on Day 1 and Day 42). After each TETRAS Perfoimance assessment, Kinesia ONE assessments should be completed twice separated by at least 30 minutes. 
All 3 maneuvers in the upper limb item (sub-items 4a, 4b, and 4c) will be completed for both aims, first for the RIGHT aim and then for the LEFT. 
h For visits with multiple TETRAS assessments, the TETRAS ADL subscale should only be assessed once. On Day 1, the ADL subscale should be completed 
pre-dose. On day 42, the ADL subscale should be completed 6 (±2) hours after the QAM dose. 
i On Day 1 and Day 42 blood samples should be collected at the following timepoints: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose. The 6-hour post-dose 
sample will be collected immediately after completion of the second Kinesia ONE assessment. When PK sampling timepoints coincide with the TETRAS 
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Study Phase 
Screening 
 
Open-label Titration 
Double-Blind 
Randomized 
Withdrawal 
Safety 
Follow-
up 
Visit Days 
(Visit Window) 
Day -28 to  
Day -1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Day 
14  
Day 
21 
Day 
28 
Day 
35 
Day 
41 
Day 
42 
Day 56 
Day 
70/ET 
(End of 
Clinical 
Trial) 
 
Day 
-2 
(-2) 
Performance timepoints or accelerometer-based assessment timepoints, the PK sample is to be obtained last. On Days 7, 21, and 56; samples should be 
collected 2 hours post-dose. Blood collection can be completed anytime on Day 70. 
j Participants will be randomized (1:1) to receive either placebo or PRAX-944 from Day 43 to Day 56. Randomization can occur on Day 37 through Day 42. 
k On Day 1 and 42, study drug must be administered in the clinic on an empty stomach (at least 1 hour before breakfast, which will be provided at the site) and 
the participant should be observed in the clinic for approximately 6 hours before discharge. On all other days, participants should be instructed to take study 
drug at least 1 hour before breakfast in the morning at home. The escalation schedule is as follows: 20 mg, Day 1 through Day 3; 40 mg, Day 4 through Day 
7; 60 mg, Day 8 through Day 14; 80 mg, Day 15 through Day 21; 100 mg, Day 22 through Day 28; and 120 mg, Day 29 through Day 42. Participants will 
receive blinded study drug on Days 43 to 56. During blinded treatment period, participants should take the same number of tablets per day as taken during 
Days 36 to 42. 


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2. 
INTRODUCTION 
2.1. 
Background and Clinical Trial Rationale 
Essential Tremor (ET) is one of the most common neurological disorders with a prevalence of 
nearly 1% (Louis 2010). It is characterized by a 6 to 12 Hz postural and kinetic tremor. Tremor 
typically occurs in the hands, arms, head, and voice, and is less common in the face, legs, and 
trunk. ET, by definition, is not associated with other neurological signs, although a resting tremor 
and impairments in balance, particularly tandem gait, have been described (Deuschl 2011). The 
diagnosis of ET is based on medical history and neurological exam as described in The 
International Parkinson and Movement Disorders Society Consensus Statement on the 
Classification of Tremors (Bhatia 2018). 
There is a range in the severity of ET; some patients require no treatment, whereas others have 
severe disability with impairment in activities of daily living (ADLs) such as dressing and eating. 
Treatments for ET include pharmacological therapies, regional injection of botulinum toxin 
(off-label usage), and surgical therapies for those with severe disability. The most effective 
pharmacological therapies are propranolol and primidone. They have limited efficacy, with about 
50% of patients having a durable yet incomplete response. Dose-limiting side effects are 
common and include bradycardia for propranolol and sedation and dizziness for primidone 
(Deuschl 2011). Surgical therapies, including deep brain stimulation and ablation of the nucleus 
ventralis intermedius of the thalamus, are effective but they are reserved for medically refractory 
patients due to the risks associated with brain surgery. Many patients who are eligible for 
surgical therapies do not elect to have these procedures (Elias 2016). Thus, there is a high unmet 
need for efficacious and well-tolerated pharmacological therapies for ET. 
While the genetics and pathophysiology of ET is not fully understood, it is thought to involve 
abnormal activity of cerebellar afferent and efferent pathways. This network consists of input 
from the inferior olive to the cerebellar cortex, and outflow through deep cerebellar nuclei to the 
ventral thalamus and cortex (Park 2013). Low voltage, T-type calcium (Ca2+)-channels in the 
inferior olive and thalamus may play a role in the pathogenesis and treatment of ET. The T-type 
Ca2+-channel family is comprised of 3 different isoforms: CaV3.1, CaV3.2, and CaV3.3. These 
channels are involved in generation of physiological and pathophysiological rhythms in the 
brain. In the harmaline rodent model of ET, synchronous neuronal discharges which are 
associated with T-type Ca2+-channels are increased. The abnormal discharges were attenuated in 
mice lacking the gene that encodes for CaV3.1, and in wildtype mice, selective knockdown of 
CaV3.1 in the inferior olive by shRNA suppressed the harmaline-induced tremor (Park 2010). 
The non-selective Ca2+-channel blocker ethosuximide was found to suppress tremor in the 
harmaline model and in a genetic model of ET, in a dose-dependent fashion (Handforth 2010). 


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In a human (electroencephalogram) EEG/polysomnography clinical trial, PRAX-944 showed 
robust suppression of the sigma frequency band during non-rapid eye movement (NREM) sleep, 
a marker of sleep spindle activity, at the 20 mg, 40 mg, and 60 mg dose levels. Sleep spindles are 
prominent oscillations of 11 to 15 Hz observed in the human scalp EEG during NREM sleep that 
are mediated by activation of T-type Ca2+-channels in the thalamus. Thus, these data suggest that 
PRAX-944 blocks T-type Ca2+-channels in the central nervous system (CNS) at well-tolerated 
doses. 
The aim of this development program is to evaluate whether oral administration of PRAX-944 
can provide therapeutic benefit to patients with ET. The study is divided into 2 parts: Part A is 
designed to study the dose titration from 20 to 40 mg every morning (QAM) (ie, 2 weeks with 7 
days at each dose level) and Part B is designed to study the dose titration from 20 to up to 
120 mg QAM with at least 14 days of dosing at the highest tolerated dose for each participant. 
2.2. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of PRAX-944 may be found in the Investigator’s Brochure (IB). 
2.3. 
Known Potential Benefits 
Since PRAX-944 has not yet been studied in the ET population, there are no known benefits. 
2.4. 
Known Potential Risks 
In the Z944-104 study, administration of 20 and 40 mg doses of PRAX-944 
on Day 1 of dosing was well tolerated, but a 60 mg single dose led to nausea and vomiting. In 
addition, a 20 mg daily dose and a 40 mg daily dose, each administered for 8 days, were 
determined to be safe and tolerable in healthy volunteers. More recently, in the completed 
PRAX-944-105 study, daily doses up to 120 mg were determined to be safe and well tolerated in 
healthy volunteers following a titration schedule nearly identical to the schedule planned for this 
clinical trial. 
The more common (5 or more in 100) or medically relevant AEs that have occurred with PRAX-
944 are as follows: feeling abnormal or dizzy, headache, nausea, elevated mood, visual 
hallucinations, drowsiness, difficulty concentrating, skin tingling, fatigue, numbness, tremor, 
poor sleep, feeling anxious, spinning sensation, vomiting, and strange dreams (see IB Section 6 
for additional information). Most of these side effects were short-lived, and all symptoms 
resolved. 
No serious AEs (SAE)s have been reported with PRAX-944. 


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Protocol PRAX-944-221, Version 6.0 
3. 
OBJECTIVES AND ENDPOINTS 
To evaluate the efficacy, safety, tolerability, and phaimacokinetics (PK) of PRAX-944 in adults 
with ET. 
3.1. 
Part A 
Objective 
Primruy 
• 
To evaluate the efficacy of PRAX-944 on 
upper limb tremor in pa1ticipants with ET 
Seconda1y 
• 
To evaluate the efficacy of PRAX-944 on 
other measures of tremor severity in 
pruticipants with ET 
• 
To evaluate the safety and tolerability of 
PRAX-944 in pa1ticipants with ET 
Explorato1y 
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Endpoint 
• 
Change from Baseline to Day 7 and Day 14 
in The Essential Tremor Rating Assessment 
Scale (TETRAS) upper limb score (bilateral 
sum of items 4a, 4b, and 4c) 
• 
Change from Baseline to Day 7 and Day 14 
in: 
o TETRAS Pe1fo1mance subscale total 
score 
o Accelerometer-based upper limb score 
(bilateral sum of items 4a, 4b, and 4c) 
o TETRAS Pe1fo1mance subscale 
individual item scores 
• 
Incidence and seve1ity of adverse events 
(AEs) 
• 
Changes in vital sign measurements 
• 
Changes in clinical laborato1y results 
• 
Changes in electrocru·diogram (ECG) 
parameters 
• 
Incidence of Columbia-Suicide Severity 
Rating Scale (C-SSRS) measured suicidal 
ideation or behavior 
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Protocol PRAX-944-221, Version 6.0 
3.2. 
Part B 
Objective 
Endpoint 
Primruy 
• To evaluate the safety and tolerability of 
• Incidence and seve1ity of AEs 
PRAX-944 in pa1ticipants with ET 
• Changes in vital sign measurements 
• Changes in clinical laborato1y results 
• Changes in ECG pru·ameters 
• Incidence of C-SSRS measured suicidal 
ideation or behavior 
Seconda1y 
• To evaluate the efficacy of PRAX-944 on 
• Change from Baseline to Day 42 in TETRAS 
upper limb tremor in pa1ticipants with ET 
Upper Limb score (bilateral sum of items 4a, 
4b, and 4c) 
• To evaluate the efficacy of PRAX-944 on 
• Change from Baseline to Day 7 and Day 21 
other measures of tremor severity in 
in TETRAS Upper Limb score (bilateral sum 
pruticipants with ET 
of items 4a, 4b, and 4c) 
• Change from Baseline to Day 7, Day 21, and 
Day 42 in the following: 
0 
TETRAS Pe1fo1mance subscale total 
score 
0 
Accelerometer-based upper limb score 
(bilateral sum of items 4a, 4b, and 4c) 
0 
TETRAS Pe1fo1mance individual item 
scores 
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Objective 
• 
To evaluate the efficacy of PRAX-944 on 
measures of disease impact in participants 
with ET 
Explorato1y 
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Protocol PRAX-944-221, Version 6.0 
Endpoint 
• 
Change from Baseline to Day 7, Day 21, and 
Day 42 in the following: 
o 
TETRAS ADL subscale score 
o 
Quality of Life in Essential Tremor 
Questionnaire (QUEST) total and 
subscale scores 
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Objective 
Endpoint 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Design 
This multi-center clinical trial will assess the efficacy, safety, tolerability, and PK of PRAX-944 
in participants aged 18 years or older who have had signs and symptoms consistent with  ET for 
at least 3 years, with an onset before age 65. 
The clinical trial will be conducted in 2 parts (Part A and Part B). Both parts will consist of 3 
periods: Screening/Baseline, Intervention, and Safety Follow-up. 
Part A of the clinical trial is open-label and will assess the safety and tolerability of PRAX-944, 
as well as the overall magnitude and pattern of change in ET severity. Daily dose levels will be 
titrated from 20 mg to 40 mg. 
Part B of the clinical trial consists of both an open-label titration phase and a randomized, 
double-blind, placebo-controlled withdrawal phase. Part B will assess the safety and tolerability 
of PRAX-944, as well as the overall magnitude and pattern of change in ET severity and the 
duration of that effect. Daily dose levels will be titrated from 20 mg to up to 120 mg during the 
open-label phase. In the randomized, double-blind, placebo-controlled withdrawal phase, 
participants will either be maintained on their final open-label dose or switched to placebo. 
Participants who received study drug in Part A are not eligible for Part B (see Exclusion 
Criterion #19). 
4.1.1. 
Screening/ Baseline Period 
The Screening period for Part A and Part B will be up to 28 days (Day -28 to Day -1). Fourteen 
additional days (ie, 42 days total) will be allowed in the Screening period for participants who 
are discontinuing primidone. 
Prior to any procedures, participants will provide written informed consent to participate in the 
clinical trial. Key Screening assessments will include medical history, demographics, physical 
examination, drug screen, clinical laboratory evaluations and serum pregnancy for women of 
childbearing potential, 12-lead ECG, vital signs, C-SSRS, assessment of ET severity using the 
TETRAS Performance subscale (including a video for independent review of eligibility), and a 
review of concomitant medications. To be eligible, potential participants who are taking 
prohibited medications will need to successfully discontinue these medications for at least 5 
half-lives or 14 days prior (whichever is the longer period of time) before the first dose of study 
drug. 
For those participants requiring the 14 additional days in the Screening period to discontinue 
primidone, all or some of the Screening assessments may need to be repeated, pending approval 
by the Sponsor’s Medical Monitor. 
For participants in Part A, following confirmation of eligibility, including review by the Sponsor 
or designee, participants will complete Baseline assessments (Day 0). Day 0 (Baseline) activities 
may be combined with Day 1 activities, provided that Baseline activities are completed before 
dosing and that dosing occurs in the morning of Day 1. In addition, Baseline efficacy 
assessments should either be conducted on Day 0 or Day 1 pre-dose, but not both to avoid 
learning effects. 


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Protocol PRAX-944-221, Version 6.0 
For participants in Part B, 
will also be completed with 
accelerometiy at Screening and via telehealth on Day -2 of the Screenin 
eriod. The Screening 
telehealth visit is needed to ensure aiiici ants can com lete the 
Following 
confirmation of eligibility, including review by the Sponsor or designee, pa11icipants will 
complete Baseline assessments (Day 1). Some Baseline assessments (as indicated in Table 3) 
may be completed on Day -1. 
4.1.2. 
Intervention Period 
4.1.2.1. 
Part A 
On Day 1, participants will receive a 20 mg dose of PRAX-944, administered in the morning. 
Paiiicipants will remain in a clinical setting under medical observation for approximately 6 
hours. TETRAS Performance assessments will be perfonned before dosing and again 6 hours 
post-dose. After the first dose, paiticipants will continue QAM dosing at home after breakfast 
through Day 7. Participants will return to the clinic on Day 7 for efficacy testing at the 20 mg 
dose level. On Day 8, the dose will increase to 40 mg QAM after breakfast through Day 14 for 
efficacy testing at the 40 mg dose level. Participants will retmn to the clinic on Day 14 for 
efficacy testing at the 40 mg dose level. Participants who agree to optional additional PK 
sampling will remain overnight in the clinic on Day 1, Day 7, and Day 14. 
Key safety measures will include clinical laborato1y evaluations, 12-lead ECG, C-SSRS, and 
vital signs (Table 2). Key efficacy assessments will include the TETRAS Perfo1mance subscale, 
(Table 2). Blood samples will be obtained for the determination of PRAX-944 plasma 
concentrations using a validated bioanalytical method and may also be used for explorato1y 
method development and/or metabolite characterization. 
AEs and concomitant medication use and procedures will be monitored from the time of 
info1med consent to Day 21 (±1 day). At that time, paiiicipants will have completed the clinical 
ti·ial. Paiiicipants who received study dmg in Part A ai·e not eligible for Part B (see Exclusion 
Criterion #19). 
4.1.2.2. 
Part B 
4.1.2.2.1. Open-label Titration Phase 
On Day 1, participants will receive a 20 mg dose of PRAX-944 on an empty stomach ( at least 1 
hour before breakfast). Paiiicipants will remain in a clinical setting under medical observation 
for approximately 6 hours. TETRAS Perfo1mance assessments will be perfo1med before dosing 
and 6 hours (±2) post-dose. 
For dosing on Day 2 through Day 41, participants will be instmcted to dose QAM at least 1 hour 
before breakfast at home. 
Paiiicipants will continue taking PRAX-944 20 mg QAM at home through Day 3. 
On Day 3, participants will receive a telephone call from site staff to inquire about AEs and 
concomitant medications, confnm dose escalation, and remind the pa11icipant about the number 
of study drug tablets to take on Day 4 through Day 7. 
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On Day 4, participants will escalate to 40 mg QAM through Day 7, when they will return to the 
clinic for safety assessments and efficacy testing. On Day 8, participants should escalate to 
60 mg QAM through Day 14. 
On Day 14, participants will receive a telephone call from site staff to inquire about AEs and 
concomitant medications, confirm dose escalation, and remind the participant about the number 
of study drug tablets to take on Day 15 through Day 21. 
On Day 15, participants should escalate to 80 mg QAM through Day 21, when they will return to 
the clinic for safety assessments and efficacy testing. On Day 22, participants should escalate to 
100 mg QAM through Day 28. 
On Day 28, participants will receive a telephone call from site staff to inquire about AEs and 
concomitant medications, confirm dose escalation, and remind the participant about the number 
of study drug tablets to take on Day 29 through Day 42. 
On Day 29, participants will escalate to 120 mg QAM through Day 42, when they will return to 
the clinic for safety assessments and efficacy testing. The dose on Day 42 will be taken in the 
clinic (see Section 4.1.2.2.2 below). 
On Day 35, participants will receive a telephone call from site staff to inquire about AEs and 
concomitant medications. 
On Day 41, participants will complete a TETRAS Performance Upper Limb assessment via a 
telehealth visit. 
If at any point during the open-label titration phase a participant does not tolerate escalation and 
the Investigator returns the participant to a lower dose level, the participant will continue 
according to the schedule outlined above, but no further dose changes will be allowed. The 
Investigator should discuss the decision to continue at a lower dose level with the Sponsor and 
Medical Monitor. Participants can only change to a lower dose level once, and no dose changes 
may occur after Day 36. 
4.1.2.2.2. Double-blind Randomized Withdrawal Phase 
On Day 42, participants will complete the final clinic visit of the open-label titration phase. 
Participants will receive their dose of PRAX-944 administered in the clinic on an empty stomach 
(at least 1 hour before breakfast). Participants will remain in a clinical setting under medical 
observation for approximately 6 hours. TETRAS Performance assessments will be performed 
before dosing and 6 hours (±2) post-dose. 
After Day 42, participants will either continue receiving PRAX-944 at their current dose or 
switch to placebo, depending on their randomization. Randomization in a 1:1 fashion may be 
completed at any time on Day 37 through 42. 


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4.1.3. 
Safety Follow-up Period 
4.1.3.1. 
Part A 
The Safety Follow-up period will take place from Day 15 to Day 21. At the end of the Safety 
Follow-up period, participants will return to the clinic on Day 21 (±1 day) for the final clinical 
trial assessments (Table 2). 
4.1.4. 
Clinical Trial Duration 
Participants will be part of the clinical trial for the following time intervals: 
4.1.4.1. 
Part A 
Screening/Baseline Period 
Up to 28 days (+14 days if on primidone) 
Intervention Period 
14 days 
Safety Follow-up Period 
7 days 
Total Participation 
Up to 49 days (63 days if on primidone) 
4.1.4.2. 
Part B 
Screening/Baseline Period 
Up to 28 days (+14 days if on primidone) 
Safety Follow-up Period 
14 days 
Total Participation 
Up to 98 days (112 days if on primidone) 
4.2. 
Scientific Rationale for Clinical Trial Design 
This is the first trial of PRAX-944 in ET. 
4.3. 
Justification for Dose 
The dose range of up to 120 mg QAM is based on the observed safety, tolerability and 
pharmacodynamic biomarker data in healthy volunteers. The
was well 
tolerated at doses of up to 40 mg/day over 8 days in the z944-104 study and 120 mg/day over 
4 days following a 27-day titration in the PRAX-944-105 clinical trial. The titration completed in 
PRAX-944-105 is nearly identical to the titration schedule used in this clinical trial. 


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4.4. 
Clinical Trial Committees 
The Sponsor will review ongoing safety data. The clinical trial may be stopped, or clinical trial 
enrollment suspended if: 
• The Sponsor, in consultation with the Principal Investigators, consider that the 
number and/or severity of AEs justify discontinuation of the clinical trial 
• The Sponsor makes a decision to do so 
4.5. 
End of Clinical Trial Definition 
A participant is considered to have completed the clinical trial if he/she has completed the 
clinical trial intervention period including the last visit as shown in the Schedule of Activities 
(SoA). 
The end of the clinical trial is defined as the date of the last visit of the last participant in the 
clinical trial. 


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5. 
POPULATION 
The intended population is participants with signs and symptoms of ET for at least 3 years who 
meet all eligibility criteria. If a participant’s signs and symptoms are judged by the investigator 
to be due to the diagnosis of ET, it is acceptable for them to also have one or more of the 
following ET plus signs: 
• 
Mild dystonic posturing 
• 
Mild rest tremor in the setting of advanced ET and in the absence of other features of 
Parkinsonism 
• 
Intention tremor 
• 
Mild increase in tandem gait difficulty 
The severity of these additional signs and the primary diagnosis of ET must be agreed upon by 
the central video reviewer. 
Source documentation should capture both the unlikely alternate diagnoses and the additional ET 
plus signs. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Number of Participants 
5.1.1. 
Part A 
Up to 12 participants are planned to be administered PRAX-944. 
5.1.2. 
Part B 
Approximately 12 participants are planned to be administered PRAX-944 for the first 42 days 
followed by randomization (1:1) to 2 additional weeks on the highest tolerated dose of PRAX-
944 or placebo. Up to 12 additional participants may be enrolled at the discretion of the Sponsor 
to ensure inclusion of a broad range of tremor severity. 
5.1.3. 
Participant Replacement 
Participants who withdraw from either Part A or Part B prior to completion of the clinical trial 
may be replaced at the discretion of the Sponsor. No more than 6 participants in either part of the 
study will be replaced. 
5.2. 
Inclusion Criteria 
A participant must meet the following criteria at Screening and Baseline (unless otherwise 
specified) to be eligible to participate in this clinical trial: 
I 1. 
Male or non-pregnant, non-lactating female aged 18 years or older. 
I 2. 
Willing and able to understand and sign an informed consent document indicating 
that he/she understands the clinical trial purpose, the clinical trial procedures, and that 
he/she is willing to participate in the clinical trial and comply with the protocol. 
I 3. 
Body mass index (BMI) at Screening between 18 and 40 kg/m2, inclusive. 


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I 4. 
Clinical diagnosis of ET consistent with Movement Disorders Society Criteria, a 
duration of ET of at least 3 years and with onset before the age of 65. 
I 5. 
Moderate to severe ET as defined by the following: 
a. A combined bilateral score of ≥10 on the TETRAS Upper Limb items 4 a, b, c. 
(UL tremor severity at Screening will be confirmed by central video review, for 
eligibility) 
OR 
b. A score of ≥2 on 2 or more of the following TETRAS activities of daily living 
(ADL) subscale items: (2) Feeding with a spoon, (3) Drinking from a glass, 
(5) Dressing, (6) Pouring, (9) Writing 
OR 
c. A score of ≥2 on 1 of the following TETRAS ADL subscale items: (2) Feeding 
with a spoon, (3) Drinking from a glass, (5) Dressing, (6) Pouring, or (9) Writing 
AND a score of ≥2 on both of the following TETRAS ADL subscale items: 
(10) Working and (12) Social Impact 
Note: ET severity at Baseline will be confirmed by the Investigator at the clinical 
trial site. 
I 6. 
Those currently receiving any medication for their ET must be willing and able to 
discontinue all but 1 tremor medication and be on a stable dose for at least 28 days. 
I 7. 
Willing to comply with medically acceptable method of contraception as defined in 
Section 5.4.3. 
5.3. 
Exclusion Criteria 
A participant who meets any of the following criteria at Screening or Baseline (unless otherwise 
specified) will be excluded from this clinical trial: 
E 1. 
Known hypersensitivity to any component of the formulation of PRAX-944. 
E 2. 
Unwilling or unable to refrain from episodic use of medication(s)/substance(s) that 
might interfere with the evaluation of tremor during the trial. Stable use of 
medication(s)/substance(s) that might impact tremor, including beta-agonist 
bronchodilators, is allowed so long as the tremor is judged by the investigator to be 
primarily due to the participant's ET diagnosis. 
E 3. 
Trauma to the nervous system within 3 months preceding the onset of tremor. 
E 4. 
Clinical evidence of psychogenic tremor as ascertained by the Investigator. 
E 5. 
History of other medical, neurological or psychiatric condition that may explain or 
cause tremor, including but not limited to Parkinson's disease, dystonia, cerebellar 
disease, family history of Fragile X syndrome, traumatic brain injury, alcohol abuse 
or withdrawal, benzodiazepine abuse or withdrawal, multiple sclerosis, 
polyneuropathy and endocrine states such as hyperthyroidism. 
E 6. 
Prior magnetic resonance-guided focused ultrasound or surgical intervention for ET 
such as deep brain stimulation or thalamotomy. 


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E 7. 
Botulinum toxin injection for ET in the 6 months prior to Screening. 
E 8. 
Unwilling or unable to discontinue primidone. 
E 9. 
Unwilling or unable to refrain from alcohol 24 hours before and during clinical trial 
visits. Or regular use of alcohol that would preclude abstinence from alcohol in this 
period, in the judgement of the Investigator. 
E 10. Substance use disorder in the judgement of the Investigator 
E 11. Sporadic use of a benzodiazepine, sleep medication or anxiolytic, that in the 
judgement of the Investigator or Sponsor would confound the assessment of tremor. 
Stable use at a consistent dose not exceeding the equivalent of 2 mg/day of lorazepam 
(see Section 6.5.2) is allowed as long as tremor persists against the background of 
regular medication use. 
E 12. Use of prescription or non-prescription products and food known to be strong 
inhibitors or inducers of CYP3A4 or known to be a P-gp substrate (see Section 6.5.1) 
which cannot be discontinued at least 5 half-lives or 14 days prior (whichever is the 
longer period of time) and withheld throughout the clinical trial, including primidone. 
E 13.  The participant has any of the following at the Screening visit: a serum total bilirubin 
value >1.5×ULN; a serum alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) value >2×ULN. As an exception, participants that present 
with elevated bilirubin in the absence of elevations in ALT or AST that fits the 
pattern of Gilbert’s syndrome may be enrolled after discussion with the medical 
monitor if their conjugated bilirubin is within the ULN. 
E 14. Criterion removed from protocol in Version 5.0. 
E 15. History of any suicide attempt within the past 2 years. 
E 16. History of structural heart disease (eg, congestive heart failure, depressed ejection 
fraction or left ventricular hypertrophy) or clinically significant cardiac arrhythmias 
(eg ventricular tachycardia) excluding sinus arrhythmia. 
E 17. History of cancer treated with chemotherapy 
E 18. Any other significant disease, disorder, lab abnormalities, or environmental factor 
that, in the opinion of the Investigator or Sponsor, may either put the participant at 
risk due to participation in the clinical trial, may influence or confound the result of 
the clinical trial, or affect the participant’s ability to participate in the clinical trial. 
E 19. Has previously received treatment with PRAX-944 in any clinical trial (including 
Part A of the current trial for participants enrolling in Part B) 
5.4. 
Lifestyle Considerations 
Participants must refrain from donating plasma, blood, or blood products (other than for this 
clinical trial) from Day -1 until 93 days following last dose of study drug. Participants must 
refrain from adopting any new exercise programs during the trial. 
5.4.1. 
Meals and Dietary Restrictions 
Grapefruits and grapefruit juice must be avoided during participation in the clinical trial. 


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Participants should be instructed to refrain from alcohol 24 hours before and during clinical trial 
visits. 
For Part B on Day 1 and Day 42, PRAX-944 is to be administered in the clinic on an empty 
stomach (at least 1 hour before breakfast). Only water and allowable concomitant medications 
are permitted prior to breakfast on Day 1 and Day 42. For dosing on other days, participants 
should be instructed to dose QAM at least 1 hour before breakfast. 
5.4.2. 
Activity Restrictions 
Because PRAX-944 may cause sedation and dizziness, caution must be used in activities 
requiring mental alertness such as driving a car or operating heavy machinery. This impairment 
may be made worse by other medications that also cause sedation or reduce alertness. 
5.4.3. 
Contraception 
The effects of PRAX-944 on fetal development have not been ascertained. As such, all 
participants must agree to an approved form, or forms, of contraception. Participants will be 
provided information on acceptable methods of contraception as part of the informed consent 
process and will sign an informed consent form (ICF) stating that they understand the 
requirements for avoidance of pregnancy, donation of ova, and sperm donation during and after 
the course of this clinical trial. The approved options are listed below. Every participant must 
agree to 1 of the 3 main options (1, 2 or 3): 
1. 
Male or female participants may agree to total (true) abstinence (when this is in line 
with their preferred and usual lifestyle). Total (true) abstinence is defined as the strict 
avoidance of all forms of sexual activity. In males, this must extend from Day -1 
through 90 days + 5 half-lives (ie, total of 93 days) after the last dose of study drug. 
In females, this must extend from Day -1 through 30 days + 5 half-lives (ie, total of 
33 days) after the last dose of study drug. Periodic abstinence (eg, calendar, 
ovulation, symptothermal post-ovulation methods) and withdrawal are not acceptable 
methods. 
2. 
Participants do not need to use contraception if either they or their partner are sterile. 
Sterility is defined as follows: 
a. A female is considered to be surgically sterile if she has had 1 of the following 
procedures: tubal ligation, tubal occlusion, hysterectomy, bilateral oophorectomy, 
or bilateral salpingectomy. 
b. A female is considered to be postmenopausal and sterile if it has been at least 2 
years since last regular menses and follicle-stimulating hormone (FSH) >40 IU/L, 
or at least 5 years since last regular menses, confirmed before any study drug is 
administered. 
c. A male participant is considered sterile if he is at least 1-year post vasectomy and 
has obtained documentation of the absence of sperm in their ejaculate. 
3. 
If neither option 1 nor option 2 criteria are met, then the participant must agree to 
using a combination of 2 of the highly effective methods listed below (a+a, a+b or 
a+c or b+c): 
a. Barrier contraception with or without spermicide, eg, male condom or female 
diaphragm with or without spermicide (foam, gel, film, cream, or suppository); 


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b. Use of oral, injected, or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy; 
c. Placement of an intrauterine device or intrauterine system. 
Note: 
• A participant can agree to using 2 methods, 1 of which is primarily dependent on their 
partner. For example, a male participant can agree to a barrier with spermicide and for 
his female partner to use oral hormonal contraception. Similarly, a female participant 
can agree to using oral hormonal contraception and for her male partner to use a 
barrier with spermicide. 
• Male participants must use 2 highly effective methods from Day -1 through 90 days + 
5 half-lives (3 days) after the last dose of study drug (ie, 93 days). 
• Female participants must use 2 highly effective methods from Day -1 through 30 days 
+ 5 half-lives (3 days) after the last dose of study drug (ie, 33 days). 
5.4.4. 
Sperm and Ova Donation 
• Male participants must refrain from sperm donation from Day -1 through 90 days + 5 
half-lives (+3 days) after the last dose of study drug. 
• Female participants must refrain from ova donation from Day -1 through 30 days + 5 
half-lives (+3 days) after the last dose of study drug. 
5.5. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently entered in the clinical trial. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this clinical trial (screen failure) may 
be rescreened after consultation with the Sponsor and Medical Monitor. 


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6. 
CLINICAL TRIAL INTERVENTION 
Clinical trial intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a clinical trial participant according 
to the clinical trial protocol. 
6.1. 
Study Drug(s) Administered 
20 mg PRAX-944 
or matching placebo will be administered orally and provided in 
pre-packaged containers to the participants. 
6.1.1. 
Part A 
All participants will receive PRAX-944 orally, 20 mg QAM for 7 days and 40 mg QAM for 7 
days. 
6.1.2. 
Part B 
6.1.2.1. 
Open-label Titration 
The planned titration schedule for PRAX-944 is as follows: 
• 20 mg QAM for 3 days 
• 40 mg QAM for 4 days 
• 60 mg QAM for 7 days 
• 80 mg QAM for 7 days 
• 100 mg QAM for 7 days 
• 120 mg QAM for 14 days 
-


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Table 4: 
Study Drug Information 
ARM Name 
Intervention Name 
Type 
Dose Formulation 
Unit Dose Strength(s) 
Dosage Level(s) 
Route of 
Administration 
Sourcing 
Packaging and 
Labeling 
Confidential 
Open-Label Part A 
• 
20 mgQAM 
Day 1 through Day 7 
• 
40mgQAM 
Day 8 through Day 14 
Open-label Part B 
PRAX-944 
Drug 
Modified-release tablet 
20 mg 
• 
20mgQAM 
Day 1 through Day 3 
• 
40mgQAM 
Day 4 through Day 7 
• 
60 mgQAM 
Day 8 through Day 14 
• 
80mgQAM 
Day 15 through Day 21 
• 
100 mg QAM 
Day 22 through Day 28 
• 
120 mgQAM 
Day 29 through Day 42 
Double-blind PRAX-944 
• 
120 mg or highest 
tolerated dose QAM 
Day 43 through Day 56 
Oral 
Provided centrally by the Sponsor 
Double-blind Placebo 
Placebo 
Placebo 
Tablet 
Placebo 
• 
Placebo QAM 
Day 43 through Day 56 
None 
Study drug will be provided in pre-packaged containers. Each container will be labeled as required per country 
requirements. 
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6.2. 
Preparation/Handling/Storage/Accountability 
The following requirements for handling, storing, and accounting for study drug must be 
followed: 
6.3. 
1.
The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study drug received and any discrepancies are 
reported and resolved before use of the study drug.
2.
Only participants enrolled in the clinical trial may receive study drug and only 
authorized site staff may supply or administer study drug. All study drug must be 
stored in a secure, environmentally controlled area in accordance with the labeled 
storage conditions with access limited to the Investigator and authorized site staff.
3.
The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study drug accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4.
Further guidance and information, including for the final disposition of unused study 
drugs are provided in the Pharmacy Manual.
Randomization and Blinding
This trial includes both open-label (unblinded) and double-blind phases. 
Study drug will be dispensed at the clinical trial visits as summarized in the SoA (Table 2 and 
Table 3). Returned study drug must not be re-dispensed. 
Randomization in a 1:1 fashion to one of these groups may be completed at any time on Day 37 
through 42. The assignments will be blinded to all participants, Investigators, site personnel, and 
Sponsor personnel. 
Replacement randomization numbers will be used as needed for any participant that is replaced 
in Part B. 
6.3.1. 
Breaking the Blind 
In the event of a medical emergency, where knowledge of the study drug assignment is needed to 
medically treat the participant, the treatment assignment of an individual participant can be 
obtained via code break envelopes. Whenever possible, the Principal Investigator should consult 
with the Medical Monitor or the Sponsor Medical Director prior to unblinding a participant. If 
that is not possible, the Investigator may unblind to treat a medical emergency without 
consultation. Code breaks must be promptly communicated to the Medical Monitor and Sponsor 
Medical Director and detailed in the source documentation. 
6.4. 
Study Drug Compliance 
Participant compliance with study drug will be assessed at each visit. Compliance will be 
assessed throughout the clinical trial by participant reporting, measuring plasma exposure, and 
return of used and unused PRAX-944 containers. This clinical trial will also employ a 
medication adherence monitoring platform (“Platform”). The Platform uses artificial intelligence 


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on smartphones to confirm medication ingestion. In addition, built-in reminders and a 
communication system allow real-time intervention in case of drug interruptions. 
Deviation(s) from the prescribed dosage regimen should be documented. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving from 30 days prior to Screening or 
receives during the clinical trial must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency of administration 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 


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6.5.2. 
Permitted Medications 
Participants may take only 1 concomitant medication for their ET and must be on stable doses of 
that 1 medication for at least 28 days prior to Screening in the clinical trial. Stable use at a 
consistent dose not exceeding the equivalent of 2 mg/day of lorazepam is allowed as long as 
tremor persists against the background of regular medication use (sporadic use of a 
benzodiazepine, sleep medication or anxiolytic, that in the judgement of the Investigator or 
Sponsor would confound the assessment of tremor, is not allowed). Concomitant use of 
allowable benzodiazepines must be limited to a daily dosage equivalent of 2 mg of lorazepam 
(refer to Appendix 3). 
6.6. 
Dose Modification 
No dose modifications are permitted in Part A or the Part B double-blind randomized withdrawal 
phase. 
In the Part B open-label titration phase, participants may return to a lower dose of PRAX-944 
after escalating due to tolerability or safety concerns. The Investigator should discuss the 
decision to continue at a lower dose level with the Sponsor and Medical Monitor. Participants 
can only change to a lower dose level once. No dose changes are permitted after Day 36. 
The Sponsor may discontinue any dose of PRAX-944 based on ongoing monitoring of safety and 
tolerability. 
6.7. 
Intervention After the End of the Clinical Trial 
There is no intervention following the end of the clinical trial. Participants will continue to 
receive standard of care for what is normally expected for their condition. 


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7. 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Drug 
In rare instances, it may be necessary for a participant to permanently discontinue study drug. If 
study drug is permanently discontinued, the participant will remain in the clinical trial to be 
evaluated for safety and efficacy. See the SoA for data to be collected at the time of early 
termination for each part, if applicable. 
7.1.1. 
Temporary Discontinuation 
Temporary discontinuations of study drug is allowed on a case-by-case basis, pending approval 
from the Sponsor. 
7.1.2. 
Rechallenge 
Rechallenges of study drug are allowed on a case-by-case basis in Part A, pending approval from 
the Sponsor. 
One dose reduction is permitted in Part B but thereafter rechallenge is not allowed. No dose 
changes after Day 36 are allowed. 
7.2. 
Participant Discontinuation/Withdrawal from the Clinical Trial 
A participant may withdraw from the clinical trial at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
At the time of discontinuing from the clinical trial, if possible, an early termination visit should 
be conducted, as shown in the SoA. See SoA for data to be collected at the time of clinical trial 
discontinuation and follow-up and for any further evaluations that need to be completed for each 
part. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the clinical trial, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site clinical trial records. 
Participants who do not complete 14 days of study drug in Part A or 56 days of study drug in 
Part B or do not complete their scheduled safety, efficacy, or PK assessments may be replaced to 
ensure a sufficient number of participants are evaluable. No more than 6 participants in either 
part of the study will be replaced. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical trial site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
clinical trial visit: 


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• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the clinical trial. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the clinical trial. 


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8. 
CLINICAL TRIAL ASSESSMENTS AND PROCEDURES
Clinical trial procedures and their timing are summarized in the SoA (Table 2 and Table 3). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study drug. If this 
discussion is not possible and the concern is urgent, the Investigator may discontinue study drug 
without consultation, but these situations are expected to be rare. 
Adherence to the clinical trial design requirements, including those specified in the SoA, is 
essential and required for clinical trial conduct. 
All Screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screen failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of the ICF may be utilized for Screening or Baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within the time 
frame defined in the SoA (Table 2 and Table 3). 
For Part A, the amount of blood collected from each participant over the duration of the clinical 
trial, including any extra assessments that may be required, will be approximately 50 mL with 
sparse sampling for PK or 180 mL with serial sampling for PK. Repeat or unscheduled samples 
may be taken for safety reasons or for technical issues with the samples. 
For Part B, the amount of blood collected from each participant over the duration of the clinical 
trial, including any extra assessments that may be required, will be approximately 115 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
A suggested order of assessments for Part B is provided in the Assessment Manual. 
8.1. 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Table 2 and Table 3). 
Efficacy will be measured using the following instruments: 
8.1.1. 
TETRAS 
The TETRAS was developed by the Tremor Research Group (TRG; 
www.tremorresearchgroup.org) to quantify ET severity and its impact on ADLs. This scale 
requires only pen and paper and can be completed in about 10 minutes. The full scale has 2 
sections, the Performance and ADL subscales, which are highly correlated. Upper extremity 
action tremor is the main focus of both parts of this scale since it is the main source of disability. 
However, action tremor is also assessed in the head, face, voice, and lower limbs. The TETRAS 
scale demonstrated face validity, inter- and intra-rater reliability, and sensitivity to change (Elble 
2016). 
For Part B, TETRAS can be completed anytime at Screening and Day 70. On other days, the 
following timing should be followed: 
•
Day 1: pre-dose and 6 (±2) hours after a 20 mg QAM dose


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• Day 7: 6 (±2) hours after a 40 mg QAM dose 
• Day 21: 6 (±2) hours after an 80 mg (or highest tolerated dose) QAM dose 
• Day 42: pre-dose and 6 (±2) hours after a 120 mg (or highest tolerated dose) QAM 
dose 
• Day 56: 6 (±2) hours post-dose 
For visits with multiple TETRAS assessments, the TETRAS ADL subscale should only be 
assessed once. On Day 1, the ADL subscale should be completed pre-dose. On day 42, the ADL 
subscale should be completed 6 (±2) hours after the QAM dose. 
8.1.1.1. 
Performance Subscale 
There are 9 items covering different body regions in the Performance subscale. Each 
Performance subscale item is rated on a scale of 0 to 4, with higher scores indicating higher 
tremor severity. Item 4 of the Performance subscale is the upper limb item. It is comprised of 6 
sub-items (4a, 4b, and 4c assessed for both the right and left upper limbs). The Performance 
subscale score is calculated as the sum of all 9 items and ranges from 0 to 64. Toward 
interpreting certain items (eg, Archimedes Spirals, handwriting and dot approximation), it is 
important to note whether the participant’s dominant hand is their left or their right. 
8.1.1.2. 
Upper Limb Item 
Item 4 of the Performance subscale is the upper limb item. For this item, 3 tasks are performed 
on each side of the body: 4a) postural tremor with upper limbs held forward and horizontally, 4b) 
postural tremor with upper limbs extended laterally and horizontally, with the elbows flexed and 
hands positioned close to each other near the chin (“wing beating position”), and 4c) kinetic 
tremor during finger-nose (or chin)-finger movements. As each of the upper limb items is rated 
independently for the right and left side of the body, the upper limb item is comprised of 6 
sub-items. Each sub-item is rated on a scale from 0 to 4, with higher scores indicating higher 
tremor amplitude of the upper limb. The upper limb total score is the sum of these 6 sub-items 
and ranges from 0 to 24. 
The upper limb item will be assessed via clinician, Kinesia ONE (accelerometer), and video 
rating by an independent rater. The initial assessment of the upper limb item will be performed 
by the clinician with each task being performed for each side. The participant will then perform 
the same tasks while wearing an accelerometer. The accelerometer will record rotations and 
accelerations in the 3D space over time. As with the clinician assessment, each task will be 
performed for each side first for the right arm and then for the left. For the purposes of 
confirming eligibility, an independent central rater will score a video of the initial assessment 
described above. 
For Part B, Kinesia ONE assessments must be completed immediately after the TETRAS 
Performance assessments (including both pre-dose and post-dose assessments on Day 1 and 
Day 42). Kinesia ONE assessments should be completed twice at each timepoint with the 
2 assessments separated by at least 30 minutes. 


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8.1.1.4. 
TETRAS Telehealth Assessment 
The TETRAS Performance subscale upper limb item (item #4) will be conducted by the site rater 
using televideo technology while the participant is at home. The purpose of this assessment is to 
compare upper limb item scores obtained via a telehealth visit to scores obtained in the clinic to 
assess the reliability of telehealth assessments. 
8.1.1.5. 
TETRAS Activities of Daily Living (ADL) 
The TETRAS ADL subscale is a 12-item assessment of typical daily activities that are impacted 
by tremor. Activities are assessed in the following functional domains: speaking, feeding, 
drinking, personal hygiene, dressing, writing, and social activity. The impact to each function is 
rated on a 5-point Likert scale from 0 to 4. The ADL subscale score is calculated as the sum of 
all 12 items and ranges from 0 to 48. 


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8.1.4. 
Quality of Life in Essential Tremor Questionnaire (QUEST; Part B Only) 
The QUEST is a brief, 30-item, patient-reported ET-speciﬁc quality of life scale. The scale 
contains 5 subscales that cover physical, psychosocial, communication, hobbies/leisure, and 
work/finance dimensions. The individual items are rated either on a 5-level Likert scale from 0 to 
4 (never, rarely, sometimes, frequently, always) or a 2-level scale from 0 (no) to 4 (yes) relative 
to the respondent's current situation. Five items could also be rated as not applicable. 
Respondents are also asked to indicate which tremor was perceived to impact a function or be 
associated with the feeling or attitude in question. The QUEST total and subscale scores are 
calculated as the sum of all applicable items divided by the number of applicable items times 
100. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 2 and Table 3). 
AEs will be evaluated and reported (Section 8.4). Safety will be assessed as described below. 
8.2.1. 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, and neurological systems. Height and weight will also be measured 
and recorded (at Screening only). 
8.2.2. 
Vital Sign Measurements 
This assessment will measure changes in vital sign measurements, specifically of the following: 
• Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• Blood pressure (systolic and diastolic) and pulse measurements will be preceded by at 
least 5 minutes of rest, in a quiet setting without distractions (eg, tablets, television, 


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mobile phones). These measurements will be assessed after the participant has been 
supine for at least 5 minutes, and standing for at least 2 minutes. 
8.2.3. 
Electrocardiograms 
This assessment will measure changes in ECG parameters, specifically: 
•
ECGs will be obtained as outlined in the SoA using an ECG machine that
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.
ECGs will be read centrally.
•
Triplicate measurement will be taken at Screening only; for all other timepoints,
single measurement is acceptable. When triplicate ECGs are required, 3 individual
ECG tracings should be obtained as closely as possible in succession, but no more
than 2 minutes apart.
8.2.4. 
Clinical Safety Laboratory Assessments 
This assessment will measure changes in laboratory values, specifically: 
•
The Investigator must review the laboratory report, document this review, and record
laboratory values. Any clinically significant, adverse changes occurring during the
clinical trial should be documented as AEs. Laboratory-assessment related AEs
should be documented and follow as with other AEs.
•
All laboratory tests with values considered clinically significantly abnormal during
participation in the study drug should be repeated until the values return to normal or
baseline or are no longer considered clinically significant by the Investigator or
Medical Monitor.
•
Clinically significant abnormal laboratory findings are those which are not associated
with the underlying disease, unless judged by the Investigator to be more severe than
expected for the participant's condition.
•
See Appendix 1 for the list of clinical laboratory tests to be performed and to the SoA
(see Table 2 and Table 3) for the timing and frequency.
Refer to the Laboratory Manual for additional details on sample handling and processing. 
8.2.4.1. 
Monitoring for Safety Laboratory Assessments of Special Interest 
Renal function monitoring will be based on the Kidney Disease Improving Global Outcomes 
(KDIGO) guidelines and criteria for acute kidney injury (AKI)(Kellum 2012). According to the 
KDIGO guidelines, AKI is defined as any of the following: 
•
Increase in SCr by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours; or
•
Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred
within the prior 7 days
If a participant’s laboratory values exceed these thresholds, dosing of that participant will be 
stopped and the laboratory tests will be repeated. Pending the results of these tests, a discussion 
will occur to determine pausing, stopping or continuing dosing the specific participant and/or the 
remainder of the participants in the study. Throughout the duration of the clinical trial, 


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participants should immediately notify the study team if there are any significant changes in their 
urine frequency or volume. 
8.2.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Measurements 
The C-SSRS was developed by researchers at Columbia University as a tool to help 
systematically assess suicidal ideation and behavior in participants during participation in a 
clinical trial of centrally-acting drugs (Posner 2011). The C-SSRS is composed of 5 questions 
addressing suicidal behavior and 5 questions addressing suicidal ideation, with sub-questions 
assessing the severity. Two versions of the C-SSRS will be used in this clinical trial: the 
Baseline/Screening Version (at the Screening visit) and the Since Last Visit Version (at all other 
visits). It takes approximately 5 to 10 minutes to administer the C-SSRS. The tool should be 
administered via interview with the participant (by a trained operator/interviewer). 
8.3. 
Pharmacokinetic Assessments 
Blood samples will be collected for measurement of blood concentrations of PRAX-944 as 
specified in the SoA (Table 2 and Table 3). Samples collected may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the clinical trial. PRAX-944 
plasma samples may also be used for additional exploratory method development and/or 
metabolite characterization purposes. 
Refer to the Laboratory Manual for additional details on sample handling and processing. 
8.4. 
Adverse and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 2. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or clinical trial procedures, or that 
caused the participant to discontinue the clinical trial. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AE and SAE information will be collected from the signing of the ICF until the end of the 
clinical trial at the time points specified in the SoA. 
All SAEs and AEs of special interest will be recorded and reported to the Sponsor or designee 
immediately and under no circumstance should this exceed 24 hours, as indicated in Appendix 2. 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
8.4.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2. 


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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and AEs of special interest will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-
up. Further information on follow-up procedures is given in Appendix 2. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
drug under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. The Sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the regulatory 
authority, Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.4.5. 
AEs of Special Interest 
Any event of seizure, seizure-like phenomena, loss of consciousness, altered state of 
consciousness, tardive dyskinesia, acute dystonic reactions, akathisia, or acute Parkinsonian 
symptoms (eg, bradykinesia, tremor, cogwheel rigidity, mask-like faces) will be regarded as an 
adverse event of special interest in this trial and must be reported to the Sponsor within 24 hours. 
8.4.6. 
Pregnancy 
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study drug through completion of the pregnancy. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy. 
Male participants will be instructed via the ICF to immediately inform the Investigator if their 
female partner becomes pregnant 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 


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8.4.7. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Fluctuations of individual items on the efficacy assessments that are consistent with the typical 
course of ET should not be interpreted as worsening or improvements of the overall condition. 
Changes in disease severity should be determined by the Investigator based on an assessment of 
the participant’s overall condition. 
8.6. 
Treatment of Overdose 
The Sponsor does not recommend specific treatment for an overdose and care should be 
supportive in keeping with local institutional practices. 
In the event of a documented or suspected overdose, the Investigator/treating physician should: 
•
Ensure the participant receives necessary medical care
•
Contact the Medical Monitor immediately
•
Closely monitor the participant for any AE/SAE, including laboratory abnormalities
The effects of overdose of PRAX-944 are unknown. As such, no specific antidote for PRAX-944 
overdose is known. Although it is not expected that overdose will occur in this clinical trial, 
participants should be managed with appropriate supportive care should overdose with 
PRAX-944 inadvertently occur. Please also see the mitigation of overdose risk Section 6.10 in 
the IB. 
Risks unrelated to PRAX-944 include those from collection of blood samples, including 
bruising, pain at the site, swelling, redness, bleeding, or infection. 
8.7. 
Genetics 
Genetics are not evaluated in this clinical trial. 
8.8. 
Health Economics/Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Recourse Utilization and Health Economics parameters are not 
evaluated in this clinical trial. 


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9. 
STATISTICAL CONSIDERATIONS 
This section outlines the general statistical methods contributing to the clinical trial design and 
planned analysis of clinical trial data. A comprehensive statistical analysis plan (SAP) will be 
developed and finalized prior to database lock and will provide a more detailed description of 
analysis sets, endpoint derivations (including any procedures for missing data), and analysis 
methods (including mock tables and listings). 
9.1. 
Sample Size Determination 
The sample size of each part (up to 12 participants) is a convenience sample. The sample size 
was not selected according to any statistical power calculation. Instead, the sample size was 
determined according to feasibility and is thought to provide sufficient efficacy and safety data to 
inform the development of future controlled studies with PRAX-944 in participants with ET. 
Part B sample size may be increased to up to 24 participants to ensure inclusion of a broad range 
of tremor severity. In the open-label phases of the trial (Part A and Part B, open-label titration), a 
sample size of at least 10 participants would provide an 80% probability of observing at least 1 
AE with an underlying incidence of 15% or greater. In addition, 10 participants should also 
provide approximately 80% power to detect an effect size of 1.0 on the primary endpoint of 
change from Baseline in TETRAS Upper Limb score. 
9.2. 
Populations for Analyses 
All data analyses will be performed using at least 1 of the following analysis sets. 
Analysis Set 
Description 
Enrolled Analysis Set 
All participants who sign an ICF and are provided with an enrollment 
number. The Enrolled Analysis Set will be used for all participant 
disposition analyses. 
Safety Analysis Set 
All participants who received at least 1 dose of study drug. Participants 
will be classified according to actual intervention received. The Safety 
Analysis Set will be used for all demographic, baseline characteristics, 
prior/concomitant medication, study drug exposure, and safety 
analyses. 
Full Analysis Set 
All participants who took at least 1 dose of study drug and have a valid 
baseline TETRAS assessment and at least 1 valid post-baseline 
TETRAS assessment. The Full Analysis Set will be used for the 
analysis of all efficacy data. 
PK Analysis Set 
The PK Analysis Set includes all participants who received at least 1 
dose of study drug and have at least 1 evaluable plasma concentration. 
The PK Analysis Set will be used for the analysis of plasma 
concentrations and PK parameters. 
9.3. 
Statistical Analyses 
The SAP will be developed and finalized prior to database lock and will describe the participant 
populations to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. For all data displays, separate summaries will be generated for each part of the 
clinical trial. For the randomized portion of Part B, data will be summarized by the randomized 


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continuation ti·eatment. Safety, tolerability, PK and efficacy variables will be summarized using 
descriptive statistics. Descriptive sUIIllnaries for categorical variables will include counts and 
percentage. Descriptive summaries for continuous variables will include number of participants 
(n), mean, standard deviation (SD), median, minimum, and maximum. Where appropriate, 95% 
confidence intervals (Cls) may be reported. Summaries will be presented by time point, where 
appropriate. 
Unless specified othe1wise, all data recorded will be listed by pa1ticipant. 
9.3.1. 
Efficacy Analyses 
Reported values and change from baseline values in TETRAS Upper Limb score, TETRAS 
Perfonnance subscale total and individual scores, TETRAS Upper Limb accelerometer score, 
TETRAS Upper Limb telehealth score, TETRAS ADL Subscale score, 
, QUEST 
total and subscale scores, 
will be 
summarized by time point. In additio 
scores will also be analyzed using 
paired t-tests or similar methods. For 
, repo1ted values will be 
summarized by time point. 
9.3.2. 
Safety Analyses 
Adverse event data will be coded using the Medical Dictionaiy for Regulatory Activities 
(MedDRA). The number and percentage of paiticipants experiencing any ti·eatment-emergent 
AE (TEAE) will be summai·ized by system organ class (SOC) and prefened tenn (PT). In 
addition, TEAEs will be sUIIllnarized siinilarly by maximum severity and maximum relationship 
to PRAX-944. SAEs and TEAEs leading to discontinuation of PRAX-944 will be listed. 
Reported values and change from baseline values in vital signs, ECG parameters, and 
hematology and clinical chemistiy laborato1y pai·ameters will be sUIIllnai·ized by time point. 
For the C-SSRS, the incidence of suicidal ideation/behavior at any time will be sUIIllnai·ized for 
each C-SSRS ideation, behavior, and ideation/behavior indicator. 
9.3.3. 
Pharmacokinetic Analyses 
For Pait A, standard PK parameters will be estimated using noncompa1tmental methods based on 
the concenti·ation-time data. These parameters will include, where possible, Cmax, T max, t112, 
AUCo-tau, CL/F, and Vd/F. Explorato1y analyses examining the relationship between PK and 
efficacy parameters may be perfonned for the PK Analysis Set. 
The PK parameters described ai·e those nonnally calculated for this type of clinical trial; 
however, the actual parameters calculated may vaiy depending on the availability and viability of 
the data obtained. Other parameters may be added as appropriate. Final PK parameters to be 
repo1ted will be detailed in the SAP or a separate PK analysis plan. 
9.3.4. 
Other Analyses 
PK and selected efficacy data. may be utilized in a population PK analysis, which will be 
presented separately from the main clinical study repo1t (CSR). 
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9.3.5. 
Interim Analyses 
No formal interim analysis is planned for this clinical trial. Clinical trial data from Part A and 
open-label data from Part B will be reviewed on an ongoing basis. 


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10. 
REGULATORY, ETHICAL, AND CLINICAL TRIAL 
OVERSIGHT CONSIDERATIONS 
10.1. 
Regulatory and Ethical Considerations 
This clinical trial will be conducted in accordance with this protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the Investigator and reviewed and approved by the IRB/IEC 
before the clinical trial is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the clinical trial design, except for changes necessary to eliminate an immediate 
hazard to clinical trial participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the clinical trial to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the clinical trial at the site and adhering to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
10.2. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the clinical trial 
and for 1 year after completion of the clinical trial. 
10.3. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the clinical trial to the 
participant or his/her legally authorized representative and answer all questions regarding the 
clinical trial. 
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of local regulations, ICH 
guidelines, and the IRB/IEC or clinical trial center. 


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The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the clinical trial and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the clinical trial. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 
10.4. 
Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal clinical trial-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.5. 
Data Quality Assurance 
All participant data relating to the clinical trial will be recorded on printed or electronic case 
report forms (eCRFs) unless transmitted to the Sponsor or designee electronically (eg, laboratory 
data). The Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the case report form (CRF). 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The Investigator must permit clinical trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this clinical trial including 
quality checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
Clinical trial monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the clinical trial 
is being conducted in accordance with the currently approved protocol and any other clinical trial 
agreements, ICH GCP, and all applicable regulatory requirements. 


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10.6. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
clinical trial. 
The required source data should include sequential notes containing at least the following 
information for each participant: 
• participant identification (name, date of birth, sex) 
• documentation that participant meets eligibility criteria, ie, history, physical 
examination, and confirmation of diagnosis (to support inclusion and exclusion 
criteria) 
• participation in trial (including trial number) 
• trial discussed and date of informed consent 
• dates of all visits 
• documentation that protocol-specific procedures were performed 
• results of efficacy parameters, as required by the protocol 
• start and end date (including dose regimen) of trial medication (preferably drug 
dispensing and return should be documented as well) 
• record of all AEs and other safety parameters (start and end date, and preferably 
including causality and intensity) 
• concomitant medication (including start and end date, dose if relevant; dose changes 
should be motivated) 
• date of trial completion and reason for early discontinuation, if applicable 
10.7. 
Clinical Trial Files and Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
clinical trial to be fully documented and the clinical trial data to be subsequently verified. These 
documents should be classified into at least the following 2 categories: (1) Investigator’s clinical 
trial file, and (2) participant clinical source documents. 
The Investigator’s clinical trial file will contain the protocol/amendments, CRF and query forms, 
IRB and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence. 
All clinical trial documents must be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region (ie, United States, Europe, or Japan) and 
until there are no pending or contemplated marketing applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities have been notified. Investigators may be 


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required to retain documents longer if required by applicable regulatory requirements, by local 
regulations, or by an agreement with the Sponsor. The Investigator must notify the Sponsor 
before destroying any clinical trial records. 
Should the Investigator wish to assign the clinical trial records to another party or move them to 
another location, the Sponsor must be notified in advance. If the Investigator cannot guarantee 
this archiving requirement at the clinical trial site for any or all of the documents, special 
arrangements must be made between the Investigator and the Sponsor to store these in sealed 
containers outside of the site so that they can be returned sealed to the Investigator in case of a 
regulatory audit. 
10.8. 
Clinical Trial and Site Closure 
The Sponsor reserves the right to close the clinical trial site or terminate the clinical trial at any 
time for any reason at the sole discretion of the Sponsor. Clinical trial sites will be closed upon 
clinical trial completion. A clinical trial site is considered closed when all required documents 
and clinical trial supplies have been collected and a clinical trial site closure visit has been 
performed. 
The Investigator may initiate clinical trial site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a clinical trial site by the Sponsor or Investigator may include 
but are not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study drug development 
10.9. 
Clinical Study Report 
A CSR will be prepared and provided to the regulatory agency(ies). The Sponsor will ensure that 
the report meets the standards set out in the ICH Guideline for Structure and Content of Clinical 
Study Reports (ICH E3). An abbreviated report may be prepared as applicable. 
10.10. 
Publication Policy 
The results of this clinical trial may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of clinical trial results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multi-center studies only in their entirety and not as individual site data. In this 
case, a coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 


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11. 
REFERENCES
Bhatia KP, Bain P, Bajaj N, Elble RJ, Hallett M, Louis ED, Raethjen J, Stamelou M, Testa CM, 
Deuschl G. Tremor Task Force of the International Parkinson and Movement Disorder Society. 
Consensus Statement on the classification of tremors. from the task force on tremor of the 
International Parkinson and Movement Disorder Society. Mov Disord. 2018;33:75-87. 
Deuschl G, Raethjen J, Hellriegel H, Elble R. Treatment of patients with essential tremor. Lancet 
Neurol. 2011;10:148-161. 
Dieterle F, Sistare F, Goodsaid F, Papaluca M, Ozer JS, Webb CP, Baer W, Senagore A, 
Schipper MJ, Vonderscher J, Sultana S, Gerhold DL, Phillips JA, Maurer G, Carl K, Laurie D, 
Harpur E, Sonee M, Ennulat D, Holder D, Andrews-Cleavenger D, Gu YZ, Thompson KL, 
Goering PL, Vidal JM, Abadie E, Maciulaitis R, Jacobson-Kram D, Defelice AF, Hausner EA, 
Blank M, Thompson A, Harlow P, Throckmorton D, Xiao S, Xu N, Taylor W, Vamvakas S, 
Flamion B, Lima BS, Kasper P, Pasanen M, Prasad K, Troth S, Bounous D, Robinson-Gravatt D, 
Betton G, Davis MA, Akunda J, McDuffie JE, Suter L, Obert L, Guffroy M, Pinches M, Jayadev 
S, Blomme EA, Beushausen SA, Barlow VG, Collins N, Waring J, Honor D, Snook S, Lee J, 
Rossi P, Walker E, Mattes W. Renal biomarker qualification submission: a dialog between the 
FDA-EMEA and Predictive Safety Testing Consortium. Nat Biotechnol. 2010;28:455-462. 
Elble RJ. The Essential Tremor Rating Assessment Scale. J Neurol Neuromed. 2016;1:34-38. 
Elias WJ, Lipsman N, Ondo WG, Ghanouni P, Kim YG, Lee W, Schwartz M, Hynynen K, 
Lozano AM, Shah BB, Huss D, Dallapiazza RF, Gwinn R, Witt J, Ro S, Eisenberg HM, Fishman 
PS, Gandhi D, Halpern CH, Chuang R, Butts Pauly K, Tierney TS, Hayes MT, Cosgrove GR, 
Yamaguchi T, Abe K, Taira T, Chang JW. A Randomized Trial of Focused Ultrasound 
Thalamotomy for Essential Tremor. N Engl J Med. 2016;375:730-739. 
Farinde A. Benzodiazepine Equivalency Table. 2018; 
https://emedicine.medscape.com/article/2172250-overview. 
Guy W. Assessment Manual for Psychopharmacology: Clinical Global Impression (CGI). Vol 
76-338. Rockville, MD: US Dept of Health Education and Welfare; 1976.
Handforth A, Homanics GE, Covey DF, Krishnan K, Lee JY, Sakimura K, Martin FC, Quesada 
A. T-type calcium channel antagonists suppress tremor in two mouse models of essential tremor. 
Neuropharmacology. 2010;59:380-387.
Kellum JA, Lameire N, Aspelin P, Barsoum RS, Burdmann EA, Goldstein SL, Herzog CA, 
Joannidis M, Kribben A, Levey AS, MacLeod AM, Mehta RL, Murray PT, Naicker S, Opal SM, 
Schaefer F, Schetz M, Uchino S. Kidney disease : Improving global outcomes (KDIGO) acute 
kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney 
International Supplements. 2012;2:1-138. 
Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on 
the worldwide prevalence of essential tremor. Mov Disord. 2010;25:534-541. 
Park YG, Park HY, Lee CJ, Choi S, Jo S, Choi H, Kim YH, Shin HS, Llinas RR, Kim D. 
Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive. Proc Natl Acad Sci U S A. 
2010;107:10731-10736. 
Park YG, Kim J, Kim D. The potential roles of T-type Ca2+ channels in motor coordination. 
Front Neural Circuits. 2013;7:172. 


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Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity 
and internal consistency findings from three multisite studies with adolescents and adults. Am J 
Psychiatry. 2011;168:1266-1277. 
Rinn JL, Rozowsky JS, Laurenzi IJ, Petersen PH, Zou K, Zhong W, Gerstein M, Snyder M. 
Major molecular differences between mammalian sexes are involved in drug metabolism and 
renal function. Dev Cell. 2004 Jun 6(6):791-800 
Ruoppolo M, Caterino M, Albano L, Pecce R, Di Girolamo MG, Crisci D, Costanzo M, Milella 
L, Franconi F, Campesi I. Targeted metabolomic profiling in rat tissues reveals sex differences. 
Sci Rep. 2018 Mar 16 8(1):4663 
Sabolić, I Asif, A.R., Budach, W.E. et al. Gender differences in kidney function. Pflugers Arch - 
Eur J Physiol 2007;455:397-429 
Trevisan A, Chiara F, Mongillo M, Quintieri L, Cristofori P. Sex-related differences in renal 
toxicodynamics in rodents. Expert Opin Drug Metab Toxicol. 2012 Sep 8(9):1173-1188 


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12. 
APPENDICES 
APPENDIX 1. CLINICAL LABORATORY EVALUATIONS 
The tests detailed in Appendix Table 1 will be performed by a central laboratory. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the clinical trial as determined necessary 
by the Investigator or required by local regulations. 
Appendix Table 1: Protocol-Required Laboratory Assessments 
Clinical Chemistry 
Hematology 
Urinalysis 
Alanine aminotransferase (ALT) 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Bicarbonate 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Glucose 
Potassium 
Sodium 
Total and direct bilirubin 
Total protein 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential (absolute): 
o Basophils 
o Eosinophils 
o Lymphocytes 
o Monocytes 
o Neutrophils 
Bilirubin 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Blood 
pH 
Specific gravity 
Protein 
Urobilinogen 
Microscopic exam including 
bacteria, casts, crystals, 
epithelial cells, RBCs, and 
WBCs (if protein, leukocyte 
esterase, nitrite, or blood is 
positive) 
Drug Screen 
Coagulation Factors 
(Screening only) 
Other Tests 
Including but not limited to: 
Amphetamines 
Barbiturates 
Benzodiazepines (Stable use of 
≤2 mg of lorazepam/day is 
allowed) 
Cannabinoids (THC) 
Cocaine (metabolite) 
Methadone 
Opiates 
Phencyclidine 
Activated partial thromboplastin 
time 
Prothrombin time and 
international normalized ratio  
Serum and urine pregnancy, 
(women of childbearing 
potential only) 
Viral Serology Screen (at 
Screening only): Hepatitis B 
surface antigen (HBsAg) and 
Hepatitis C virus (HCV) 
antibody and HIV 
antibody/antigen 
Urinary albumin 
Urinary creatinine (Part A 
only) 


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APPENDIX 2. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES 
FOR RECORDING, EVALUATING, FOLLOW-UP, AND 
REPORTING 
Definition of Adverse Events 
AE Definition 
• 
An AE is any untoward medical occunence in a patient or clinical trial pruticipant, temporally 
associated with the use of study chug, whether or not considered related to the study chug. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study drng. 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or minalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgement of the 
Investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study chug administration even though it may have 
been present before the start of the clinical trial. 
• 
Signs, symptoms, or the clinical sequelae of a suspected chug-ch11g interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study chug or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-hruming intent. Such overdoses should be 
reported regru·dless of sequelae. 
• 
For efficacy studies: "Lack of efficacy" or "failure of expected phrumacological action" per se will 
not be reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which 
ru·e associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the pruticipant's condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the pruticipant's condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untowru·d medical occmTence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the strut of the clinical tI'ial that do not worsen. 
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Protocol PRAX-944-221, Version 6.0 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
• The te1m 'life-threatening' in the definition of'sedous' refers to an event in which the participant 
was at 1isk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
C. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency wai·d for obse1vation and/or treatment that would 
not have been approp1iate in the physician's office or outpatient setting. Complications that occur 
dming hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
se1ious cdte1ia, the event is se1ious. When in doubt as to whether "hospitalization" occuned or was 
necessa1y, the AE should be considered se1ious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline 
is not considered an AE. 
d. 
Results in persistent disability/incapacity 
• The te1m disability means a substantial dismption of a person's ability to conduct n01mal life 
functions. 
• This defmition is not intended to include expe1iences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diaiThea, influenza, and accidental trauma ( eg, 
sprained ankle) which may interfere with or prevent eve1yday life functions but do not constitute a 
substantial dismption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Important Medical Event: 
• Medical or scientific judgement should be exercised in deciding whether SAE repo1ting is 
appropriate in other situations such as impo1tant medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the pa1ticipant or may require 
medical or surgical inte1vention to prevent one of the other outcomes listed in the above definition. 
These events should usually be considered sedous. 
• Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalization, or development of dmg dependency or dmg abuse. 
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Praxis Precision Medicines 
Protocol PRAX-944-221, Version 6.0 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(eg, hospital progress notes, laborato1y reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE info1mation in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the pa1ticipant's medical records in 
lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for ce1tain cases are requested. In this case, 
all paiticipant identifiers, with the exception of the paiticipant number, will be redacted on the 
copies of the medical records before submission. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical info1mation. Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported dudng the clinical 
tiial and assign it to one of the following categories: 
• 
Mild: An event that is easily tolerated by the pa1ticipant, causing minimal discomfo1t and not 
inte1fe1ing with eve1yday activities. 
• 
Moderate: An event that causes sufficient discomfo1t and interferes with n01mal eve1yday 
activities. 
• 
Severe: An event that prevents n01mal eve1yday activities. An AE that is assessed as severe should 
not be confused with an SAE. Severe is a catego1y utilized for rating the intensity of an event; and 
both AEs and SAEs can be assessed as severe. 
An event is defined as 'serious' when it meets at least 1 of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study dmg and each occunence of 
each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there ai·e facts, evidence, and/or ai·guments 
to suggest a causal relationship, rather than a relationship cannot be mled out. 
• 
The Investigator will use clinical judgement to dete1mine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study dmg administration will be considered and 
investigated. 
• 
The Investigator will also consult the Investigator's Brochure (IB) and/or Product Info1mation, for 
marketed products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occlllTed and the Investigator has minimal 
info1mation to include in the initial repo1t. However, it is very important that the Investigator 
always make an assessment of causality for every event before the initial transmission of the 
SAE data. 
• 
The Investigator may change his/her opinion of causality in light of follow-up info1mation and send 
an SAE follow-up report with the updated causality assessment. 
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Praxis Precision Medicines 
Protocol PRAX-944-221, Version 6.0 
• 
The causality assessment is one of the criteria used when dete1mining regulato1y repo1ting 
requirements. 
• 
A medically qualified Investigator must assess the relationship of any AE (including SAEs) to the 
use of the study diug, as related or not related, based on clinical judgement and using all available 
info1mation, and may include consideration of the following factors: 
o Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other diugs, and presence of environmental or genetic factors. 
o The temporal association between study diug exposure and onset of the AE. 
o Whether the manifestations of the AE are consistent with known actions or toxicity of the 
study diug. 
o The AE resolved or improved with decreasing the dose or stopping use of the study diug 
(dechallenge). Judgement should be used if multiple products are discontinued at the same 
time. 
• 
The causal relationship between the study diug and the AE will be assessed using one of the 
following categories: 
o Not Related: Factors consistent with an assessment of Not Related include: 
• 
Temporal relationship is lacking (eg, the event did not occur within a 
reasonable time frame following administration of the study diug); or 
• 
Other causative factors more likely explain the event (eg, a pre-existing 
condition, other concomitant treatments). 
o Related: Factors consistent with an assessment of Related include: 
• 
There is a positive temporal relationship (eg, the event occuned within a 
reasonable time frame following administration of study diug); or 
• 
The AE is more likely explained by the investigational product than by another 
cause (ie, the AE shows a pattern consistent with previous knowledge of the 
investigational product or the class of the study di11g). 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to pe1fo1m or a1rnnge for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor or Medical Monitor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laborato1y tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 
• 
New or updated info1mation will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data within 24 hours of receipt of the info1mation. 
Reporting of SAEs 
SAE Reporting 
• 
Email transmission of the SAE fo1m is the prefened method to transmit this info1mation. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete and sign 
the SAE fo1m within the designated repo1ting time frames. 
• 
Contact Info1mation for SAE repo1ting: Safety@novotech-cro.com 
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APPENDIX 3. ACCEPTABLE BENZODIAZEPINES FOR 
CONCOMITANT USE 
Benzodiazepine Equivalency 
Approximately 
Equivalent Oral 
Dose, mg 
Time to Peak Level, 
hours 
Half-life, hours 
Alprazolam (Xanax) 
≤1 
1-2
12 
Bromazepam (Lexotan) 
≤6 
1-4
20 
Chlordiazepoxide (Librium) 
≤25 
1-4
100 
Clonazepam (Klonopin) 
≤0.5 
1-4
34 
Clorazepate (Tranxene) 
≤15 
0.5-2
100 
Diazepam (Valium) 
≤10 
1-2
100 
Flurazepam (Dalmane) 
≤30 
0.5-1
100 
Lorazepam (Ativan) 
≤2 
1-4
15 
Nitrazepam (Mogadon) 
≤10 
0.5-2
30 
Oxazepam (Serax) 
≤30 
1-4
8 
Quazepam (Doral) 
≤20 
1.5
25-41
Temazepam (Restoril) 
≤20 
2-3
11
Triazolam (Halcion) 
≤0.5 
1-2
2
Adapted from: Farinde A. Benzodiazepine Equivalency Table 2018 [cited 2018 December 20]. Available from: 
https://emedicine.medscape.com/article/2172250-overview (Farinde 2018) 

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PRAX-944-221, SAP Version Final 1.0 
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STATISTICAL ANALYSIS PLAN 
Protocol Number: PRAX-944-221 
Protocol Title:   A Phase 2 Clinical Trial Evaluating the Efficacy, Safety, Tolerability, and 
Pharmacokinetics of PRAX-944 in Adults with Essential Tremor  
Version Number: 1.0 
Version Date: 31 January 2022 
NCT Number: NCT05021978


 
 
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TABLE OF CONTENTS 
 
APPROVALS ................................................................................................................................ 5 
DEFINITIONS AND ABBREVIATIONS .................................................................................... 6 
1 
OVERVIEW ...................................................................................................................... 8 
2 
STUDY DETAILS............................................................................................................. 9 
2.1 
Study Objectives ............................................................................................................. 9 
2.2 
Study Design ................................................................................................................. 11 
2.3 
Determination of Sample Size ...................................................................................... 13 
3 
ANALYSIS SETS .......................................................................................................... 14 
3.1 
Enrolled Analysis Set .................................................................................................... 14 
3.2 
Safety Analysis Set ....................................................................................................... 14 
3.3 
Randomized Withdrawal Safety Analysis Set .............................................................. 14 
3.4 
Full Analysis Set ........................................................................................................... 14 
3.5 
Randomized Withdrawal Analysis Set ......................................................................... 14 
3.6 
Pharmacokinetic Analysis Set....................................................................................... 15 
4 
DEFINITION OF STUDY VARIABLES .................................................................... 16 
4.1 
Participant Disposition .................................................................................................. 16 
4.2 
Protocol Deviations ....................................................................................................... 17 
4.3 
Demographic and Baseline Characteristics .................................................................. 17 
4.3.1 
Age ............................................................................................................................. 17 
4.3.2 
Sex.............................................................................................................................. 17 
4.3.3 
Ethnicity ..................................................................................................................... 18 
4.3.4 
Race............................................................................................................................ 18 
4.3.5 
Dominant Hand .......................................................................................................... 18 
4.3.6 
Height ......................................................................................................................... 18 
4.3.7 
Weight ........................................................................................................................ 18 
4.3.8 
Body mass index ........................................................................................................ 18 
4.4 
Other Variables ............................................................................................................. 18 
4.5 
Medical History ............................................................................................................ 18 
4.6 
Essential Tremor Medical History ................................................................................ 19 
4.7 
Prior and Concomitant Medications ............................................................................. 19 
4.8 
Study Drug Exposure .................................................................................................... 20 
4.9 
Efficacy Variables ......................................................................................................... 20 
4.9.1 
TETRAS .................................................................................................................... 20 


 
 
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4.9.4 
Quality of Life in Essential Tremor Questionnaire (QUEST) ................................... 23 
 
 
 
 
4.10 
Safety Variables ............................................................................................................ 24 
4.10.1 
Adverse Events .......................................................................................................... 24 
4.10.2 
Laboratory Test Results ............................................................................................. 27 
4.10.3 
Vital Sign Results ...................................................................................................... 27 
4.10.4 
Electrocardiogram Results ......................................................................................... 28 
4.10.5 
Physical Examination................................................................................................. 29 
4.10.6 
Columbia–Suicide Severity Rating Scale .................................................................. 29 
4.11 
Pharmacokinetic Variables ........................................................................................... 30 
5 
ANALYSIS METHODS ............................................................................................. 31 
5.1 
Participant Disposition .................................................................................................. 32 
5.2 
Protocol Deviations ....................................................................................................... 32 
5.3 
Demographics and Other Baseline Characteristics ....................................................... 32 
5.4 
Medical History ............................................................................................................ 32 
5.5 
Essential Tremor Medical History ................................................................................ 32 
5.6 
Prior and Concomitant Medications ............................................................................. 33 
5.7 
Efficacy Analyses ......................................................................................................... 33 
5.7.1 
Primary efficacy analysis ........................................................................................... 33 
5.7.2 
Secondary Efficacy Analysis ..................................................................................... 34 
5.7.3 
Exploratory Efficacy Analysis ................................................................................... 35 
5.7.4 
Subgroup Analyses .................................................................................................... 37 
5.8 
Safety Analyses ............................................................................................................. 37 
5.8.1 
AEs ............................................................................................................................. 37 
5.8.2 
Laboratory Test Results ............................................................................................. 38 
5.8.3 
Vital Sign Results ...................................................................................................... 38 
5.8.4 
ECG Results ............................................................................................................... 38 
5.8.5 
C-SSRS ...................................................................................................................... 39 
5.9 
Pharmacokinetic Analyses ............................................................................................ 39 
5.9.1 
Plasma Concentrations ............................................................................................... 39 
5.9.2 
Plasma PK Parameters ............................................................................................... 39 
6 
INTERIM ANALYSES ................................................................................................... 40 
----


 
 
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7 
CHANGES TO PLANNED ANALYSES ................................................................ 41 
7.1 
Changes to Analysis as Described in Protocol ............................................................. 41 
7.2 
Changes to Approved Version of the SAP ................................................................... 41 
8 
REFERENCES ................................................................................................................ 42 
 


Praxis Precision Medicines 
PRAX-944-221, SAP Version Final 1.0 
APPROVALS 
CATO SMS 
.... 
, Statistician 
Date (DD-MMM-
YYYY) 
Praxis Precision Medicines 
.... 
, Head of Clinical Data Sciences 
Date (DD-MMM-
YYYY) 
, Medical Director 
Date (DD-MMM-
YYYY) 
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DEFINITIONS AND ABBREVIATIONS 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-tau 
area under the concentration vs time curve from the time of dosing 
through the dosing interval 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CI 
confidence interval 
CL/F 
apparent systemic clearance following oral administration 
Cmax 
maximum observed concentration 
CRF 
case report form 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
essential tremor 
FSH 
follicle-stimulating hormone 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
ICH 
International Council for Harmonisation 
KDIGO 
Kidney Disease Improving Global Outcomes 


 
 
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MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligrams 
 
 
PK 
pharmacokinetic 
PS 
performance subscale 
PT 
preferred term 
QAM 
every morning 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SoA 
Schedule of Activities 
SOC 
system organ class 
t½ 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TETRAS 
The Essential Tremor Rating Assessment Scale 
Tmax 
time to maximum observed concentration 
ULN 
upper limit of normal 
Vd/F 
apparent volume of distribution after non-intravenous administration 
WBC 
white blood cell 


 
 
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1 
OVERVIEW 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Protocol PRAX-
944-221 (A Phase 2 Clinical Trial Evaluating the Efficacy, Safety, Tolerability, and Pharmacokinetics of 
PRAX-944 in Adults with Essential Tremor), Final Version 6.0 dated 11 August 2021.  
 
The statistical analyses and summaries described in this SAP will follow the International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 
guideline for Statistical Principles for Clinical Trials (ICH E9 Expert Working Group, 1999) and will 
form the basis of the results sections of the clinical study report (CSR) in accordance with the ICH 
guideline for Structure and Content of Clinical Study Reports (ICH Harmonised Tripartite Guideline E3, 
1995).  This SAP will be finalized and fully executed before database lock and unblinding of treatment 
codes. Any changes to the analyses that are not included in this SAP will be documented in the CSR. 
 


Praxis Precision Medicines 
PRAX-944-221, SAP Version Final 1.0 
2 
STUDY DETAILS 
2.1 
Study Objectives 
A list of the specific protocol objectives for each study part along with their respective endpoints are 
listed in the tables below: 
Part A 
Objective 
ndpoint 
!Primary 
rro evaluate the efficacy of PRAX-944 on upper limb 
le Change from Baseline to Day 7 and Day 14 in The 
~:remor in participants with ET 
Essential Tremor Rating Assessment Scale 
(TETRAS) upper limb score (bilateral sum of items 
4a, 4b, and 4c) 
Secondary 
tto evaluate the efficacy of PRAX-944 on other measures1e 
Change from Baseline to Day 7 and Day 14 in: 
K>f tremor severity in pa1ticipants with ET 
le TETRAS perfonnance subscale total score 
le Accelerometer-based upper limb score (bilateral sum 
of items 4a, 4b, and 4c) 
le TETRAS perfonnance subscale individual item 
scores 
tto evaluate the safety and tolerability of PRAX-944 in 
le Incidence and severity of adverse events (AEs) 
tparticipants with ET 
le Changes in vital sign measurements 
le Changes in clinical laboratory results 
le Changes in electrocardiogram (ECG) parameters 
le Incidence of Columbia-Suicide Severity Rating Scale 
(C-SSRS) measured suicidal ideation or behavior 
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Praxis Precision Medicines 
PartB 
Objective 
'mary 
o evaluate the safety and tolerability of PRAX-944 in 
articipants with ET 
Secondary 
o evaluate the efficacy of PRAX-944 on upper limb 
·emor in pa1ticipants with ET 
o evaluate the efficacy of PRAX-944 on other measures 
f tremor severity in pa1ticipants with ET 
o evaluate the efficacy of PRAX-944 on measures of 
isease impact in pa1ticipants with ET 
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PRAX-944-221, SAP Version Final 1.0 
ndpoint 
Incidence and severity of AEs 
Changes in vital sign measurements 
Changes in clinical laboratory results 
Changes in ECG parameters 
Incidence of C-SSRS measured suicidal ideation or 
behavior 
Change from Baseline to Day 42 in TETRAS Upper 
Limb score (bilateral sum of items 4a, 4b, and 4c) 
Change from Baseline to Day 7 and Day 21 in 
TETRAS Upper Limb score (bilateral sum of items 
4a, 4b, and 4c) 
Change from Baseline to Day 7, Day 21, and Day 42 
in the following: 
TETRAS Perfonnance subscale total score 
Accelerometer-based upper limb score (bilateral sum 
of items 4a, 4b, and 4c) 
TETRAS Perfonnance individual item scores 
Change from Baseline to Day 7, Day 21, and Day 42 
in the following: 
TETRAS ADL subscale score 
Quality of Life in Essential Tremor Questionnaire 
(QUEST) total and subscale scores 
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2.2 
Study Design 
This multi-center clinical trial will assess the efficacy, safety, tolerability, and PK of PRAX-944 in 
participants aged 18 years or older who have had signs and symptoms consistent with ET for at least 3 
years with onset before age 65. The clinical trial will be conducted in 2 parts (Part A and Part B). 
 
• Part A of the clinical trial is open-label and will assess the safety and tolerability of PRAX-944, 
as well as the overall magnitude and pattern of change in ET severity. Daily dose levels will be 
titrated from 20 mg to 40 mg. 
• Part B of the clinical trial consists of both an open-label titration phase and a randomized, double-
blind, placebo-controlled withdrawal phase. Part B will assess the safety and tolerability of 
PRAX-944, as well as the overall magnitude and pattern of change in ET severity and the 
duration of that effect. Daily dose levels will be titrated from 20 mg to up to 120 mg during the 
open-label phase. In the randomized, double-blind, placebo-controlled withdrawal phase, 
participants will either be maintained on their final open-label dose or switched to placebo. 
 
Both parts will consist of 3 periods: Screening/Baseline, Intervention, and Safety Follow-up. 
 
Screening/Baseline Period 
The Screening period for Part A and Part B will be up to 28 days (Day -28 to Day -1). Fourteen 
additional days (ie, 42 days total) will be allowed in the Screening period for participants who are 
discontinuing primidone. 
 
Prior to any clinical trial procedures, participants will provide their consent to participate in the clinical 
trial. Screening assessments are as noted in the study Schedule of Activities (SoA; see Appendix 1). 


 
 
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Part A: 
Following confirmation of eligibility, including review by the Sponsor or designee, participants will 
complete Baseline assessments (Day 0). Day 0 (Baseline) activities may be combined with Day 1 
activities, provided that Baseline activities are completed before dosing and that dosing occurs in the 
morning of Day 1. Baseline efficacy assessments should either be conducted on Day 0 or Day 1 pre-dose. 
 
Part B: 
For participants in Part B, 
 will also be completed with accelerometry at 
Screening and via telehealth on Day -2 of the Screening period. Additional assessments added to Part B 
screening include 
Following confirmation of eligibility, including review by 
the Sponsor or designee, participants will complete Baseline assessments (Day 1). Some Baseline 
assessments (as indicated in SoA; see Appendix 1) may be completed on Day -1. 
 
Intervention Period 
Part A: 
On Day 1, participants will receive a 20 mg dose of PRAX-944, administered in the morning. 
Participants will remain in a clinical setting under medical observation for approximately 6 hours. 
TETRAS performance assessments will be performed before dosing and 6 hours post-dose. After the first 
dose, participants will continue QAM dosing at home through Day 7. On Day 8, the dose will increase to 
40 mg QAM from Day 8 to Day 14. Participants will return to the clinic on Day 14.  
 
Safety and efficacy assessments will be obtained as described in the SoA (see Appendix 1). Participants 
who agree to optional additional PK sampling will remain overnight in the clinic on Day 1, Day 7, and 
Day 14. 
 
Part B: 
The open-label titration phase will begin on Day 1, participants will receive a 20 mg dose of PRAX-944 
on an empty stomach. Participants will remain in a clinical setting under medical observation for 
approximately 6 hours. TETRAS Performance assessments will be performed before dosing and 6 hours 
(±2) post-dose. 
 
For dosing on Day 2 through Day 41, participants will be instructed to dose QAM at home. On Day 4, 
participants will escalate to 40 mg QAM through Day 7; on Day 8, participants should escalate to 60 mg 
QAM through Day 14; on Day 15, participants should escalate to 80 mg QAM through Day 21; on Day 
22, participants should escalate to 100 mg QAM through Day 28; and on Day 29, participants will 
escalate to 120 mg QAM through Day 42, when they will return to the clinic for safety assessments and 
efficacy testing. On Day 41, participants will complete a TETRAS Performance Upper Limb assessment 
via a telehealth visit. Safety and efficacy assessments will be obtained during the open-label titration 
phase as indicated in the SoA (see Appendix 1). 
 


 
 
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If at any point during the open-label titration phase a participant does not tolerate escalation and the 
Investigator returns the participant to a lower dose level, the participant will continue according to the 
schedule outlined above, but no further dose changes will be allowed. 
 
On Day 42, participants will complete the final clinic visit of the open-label titration phase. After Day 42, 
participants will begin the double-blind randomized withdrawal phase and either continue receiving PRAX-
944 at their current dose or switch to placebo, depending on their randomization. Randomization in a 1:1 
fashion may be completed at any time on Day 37 through 42. On Day 43 through Day 56, participants will 
take their assigned dose QAM and return to clinic on Day 56 for safety assessments and efficacy testing. 
 
Safety Follow-up Period 
Part A: 
The Safety Follow-up period will take place from Day 15 to Day 21. At the end of the Safety Follow-up 
period, participants will return to the clinic on Day 21 for the final clinical trial assessments. 
 
 
2.3 
Determination of Sample Size 
Up to 12 participants are planned to be administered PRAX-944 in Part A.  Approximately 12 
participants are planned to be administered PRAX-944 in Part B.  Up to 12 additional participants may be 
enrolled at the discretion of the Sponsor to ensure inclusion of a broad range of tremor severity. 
 
The sample size of each part is a convenience sample. The sample size was not selected according to any 
statistical power calculation. Instead, the sample size was determined according to feasibility and is 
thought to provide sufficient efficacy and safety data to inform the development of future controlled 
studies with PRAX-944 in participants with ET. In the open-label phases of the trial (Part A and Part B, 
open-label titration), a sample size of at least 10 participants would provide an 80% probability of 
observing at least 1 AE with an underlying incidence of 15% or greater. In addition, 10 participants 
should also provide approximately 80% power to detect an effect size of 1.0 on the primary endpoint of 
change from baseline in TETRAS Upper Limb score. 


 
 
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3 
ANALYSIS SETS 
An analysis data set will be created for efficacy, safety, and PK assessment. In addition to raw data 
values, each analysis data set will include derived variables as specified in Section 4 (eg, baseline, total, 
and change from baseline values). All analysis data sets will also include key demographic information 
(including, but not limited to: study, center, subject identifier, age, gender, race, ethnic group, 
randomization number, analysis set eligibility flags, study treatment start and stop dates, reason for 
treatment discontinuation, randomized treatment [where applicable], and actual treatment received). 
 
All data analyses will be performed using at least one of the below specified analysis sets. Participant 
eligibility for each analysis set will be finalized before database lock and unblinding of the data, where 
applicable. 
 
3.1 
Enrolled Analysis Set 
The enrolled analysis set includes all participants who sign informed consent and are provided with an 
enrollment number. The enrolled analysis set will be used for all participant disposition analyses. 
 
3.2 
Safety Analysis Set 
The safety analysis set includes all participants who received at least 1 dose of study drug. Participants 
will be classified according to actual treatment received. The safety analysis set will be used for all 
demographic, baseline characteristics, prior/concomitant medication, study drug exposure, and safety 
analyses.  
 
3.3 
Randomized Withdrawal Safety Analysis Set 
The randomized withdrawal safety analysis set includes all participants who received at least 1 dose of 
blinded study drug in the randomized withdrawal phase of Part B. Participants will be classified 
according to actual treatment received. The randomized withdrawal safety analysis set will be used for all 
demographic, baseline characteristics, prior/concomitant medication, study drug exposure, and safety 
analyses for the randomized withdrawal phase of Part B. 
3.4 
Full Analysis Set 
The full analysis set includes all participants who took at least 1 dose of study drug and have a valid 
baseline TETRAS assessment and at least 1 valid post-baseline TETRAS assessment. The full analysis 
set will be used for the analysis of all efficacy data, unless otherwise indicated. 
 
3.5 
Randomized Withdrawal Analysis Set 
The randomized withdrawal analysis set is a subset of the full analysis set and includes all participants 
who were randomized into the double-blind, randomized withdrawal phase of Part B and have a valid 
Day 42 TETRAS assessment and at least 1 valid TETRAS assessment after Day 42. The randomized 
withdrawal analysis set will be used for the analysis of all efficacy data collected during the randomized 
withdrawal phase. 
 


 
 
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3.6 
Pharmacokinetic Analysis Set 
The pharmacokinetic (PK) analysis set includes all participants that received at least 1 dose of study drug 
and have sufficient PK concentration data for analysis. The PK Analysis set will be used for the 
descriptive statistical analysis of plasma concentrations and PK parameters. 
 


 
 
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4 
DEFINITION OF STUDY VARIABLES 
The following definitions will be used throughout the analysis plan for this study: 
 
Study Day 
Study day calculations (ex. study day of an event or a visit) will be defined as follows, assuming non-missing 
dates:  
• 
Study Day = Date of event – Reference date + 1, when the date of interest occurs on or after the 
reference date; 
• 
Study Day = Date of event – Reference date, when the date of interest occurs before the reference date; 
 
If either date is missing, study day calculations will not be performed.   
 
For this study, the reference date used will be the treatment start date. Based on the calculations above, there will 
be no study day zero. 
 
Baseline and Change from Baseline 
Unless otherwise specified, the baseline value is defined as the last non-missing value collected prior to receiving 
first dose of study drug. Values collected after the time of treatment start will be excluded from the calculation of 
baseline as applicable. Post-baseline values will be defined as those collected after the treatment start date (and 
time, as applicable).   
 
Change from baseline will be defined as: assessment value – baseline value. Change from baseline values will only 
be derived for post-baseline assessments. 
 
Randomization Baseline and Change from Randomization  
The randomization baseline value, used as the reference value for double-blind randomized withdrawal phase 
efficacy endpoints, is defined as the Day 42 post-dose value. If the Day 42 post-dose value is unavailable, the 
randomization baseline value will be considered missing.   
 
Change from randomization will be defined as: assessment value – randomization baseline value. Change from 
randomization values will only be derived for assessments conducted after the randomized treatment start date (and 
time, as applicable).   
 
4.1 
Participant Disposition 
The participant number, informed consent date, and protocol version at time of consent (if applicable) 
will be recorded in the electronic case report form (eCRF). 
 
In addition, study completion status, the date of study completion or early withdrawal, reason for early 
withdrawal, adverse event number (if applicable), and description of primary reason will be recorded in 
the eCRF. Study completion status will be recorded as “Yes” or “No”. The reason for early withdrawal 
will be recorded as “Adverse Event”, “Withdrawal of consent”, “Lost to follow-up”, “Safety reasons”, 
“Investigator’s decision”, “Non-compliance to protocol”, or “Other”.  


 
 
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The duration of time in study, in days, will be calculated as (Study Completion or Discontinuation Date) - 
(Informed Consent date) + 1. 
 
The following durations within the clinical trial are expected as follows, per the protocol: 
• Part A: ≤49 days (63 days if on primidone) 
• Part B: ≤98 days (112 days if on primidone) 
 
4.2 
Protocol Deviations 
The failure to meet any eligibility criteria and the specific criteria not met will be recorded in the eCRF.  
 
All participant data will be reviewed for the occurrence of protocol deviations. The Sponsor project team 
will review all protocol deviations and their major/minor classifications prior to database lock. Deviation 
categories will include the following: 
• Procedure / Assessment outside protocol window  
• Procedure / Assessment not done  
• Order of Procedure / Assessment  
• Missed Visit  
• Visit outside protocol window  
• Inclusion / Exclusion  
• Informed Consent  
• Study Drug Administration  
• Documentation 
• Study Restrictions  
• COVID-19: Visit missed  
• COVID-19: Assessment not performed 
• COVID-19: Other 
• Other 
 
4.3 
Demographic and Baseline Characteristics 
The following variables are captured and/or derived for this study. 
 
4.3.1 
Age 
The age in years at informed consent will be recorded in the eCRF. 
 
4.3.2 
Sex 
Sex will be recorded in the eCRF as “Male” or “Female”. 
 


 
 
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4.3.3 
Ethnicity 
Ethnicity will be recorded in the eCRF as “Hispanic or Latino”, “Not Hispanic or Latino”, “Not 
reported”, or “Unknown”.  
 
4.3.4 
Race 
Race will be recorded in the eCRF as one or more of the following: “Black or African American”, 
“American Indian or Alaska Native”, “Asian”, “Native Hawaiian or Other Pacific Islander”, "White", 
“Other”, or “Not reported”. Multiple race categories can be selected. 
 
4.3.5 
Dominant Hand 
Dominant hand will be recorded in the eCRF as “Right” or “Left”. 
 
4.3.6 
Height 
Height in centimeters (cm) will be recorded in the eCRF. 
 
4.3.7 
Weight 
Weight in kilograms (kg) will be recorded in the eCRF. 
 
4.3.8 
Body mass index 
Body mass index (BMI; kg/m2) will be derived in the eCRF, provided that weight and height are 
available. 
 
4.4 
Other Variables 
Drug screen and alcohol results will be collected at Screening. The assessment date, time, and result will 
be recorded in the eCRF. The result will be recorded as "Positive" or "Negative".  For positive drug 
screen results, those drugs of abuse testing positive will also be captured in the eCRF. Categories for 
positive drug tests include the following: Amphetamines, Barbiturates, Benzodiazepines, Cannabinoids, 
Cocaine, Methadone, Opiates, Phencyclidine, and Other. 
 
4.5 
Medical History 
For those participants reporting medical history, the medical condition, onset date, ongoing indicator 
(Yes/No), end date (if applicable), and treatment indicator (Yes/No) will be recorded in the eCRF. Each 
medical history condition will be coded using Medical Dictionary for Regulatory Affairs (MedDRA) 
version 22.0. 
 


 
 
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4.6 
Essential Tremor Medical History 
Details on essential tremor medical history will be recorded in the eCRF including year of tremor onset, 
ET diagnosis, prior and current medications for ET (Yes/No), family history (Yes/No), ET worsening 
over the past 3 years (Yes/No), and effect of alcohol on ET symptoms: if symptoms decrease (Yes/No), 
by how much (Minimal decrease/Moderate decrease/Substantial decrease), and how many standard 
alcohol containing cause symptoms to decrease (<1, 1, 2, 3, >3). 
 
4.7 
Prior and Concomitant Medications 
For each prior and concomitant medication, the medication name, indication, dose, frequency, route, start 
date, ongoing indicator, stop date (for those medications not ongoing) will be recorded in the eCRF.  
Each medication will be coded using the World Health Organization Drug Dictionary (WHODrug) 
version March 2019. 
 
Each medication will be classified according to the study period in which its use occurred (ie, Prior, 
Concomitant). Prior medications are those that started and ended before the initiation of study drug. 
Concomitant medications are (i) those that started before initiation of study drug and continued after 
initiation of study drug or (ii) those that started after initiation of study drug. Any medications starting on 
the same day as the initiation of study drug will be considered concomitant. 
 
For Part B, medications will be further classified as concomitant for the double-blind randomized 
withdrawal phase following initiation of randomized study drug. Concomitant medications from the 
open-label titration phase will not include events occurring within the randomized withdrawal phase. 
Concomitant medications taken within the safety follow-up period for a participant will be classified as 
occurring during his/her last phase of participation (ie, if a participant does not enter the double-blind 
randomized withdrawal phase any post-treatment medications will be reported as part of the open-label 
titration). 
 
If the start date (or stop date) of a medication is completely unknown (ie, the day, month, and year are all 
missing) or only the study day is known, then the start date (or stop date) will not be imputed.  Unless the 
stop date is before the start date of study drug, then the medication will be considered concomitant.   
 
For a partial start date of medication, the following conventions will be used for imputing the start date: 
• If the year is present and the month and day are missing, then the month and day will be set to 
January 1. 
• If the year and day are present and the month is missing, then the month will be set to January. 
• If the year and month are present and the day is missing, then the day will be set to the first day of 
the month. 
• If the imputed start date of medication is after the non-imputed end date of medication, then the 
start date will be set to the stop date of medication. 
 
For a partial stop date of medication, the following conventions will be used for imputing the stop date: 
• If the year is present and the month and day are missing, then the month and day will be set to 
December 31. 


 
 
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• If the year and day are present and the month is missing, then the month will be set to December. 
• If the year and month are present and the day is missing, then the day will be set to the last day of 
the month. 
 
4.8 
Study Drug Exposure 
For study drug exposure, date of administration, time of administration, and dose recorded in the eCRF. 
The overall duration of exposure to study drug (in days) will be calculated for Study Part, by dose level 
and overall, as follows:  
• Duration of Exposure to study drug (days) = Date of Last Dose – Date of First Dose + 1 
 
Overall percent compliance will be calculated as the total number of days drug was received divided by 
the total number days drug was expected to be received during the subject’s participation in the study. In 
addition, overall compliance will also be categorized as: 
• Compliance < 80% 
• 80% ≤ Compliance ≤ 120% 
• Compliance >120% 
 
In Part B, separate compliance estimates will be calculated for the open-label titration phase and the 
double-blind, randomized withdrawal phase. 
 
4.9 
Efficacy Variables 
4.9.1 
TETRAS  
The TETRAS is a scale used to quantify essential tremor severity and its impact on activities of daily 
living (ADLs). The full scale consists of 2 components, the Performance and ADL subscales which are 
highly correlated. Upper extremity action tremor is the main focus of both parts of this scale since it is 
the main source of disability. However, action tremor is also assessed in the head, face, voice, and lower 
limbs. 
 
4.9.1.1 
Performance subscale 
The performance subscale consists of 9 items covering different body regions. Each item is rated on a 
scale of 0 to 4, including 0.5 increments if a rating cannot be reconciled between two whole numbers, 
with higher scores indicating higher tremor amplitude. Item 4 of the performance subscale is the upper 
limb item. It is comprised of 6 sub-items (4a, 4b, and 4c assessed for both the right and left upper limbs). 
The upper limb total score is the sum of these 6 items and ranges from 0 to 24. The timepoint, blinded 
TETRAS code, date and time of assessment, rater ID, an indicator of whether the assessment was 
performed (Yes/No), and the individual item scores will be recorded in the eCRF. 
 
The full performance subscale score is calculated as the sum of item 1 (head), item 2 (face), item 3 
(voice), each of the 6 sub-items for item 4 (upper limb), the maximum of the 4 sub-items for item 5 
(lower limb), 2 sub-items (right and left side) for item 6 (Archimedes spirals), item 7 (handwriting), 2 


 
 
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sub-items (right and left side) for item 8 (dot approximation), and item 9 (standing) for a total score 
ranging from 0 to 64 from 16 sub-items.   
 
The TETRAS performance subscale will be collected at the following timepoints: 
 
Part A: 
• Screening, Day 0 and Day 21: completed anytime 
• Day 1: pre-dose and 6 (±2) hours post-dose 
• Day 7 and Day 14: 6 (±2) hours post-dose 
 
Part B: 
• Screening and Day 70: completed anytime 
• Day 1: pre-dose and 6 (±2) hours after a 20 mg qAM dose 
• Day 7: 6 (±2) hours after a 40 mg qAM dose 
• Day 21: 6 (±2) hours after an 80 mg (or highest tolerated dose) qAM dose 
• Day 42: pre-dose and 6 (±2) hours after a 120 mg (or highest tolerated dose) qAM dose 
 
 
 
4.9.1.2 
Upper limb item 
The upper limb item will be assessed via clinician (ie, site rater), Kinesia ONE (accelerometer), and 
video rating by an independent rater. In Item 4 of the performance subscale, the clinician will assess 3 
tasks performed on each side of the body:  4a) postural tremor with upper limbs held forward and 
horizontally (“outstretched” position), 4b) postural tremor with upper limbs extended laterally and 
horizontally, with the elbows flexed and hands positioned close to each other near the chin (“wing 
beating position”), and 4c) kinetic tremor during finger-nose (or chin)-finger movements. As each of the 
upper limb items is rated independently for the right and left side of the body, the upper limb item is 
comprised of 6 sub-items. Each sub-item is rated on a scale from 0 to 4 including 0.5 increments, with 
higher scores indicating higher tremor amplitude of the upper limb. The upper limb total score is the sum 
of these 6 sub-item scores and ranges from 0 to 24. The baseline TETRAS upper limb score will be 
categorized as <10 or ≥10. 
 
4.9.1.3 
Combined upper limb 
The combined upper limb score is the sum of the 6 sub-item scores of the upper limb item and the 
handwriting and spirals scores.  The combined upper limb score ranges from 0 to 32.  
 
4.9.1.4 
Accelerometer 
After the TETRAS Performance Subscale is performed by the clinician, the participant will then perform 
the TETRAS upper limb tasks while wearing a Kinesia ONE accelerometer. The accelerometer will 
record coordinates and accelerations in the 3D space over time. All 3 maneuvers in the upper limb 
assessments will be completed for both arms, first for the right arm and then for the left. Kinesia ONE 
assessments should be completed twice at each timepoint with the 2 assessments separated by at least 30 
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minutes. The timepoint, date and time of both assessments, and an indicator of whether the accelerometer 
assessment was performed (Yes/No) will be recorded in the eCRF.  
 
Each upper limb sub-item is scored on a scale from 0 to 4 including to 0.1 increments and will be 
provided by the Kinesia ONE accelerometer vendor. The accelerometer upper limb total score, ranging 
from 0 to 24, is the sum of these 6 sub-items and ranges from 0 to 24. For each timepoint, the average 
score of the two Kinesia ONE assessments will be calculated to be used for analysis. If only one 
assessment is performed, the single score will be used for analysis. 
 
 
4.9.1.6 
Teleheath Assessment 
The TETRAS Performance Subscale upper limb item (item #4) will be conducted by the site rater using 
televideo technology while the participant is at home. The date and time of telehealth assessment, rater 
ID, an indicator of whether the assessment was performed (Yes/No), and the individual item scores will 
be recorded in the eCRF. The upper limb score will be calculated as the sum of all 6 sub-items. 
 
4.9.1.7 
Activities of Daily Living (ADL) 
The TETRAS ADL subscale is a 12-item assessment of typical daily activities that are impacted by 
tremor that will be collected for Part B only. Activities are assessed in the following functional domains: 
speaking, feeding, drinking, personal hygiene, dressing, writing, and social activity. The impact to each 
function is rated on a 5-point Likert scale from 0 to 4. The ADL subscale score is calculated as the sum 
of all 12 items and ranges from 0 to 48 with higher scores reflecting higher impact. The date and time of 
the ADL subscale, rater ID, an indicator of whether the assessment was performed (Yes/No), and the 
individual item scores will be recorded in the eCRF. The subscale score will be derived directly in the 
eCRF. 
 


 
 
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4.9.4 
Quality of Life in Essential Tremor Questionnaire (QUEST) 
The QUEST is a patient-reported ET-specific quality of life scale that will be collected for Part B only. 
The scale contains 5 subscales that cover physical, psychosocial, communication, hobbies/leisure, and 
work/finance dimensions. The individual items are rated either on a 5-level Likert scale from 0 to 4 
(Never, Rarely, Sometimes, Frequently, Always) or a 2-level scale from 0 (No) to 4 (Yes) relative to the 
respondent's current situation. Five items could also be rated as not applicable. The QUEST total and 
subscale scores are calculated as the sum of all applicable items divided by the number of applicable 
items times 100. The subscale scores will be derived directly in the eCRF. 
 
Participants are also asked to rate their overall health status and quality of life on scale from 0 to 100 by 5 
point increments, if tremor has interfered with their sexual satisfaction (Yes/No), if they have had side 
effects from tremor medication (Yes/No), if they are satisfied by tremor control achieved by tremor 
medication (Yes/No), and to describe their work status (Never Worked, Not working, retired because of 
tremor, Not working, retired NOT due to tremor, Working full time, Working part time). Additionally, 
the participant is asked to report how many hours in a typical day they experience tremor in any body 
part (0 to 24) and the severity of tremor in the head, voice, right arm/hand, left arm/hand, right leg/foot, 
and left leg/foot on a scale from 0 to 4 (None, Mild, Moderate, Marked, Severe). 


 
 
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An indicator of whether the QUEST was performed (Yes/No), the date and time of assessment, rater ID, 
and individual item scores will be recorded on the eCRF.  
 
4.10 
Safety Variables 
4.10.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical trial participant, 
temporally associated with the use of study drug, whether or not considered related to the study drug. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of study drug. 
 
AEs are collected from the time the informed consent form is signed until study participation is 
completed. For each AE, the following data will be recorded in the eCRF: verbatim text, start date, stop 
date (or ongoing), outcome, investigator’s assessment of severity, relationship to study drug, relationship 
to study procedures, relationship to disease under study, action taken with study drug, administration of 
concomitant therapy, concomitant therapy type, assessment of seriousness, and criteria for seriousness. 
For any AEs leading to death, the date of death and assessment cause of seriousness. death will also be 
recorded in the eCRF. The verbatim text will be coded using MedDRA version 22.0. 
 
• Action taken with study drug will be recorded as “None”, “Study drug interrupted”, “Study drug 
withdrawn”, “Study drug dose changed” or “Not applicable”; 


 
 
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• Outcome will be recorded as “Recovered”, “Recovered with sequelae”, “Not recovered”, “Fatal”, 
or “Unknown”; 
• Relationship to study procedures and study drug will be recorded as “Not Related” or “Related”; 
• Investigator’s assessment of severity will be recorded as “Mild”; “Moderate”; or “Severe”; 
• Assessment of seriousness will be recorded as “Y” or “N”. 
 
A flag for AEs of special interest (AESIs) will be defined to include any event of seizure, seizure-like 
phenomena, loss of consciousness, or altered state of consciousness as defined in Section 8.4.5 of the 
protocol.  As a result of an FDA request documented in a study note to file, these additional events will 
also be included as AESIs: tardive dyskinesia, acute dystonic reactions, akathisia, and Parkinsonian 
symptoms (bradykinesia, tremor, cogwheel rigidity, mask-like facies). Search criteria for defining these 
AESIs according to MedDRA preferred terms are included in Appendix 2. In accordance with these 
search criteria, a flag will be created to indicate whether or not the event was an AESI (Y/N). 
 
A flag for AEs leading to study drug withdrawal will be calculated as: 
• IF the action taken with study drug is “Study drug withdrawn”, THEN set the AE leading to study 
drug withdrawal flag equal to “Y”. 
• OTHERWISE, set the AE leading to study drug withdrawal flag equal to “N”. 
 
Treatment emergent AEs (TEAEs) are defined as those AEs occurring or worsening after the first dose of 
study drug. If an AE start date is completely missing (ie, in which the day, month, and year are all 
unknown), then the AE start date will be set to the date of first dose of study drug. For a partial AE start 
date, the following conventions will be used for imputing the AE start date: 
 
• When the year is present and the month and day are missing: 
− If the year of AE start = the year of first dose of study drug, then the month and day will be set 
to the month and day of first dose of study drug. 
− If the year of AE start < the year of first dose of study drug, then the month and day will be set 
to December 31st. 
− If the year of AE start > the year of first dose of study drug, then month and day will be set to 
January 1st. 
 
• When the year and day are present and the month is missing: 
− If the year of AE start = the year of first dose of study drug, then the month will be set to the 
month of first dose of study drug. 
− If the year of AE start < the year of first dose of study drug, then the month will be set to 
December. 
− If the year of AE start > the year of first dose of study drug, then the month will be set to 
January. 
 
• When the month and year are present and the day is missing: 
− If the year of AE start = the year of first dose of study drug and 


 
 
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− the month of AE start = the month of first dose of study drug, then the day will be set to the 
day of first dose of study drug. 
− the month of AE start < the month of first dose of study drug, then the day will be set to the 
last day of the month. 
− the month of AE start > the month of first dose of study drug, then the day will be set to the 
1st day of the month. 
− If the year of AE start < the year of first dose of study drug, then the day will be set to the last 
day of the month. 
− If the year of AE start > the year of first dose of study drug, then the day will be set to the 1st 
day of the month. 
− If the imputed AE start date is after the AE stop date, then the AE start date will be set to the 
AE stop date. 
 
For Part B, AEs will be identified as TEAEs for the double-blind randomized withdrawal phase based on 
the first dose of randomized study drug.  AEs reported during the open-label titration period will not 
include events occurring within the randomized withdrawal phase.  Events occurring within the safety 
follow-up period for a participant will be classified as occurring during his/her last phase of participation 
(ie, if a participant does not enter the double-blind randomized withdrawal phase any post-treatment AEs 
will be reported as part of the open-label titration).   
 
If an AE is imputed for Part B and is attributed to the open-label titration or double-blind randomized 
withdrawal phase, it should be checked for plausibility. If an imputed AE onset date could potentially 
have started during a subsequent phase (eg, if the onset date had been imputed as the 1st of a particular 
month falling into the open-label titration phase, but it plausibly could have started later in the month 
during the double-blind randomized withdrawal phase), the AE should be identified as TEAE for any 
plausible phases. 
 
For each AE, a treatment emergent flag will be calculated using the recorded AE start date (or imputed 
start date, where applicable). Additional treatment emergent flags will be created for each dose level. 
 
Adverse events occurring during PRAX-944 titration will be assigned to a dose level based on the onset 
date/time of the adverse event relative to the first dose date/time of study drug administration at each 
dose level.  Specifically, if an AE occurs after the first dose of study drug at a participant’s actual dose 
level and prior to the first dose at the next dose level, the AE will be assigned within a participant’s actual 
dose level in the adverse event summary.  If the date was imputed and could plausibly occurred during a 
subsequent dose level, the AE should be identified as TEAE for subsequent and plausible dose levels. 
 
If the time is missing (either for the adverse event or study drug administration), then the AE date (and 
relative study day) will be used to determine in which dose level the AE should be assigned, assuming 
that the AE occurred after the dose taken on the specified day. An adverse event will only be reported 
within the dose level in which the AE started (eg, an adverse event that starts within the 40 mg dose level 
and continues into the 80 mg dose level will only be reported in the 40 mg dose level). 
 
In addition, each AE will also be categorized into the study period in which it started: prior to first dose 
(ie, Screening/Baseline period), during the Intervention period (Part A), open-label titration phase (Part 


 
 
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B), double-blind randomized withdrawal phase (Part B), or during the Safety Follow-up period. AEs 
categorized under multiple study periods will be identified as needed. AEs starting during the Safety 
Follow-up period will be defined as any event with a start date occurring after the last date in the 
Intervention Period, according to the SoAs for each respective study part. AEs with an onset after Day 56 
will be reported based on the last dose level received during the study and last phase of participation 
(open-label titration or double-blind randomized withdrawal phase). 
 
4.10.2 
 Laboratory Test Results 
Blood and urine samples will be collected by site staff for clinical laboratory testing. Urine pregnancy 
tests will be performed at the site and will be recorded in the eCRF as “Positive” or “Negative”. All other 
samples will be analyzed at the central laboratory. For all samples collected, the following data will be 
recorded in the eCRF: test category (ie, Chemistry, Hematology, Urinalysis, Coagulation, Pregnancy 
Test, Viral Serology or Urine Drug Screen), sample collection date, and sample time. For urine 
pregnancy tests, the result will also be recorded in the eCRF as “Positive” or “Negative”. An indicator for 
whether a repeat sample was taken (Yes/No) will also be recorded in the eCRF for each sample collected. 
 
Collected laboratory samples will then be processed at the central laboratory for the calculation of 
reported values for the laboratory tests listed in Appendix 3.  Central laboratory data will include test 
category, lab test name, reported result, reported unit, reported reference range (ie, low and high), and 
abnormal indicator. Data from the central laboratory will be combined with the laboratory eCRF data 
prior to analysis. 
 
Change from baseline values to each post-baseline assessment will be calculated for all continuous 
laboratory tests. 
 
4.10.3 
 Vital Sign Results 
The following vital sign data will be recorded in the eCRF: assessment date, height, weight, BMI, as well 
as standing and supine temperature, pulse rate, respiratory rate, supine systolic blood pressure (BP), and 
diastolic BP. An indicator for whether a repeat assessment was taken (Yes/No) will also be recorded in 
the eCRF for each assessment. 
 
Change from baseline values to each post-baseline assessment will be calculated for pulse rate, 
respiratory rate, systolic BP, and diastolic BP.  In addition, potentially clinically important flags will be 
derived for systolic BP, diastolic BP, pulse rate, and respiratory rate (see Table 1). 


 
 
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Table 1: Potentially Clinically Important Criteria for Vital Sign Results 
ECG measure 
Lower PCI criterion 
Upper PCI criterion 
Pulse rate 
 
≤50 bpm 
≥130 bpm 
Systolic BP 
<90 mmHg 
>130 mmHg 
Diastolic BP 
<50 mmHg 
>85 mmHg 
Change in systolic BP 
decrease ≥30 mmHg 
increase ≥30 mmHg 
Change in diastolic BP 
decrease ≥30 mmHg 
increase ≥30 mmHg 
BP = blood pressure; PCI = potentially clinically important 
 
4.10.4 
 Electrocardiogram Results 
Standard 12-lead electrocardiograms (ECGs) will be performed after the participant has been supine for 
approximately 5 minutes. All ECGs will be performed using the equipment supplied by the central ECG 
vendor. For all ECGs performed, the following data will be recorded in the eCRF: assessment date, 
triplicate timepoint, timepoint performed indicator (Yes/No), and time of assessment. 
 
Electronic ECG tracings will be analyzed for the calculation of reported values for the following ECG 
tests: heart rate, RR interval, PR interval, QRS duration, QT interval, corrected QT interval using the 
Bazett formula (QTcB), corrected QT interval using the Fridericia formula (QTcF), evaluator 
interpretation, and abnormal findings.  ECG vendor data will include ECG test name, reported 
result/finding, reported unit, standard result/finding, standard unit, and lead location. The evaluator 
interpretation result will be recorded as “NORMAL”, “ABNORMAL”, or “UNABLE TO EVALUATE”. 
Data from the ECG vendor will be combined with the ECG eCRF data prior to analysis. 
 
Change from baseline values to each post-baseline assessment will be calculated for heart rate, RR 
interval, PR interval, QRS duration, QT interval, and QTcF interval. In addition, potentially clinically 
important flags will be calculated for heart rate, PR interval, QRS duration, QT interval, QTcB interval, 
QTcF interval, change from baseline in heart rate, and change in QT, QTcB, and QTcF intervals (see 
Table 2). 
 
Table 2: Potentially Clinically Important Criteria for ECG Results 
ECG measure 
Lower PCI criterion 
Upper PCI criterion 
Heart rate 
 
≤50 bpm 
≥130 bpm 
PR interval 
 
≥180 msec 
QRS duration 
 
≥100 msec 
QT interval 
 
≥450 msec 
QTcB interval 
 
≥450 msec 
QTcF interval 
 
≥450 msec 
Change in QTcB 
 
increase ≥30 msec 
Change in QTcF 
 
increase ≥30 msec 
ECG = electrocardiogram; PCI = potentially clinically important 
 


 
 
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4.10.5 
Physical Examination 
Physical examinations will be performed per the SOA. The date of the physical exam will be recorded in 
the eCRF. Any significant findings from physical examinations should be reported as either medical 
history or adverse events. 
 
4.10.6 
 Columbia–Suicide Severity Rating Scale 
The Columbia–Suicide Severity Rating Scale (C-SSRS; available at www.cssrs.columbia.edu) is a semi-
structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and 
behaviors during the assessment period. The interview includes definitions and suggested questions to 
solicit the type of information needed to determine if a suicide-related thought or behavior has occurred. 
The C-SSRS has a “Screening/Baseline” version that will be completed at the Screening Visit (Visit 1) 
and a “Since Last Visit” version that will be completed at all other visits. Both versions contain all 11 
categories of suicidal ideation and behavior defined in the Food and Drug Administration (FDA) 
guidance document on suicidal behavior and ideation (FDA, 2012).  Each category is assessed using a 
single question requiring a “Yes” or “No” response with follow-up questions for any “Yes” responses. 
The assessment date and each C-SSRS response will be recorded in the eCRF. 
 
In addition, three C-SSRS composite indicator variables will be calculated as follows: 
 
4.10.6.1 
 C-SSRS Suicidal Ideation Indicator 
A composite indicator of C-SSRS suicidal ideation will be calculated as: 
• If the response to any one of the five suicidal ideation questions is “Yes”, THEN set the suicidal 
ideation indicator equal to 1. 
• OTHERWISE, set the suicidal ideation indicator equal to 0. 
 
4.10.6.2 
 C-SSRS Suicidal Behavior Indicator 
A composite indicator of C-SSRS behavior ideation will be calculated as:  
• IF the response to any one of the five suicidal behavior questions is “Yes”, THEN set the suicidal 
behavior indicator equal to 1. 
• OTHERWISE, set the suicidal behavior indicator equal to 0. 
 
4.10.6.3 
 C-SSRS Suicidal Ideation or Behavior Indicator 
A composite indicator of C-SSRS suicidal ideation or behavior will be calculated as: 
• IF the response to any one of the 5 suicidal ideation questions or any of the 5 suicidal behavior 
questions is “Yes”, THEN set the suicidal ideation or behavior indicator equal to 1. 
• OTHERWISE, set the suicidal ideation or behavior indicator equal to 0. 
 


 
 
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4.11 
 Pharmacokinetic Variables 
Plasma samples will be collected by site staff for PK testing. For all PK samples collected, the following 
data will be recorded in the eCRF: scheduled timepoint, sample collection date, and sample collection 
time. A validated bioanalytical method will be utilized for the determination of plasma concentrations of 
PRAX-944 and its metabolites, as applicable.  For Part A, PK parameters of parent drug and primary 
metabolites (M15, M23, and M32) will be estimated from concentration-time data using 
noncompartmental methods as described in a separate PK analysis plan. 
 


 
 
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5 
ANALYSIS METHODS 
Analysis will be carried out using SAS® (version 9.4 or newer, SAS Institute Inc, Cary, NC). Templates 
for the summary tables, figures, and participant data listings will be available separately. Data listings 
will include all data recorded for all enrolled participants; where captured, data entered for screen failure 
participants will be flagged in the listings.  
 
For all data displays, separate summaries will be generated for each part and phase (open-label titration 
and double-blind randomized withdrawal) of the clinical trial.  
 
• Part A: All summaries except those for adverse events will use a single "PRAX-944 Overall" 
column.  Summaries of adverse events will use the following columns: "PRAX-944 20 mg qAM", 
"PRAX-944 40 mg qAM ", and "PRAX-944 Overall". 
 
• Part B: Summaries of disposition and PK will be presented for all of Part B (i.e., not by phase) 
and will use a single “PRAX-944” column.   
 
• Part B Open-label Titration: Summaries of demographics, baseline characteristics, medical 
history, prior and concomitant medications, study drug exposure, efficacy, and all safety except 
adverse events will include a "PRAX-944 Overall" column. Summaries of adverse events will 
include columns for "PRAX-944 20 mg qAM", "PRAX-944 40 mg qAM ", "PRAX-944 60 mg 
qAM ", "PRAX-944 80 mg qAM ", "PRAX-944 100 mg qAM ", "PRAX-944 120 mg qAM ", and 
"PRAX-944 Overall".  
 
• Part B Randomized Withdrawal: Summaries of demographics, baseline characteristics, medical 
history, prior and concomitant medications, study drug exposure, efficacy, and all safety except 
adverse events will include the columns "Placebo" and "PRAX-944” for the randomized 
withdrawal phase. Summaries of adverse events will include columns for "Placebo" and "PRAX-
944". 
 
Descriptive statistics for continuous data will include number of participants (n), mean, standard 
deviation (SD), median, minimum, and maximum.  Summaries of change from baseline variables will 
include only participants who have both a baseline value and corresponding value at the timepoint of 
interest. Descriptive statistics for categorical data will include frequency and percentage.  Where 
appropriate, descriptive statistics may be presented with 95% confidence intervals (CIs).  
 
The minimum and maximum will be reported with the same degree of precision (ie, the same number of 
decimal places) as the recorded data. Measures of location (eg, mean and median) will be reported to 1 
degree of precision more than the recorded data, and measures of spread (eg, standard deviation) will be 
reported to 2 degrees of precision more than the recorded data. 
 
Any changes to the analyses that are not included in this SAP will be documented in the CSR. 
 


 
 
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5.1 
Participant Disposition 
All participants in the enrolled analysis set will be included in disposition summaries. The number of 
participants screened, screen failed, randomized, completed, and discontinued from the study, as well as 
reason for discontinuation, will be summarized by treatment group and overall. The number of 
participants in each analysis set will also be summarized. All disposition data will be listed by 
participant. 
 
5.2 
Protocol Deviations 
Major protocol deviations will be summarized by treatment group and overall using the safety analysis 
set.  All inclusion/exclusion criteria and protocol deviation data will be listed by participant. 
 
5.3 
Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be provided by 
treatment group and overall using the safety analysis set and randomized withdrawal safety analysis set.  
These tabulations will include the following variables: 
• Age 
• Sex 
• Ethnicity 
• Child-bearing potential 
• Race 
• Dominant Hand 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) 
• Baseline TETRAS upper limb score category (<10, ≥10) 
 
All demographics and other baseline characteristics data will be listed by participant. 
 
5.4 
Medical History 
Descriptive summaries of medical history will be provided by treatment group and overall using the 
safety analysis set and randomized withdrawal safety analysis set.  Medical history will be displayed by 
MedDRA system organ class (SOC) and preferred term.  All medical history data will be listed by 
participant. 
 
5.5 
Essential Tremor Medical History  
Descriptive summaries of essential tremor medical history will be provided by treatment group and 
overall using the safety analysis set and randomized withdrawal safety analysis set.  ET medical history 
data will also be listed by participant. 
 


 
 
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5.6 
Prior and Concomitant Medications 
Descriptive summaries of prior medications will be provided by treatment group and overall using the 
safety analysis set and randomized withdrawal safety analysis set.  Both prior and concomitant 
medications will be displayed by Anatomical Therapeutic Chemical (ATC) classification level 3 and 
preferred term.  All prior and concomitant medication data will be listed by participant. 
 
5.7 
Efficacy Analyses 
Unless otherwise indicated, all efficacy data will be analyzed by part using the full analysis set. In 
summaries of change from baseline variables, only participants with both baseline and change from 
baseline values will be included. Summaries based on the full analysis set will include all timepoints, 
regardless of period, and will include changes from baseline where appropriate. Unless stated otherwise, 
summaries of efficacy endpoints will additionally include displays based on the randomized withdrawal 
analysis set, including randomization baseline and change from randomization, where applicable, to 
report data collected after receipt of randomized treatment. Summaries based on the randomized 
withdrawal set will also include open-label titration results and changes from baseline. All efficacy data 
will be listed; the listings will include all reported and derived values as well as rater ID, where 
applicable. Analysis of TETRAS scores may be performed for dominant hand only. 
 
5.7.1 
Primary efficacy analysis 
For Part A, the change from baseline in TETRAS upper limb score to each post-dose timepoint will be 
analyzed using Mixed Model Repeated Measures (MMRM) methods using the full analysis set. The 
model will include timepoint as a fixed effect and the baseline TETRAS upper limb score as a covariate. 
Within subject variability will be modeled using an unstructured covariance pattern. In case of 
convergence problems, a banded Toeplitz structure for the covariance pattern will be used. Model based 
point estimates (ie, least square [LS] means), standard error, 95% confidence interval, and p-value will be 
reported for each timepoint. Reported p-values will test the LS mean for each timepoint versus zero.   
Similar MMRM methods will be used for the open-label titration phase of Part B. The SAS code to be 
used for the MMRM analysis is provided below:  
 


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Line-plots of the estimated LS means will be used to graphically illustrate the TETRAS upper limb 
scores over time.  
For Part A and both phases of Part B, the TETRAS upper limb score as measured by the clinician will be 
summarized using descriptive statistics for the reported, change from baseline, and change from 
randomization (where applicable) values by timepoint. TETRAS upper limb data will be listed by study 
part, participant, and visit. 
5.7.2 
Secondary Efficacy Analysis 
5.7.2.1 
Accelerometer-based upper limb score 
For each timepoint, the average score of the two Kinesia ONE assessments will be used for analysis.  
For Part A and both phases of Part B, the Kinesia ONE upper limb score will be summarized using 
descriptive statistics for the reported, change from baseline, and change from randomization (where 
applicable) values by timepoint. MMRM methods similar to those described in Section 5.7.1 will be used 
for the change from baseline and change from randomization in Kinesia ONE upper limb scores. Kinesia 
ONE data will be listed by study part, participant, and visit.  
Line-plots of the estimated LS means will be used to graphically illustrate the Kinesia ONE upper limb 
scores over time.  
5.7.2.2 
TETRAS combined upper limb score 
For Part A and both phases of Part B, the TETRAS combined upper limb score as measured by the 
clinician will be summarized using descriptive statistics for the reported, change from baseline, and 
change from randomization (where applicable) values by timepoint. MMRM methods similar to those 
described in Section 5.7.1 will be used for the change from baseline and change from randomization in 


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TETRAS combined upper limb scores. TETRAS combined upper limb data will be listed by study part, 
participant, and visit. 
Line-plots of the estimated LS means will be used to graphically illustrate the TETRAS combined upper 
limb scores over time.  
5.7.2.3 
TETRAS performance subscale total score 
For Part A and both phases of Part B, the TETRAS performance subscale total score as measured by the 
clinician will be summarized using descriptive statistics for the reported, change from baseline, and 
change from randomization (where applicable) values by timepoint. MMRM methods similar to those 
described in Section 5.7.1 will be used for the change from baseline and change from randomization in 
TETRAS performance subscale scores. TETRAS performance subscale data will be listed by study part, 
participant, and visit. 
5.7.2.5 
TETRAS ADL subscale score 
In Part B, the TETRAS ADL subscale total score as measured by the clinician will be summarized using 
descriptive statistics for the reported, change from baseline, and change from randomization (where 
applicable) values by timepoint. MMRM methods similar to those described in Section 5.7.1 will be used 
for the change from baseline and change from randomization in TETRAS ADL subscale scores. 
TETRAS ADL data will be listed by study part, participant, and visit. 
5.7.2.6 
QUEST total and subscale score 
In Part B, the QUEST total and subscale scores will be summarized using descriptive statistics for the 
reported, change from baseline, and change from randomization (where applicable) values by timepoint. 
MMRM methods similar to those described in Section 5.7.1 will be used for the change from baseline and 
change from randomization in QUEST scores. QUEST data will be listed by study part, participant, and 
visit. 


 
 
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5.7.3.3 
Telehealth Assessments 
In Part B, the TETRAS upper limb score as assessed by telehealth will be summarized using descriptive 
statistics for reported and change from baseline values at Day 41. Telehealth assessment data will not be 
summarized for the randomized withdrawal analysis set as no telehealth assessments were performed 
during the randomized withdrawal phase. TETRAS telehealth data will be listed by participant and visit. 
 
 
 


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5.7.4 
Subgroup Analyses 
In Part B, subgroup analyses for patients having a baseline TETRAS upper limb score of 10 or higher 
will be performed for primary and secondary efficacy endpoints, as well as the TETRAS modified total 
score. 
5.8 
Safety Analyses 
For all safety variables, descriptive statistics will be presented by study part, treatment group, and visit 
(where applicable) using the safety analysis set and randomized withdrawal safety analysis set.  In 
summaries of change from baseline safety variables, only participants with both baseline and change 
from baseline values will be included.  No formal hypothesis testing will be performed for any safety 
variable. 
5.8.1 
AEs 
The overall incidence of participants having at least one AE in each of the following categories will be 
summarized by treatment group and dose level, as defined in Section 5: 
•
Any TEAE
•
Any serious adverse event (SAE)
•
Any AE leading to death
•
Any AESI
•
Any TEAE leading to study drug withdrawal
•
Any related TEAE
The overall AE incidence summary, as well as summaries identified in subsequent sections, will be 
reported by part and phase.  Part A and Part B open-label titration phase summaries will be based on the 
safety analysis set.  Part B double-blind randomized withdrawal phase summaries will be based on the 
randomized withdrawal analysis set.   
All AE data will be listed by study part and participant.  Separate listings will be presented for SAEs, 
AEs leading to death, and TEAEs leading to study drug withdrawal. 
5.8.1.1 
TEAEs 
The incidence of TEAEs will be summarized by SOC and preferred term.  Each participant will be 
counted only once per SOC and preferred term.  The incidence of TEAEs by preferred term will also be 
summarized. 


 
 
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5.8.1.2 
TEAEs Leading to Study Drug Withdrawal 
The incidence of TEAEs leading to study drug withdrawal will be summarized by SOC and preferred 
term.  Each participant will be counted only once per SOC and preferred term. 
 
5.8.1.3 
TEAEs Related to Study Drug 
The incidence of TEAEs related to study drug will be summarized by SOC and preferred term. Each 
participant will be counted only once per preferred term. 
 
5.8.1.4 
TEAEs by Maximum Severity 
The incidence of TEAEs will be summarized by maximum severity, SOC, and preferred term, where 
Severe > Moderate > Mild.  Each participant will be counted only once per preferred term and most 
severe category reported. If missing, severity will be categorized as Severe for summary purposes. 
 
5.8.2 
Laboratory Test Results 
Descriptive statistics for all reported and change from baseline values will be summarized by test 
category, laboratory test, and visit. Only the original assessment for each visit day will contribute to 
descriptive statistics; repeat or unscheduled assessments will not be included in the calculation of 
descriptive statistics by visit. All laboratory test results data (including pregnancy test and urine drug 
screen data and any repeat or unscheduled assessments) will be listed by study part, participant, and visit. 
 
Descriptive statistics for all reported and change from baseline values for KIM-1, urine creatinine, and 
KIM-1 per urine creatinine ratio will be summarized by test and visit. Results will be listed by study part, 
participant, and visit. 
 
5.8.3 
Vital Sign Results 
Descriptive statistics for all reported and change from baseline values will be summarized by visit. Only 
the original assessment for each timepoint will contribute to these summaries; repeat or unscheduled 
assessments will not be included in the calculation of descriptive statistics by timepoint. The number and 
percentage of participants with PCI values at any time will be tabulated by treatment group. Summaries 
of PCI values will include all assessments regardless of whether an original, repeat, or unscheduled 
assessment.  All vital sign results data will be listed by study part, participant, and visit. 
 
5.8.4 
ECG Results 
Descriptive statistics for all reported and change from baseline values will be summarized by visit.  Only 
the original assessment for each visit will contribute to these summaries; repeat or unscheduled 
assessments will not be included in the calculation of descriptive statistics.  The number and percentage 
of participants with PCI values at any time will be tabulated by treatment group; the number and 
percentage of participants with abnormal ECG findings will be presented similarly.  Summaries of PCI 
values and abnormal ECG findings will include all assessments regardless of whether an original, repeat, 
or unscheduled assessment.  All ECG results data will be listed by study part, participant, and visit. 


 
 
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5.8.5 
C-SSRS 
The C-SSRS will be evaluated based on methods described by Nilsson et al. (2013). The number and 
percentage of participants with any suicidal ideation and/or suicidal behavior following the first dose of 
study drug will be tabulated.  
 
For the composite endpoint of suicidal ideation, the number and percent of participants who experience 
any one of the five suicidal ideation events at least once during dosing through follow-up will be 
tabulated. 
 
For the composite endpoint of suicidal behavior, the number and percent of participants who experience 
any one of the five suicidal behavior events at least once during dosing through follow-up will be 
tabulated. 
 
For the composite endpoint of suicidal ideation or behavior, the number and percent of participants who 
experience any one of the ten suicidal ideation or behavior events at least once during dosing through 
follow-up will be tabulated. 
 
5.9 
 Pharmacokinetic Analyses 
5.9.1 
 Plasma Concentrations 
For each study part, plasma concentrations will be summarized by visit and nominal sampling time using 
descriptive statistics. For concentration summaries, plasma concentrations below the level of 
quantification (BLQ) will be set to zero.  Descriptive statistics for plasma concentrations will include n, 
number of participants with concentrations below the level of quantification (BLQ), mean, SD, 
coefficient of variation (CV%), geometric CV%, geometric mean, median, minimum, and maximum.  All 
plasma concentration data will be listed by study part, participant, and visit.   
 
Plasma concentrations will also be presented graphically. 
 
5.9.2 
 Plasma PK Parameters 
PK parameters will not be estimated for this study as no participants from Part A agreed to participate in 
the optional overnight PK sampling. 


 
 
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6 
INTERIM ANALYSES  
No formal interim analysis is planned for this clinical trial. 


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7 
CHANGES TO PLANNED ANALYSES 
7.1 
Changes to Analysis as Described in Protocol 
The protocol specifies an exploratory objective “to characterize the pharmacokinetic (PK) profile of 
PRAX-944 following multiple dose administration” for Part A.  This objective will not be assessed as no 
participants from Part A agreed to participate in the optional overnight PK sampling. 
The order of the endpoints supporting the objective “to evaluate the duration of PRAX-944 effect on 
upper limb tremor, other measures of tremor severity, measures of disease impact, mood, and global 
measures of disease state in participants with ET” as specified in the protocol has been updated to reflect 
the importance of direct measures of movement (ie, accelerometry) and activities of daily living. 
The protocol includes a Day 0 (Baseline) visit in the SoA for Part A. However, for simplicity and 
consistency across both parts of the study, the derived study day variable as defined in Section 4 will not 
include a study day 0. 
The TETRAS combined upper limb score (derived as the sum of the 6 TETRAS upper limb sub-items, 
the handwriting item, and the spirals item scores) has been included as another TETRAS based measure 
of upper limb tremor.   
7.2 
Changes to Approved Version of the SAP 
Not applicable. 


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8 
REFERENCES 
1. ICH (1995). ICH Harmonised Tripartite Guideline: Structure and Content of Clinical Study 
Reports E3. Step 4, 30 November 1995. Retrieved from
https://database.ich.org/sites/default/files/E3 Guideline.pdf
2. ICH E9 Expert Working Group (1999). Statistical Principles for Clinical Trials. Statistics in 
Medicine, 18,1905–1942.
3. FDA (2012). Guidance for Industry: Suicidal Ideation and Behavior - Prospective Assessment of 
Occurrence in Clinical Trials, Draft Guidance. Revision 1, August 2012. Retrieved from
https://www.fda.gov/media/79482/download
4. Nilsson ME, Suryawanshi S, Gassmann‐Mayer C, Dubrava S, McSorley P, and Jiang K. (2013). 
Columbia–Suicide Severity Rating Scale Scoring and Data Analysis Guide. Retrieved from 
https://cssrs.columbia.edu/wp-content/uploads/ScoringandDataAnalysisGuide-for-Clinical-Trials-
1.pdf
5. Beck, A. T., Steer, R. A., Brown, G. K. (1996). BDI-II Manual. San Antonio, TX: Psychological
Corporation.
---


 
 
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APPENDIX 1 
SCHEDULE OF ACTIVITIES 
 
Schedule of Activities for Part A 
Visit Days 
Day -28 to 
Day -1 
(Screening) 
Day 0* 
(Baseline) 
Day 1 
Day 7 (±1) 
Day 14 (±1) 
Day 21 (±1) 
End of Clinical 
Trial or 
Early Termination 
CLINICAL TRIAL ENTRY AND GENERAL ASSESSMENTS 
Informed Consent 
X 
Inclusion/ Exclusion 
X 
X 
Demographic Data 
X 
Medical History 
X 
Body Weight/ Height 
X 
Drug/ Alcohol Screen a 
X 
X 
Pregnancy test 
X (serum) 
X (urine) 
X (urine) 
SAFETY ASSESSMENTS 
Vital Signs b 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
Clinical Laboratory Tests c 
X 
X 
X 
X 
X 


 
 
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12-lead ECG d 
X 
X 
X 
X 
C-SSRS (Baseline/Screening) 
X 
C-SSRS (Since Last Visit) 
X 
X 
X 
X 
AE Monitoring 
X 
Concomitant Meds/ Procedures 
X 
EFFICACY ASSESSMENTS 
TETRAS Performance e 
X 
X 
X 
X 
X 
X 
PHARMACOKINETICS 
Blood Collection for Study Drug Concentration 
(sparse sampling) h 
X 
X 
X 
Blood Collection for Study Drug Concentration 
(serial sampling) i 
O 
O 
O 
STUDY DRUG 
Study Drug Administration j 
X 


 
 
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AE=adverse event; 
 C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; O=optional; 
 TETRAS=The Essential Tremor Rating Assessment Scale. 
* Day 0 (Baseline) activities may be combined with Day 1 activities, provided that Baseline activities are completed before dosing in the morning. 
a Urine sample for assessment of selected drugs and a breath sample for alcohol screen. 
b Vital signs (pulse rate, respiratory rate, temperature, and blood pressure [after the participant has been supine for at least 5 minutes and standing for at least 2 minutes]). On Day 1, should be performed 2 and 6 hours 
after dosing (±30 min). 
c Including CBC, clinical chemistry, coagulation factors, viral serology screen, exploratory urine biomarkers, urinalysis and urine albumin. Coagulation factors and viral serology screen collected at Screening only. 
d Triplicate measurement will be taken at Screening only; for all other timepoints, single measurement is acceptable. 
e Screening, Day 0 and Day 21: completed anytime; Day 1, pre-dose and 6 (±2) hours post-dose; Day 7 and Day 14 6 (±2) hours post-dose. 
f The TETRAS Performance assessment will be captured on video for central reading. The local rater will rate the same TETRAS Performance assessment that is captured on video. The Screening video will be independently 
assessed for eligibility. 
g To be performed 2 consecutive times separated by at least 30 minutes, the first time immediately after the post-dose TETRAS Performance assessment. All 3 maneuvers in the upper limb item (sub- items 4a, 4b, and 4c) will 
be completed for both arms, first for the RIGHT arm and then for the LEFT. 
h Day 1: 0 (pre-dose); post-dose immediately after completion of the 2nd accelerometer-based upper limb assessment; When PK sampling timepoints coincide with the TETRAS Performance timepoints or 
accelerometer-based assessment timepoints the PK sample is to be obtained last. 
i Optional samples collected at sites that have capabilities to perform serial sample collection: Day 1, 7 and 14: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose. All collection times up to 4 hours post-dose have a 
±15 min window and a ±30 min window thereafter. 24-hour timepoint samples are to be taken prior to the AM dose. When PK sampling timepoints coincide with the TETRAS Performance timepoints or accelerometer-based 
assessment timepoints the PK sample is to be obtained last. 
j Administered in clinic on Day 1. All other days it should be taken in the morning, within 30 minutes after breakfast. On Day 1 participant should be observed in clinic for approximately 6 hours before discharge. Study drug 
is dispensed (20 mg QAM for Day 1 to Day 7; 40 mg QAM for Day 8 to Day 14). 
D-


 
 
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Schedule of Activities for Part B 
Study Phase 
Screening 
 
Open-label Titration 
Visit Days 
(Visit Window) 
Day -28 to Day -1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Day 
14  
Day 
21 
Day 
28 
Day 
35 
Day 
41 
Day 
42 
 
Day -2 
(-2) 
CLINICAL TRIAL ENTRY AND GENERAL ASSESSMENTS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X* 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
Drug/Alcohol Screen a 
X 
 
X* 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
(serum) 
 
X (urine)* 
 
 
 
 
 
 
 
 
SAFETY ASSESSMENTS 
Vital Signs b 
X 
 
X 
 
X 
 
X 
 
 
 
X 


 
 
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Study Phase 
Screening 
 
Open-label Titration 
Visit Days 
(Visit Window) 
Day -28 to Day -1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Day 
14  
Day 
21 
Day 
28 
Day 
35 
Day 
41 
Day 
42 
 
Day -2 
(-2) 
Physical Examination 
X 
 
X* 
 
 
 
 
 
 
 
 
Clinical Laboratory 
Tests c 
X 
 
X* 
 
X 
 
X 
 
 
 
X 
12-lead ECG d 
X 
 
X* 
 
X 
 
X 
 
 
 
X 
C-SSRS 
(Baseline/Screening) 
X 
 
 
 
 
 
 
 
 
 
 
C-SSRS (Since Last 
Visit) 
 
 
X* 
 
X 
 
X 
 
 
 
X 


 
 
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Study Phase 
Screening 
 
Open-label Titration 
Visit Days 
(Visit Window) 
Day -28 to Day 
-1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Day 
14  
Day 
21 
Day 
28 
Day 
35 
Day 
41 
Day 
42 
 
Day -2 
(-2) 
SAFETY ASSESSMENTS 
Phone Call Check-in 
 
 
 
X 
 
X 
 
X 
X 
 
 
AE Monitoring 
X 
Concomitant Meds/ 
Procedures 
X 
EFFICACY ASSESMENTS 
TETRAS Performance e 
X 
 
X 
 
X 
 
X 
 
 
 
X 


 
 
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Study Phase 
Screening 
 
Open-label Titration 
Visit Days 
(Visit Window) 
Day -28 to Day 
-1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Day 
14  
Day 
21 
Day 
28 
Day 
35 
Day 
41 
Day 
42 
 
Day -2 
(-2) 
QUEST 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
Study Phase 
Screening 
 
Open-label Titration 
Visit Days 
(Visit Window) 
Day -28 to Day 
-1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Day 
14  
Day 
21 
Day 
28 
Day 
35 
Day 
41 
Day 
42 
 
Day -2 
(-2) 
EFFICACY ASSESMENTS 
PHARMACOKINETICS 
Blood Collection for Study 
Drug Concentrationi 
 
 
X 
 
X 
 
X 
 
 
 
X 


 
 
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Study Phase 
Screening 
 
Open-label Titration 
Visit Days 
(Visit Window) 
Day -28 to Day 
-1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Day 
14  
Day 
21 
Day 
28 
Day 
35 
Day 
41 
Day 
42 
 
Day -2 
(-2) 
STUDY DRUG 
Randomizationj 
 
 
 
 
 
 
 
 
 
 
X 
Study Drug Dispensing 
 
 
X 
 
X 
 
X 
 
 
 
X 
Study Drug 
Administrationk 
 
 
 
X 
(open label) 
ADL=Activities of Daily Living; AE=adverse event; 
 CBC=complete blood count; 
 C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; Meds=Medications; 
; PK=pharmacokinetics; 
QAM=every morning; QUEST=Quality of Life in Essential Tremor Questionnaire; TETRAS=The Essential Tremor Rating Assessment Scale. 
* May be performed on Day -1. 
a Urine sample for assessment of selected drugs and a breath sample for alcohol screen. 
b Vital signs include pulse rate, respiratory rate, temperature, and blood pressure. Blood pressure must be measured once after the participant has been supine for at least 5 minutes and once after the participant 
has been standing for at least 2 minutes. On Day 1, vital signs should be measured pre-dose, 2 hours post-dose (±30 min), and 6 hours post-dose (±30 min). 
c Including CBC, clinical chemistry, coagulation factors, viral serology screen, urinalysis, and urine albumin. Coagulation factors and viral serology screen collected at Screening only. 
d A triplicate measurement must be taken at Screening only; for all other timepoints, a single measurement is acceptable. 
e TETRAS can be completed anytime at Screening and Day 70. On other days, the following timing should be followed: Day 1: pre-dose and 6 (±2) hours after a 20 mg QAM dose Day 7: 6 (±2) hours after a 
40 mg QAM dose Day 21: 6 (±2) hours after an 80 mg (or highest tolerated dose) QAM dose Day 42: pre-dose and 6 (±2) hours after a 120 mg (or highest tolerated dose) QAM dose Day 56: 6 (±2) hours post-
dose 
f The TETRAS Performance assessment will be captured on video for central reading. The local rater must rate the same TETRAS Performance assessment as that which is captured on video for central 
reading. The Screening video will also be independently assessed for eligibility. 


 
 
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Study Phase 
Screening 
 
Open-label Titration 
Visit Days 
(Visit Window) 
Day -28 to Day 
-1 
Day 1 
(Baseline) 
Day 
3 
Day 
7 
Day 
14  
Day 
21 
Day 
28 
Day 
35 
Day 
41 
Day 
42 
 
Day -2 
(-2) 
g Kinesia ONE assessments must be completed immediately after the TETRAS Performance assessments (including both pre-dose and post-dose assessments on Day 1 and Day 42). After each TETRAS 
Performance assessment, Kinesia ONE assessments should be completed twice separated by at least 30 minutes. All 3 maneuvers in the upper limb item (sub-items 4a, 4b, and 4c) will be completed for both 
arms, first for the RIGHT arm and then for the LEFT. 
h For visits with multiple TETRAS assessments, the TETRAS ADL subscale should only be assessed once. On Day 1, the ADL subscale should be completed pre-dose. On day 42, the ADL subscale should be 
completed 6 (±2) hours after the QAM dose. 
i On Day 1 and Day 42 blood samples should be collected at the following timepoints: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose. The 6-hour post-dose sample will be collected immediately after 
completion of the second Kinesia ONE assessment. When PK sampling timepoints coincide with the TETRAS Performance timepoints or accelerometer-based assessment timepoints, the PK sample is to be 
obtained last. On Days 7, 21, and 56; samples should be collected 2 hours post-dose. Blood collection can be completed anytime on Day 70. 
j Participants will be randomized (1:1) to receive either placebo or PRAX-944 from Day 43 to Day 56. Randomization can occur on Day 37 through Day 42. 
k On Day 1 and 42, study drug must be administered in the clinic on an empty stomach (at least 1 hour before breakfast, which will be provided at the site) and the participant should be observed in the clinic 
for approximately 6 hours before discharge. On all other days, participants should be instructed to take study drug at least 1 hour before breakfast in the morning at home. The escalation schedule is as follows: 
20 mg, Day 1 through Day 3; 40 mg, Day 4 through Day 7; 60 mg, Day 8 through Day 14; 80 mg, Day 15 through Day 21; 100 mg, Day 22 through Day 28; and 120 mg, Day 29 through Day 42. Participants 
will receive blinded study drug on Days 43 to 56. During blinded treatment period, participants should take the same number of tablets per day as taken during Days 36 to 42. 
 


 
 
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APPENDIX 2 
ADVERSE EVENTS OF SPECIAL INTEREST  
 
FDA Requested AESI Terms 
MedDRA Preferred Term Search Criteria for Defining AESI  
Any event of seizure, seizure-like phenomena 
Seizure 
Seizure like phenomena 
Generalised tonic-clonic seizure 
Seizure cluster 
Simple partial seizures 
Focal dyscognitive seizures 
Seizure anoxic 
Petit mal epilepsy 
Atonic seizure 
Clonic convulsion 
Febrile convulsion 
Tonic convulsion 
Autonomic seizure 
Partial seizures 
Generalised onset non-motor seizure 
Partial seizures with secondary generalisation 
Loss of consciousness and altered state of 
consciousness 
Loss of consciousness 
Depressed level of consciousness 
Consciousness fluctuating 
Slow response to stimuli 
Hyporesponsive to stimuli 
Unresponsive to stimuli 
Stupor 
Syncope 
Tardive dyskinesia 
Tardive dyskinesia 
Acute dystonic reactions 
Dystonia 
Oromandibular dystonia 
Torticollis 
Blepharospasm 
Pharyngeal dystonia 
Writer’s cramp 
Early onset primary dystonia 
Oculogyric crisis 
Opisthotonus 
Trismus 
Tic 
Emprosthotonus 
Akathisia 
Akathisia 
Acute Parkinsonian symptoms 
Parkinsonism 
Parkinsonian gait 
Tremor  
Parkinsonian rest tremor 
Bradykinesia 


 
 
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FDA Requested AESI Terms 
MedDRA Preferred Term Search Criteria for Defining AESI  
Cogwheel rigidity 
Reduced facial expression 
 


 
 
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APPENDIX 3 
CLINICAL LABORATORY EVALUATIONS 
 
The tests detailed in Table 3 will be performed by a central laboratory. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 of the 
protocol. 
Additional tests may be performed at any time during the clinical trial as determined necessary by the 
Investigator or required by local regulations. 
 
 
Table 3 
Protocol-Required Laboratory Assessments 
Clinical Chemistry 
Hematology 
Urinalysis 
Alanine aminotransferase (ALT)  
Alkaline phosphatase 
Aspartate aminotransferase (AST)  
Blood urea nitrogen (BUN) 
Calcium 
Creatinine  
Glucose  
Potassium  
Sodium 
Total and direct bilirubin 
Total protein 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential (absolute): 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
Bilirubin  
Glucose  
Ketones 
Leukocyte esterase  
Nitrite 
Blood  
pH 
Specific gravity  
Protein  
Urobilinogen 
Microscopic exam including bacteria, 
casts, crystals, epithelial cells, RBCs, and 
WBCs (if protein, leukocyte esterase, 
nitrite, or blood is positive) 


 
 
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Drug Screen 
Coagulation Factors 
(Screening only) 
Other Tests 
Including but not limited to:  
Amphetamines 
Barbiturates 
Benzodiazepines (Stable use of ≤2 
mg of lorazepam/day is allowed) 
Cannabinoids (THC) 
Cocaine (metabolite)  
Methadone 
Opiates 
Phencyclidine 
Activated partial thromboplastin time 
Prothrombin time and international 
normalized ratio 
Serum and urine pregnancy, (women of 
childbearing potential only) 
Viral Serology Screen (at Screening only): 
Hepatitis B surface antigen (HBsAg) and 
Hepatitis C (HCV) antibody and HIV 
antibody/antigen 
Urinary albumin  
Urinary creatinine (Part A only)