Clinical trial NCT05122650
Conditions: Essential Tremor
Keywords: JZP385 T-type calcium channels Movement disorder Tremor Moderate to severe essential tremor
Sponsor: Jazz Pharmaceuticals
Start date: 2021-12-06; Completion date: 2024-05-30
Enrollment: 420 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 12-week, double-blind, placebo-controlled, randomized, parallel-group, multicenter study of the safety and efficacy of JZP385 in the treatment of adult participants with moderate to severe ET.

Detailed description:

Arms: arm 1: Participants will initially receive 5 mg/day from Day 1 through Day 7, and 10 mg/day starting on Day 8. arm 2: Participants will initially receive 5 mg/day from Day 1 through Day 7, 10 mg/day from Day 8 through Day 14, and 20 mg/day starting on Day 15. arm 3: Participants will initially receive 5 mg/day from Day 1 through Day 7, 10 mg/day from Day 8 through Day 14, 20 mg/day from Day 15 through Day 21, and 30 mg/day starting on Day 22. arm 4: Participants will receive placebo from Day 1.
Interventions: intervention 1: JZP385 intervention 2: Placebo
Intervention descriptions: intervention 1: JZP385 capsules will be administered orally (PO) once daily in the morning on an empty stomach for 12 weeks. intervention 2: Placebo capsules will be administered orally (PO) once daily in the morning on an empty stomach for 12 weeks.

Protocol documents:
Prot_000.pdf: 
Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
 
TITLE PAGE 
Protocol Title: A Phase 2b, 12-week, Double-blind, Placebo-controlled, Randomized, 
Parallel-group, Multicenter Study of the Safety and Efficacy of JZP385 in the 
Treatment of Adults with Moderate to Severe Essential Tremor 
Study Number: JZP385-201 
Protocol Number: JZP385-201-04  
Amendment Number: Amendment 04 
Compound: JZP385 
Brief Title: A Study of JZP385 in Adults with Moderate to Severe Essential Tremor 
Study Phase: Phase 2b 
Sponsor Name: Cavion, Inc., a subsidiary of Jazz Pharmaceuticals, Inc. 
Legal Registered Address: 3170 Porter Drive, Palo Alto, CA, USA 94304 
Regulatory Agency Identifier Number(s): IND: 130296 
EudraCT Number: 2020-002463-61 
Refer to the final page of this protocol for electronic signature and date of approval. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Sponsor Signatory: 
 MD 
 
Clinical Development, 
Neuroscience 
Jazz Pharmaceuticals, Inc. 
Date 
Investigator Signatory: 
{Please see appended electronic signature page.} 
[Name] 
[Title] 
Date 
medical monitor name and contact information can be found in the Trial Site Binder (or 
equivalent).  
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 04 
Please see appended electronic signature 
page for the date. 
Amendment 03 
07 October 2022 
Amendment 02 
15 November 2021 
Amendment 01 
19 May 2021 
Original Protocol 
26 January 2021 
Amendment 04 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The overall rationale for this amendment is to facilitate participant enrollment by allowing 
participants to enter the study without having to discontinue concomitant antitremor medications, 
unless these medications (eg, primidone) are prohibited in accordance with other exclusion 
criteria.  
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis (Table 1) 
3 Objectives, Estimands and 
Endpoints 
9.4.1.2 Intercurrent Event 
Strategies 
9.4.2 Primary Estimand 
9.4.3.1 Secondary Estimand 
A new type of intercurrent event 
was added to account for any 
changes in concomitant 
medications after initiation of 
study intervention. 
To align with the allowance of 
concomitant use of antitremor 
medication. 
1.3 Schedule of Assessments 
5.1 Inclusion Criteria 
8.2.2 Tremor Research Group 
Essential Tremor Rating 
Assessment Scale – 
Performance Subscale 
(Table 5) 
Clarification was added that the 
TETRAS-ADL subscale and the 
CGI-S scale are to be performed 
at Screening Visit 1 only for 
participants who do not need to 
washout from medications that 
impact tremor; otherwise, these 
assessments should be 
performed at Screening Visit 2. 
To align with the allowance of 
concomitant use of antitremor 
medication. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
2.3.1 Risk Assessment 
2.3.3 Overall Benefit: Risk 
Summary 
Clarification was added that the 
potential risks associated with 
discontinuation of prior 
medications are relative to 
protocol-prohibited medications. 
To ensure potential risks regarding 
discontinuation of any prior 
medications are clearly understood. 
The statement relative to the 
potential risk of untreated 
symptoms of ET for those who 
are randomized to placebo was 
modified to specify the risk 
applies only to those who 
discontinue protocol-prohibited 
antitremor medication (eg, 
primidone) in order to 
participate in the study. 
To align with the allowance of 
concomitant use of anti-tremor 
medication. 
1.1 Synopsis (Table 3) 
4.1 Overall Design 
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding 
9.4.2 Primary Estimand 
9.4.3 Secondary Estimand 
Stratification at randomization 
will include a stratum relative to 
whether the participant is taking 
antitremor medication at the 
Baseline Visit. 
Concomitant use of antitremor 
medication(s) may impact response 
to treatment with JZP385.  
5.1 Inclusion Criteria 
A note was modified in 
Inclusion Criterion #3a relative 
to medication washout and 
screening for study entry. 
Clarification. 
Inclusion Criterion #4 was 
updated to clarify that male 
partners of WOCBP are 
required to use barrier 
protection from the first dose of 
study intervention until 30 days 
after the last dose of study 
intervention. 
Clarification 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
Inclusion Criterion #7 was 
added to require that, for 
participants who are being 
treated with antitremor 
medication, the dosage of 
medication must be stable for at 
least 6 weeks prior to their 
Screening Visit, and they do not 
anticipate any changes during 
the study. For participants not 
taking antitremor medication 
upon entering the study, they 
must have refrained from taking 
any antitremor medication 
within 6 weeks prior to their 
Screening Visit and not 
anticipate taking concomitant 
antitremor medication during 
participation in the study. 
To clarify restrictions surrounding 
stability of dosage for concomitant 
antitremor medications (or lack of 
use of antitremor medications).  
5.2 Exclusion Criteria 
Exclusion Criterion #6 was 
updated to indicate that 
participants with a history of 
Gilbert’s syndrome may be 
eligible for the study. 
To allow inclusion of participants 
with Gilbert's syndrome as 
UGT1A1 is not involved in 
JZP385 metabolism. 
Exclusion Criterion #13 was 
modified to remove the 
exclusion of antitremor 
medications. 
To align with the allowance of 
concomitant use of antitremor 
medication. 
Information on timing of 
discontinuation of primidone 
relative to study intervention 
was moved from Exclusion 
Criterion #13 to #14. 
Modification of an exclusion 
criterion resulted in moving 
information as appropriate. 
Exclusion Criterion #17 was 
modified to clarify that 
participants should refrain from 
using 
medication(s)/substance(s) that 
might produce tremor or 
interfere with the evaluation of 
tremor prior to discharge on 
study visit days. 
Clarification 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
Exclusion Criterion #21 was 
updated to indicate that 
screening laboratory tests may 
be repeated as needed. 
To allow repeat screening 
laboratory tests to be performed 
more than once in circumstances in 
which these additional tests are 
needed to confirm eligibility. 
Information about the exclusion 
of medical and recreational use 
of cannabinoids (including 
CBD) was moved from 
Exclusion Criterion #13a to #22. 
Modification of an exclusion 
criterion resulted in moving 
information as appropriate. 
1.3 Schedule of Assessments 
5.4 Screen Failures 
8 Study Assessments and 
Procedures 
8.2.2 Tremor Research Group 
Essential Tremor Rating 
Assessment Scale – 
Performance Subscale 
(Table 5) 
Rescreened participants, who 
had previously met the inclusion 
criterion relative to ET 
diagnosis confirmed by EAC 
(Inclusion Criterion #2), will not 
be assessed again for that 
criterion when rescreened and 
will not complete the 
TETRAS-PS at screening. 
This procedure lessens the burden 
on potential participants permitted 
to be rescreened for entry into the 
study without impacting the 
study’s integrity, as an ET 
diagnosis is not anticipated to 
change.  
8.1.1 Informed Consent 
Clarified that no study 
procedures, including washout 
of prior medications, may be 
undertaken before signing the 
ICF. 
Clarification 
8.1.4. Medication Review 
(Prior or Concomitant 
Medications) 
Medication(s) taken for ET 
should be reviewed within the 
prior 6 weeks (as opposed to 
prior 30 days) for all other 
medications. 
To ensure complete information on 
ET medication history is collected 
to align and confirm with new 
eligibility criteria specifications. 
Appendix 1: Abbreviations 
and Definitions 
The abbreviations CBD (for 
cannabidiol) and PRN were 
added. 
CBD and PRN are used in the body 
of the protocol. 
General/Throughout 
Amendment 03 Summary of 
Changes was moved to 
Appendix 8: Protocol 
Amendment History 
Formatting standard 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
The sponsor’s signatory for the 
protocol was changed. 
Organizational change 
Where appropriate, the term 
“treatment” was changed to 
“study intervention.” 
The term TETRAS composite 
outcome score was made 
consistent.  
For consistency of terms 
throughout the protocol 
Stratification at baseline 
regarding the Baseline TETRAS 
composite outcome score was 
corrected from “≤ 17 and > 17” 
to “≤ 17 or > 17.”  
Correction 
JZP385 (as opposed to 
suvecaltamide) is used 
consistently throughout the 
protocol. 
Editorial 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................3 
1.
PROTOCOL SUMMARY ..........................................................................................13 
1.1. 
Synopsis ......................................................................................................................13 
1.2. 
Schema ........................................................................................................................18 
1.3. 
Schedule of Activities (SoA) ......................................................................................19 
2.
INTRODUCTION ......................................................................................................27 
2.1. 
Study Rationale ...........................................................................................................27 
2.2. 
Background .................................................................................................................28 
2.3. 
Benefit/Risk Assessment ............................................................................................30 
2.3.1. 
Risk Assessment .........................................................................................................30 
2.3.2. 
Benefit Assessment .....................................................................................................31 
2.3.3. 
Overall Benefit: Risk Summary ..................................................................................31 
3.
OBJECTIVES, ESTIMANDS AND ENDPOINTS ...................................................32 
4.
STUDY DESIGN .......................................................................................................35 
4.1. 
Overall Design ............................................................................................................35 
4.2. 
Scientific Rationale for Study Design ........................................................................35 
4.3. 
Justification for Dose ..................................................................................................36 
4.4. 
End of Study Definition ..............................................................................................37 
5.
STUDY POPULATION .............................................................................................38 
5.1. 
Inclusion Criteria ........................................................................................................38 
5.2. 
Exclusion Criteria .......................................................................................................40 
5.3. 
Lifestyle Considerations .............................................................................................44 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................44 
5.3.2. 
Caffeine, Alcohol, and Tobacco .................................................................................44 
5.4. 
Screen Failures ............................................................................................................44 
5.5. 
Criteria for Temporarily Delaying Administration of Study Intervention .................45 
6.
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................46 
6.1. 
Study Intervention(s)/Treatment(s) Administered ......................................................46 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................48 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................48 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
6.4. 
Study Intervention/Treatment Compliance .................................................................49 
6.5. 
Dose Modification ......................................................................................................49 
6.6. 
Continued Access to Study Intervention After the End of the Study .........................49 
6.7. 
Treatment of Overdose ...............................................................................................49 
6.8. 
Concomitant Therapy .................................................................................................50 
7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................51 
7.1. 
Discontinuation of Study Intervention........................................................................51 
7.1.1. 
Positive Alcohol or Urine Drug Screens ....................................................................51 
7.1.2. 
Temporary Discontinuation/Study Intervention Interruption .....................................51 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................52 
7.3. 
Lost to Follow-up .......................................................................................................52 
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................................53 
8.1. 
General Administrative Procedures ............................................................................54 
8.1.1. 
Informed Consent .......................................................................................................54 
8.1.2. 
Assignment of Participant Number ............................................................................54 
8.1.3. 
Medical History ..........................................................................................................54 
8.1.4. 
Medication Review (Prior and Concomitant Medications) ........................................54 
8.1.5. 
Inclusion and Exclusion Criteria Review ...................................................................54 
8.1.6. 
Timing of Study Intervention Dosing .........................................................................55 
8.1.7. 
Montreal Cognitive Assessment .................................................................................55 
8.2. 
Efficacy Assessments .................................................................................................55 
8.2.1. 
Tremor Research Group Essential Tremor Rating Assessment Scale – 
Activities of Daily Living ...........................................................................................55 
8.2.2. 
Tremor Research Group Essential Tremor Rating Assessment Scale – 
Performance Subscale .................................................................................................56 
8.2.3. 
Clinical Global Impression of Severity ......................................................................57 
8.2.4. 
Quality of Life in Essential Tremor Questionnaire ....................................................58 
8.2.5. 
Clinical Global Impression of Change .......................................................................58 
8.2.6. 
Patient Global Impression of Change .........................................................................58 
8.2.7. 
36-item Short Form Health Survey Version 2 ............................................................58 
8.2.8. 
Essential Tremor Embarrassment Assessment ...........................................................58 
8.3. 
Safety Assessments .....................................................................................................59 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
8.3.1. 
Physical Examinations ................................................................................................59 
8.3.2. 
Vital Signs ..................................................................................................................59 
8.3.3. 
Electrocardiograms .....................................................................................................59 
8.3.4. 
Clinical Safety Laboratory Assessments ....................................................................60 
8.3.5. 
Pregnancy Testing ......................................................................................................60 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................60 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................61 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................61 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................61 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................61 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................62 
8.4.5. 
Pregnancy ...................................................................................................................62 
8.4.6. 
Adverse Events of Special Interest and Other Reportable Experiences .....................63 
8.4.7. 
Other Reportable Experiences: Overdose, Medication Errors, and Misuse ...............63 
8.5. 
Pharmacokinetics ........................................................................................................63 
8.6. 
Pharmacogenomics .....................................................................................................63 
8.7. 
Biomarkers ..................................................................................................................63 
8.8. 
Immunogenicity Assessments ....................................................................................64 
8.9. 
Health Economics .......................................................................................................64 
9.
STATISTICAL CONSIDERATIONS .......................................................................65 
9.1. 
Statistical Hypotheses .................................................................................................65 
9.2. 
Sample Size Determination ........................................................................................65 
9.3. 
Analysis Sets ...............................................................................................................66 
9.4. 
Statistical Analyses .....................................................................................................66 
9.4.1. 
General Considerations ...............................................................................................66 
9.4.1.1. 
Multiplicity Adjustments ............................................................................................66 
9.4.1.2. 
Intercurrent Event Strategies ......................................................................................67 
9.4.1.3. 
Pooling of Investigational Centers ..............................................................................68 
9.4.1.4. 
Dropouts and Missing Data ........................................................................................68 
9.4.2. 
Primary Estimand .......................................................................................................68 
9.4.3. 
Secondary Estimands and Endpoints ..........................................................................69 
9.4.3.1. 
Key Secondary Estimand ............................................................................................69 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
9.4.3.2. 
Secondary Endpoints ..................................................................................................70 
9.4.4. 
Tertiary/Exploratory Endpoints ..................................................................................71 
9.4.5. 
Safety Analysis ...........................................................................................................71 
9.4.6. 
Pharmacokinetic Analysis ..........................................................................................72 
9.5. 
Interim Analysis ..........................................................................................................72 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ..................................................................................................73 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................73 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................73 
10.1.2. 
Financial Disclosure ...................................................................................................73 
10.1.3. 
Informed Consent Process ..........................................................................................73 
10.1.4. 
Data Protection ...........................................................................................................74 
10.1.5. 
Committees Structure .................................................................................................74 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................74 
10.1.7. 
Data Quality Assurance ..............................................................................................75 
10.1.8. 
Source Documents ......................................................................................................75 
10.1.9. 
Study and Site Start and Closure ................................................................................76 
APPENDIX 1. ABBREVIATIONS AND DEFINITIONS ........................................................77 
APPENDIX 2. REFERENCES ...................................................................................................80 
APPENDIX 3. CLINICAL LABORATORY TESTS ................................................................84 
APPENDIX 4. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ...............................................86 
APPENDIX 5. CONTRACEPTIVE AND BARRIER GUIDANCE .........................................91 
APPENDIX 6. GENETICS .........................................................................................................94 
APPENDIX 7. CRITERIA FOR DIAGNOSIS OF ESSENTIAL TREMOR ............................95 
APPENDIX 8. PROTOCOL AMENDMENT HISTORY ..........................................................96 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
LIST OF TABLES 
Table 1: 
Primary and Key Secondary Objectives and Estimands .............................................14 
Table 2: 
Secondary and Exploratory Objectives and Endpoints ..............................................15 
Table 3: 
Overall Study Design ..................................................................................................17 
Table 4: 
Study Treatment/Intervention .....................................................................................47 
Table 5: 
TETRAS-PS Assessments ..........................................................................................57 
Table 6: 
Protocol-required Safety Laboratory Tests .................................................................84 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
1.
PROTOCOL SUMMARY
1.1. 
Synopsis
Protocol Title: 
A Phase 2b, 12-week, Double-blind, Placebo-controlled, Randomized, Parallel-group, 
Multicenter Study of the Safety and Efficacy of JZP385 in the Treatment of Adults with 
Moderate to Severe Essential Tremor 
Brief Title: A Study of JZP385 in Adults with Moderate to Severe Essential Tremor (ET) 
Rationale: 
This is a 12-week, double-blind, placebo-controlled, randomized, parallel-group, multicenter 
study of the safety and efficacy of JZP385 (also known as CX-8998, suvecaltamide, and 
MK-8998) in the treatment of adult participants with ET, as defined by the Movement Disorder 
Society (MDS) Consensus Statement on the Classification of Tremors from the Task Force on 
Tremor of the International Parkinson’s and MDS. This study was designed to be consistent with 
the United States (US) Food and Drug Administration (FDA) Guidance for Industry on 
Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, the 
International Conference on Harmonisation (ICH) E1A and E8 Guidance, and with the ethical 
principles in these guidances that originate from the Declaration of Helsinki. A phase 2a study, 
CX‑8998-CLN2-001 (T-CALM), provided proof-of-concept and informed the design of this 
study.  
The target patient population is participants with moderate to severe ET, which was selected to 
reflect the patient population within clinical practice for whom a therapeutic intervention for ET 
would be considered. Patients with mild ET are typically not treated with medication, as the 
tremor is not usually associated with significant functional disability. Essential tremor severity 
level in this study will be defined by eligibility criteria on the patient-rated (Tremor Research 
Group Essential Tremor Rating Assessment Scale [TETRAS] – Activities of Daily Living 
[TETRAS-ADL]) and clinician-rated (Clinical Global Impression of Severity [CGI-S]) measures 
of disability. The inclusion of a placebo control group in this study is necessary to determine the 
efficacy and safety of JZP385. 
The primary endpoint for the study is a composite of the sum of modified items 1 to 11 of the 
TETRAS-ADL subscale and modified items 6 and 7 of the TETRAS-PS (ie, TETRAS composite 
outcome score). The TETRAS-ADL subscale is a patient-rated scale of the impact of tremor on 
day-to-day functioning administered by a trained interviewer. The TETRAS-ADL subscale 
directly measures how a patient functions by assessing activities impacted by tremor, such as 
eating and drinking, dressing and personal hygiene, carrying items, and fine motor skills. The 
TETRAS-ADL demonstrated sensitivity to change with JZP385 in the T-CALM study (see the 
JZP385 Investigator’s Brochure [IB] for full results). The TETRAS-PS is a valid and reliable 
clinical rating scale that has demonstrated sensitivity to change with treatment and is 
recommended by the MDS Task Force to assess tremor severity. Items 6 (drawing an 
Archimedes spiral) and 7 (handwriting) of the TETRAS-PS evaluate the impact of upper limb 
tremor on performance, and thus represent an objective measure of the impact of upper limb 
tremor on functional tasks. Together, the items from the TETRAS-ADL subscale and 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Table 3: 
Overall Study Design 
Overall Design 
Study Phase 
Phase 2b 
Clinical Indication 
Essential Tremor 
Study Type 
Interventional 
Type of Design 
Randomized, parallel-group, 4-arm, multicenter  
Randomization will be stratified by the following: 
•
The select modified items from the TETRAS-ADL subscale
and TETRAS-PS (ie, TETRAS composite outcome score)a
(≤ 17 or > 17), as assessed at the Baseline Visit
•
The use of concomitant antitremor medication (Yes or No)
Type of Control 
Placebo Control 
Study Blinding 
Double-blind (Interactive response technology [IRT]) 
Population 
Participants with moderate to severe ET 
Number of Participants 
Approximately 400 participants will be randomized, with 
approximately 100 participants randomized to each treatment arm 
and 80 evaluable participants in each treatment arm of the study. 
Duration of Participation 
The study starts from the time participants sign the informed consent 
form (ICF) through the end of the study procedures/contact. The 
study comprises 3 periods: up to 35 days Screening Period (an 
additional 28 days are permitted for participants who require washout 
of primidone) including Baseline, followed by a 12-week Double-
blind Treatment Period, and a 2-week Safety Follow-up Period. Each 
participant will be enrolled for approximately 19 weeks.  
Number of Treatment Arms 
4 
Treatment Groups 
10, 20, or 30 mg/day JZP385, or placebo 
Data Monitoring Committee 
Not applicable 
a The TETRAS composite outcome score is the sum of modified items 1 to 11 of the TETRAS-ADL subscale and 
modified items 6 and 7 of the TETRAS-PS. For TETRAS-ADL, each item is modified from 5 response items to 
4 response items by collapsing options 0 and 1 together and for TETRAS-PS, each item is modified from 9 response 
items (due to 0.5 scoring increments) to 4 response items. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
1.2. 
Schema 
*An additional 28 days during the Screening Period are permitted for participants who require washout of
primidone.
Note: All JZP385 doses will be administered once daily on a mg/day basis.
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
a An additional 28 days during the Screening Period is permitted for participants who require washout of primidone. Potential participants who do not meet the 
criteria for participation in this study (screen failure) may be rescreened once provided the rescreening is approved by the study medical monitor. Potential 
participants screened an additional time (rescreened) who had previously met the inclusion criteria relative to ET diagnosis confirmed by the EAC (Inclusion 
Criterion #2) will not be assessed again relative to that criterion as part of the rescreening process and will not have to complete the TETRAS-PS assessment at 
Screening Visit 1 or 2, as applicable.  
b Screening Visit 2 is only for participants who need to washout of medications that impact tremor (eg, primidone) prior to Baseline. 
c All SAEs will be followed until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up (Section 8.4.3). 
d If participant discontinues study intervention and requires an E/D Visit, the Safety FU should be 2 weeks after the E/D visit. 
e Clinic visits at Week 1, Week 4, Week 8, E/D, and EoS/Safety FU may be conducted remotely, if required due to the COVID-19 pandemic, and with approval 
from the sponsor’s medical monitor. The TETRAS-PS will not be performed at remote visits, and PK samples may not be collected. 
f Phone contacts at Weeks 2 to 3, Weeks 5 to 7 and Weeks 9 to 11 may be converted to clinic visits if required due to local regulations or local requirements. If 
performed in-clinic, dispensing of study intervention may occur and urine pregnancy testing should be completed for WOCBP. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
2.
INTRODUCTION
Essential tremor (ET) is a serious, progressive, and chronically debilitating neurological disorder 
that can profoundly affect activities of daily living. Essential tremor is arguably the most 
common movement disorder among adults, but prevalence estimates vary. In a meta-analysis of 
28 population-based studies from 19 countries, the estimated pooled prevalence across all ages 
was 0.9%. Prevalence of ET increases markedly with age; across studies, the estimated pooled 
prevalence in adults ≥ 65 years of age was 4.6%, with prevalence estimates in individual studies 
ranging from 0.8 to 20.5% (Louis and Ferreira, 2010). More recent meta-analyses have estimated 
the global prevalence of ET at 0.32% (Song, 2021) and 1.33% (Louis and McCreary, 2021). 
These meta-analyses similarly demonstrated an increased prevalence of ET with age; Song and 
colleagues estimate the prevalence of ET in adults aged ≥ 80 years at 2.87% and Louis and 
McCreary estimate the prevalence of ET in adults ≥ 65 years of age at 5.79%. 
Essential tremor is characterized by an action tremor in the hands and arms that is bilateral and 
often slightly asymmetric. The tremor presents during voluntary movement (kinetic tremor) or 
while maintaining a fixed position against gravity (postural and orthostatic tremor). In patients 
with ET, tremor may also be present in the head, voice, and jaw, and less commonly the face or 
trunk (Louis, 2018). In the majority of individuals, tremor progresses slowly, starting on one side 
of the body and eventually affecting both sides, and further spreading to other regions of the 
body (National Institute of Neurological Disorders and Stroke [NINDS] 2019; NINDS 2020). In 
addition to motor features, there is increasing recognition that patients with ET exhibit 
significant non-motor symptoms including cognitive deficits, anxiety, social phobia, depression, 
and sleep disturbances (Louis, 2016; Musacchio, 2016; Sengul, 2015). 
Study CX-8998-CLN2-001 was a phase 2, randomized, double-blind, multicenter, placebo-
controlled, dose-titration study that assessed the efficacy and safety of immediate release (IR) 
JZP385 (also known as CX-8998, suvecaltamide, and MK-8998) in doses up to 20 mg/day 
(10 mg twice daily [BID]) for reducing the severity of tremor in participants with ET. This study 
demonstrated proof-of-concept, informed the design of the current phase 2b study, and provided 
preliminary evidence to support improvement in symptoms of ET with JZP385 treatment. 
Detailed results are available in the JZP385 Investigator’s Brochure (IB).  
2.1. 
Study Rationale 
Based on the proof-of-concept findings in the T-CALM study, in which adult participants with 
ET were treated with JZP385, as well as the high unmet need for therapies that better treat the 
significant impact of tremor on patients’ day-to-day functioning, Jazz Pharmaceuticals is 
conducting the present study with JZP385 to evaluate efficacy, safety, and PK information in this 
population. The dose-response at 3 doses of JZP385 will also be evaluated. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
2.2. 
Background 
Essential tremor has no cure, but symptomatic treatment of ET with drug therapies is considered 
when tremor interferes with a patient’s day-to-day functioning. No marketed pharmacological 
therapy has been developed specifically for the treatment of ET. All currently available 
pharmacotherapies have limitations with respect to efficacy, safety, or limited evidence from 
randomized, controlled trials to support their widespread use (Haubenberger and Hallett, 2018). 
Propranolol (a β-blocker) is approved to treat patients with ET in the United States (US) and in 
the European Union (EU). Another option is primidone, an anticonvulsant used to treat ET 
(approved only in the United Kingdom and Hungary). However, up to half of patients with ET 
do not respond to either propranolol or primidone, and over 50% of patients reportedly 
discontinue one or both medications due to lack of efficacy and/or side effects 
(Diaz and Louis, 2010; Ferreira, 2019).  
Other prescription medications are used off-label to treat ET, including topiramate, gabapentin, 
alprazolam, clonazepam, and other β-blockers. Many of these second- and third-line treatment 
options have limited data from randomized controlled trials in ET to support efficacy and the 
data do not suggest an efficacy profile that is any better than propranolol (Ferreira 2019; Hedera, 
2013). Additionally, these medications are associated with dependency, abuse, withdrawal 
symptoms due to abrupt cessation, and other troublesome side effects (Hedera 2013). 
Neurosurgical procedures, such as deep brain stimulation targeting the central intermediate 
nucleus of the thalamus or magnetic resonance imaging-guided focused ultrasound 
thalamotomy, offer treatment options for patients whose ET is severely disabling and who are 
refractory to drug therapy (Zesiewicz, 2010). Thus, the challenges with current treatments for 
ET, coupled with the significant impact on patient quality of life, support the need for additional 
therapeutic options for this patient population. 
Although the pathogenesis of ET has not been fully established, several studies have identified 
abnormal oscillations of neuronal activity in the cortico-bulbo-cerebello-thalamic pathways 
(Haubenberger and Hallett, 2018). T-type calcium channels (CaV3) are mediators of subthreshold 
oscillations and excessive rhythmicity in pathophysiologic states found in tremor (Llinás, 2003; 
Handforth, 2005; Llinás, 2007; Park, 2013). Numerous lines of pharmacological and genetic 
evidence suggest that the increased activation of CaV3 channels and excessive rhythmicity play a 
key role in neurological disorders such as ET (Park, 2010; Shipe, 2008; Handforth, 2010). For 
example, several pharmacological studies have demonstrated that drugs with antagonist activity 
at CaV3 reduce tremor in animal models (Shipe, 2008; Miwa, 2008; Handforth, 2010; Quesada, 
2011). In clinical studies, zonisamide and topiramate, which are both thought to act, in part, 
through suppression of CaV3 activity, have shown some efficacy in patients with ET. However, 
their usefulness has been limited by poor tolerability and/or excessive premature 
discontinuations of treatment, potentially due to pharmacological activity on other types of ion 
channels (Morita, 2005; Ondo, 2007; Bermejo, 2008; Chang, 2015). Selective targeting of CaV3 
channels may offer a more efficacious and better-tolerated treatment option for patients with 
chronic neurological conditions. The high selectivity of JZP385 as a CaV3 modulator, along with 
its lack of effects on other types of channels, make it a promising candidate for the treatment of 
ET.  
JZP385 is formulated as an extended-release (ER) oral dosage form, containing 
immediate-release (IR) and delayed release (DR) pellets in a hard opaque capsule. The original 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
formulation of JZP385 was an IR formulation that required BID administration. To enable 
once-daily administration, a 2-component multi-particulate (pellet) dosage form was developed 
that contains an IR pellet to deliver the required initial plasma concentration for rapid onset of 
effect and a DR pellet to maintain plasma concentrations above the target therapeutic threshold. 
The current study will use the ER JZP385 product that has the identifier of “DR2” (see Table 4). 
Preliminary evidence that JZP385 may provide a meaningful treatment option for ET was 
generated by Study CX-8998-CLN2-001 (T-CALM), a phase 2, randomized, double-blind, 
multicenter, placebo-controlled dose-titration study that assessed the efficacy and safety of the 
IR formulation of JZP385 in doses up to 20 mg/day (10 mg BID) for reducing the severity of 
tremor in participants with ET. Despite not meeting statistical significance on the primary 
endpoint (Tremor Research Group Essential Tremor Assessment Rating Scale [TETRAS] 
performance subscale [TETRAS-PS] as rated by independent video raters), numerical 
improvements, favoring JZP385, were observed on TETRAS-PS as rated by the investigators 
and the TETRAS activities of daily living (TETRAS-ADL) subscale. In addition, a numerically 
higher percentage of patients treated with JZP385 reported improvement in their overall 
condition as measured using the Clinical Global Impression of Change (CGI-C). JZP385, at 
doses up to 20 mg/day (10 mg BID) was well tolerated with the most commonly reported AEs in 
the System Organ Class (SOC) of Nervous System Disorders and Psychiatric Disorders. Most 
AEs were mild to moderate in severity. 
Four phase 1 studies in healthy male and female participants have been completed with the IR 
formulation of JZP385 (PN001, PN002, PN003, and PN005). Two phase 1 studies 
(CX-8998-CLN2-005 and JZP385-101) evaluated the PK of JZP385 and its 2 active metabolites 
(M01 and M02) following single and multiple doses of various ER formulations administered 
once daily. Preliminary PK data from Study CX-8998-CLN2-005 suggest that both ER 
formulations tested achieved reduced JZP385 maximum plasma concentration (Cmax) relative to 
the IR formulation, with limited impact on overall JZP385 plasma exposure as measured by area 
under the plasma concentration-time curve (AUC). Furthermore, a high-fat meal substantially 
delayed DR2 JZP385 time to maximum concentration (Tmax) with minimal impact on Cmax or 
overall AUC, indicating an impact of food on early (IR component of formulation) but not late 
(DR component of formulation) absorption. Study JZP385-101 characterized the PK of JZP385, 
M01, and M02, dose proportionality, and safety and tolerability following multiple doses of ER 
formulations (8, 16, 24, and 36 mg administered once daily). The study also explored the effect 
of food on both formulations. Preliminary data from this study suggest that both ER formulations 
had similar PK profiles and PK parameters following multiple daily doses of 8, 16, 24, and 36 
mg. Both formulations result in approximately dose-proportional PK of JZP385 and its major 
metabolites (M01 and M02) in the dose range of 8 to 24 mg as assessed at steady state. This 
trend holds true through the 36 mg dose level considering that ~90% of JZP385 steady state is 
achieved following 4 days of 36 mg dosing. Doses up to 36 mg/day were well-tolerated and a 
similar safety profile was observed with the ER formulations compared to the IR formulation, 
with most commonly reported AEs in the SOCs of Nervous System Disorders and Psychiatric 
Disorders. Adverse events were primarily mild to moderate in severity, were reported during the 
first week of treatment (at the 8 mg/day dose) and were transient. The exploratory evaluation of 
the effect of a high-fat high-calorie meal on JZP385 ER formulations confirmed earlier findings 
of negligible impact of food on JZP385 Cmax or AUC with a noteworthy delay in Tmax. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04  
Amendment 04 
 
 
 
 
A detailed description of the chemistry, pharmacology, efficacy, and safety of JZP385 is 
provided in the IB. 
2.3. 
Benefit/Risk Assessment 
A summary of the benefit-risk assessment for participation in Study JZP385-201 is provided in 
the subsections below.  
2.3.1. 
Risk Assessment 
Participants with ET who enroll in this study may encounter the following potential risks: 
• For participants randomized to study intervention with JZP385, the risks are expected 
to be similar to those seen in previously conducted clinical studies. In general, AE 
profiles have been consistent across populations studied (eg, ET, schizophrenia, 
healthy volunteers). Analysis of TEAEs showed that JZP385 in the dose ranges from 
1 mg to 24 mg (IR) and from 8 mg QD to 36 mg QD (ER formulations) was generally 
well tolerated by most participants. Generally, the most commonly reported AEs were 
in the SOC of Nervous System Disorders and Psychiatric Disorders; the most 
common AEs (≥ 5%) in participants with ET have included dizziness, headache, 
euphoric mood, and insomnia. Most AEs were mild or moderate in severity, were 
transient, and did not lead to study discontinuation. No clinically important trends in 
vital signs, safety laboratories, or ECG parameters have been observed in the 
completed clinical studies. The potential risks to participants will be managed and 
mitigated by the use of exclusion criteria which preclude subjects with an unstable or 
clinically significant medical condition, or who are at significant risk for 
cardiovascular complications, suicide or drug abuse from participating in the study. In 
addition, a titration schedule will be implemented such that subjects will start at a 
lower dose and titrate up to the final dose. Extensive monitoring of AEs, ECGs, 
orthostatic hypotension, and suicidal ideation and behavior will occur at frequent 
clinic visits throughout the study.  
• For participants who are randomized to the placebo treatment arm and who 
discontinued antitremor medication(s) during the screening period, there may be risks 
associated with untreated symptoms of ET.  
• Participants will be asked to discontinue protocol-prohibited medication(s) to enter 
the study. There may be risks associated with abrupt discontinuation of these 
medications, most notably, with primidone. To mitigate this risk, an extended 
screening period is implemented for participants who require washout of primidone to 
permit safe down-titration. Additionally, participants will not undergo discontinuation 
from prohibited antitremor medications and will be ineligible for the study if it is 
deemed unsafe by the investigator and medical monitor, as applicable.  
• Study procedure-related risks, including risks and/or discomfort associated with blood 
collection, electrocardiograms (ECGs), physical examinations, and completion of 
questionnaires and other assessments. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04  
Amendment 04 
 
 
 
 
2.3.2. 
Benefit Assessment 
Participants with ET who enroll in this study may experience the following benefits: 
• Receiving JZP385 for the study duration may alleviate the significant symptom 
burden associated with ET. 
• Irrespective of which study intervention a participant receives in the study, all 
participants will contribute to the process of developing new therapies in ET. 
• Participants will receive comprehensive clinical exams and clinical monitoring 
associated with the study. 
2.3.3. 
Overall Benefit: Risk Summary 
Benefits to participants include the potential to receive a therapy that may alleviate symptoms of 
ET and to contribute to the development of new therapeutics in ET, as well as receiving 
comprehensive physical examination and clinical monitoring. 
Risks to participants include those related to JZP385 treatment, the potential need to discontinue 
protocol-prohibited medication, the potential that participants who discontinued or plan to 
discontinue antitremor medications to enter the study will be treated with placebo for the study 
duration, and risks related to the study procedures. 
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of JZP385 may be found in the IB. 
 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04  
Amendment 04 
 
 
 
 
 
• 
To evaluate the efficacy of 
JZP385 to improve overall ET 
when administered once daily 
for up to 12 weeks at fixed doses 
of 10, 20, and 30 mg/day. 
• 
Change from Baseline to Week 12 on the sum of modified 
items 6 and 7a of the TETRAS-PS as summarized by each 
dose of JZP385 and placebo. 
• 
Change from Baseline to Week 12 on the sum of modified 
items 1 to 11a of the TETRAS-ADL subscale as 
summarized by each dose of JZP385 and placebo. 
• 
Proportion of participants who improved (≥ 1-point 
improvement) from Baseline to Weeks 4 and 8 on the 
CGI-S. 
• 
Change from Baseline to Weeks 4 and 8 on the TETRAS 
composite outcome scorea, TETRAS-ADL, TETRAS-PS, 
TETRAS upper limb score (item 4), and TETRAS total 
score. 
• 
Proportion of participants reported as much improved on 
the PGI-C and CGI-C at Weeks 4 and 8 
• 
Change from Baseline to Week 12 on the 36-item Short 
Form Health Survey (SF-36) as summarized by each dose 
of JZP385 and placebo. 
• 
Time course analysis on the sum of modified items 6 and 
7a of the TETRAS-PS as summarized by each dose of 
JZP385 and placebo. 
Abbreviations: AUC = area under the plasma concentration-time curve; CGI-C = Clinical Global Impression of 
Change; CGI-S = Clinical Global Impression of Severity; Cmax = maximum plasma concentration; 
C-SSRS = Columbia Suicide Severity Rating Scale; Ctau = concentration at trough; ECG = electrocardiogram; 
ET = essential tremor; ETEA = Essential Tremor Embarrassment Assessment; PGI-C = Patient Global Impression 
of Change; PK = pharmacokinetics; QUEST = Quality of life in Essential Tremor Questionnaire; SF-36 = 36-item 
Short Form Health Survey; t½ = terminal half-life; TEAE = treatment-emergent adverse event; 
TETRAS-ADL = Tremor Research Group Essential Tremor Rating Assessment Scale – Activities of Daily Living; 
TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale – Performance Subscale; 
Tmax = time to maximum concentration. 
a The TETRAS composite outcome score is the sum of modified items 1 to 11 of the TETRAS-ADL subscale and 
modified items 6 and 7 of the TETRAS-PS. For TETRAS-ADL, each item is modified from 5 response items to 4 
response items by collapsing options 0 and 1 together and for TETRAS-PS, each item is modified from 9 response 
items (due to 0.5 scoring increments) to 4 response items. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
4.
STUDY DESIGN
4.1. 
Overall Design
This is a 12-week, double-blind, placebo-controlled, randomized, parallel-group, multicenter 
study of the safety and efficacy of JZP385 in the treatment of adult participants with moderate to 
severe ET.  
The total duration of the study for each participant will be approximately 19 weeks. During the 
Screening Period, which will occur over a period of up to 35 days (an additional 28 days are 
permitted for participants who require washout of primidone), all participants will be evaluated 
for eligibility and will washout any prohibited medications. Participants may be allowed to 
rescreen once if the rescreening is approved by the medical monitor.  
Participants eligible for the study will be randomized in a 1:1:1:1 ratio to receive once daily 
doses of 10, 20, or 30 mg JZP385 or placebo during a 12-week Double-blind Treatment Period. 
Randomization will be stratified by the TETRAS composite outcome score (≤ 17 or > 17) and 
the use of concomitant antitremor medication (Yes or No), as assessed at the Baseline Visit. 
JZP385 will be administered orally (PO) once daily in the morning on an empty stomach for 
12 weeks. Dosing will be titrated as follows:  
•
Participants randomized to the 10 mg/day dose will initially receive 5 mg/day from
Day 1 through Day 7, and 10 mg/day starting on Day 8.
•
Participants randomized to the 20 mg/day dose will initially receive 5 mg/day from
Day 1 through Day 7, 10 mg/day from Day 8 through Day 14, and 20 mg/day starting
on Day 15.
•
Participants randomized to the 30 mg/day dose will initially receive 5 mg/day from
Day 1 through Day 7, 10 mg/day from Day 8 through Day 14, 20 mg/day from
Day 15 through Day 21, and 30 mg/day starting on Day 22.
Once participants reach their assigned fixed dose, they will continue on that dose for the 
remainder of the planned 12-week treatment period. No dose adjustments will be allowed. 
Participants who cannot tolerate their assigned fixed dose of JZP385 will be withdrawn from the 
study. 
Assessments of efficacy, safety, and PK will be conducted as indicated in Section 8.2, 
Section 8.3, and Section 8.5, respectively, and as described in the Schedule of Activities (SoA) 
(Section 1.3) 
4.2. 
Scientific Rationale for Study Design 
This study was designed to be consistent with the US Food and Drug Administration (FDA) 
Guidance for Industry on Providing Clinical Evidence of Effectiveness for Human Drug and 
Biological Products, the International Conference on Harmonisation (ICH) E1A and E8 
Guidance, and with the ethical principles in these guidances that originate in the Declaration of 
Helsinki. 
The target patient population is participants with moderate to severe ET, which was selected to 
reflect the patient population within clinical practice for whom a therapeutic intervention for ET 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04  
Amendment 04 
 
 
 
 
 
would be considered. Patients with mild ET are typically not treated with medication, as the 
tremor is not usually associated with significant functional disability 
(Gironell and Kulisevsky, 2009; Louis, 2010; Rajput and Rajput, 2014). Essential tremor severity 
level in this study will be defined by eligibility criteria on patient-rated (TETRAS-ADL) and 
clinician-rated (CGI-S) measures of disability. The inclusion of a placebo control group in this 
study is necessary to determine the efficacy and safety of JZP385. 
The 12-week duration (which includes up to 3 weeks of titration and a minimum of 9 weeks at 
the assigned fixed dose) is considered as adequate duration to detect efficacy and evaluate safety 
in this phase 2b study. Based on results from the T-CALM study, efficacy signals were observed 
at both time points tested: the end of Week 2 (at 16 mg/day [8 mg BID]) and the end of Week 4 
(at 20 mg/day [10 mg BID]). Adverse events were primarily reported during the first week of 
treatment and the majority of the commonly reported AEs resolved within a week of onset. A 
longer treatment duration of 12 weeks with clinic visits to assess safety at multiple time points 
(Weeks 1, 4, 8, and 12), combined with weekly phone calls for AE reporting, will allow for an 
adequate assessment of safety and durability of the treatment effect.  
The primary endpoint for the study is a composite of the sum of modified items 1 to 11 of the 
TETRAS-ADL subscale and modified items 6 and 7 of the TETRAS-PS (ie, TETRAS composite 
outcome score). The TETRAS-ADL subscale is a patient-rated scale of the impact of tremor on 
day-to-day functioning that is administered by a trained interviewer. The TETRAS-ADL 
subscale directly measures how a patient functions by assessing activities impacted by tremor, 
such as eating and drinking, dressing and personal hygiene, carrying items, and finer motor skills 
(Elble, 2012). The TETRAS-ADL demonstrated sensitivity to change with JZP385 in the 
T-CALM study (see the JZP385 IB for full results). The TETRAS-PS is a valid and reliable 
clinical rating scale that has demonstrated sensitivity to change with treatment and is 
recommended by the Movement Disorder Society (MDS) Task Force to assess tremor severity 
(Elble, 2013). Items 6 (drawing an Archimedes spiral) and 7 (handwriting) of the TETRAS-PS 
evaluate the impact of upper limb tremor on performance, and thus represent an objective 
measure of the impact of upper limb tremor on functional tasks. Together, the items from the 
TETRAS-ADL subscale and TETRAS-PS that comprise the primary endpoint represent both 
patient-rated and objective measures of the functional impact of tremor. 
The key secondary endpoint is the CGI-S. The clinician-rated CGI-S will specifically evaluate 
patients’ ability to function due to ET and will adequately complement the primary endpoint. In 
the T-CALM study, a numerically higher percentage of patients reported improvement on the 
CGI-C when treated with JZP385 at 16 and 20 mg/day (administered as 8 and 10 mg BID, 
respectively) compared to placebo. Given that the CGI-C score generally correlates with the 
CGI-S such that improvement in one follows the other (Busner and Targum, 2007), these data 
provide preliminary support that CGI-S will be sensitive to improvement with JZP385.  
4.3. 
Justification for Dose 
The doses of JZP385 being evaluated in the study are 10, 20, and 30 mg/day administered in the 
morning. In the T-CALM study conducted in patients with ET, daily doses of 16 and 20 mg/day 
JZP385 (administered as the IR formulation at doses of 8 and 10 mg BID, respectively), 
improved symptoms of tremor across several clinically meaningful endpoints, including the 
TETRAS-ADL subscale, and were safe and well tolerated. Preliminary PK data and subsequent 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04  
Amendment 04 
 
 
 
 
 
PK simulations from the relative bioavailability study (Study CX-8998-CLN2-005) indicate that 
the same daily doses of the IR and ER formulations produce similar exposures (ie, steady state 
daily AUC). Therefore, this study will further evaluate the safety and efficacy of 20 mg/day 
JZP385, in addition to a higher dose of 30 mg/day and a lower dose of 10 mg/day administered 
orally, once daily in the morning. Preliminary safety and tolerability data from study 
JZP385-101, which enrolled 100 healthy older volunteers with a mean age of 44.1 years (median 
= 42.9 years; range 23 to 76 years) indicate that titrated doses of up to 36 mg were generally safe 
and well tolerated. 
The titration schedule in this protocol is based on the PK of JZP385, as well as the titration 
experience in previous clinical studies conducted to date. Steady state levels of JZP385 are 
reached in 5 days. In the T-CALM study in patients with ET, participants received the IR 
formulation of JZP385 for 1 week each at doses of 8 and 16 mg/day before the final dose of 
20 mg/day (doses were administered as 4, 8 and 10 mg BID, respectively). Preliminary safety 
and tolerability data from study JZP385-101 also indicate that the starting dose of 8 mg/day of 
the ER formulation of JZP385, with dose escalation at weekly intervals, was generally safe and 
well tolerated in healthy volunteers. Although these data indicate the 8 mg/day dose is tolerated 
as a starting dose, all participants in this study will initially receive 5 mg/day for the first week of 
the treatment period to evaluate whether starting at a lower dose may further improve 
tolerability. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all periods of the 
study including the last scheduled procedure shown in the SoA. 
The end of the study is defined as the date of the last visit of the last participant remaining in the 
study. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04  
Amendment 04 
 
 
 
 
 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 18 to 80 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Participants who are diagnosed with ET (including ET plus) according to the MDS 
Consensus Statement on the Classification of Tremors from the Task Force on Tremor 
of the International Parkinson’s and Movement Disorder Society (Bhatia, 2018) and 
centrally reviewed by an Eligibility Adjudication Committee (EAC; see 
Section 10.1.5).  
3. Participants have moderate to severe disability associated with tremor at both the 
Screening and Baseline visits, as determined by all of the following: 
a. Score of ≥ 22 on the TETRAS-ADL subscale; and  
b. Note: This criterion has been removed in Amendment 3.  
c. CGI-S rating of at least moderate for participants’ ability to function. 
Note: Participants who need washout of a medication(s) that could impact their tremor 
assessment (eg, medications that produce tremor or that treat tremor but are prohibited 
because of potential PK drug-drug interactions with study intervention [such as 
primidone]) at Screening Visit 1 must return to the clinic for a second Screening Visit 
(Screening Visit 2). For these participants, the Screening TETRAS-ADL subscale and 
CGI-S assessments that will be used to determine eligibility will be performed at 
Screening Visit 2, after participants have washed out their medication. 
Sex and Contraceptive/Barrier Requirements 
4. Participant is male or female. 
a. Male participants: 
Male participants are eligible to participate if they agree to the following during the 
study intervention period and for at least 30 days after the last dose of study 
intervention: 
• Refrain from donating sperm. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
PLUS, either: 
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR 
•
Must agree to use contraception/barrier as detailed below:
−
Agree to use a male condom with female partner use of an additional highly
effective contraceptive method with a failure rate of < 1% per year (as
described in Appendix 5) when having sexual intercourse with a woman of
childbearing potential (WOCBP) who is not currently pregnant.
−
Agree to use a male condom when engaging in any activity that allows for
passage of ejaculate to another person.
b. Female participants:
A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
one of the following conditions applies: 
•
Is a woman of non-childbearing potential (WONCBP) as defined in Appendix 5.
OR
•
Is a WOCBP and using a contraceptive method that is highly effective, with a
failure rate of < 1%, as described in Appendix 5 during the study intervention
period and for at least 30 days after the last dose of study intervention. Note: In
addition to hormonal contraception, male partners of WOCBP are required to use
barrier protection, eg, condoms, from the first dose of study intervention until
30 days after the last dose of study intervention. The investigator should evaluate
the potential for contraceptive method failure (eg, noncompliance, recently
initiated) in relationship to the first dose of study intervention.
•
A WOCBP must have a negative highly sensitive serum pregnancy test at
Screening Visit 1 and negative urine pregnancy tests (unless serum is required by
local regulations) at the Screening Visit 2 (if applicable) and at the Baseline Visit,
see Section 8.3.5.
−
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a
serum pregnancy test is required. In such cases, the participant must be
excluded from participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention
are located in Section 8.3.5.
•
The investigator is responsible for review of medical history, menstrual history, and
recent sexual activity to decrease the risk for inclusion of a woman with an early
undetected pregnancy.
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Informed Consent 
5. Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
6. Willing and able to comply with the study design schedule and other requirements. 
Prior/Concomitant Antitremor Medications 
7. If currently treated with antitremor medications, potential participants must be on a 
stable dosage for at least 6 weeks prior to Screening Visit 1 and must not anticipate 
making any changes to their antitremor medication for the duration of the study. 
Note: Treatment with some antitremor medications (eg, primidone) is not allowed in 
accordance with other exclusion criteria. Participants not currently taking antitremor 
medications who enter the study must have not taken any antitremor medication within 
6 weeks prior to Screening Visit 1 and must not take any concomitant antitremor 
medication during the study.  
 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Female participants who are pregnant, nursing, or lactating, or plan to become pregnant 
during the study or within 90 days of study completion. 
2. Known history or current evidence of other medical or neurological conditions that 
may cause or explain the participant’s tremor in the opinion of the investigator or 
central reviewer (when applicable), including, but not limited to: 
a. Parkinson’s disease or features of atypical parkinsonism 
b. Psychogenic tremor 
c. Clinically significant symptoms or signs of dystonia, myoclonus, or ataxia 
d. Cerebellar disease other than ET 
e. Traumatic brain injury 
f. Alcohol abuse or withdrawal 
g. Mercury poisoning 
h. Hyperthyroidism 
i. Pheochromocytoma 
j. Head trauma or cerebrovascular disease within 3 months before onset of ET 
k. Multiple sclerosis 
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Amendment 04 
 
 
 
 
 
l. Clinically significant polyneuropathy in the opinion of the investigator, or 
m. Family history or diagnosis of Fragile X syndrome 
3. Considered at risk of falls in the opinion of the investigator. 
4. Has evidence at Screening of severe cognitive impairment as defined by a Montreal 
Cognitive Assessment (MoCA; score < 20) or has cognitive impairment that in the 
opinion of the investigator would prevent completion of study procedures (including 
the ability to accurately self-report on study questionnaires) or the ability to provide 
informed consent. 
5. History or presence of any acutely unstable medical condition, malignancy other than 
basal cell carcinoma or resected noninvasive cutaneous squamous cell carcinoma, or 
surgical history that could affect the safety of the participant or interfere with study 
efficacy, safety, or PK assessments; or the ability of the participant to complete the 
study per the judgment of the investigator. 
6. History or presence of gastrointestinal (including prior bariatric bypass surgery), 
hepatic (including alanine aminotransferase [ALT] or aspartate aminotransferase [AST] 
≥ 2 x upper limit of normal [ULN] or total bilirubin ≥ 1.5 ULN), or severe renal 
impairment or end-stage renal disease, or any other condition that, in the opinion of the 
investigator, may interfere with absorption, distribution, metabolism, or excretion of 
drugs. Participants with hyperbilirubinemia who have a history of Gilbert’s syndrome 
may be eligible for the study; participants whose screening laboratory test results 
demonstrate predominantly unconjugated hyperbilirubinemia must be evaluated to 
exclude other diagnoses and, subsequently, must have the diagnosis of Gilbert’s 
syndrome established in order to be eligible. 
7. Presence of significant cardiovascular disease at Screening including but not limited to 
the following:  
a. Myocardial infarction within the past year; 
b. Unstable angina pectoris; 
c. Symptomatic congestive heart failure (American College of Cardiology/American 
Heart Association stage C or D);  
d. Revascularization procedures within the past year; 
e. Ventricular cardiac arrhythmias requiring automatic implantable cardioverter 
defibrillator or medication therapy; 
f. Uncontrolled hypertension, or systolic blood pressure ≥ 155 mmHg or diastolic 
blood pressure ≥ 95 mmHg (based on the average of triplicate assessments at 
Screening Visit 1, Screening Visit 2, or Baseline); 
g. Clinically significant ECG abnormality per the investigator assessment, or 
Fridericia’s corrected QT interval (QTcF) > 450 msec for men and > 470 msec for 
women, based on the average of triplicate assessments at Screening or Baseline; or  
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Amendment 04 
 
 
 
 
 
h. Any history of cardiovascular disease or any significant cardiovascular condition 
that in the investigator’s opinion may jeopardize participant safety in the study 
8. History or presence of bipolar and related disorders, schizophrenia, schizophrenia 
spectrum disorders, or other psychotic disorders according to the Diagnostic and 
Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria. 
9. Current suicidal risk as determined from history, by presence of active suicidal ideation 
as indicated by positive response to item 4 or 5 on the C-SSRS (within the past 
24 months), or any history of suicide attempt; current or past (within 1 year) major 
depressive episode according to DSM-5 criteria. Participants with stable treated 
depression are allowed per the judgment of the investigator or the treating medical 
practitioner and the antidepressant treatment has to be stable for at least 6 months prior 
to Screening and remain stable for the duration of the study. 
10. History (within past 2 years at screening) or presence of a diagnosed substance use 
disorder (including alcohol, tobacco, and cannabis) according to DSM-5 criteria, 
known drug dependence, or seeking treatment for alcohol or substance abuse related 
disorder.  
Prior/Concomitant Therapy 
For the following exclusion criteria, please refer to the Trial Site Binder for a list of examples 
of prohibited therapies and medications. 
11. Prior magnetic resonance (MR)-guided focused ultrasound thalamotomy, surgical 
intervention (eg, deep brain stimulation, ablative thalamotomy, gamma knife 
thalamotomy), or inability to refrain from using a device for treatment of tremor for the 
duration of the treatment period.  
12. Botulinum toxin injection for the treatment of upper limb tremor in the 6 months 
before screening or planned use at any time during the study. 
13. Treatment with any medication that could produce tremor taken within 2 weeks or 
5 half-lives (whichever is longer) before the evaluation of tremor at the Screening Visit 
(Screening Visit 1 or 2, as applicable) or anticipated use at any time during 
participation in the study. Note: Regular use of sleep medications or anxiolytics 
(eg, benzodiazepines) to improve sleep or anxiety is permitted provided it will continue 
to be used at stable dosages throughout the study (ie, PRN use is not permitted). 
14. Use of prescription or nonprescription drugs or other products known to be inducers of 
CYP3A4 that are known to decrease AUC by > 30% (eg, primidone) and which cannot 
be discontinued at least 4 weeks before Baseline or planned use at any time during the 
study. Note: If a potential participant is taking primidone at screening, it must be 
discontinued at least 4 weeks prior to Screening Visit 2. 
15. Use of prescription or nonprescription drugs, or other products (eg, grapefruit, 
grapefruit juice, or Seville oranges) known to be strong or moderate inhibitors of 
CYP3A4, that cannot be discontinued 2 weeks or 5 half-lives, whichever is longer, 
before Baseline or planned use at any time during the study. 
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Amendment 04 
 
 
 
 
 
16. Use of proton pump inhibitors that cannot be discontinued at least 2 weeks before 
Baseline, or planned use at any time during the study. Occasional use of antacids or 
histamine-2 receptor antagonists will be permitted, but antacids should be taken at least 
4 hours before or after study intervention; and histamine-2 receptor antagonists should 
be taken at least 4 hours after and at least 12 hours before study intervention.  
17. Inability to refrain from use of medication/substance(s) that might produce tremor or 
interfere with the evaluation of tremor on study visit days prior to discharge such as, 
but not limited to, stimulant decongestants, beta-agonist bronchodilators, and alcohol. 
Participants who consume caffeine or use tobacco should take their regular amount of 
caffeine or tobacco on the clinic days. 
Prior/Concurrent Clinical Study Experience 
18. Received an investigational drug 30 days or 5 half-lives prior to the Baseline visit 
(whichever is longer) or plans to use an investigational drug (other than the study 
intervention) during the study. 
19. Received any study intervention in a previous JZP385 (formerly known as CX-8998 or 
MK-8998) clinical study. 
Diagnostic assessments 
20. A fall in blood pressure (ie, a decrease in systolic blood pressure ≥ 20 mm Hg or 
diastolic blood pressure ≥ 10 mm Hg), or a heart rate increase (ie, > 30 beats per 
minute) observed on the average of the triplicate orthostatic assessments at Baseline, or 
in the opinion of the investigator, the participant was symptomatic for orthostatic 
hypotension. 
21. Laboratory value(s) at screening outside the laboratory reference range that is (are) 
considered clinically significant by the investigator (clinical chemistry, hematology, 
and urinalysis). Note: Screening laboratory tests may be repeated, as needed. 
22. Urine drug screen positive at Screening for drugs of abuse (eg, phencyclidine [PCP], 
cocaine, cannabinoids (including cannabidiol [CBD]), opiates, barbiturates, 
amphetamines, methadone, or MDMA [Ecstasy]) unless explained by a medication that 
is being washed out during the Screening Period (eg, primidone) or by use of an 
allowed prescription medication (eg, benzodiazepine as outlined in Exclusion 
Criterion #13). Note: Medical or recreational use of cannabinoids (including CBD) is 
not permitted at Screening or throughout the duration of study participation. If the 
interpretation of positive results is ambiguous, or there are extenuating circumstances, 
a repeat urine drug screen may be performed if approved by the investigator and the 
medical monitor. 
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Other Exclusions 
23. Regular use of more than 3 units of alcohol per day (see also Exclusion Criterion 17). 
A unit of alcohol is defined as a 12-fluid ounce (350 mL) glass of beer (5% alcohol by 
volume), a 5-fluid ounce (150 mL) glass of wine (12% alcohol by volume), or a 
1.5 fluid ounce (44 mL) glass of spirit (40% alcohol by volume). 
24. Regular consumption of caffeine > 400 mg/day or > 4 cups of coffee per day. 
25. Allergy or sensitivity to any ingredients in the study intervention formulation or 
placebo. 
26. Any other condition and/or situation that causes the investigator or medical monitor to 
deem a participant unsuitable for the study. 
 
5.3. 
Lifestyle Considerations 
No specific restrictions to lifestyle are required for this study. 
5.3.1. 
Meals and Dietary Restrictions 
As noted in Exclusion Criterion 15, refrain from consumption of grapefruit, grapefruit juice, or 
Seville oranges from 2 weeks before the start of study intervention until after the last dose of 
study intervention.  
Participants will be instructed to take a single oral daily dose of study intervention in the 
morning, on an empty stomach, upon awakening (and no more than 1 hour after awakening). 
Participants will also be instructed to abstain from eating or drinking (except water) for 
60 minutes after taking the study intervention. 
Participants will also be instructed to refrain from eating or drinking (except water) prior to the 
clinic visit, such that study intervention is taken on an empty stomach in the clinic. Participants 
should also abstain from eating or drinking (except for water) for 60 minutes after taking study 
intervention. At clinic visits, a light breakfast should be served approximately 1 hour after dosing 
and should be consumed within 15 to 20 minutes. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
As noted in exclusion criteria 23 and 24 (Section 5.2), consumption of > 3 units of alcohol or 
> 400 mg caffeine per day is not permitted during the study. As noted in Exclusion Criterion 17, 
consumption of alcohol is prohibited on clinic days. 
Participants who consume caffeine or use tobacco should take their regular amount of caffeine or 
tobacco on clinic days, as per their regular schedule. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to receive study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
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Amendment 04 
 
 
 
 
 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any applicable SAEs (see Section 8.4.1). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once provided rescreening is approved by the medical monitor. Potential participants 
screened an additional time (rescreened) who had previously met the inclusion criterion relative 
to ET diagnosis confirmed by the EAC (Inclusion Criterion #2) will not be assessed again 
relative to that criterion as part of the rescreening process and will not have to complete the 
TETRAS-PS assessment at Screening Visit 1 or 2, as applicable. Rescreened participants should 
be assigned a new participant number. 
5.5. 
Criteria for Temporarily Delaying Administration of Study 
Intervention  
As indicated in Section 6.5, dose modifications are not permitted. See Section 7.1.2 for details 
regarding temporary interruption of study intervention. 
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Amendment 04 
 
 
 
 
 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1. 
Study Intervention(s)/Treatment(s) Administered 
The study interventions planned for use in this study are described in Table 4 below. 
 
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Table 4: 
Study Treatment/Intervention 
Treatment 
Arm 
Intervention/ 
Treatment 
Namea 
Formulation 
Unit Dose 
Strength(s)b 
Dosage 
Level(s) 
Route of 
Administration 
Use 
Sourcing 
Package 
Labeling 
Storage 
Conditions 
1 
Placebo 
Capsule 
Placebo 
3 x placebo 
QD 
Oral 
Placebo 
comparator 
Provided 
centrally 
by the 
sponsor 
Placebo 
capsules will 
be provided in 
blister cards; 
and labeled as 
required per 
country 
requirement. 
Double-
blind 
Store at 
2 to 8ºC 
2 
JZP385 
(DR2) 
Capsule 
Baseline Visit:  
5 mg JZP385 
1 x 5 mg QD 
+ 2 x placebo 
QD 
Oral 
Experimental 
Provided 
centrally 
by the 
sponsor 
JZP385 
capsules will 
be provided in 
blister cards; 
and labeled as 
required per 
country 
requirement. 
Double-
blind 
Store at 
2 to 8ºC 
Weeks 2-12: 
10 mg JZP385 
1 x 10 mg QD 
+ 2 x placebo 
QD 
3 
JZP385 
(DR2) 
Capsule 
Baseline Visit:  
5 mg JZP385 
1 x 5 mg QD 
+ 2 x placebo 
QD 
Oral 
Experimental 
Provided 
centrally 
by the 
sponsor 
JZP385 
capsules will 
be provided in 
blister cards; 
and labeled as 
required per 
country 
requirement. 
Double-
blind 
Store at 
2 to 8ºC 
Week 2:  
10 mg JZP385 
1 x 10 mg QD 
+ 2 x placebo 
QD 
Weeks 3-12: 
20 mg JZP385 
2 x 10 mg QD 
+ 1 x placebo 
QD 
4 
JZP385 
(DR2) 
Capsule 
Baseline Visit:  
5 mg JZP385 
1 x 5 mg QD 
+ 2 x placebo 
QD 
Oral 
Experimental 
Provided 
centrally 
by the 
sponsor 
JZP385 
capsules will 
be provided in 
blister cards; 
and labeled as 
required per 
country 
requirement. 
Double-
blind 
Store at 
2 to 8ºC 
Week 2:  
10 mg JZP385 
1 x 10 mg QD 
+ 2 x placebo 
QD 
Week 3: 
20 mg JZP385 
2 x 10 mg QD 
+ 1 x placebo 
QD 
Weeks 4-12: 
30 mg JZP385 
3 x 10 mg QD 
Abbreviations: mg = milligram; QD = once daily. 
a The JZP385 DR2 formulation is delayed release formulation 2 ie, capsules containing a combination of IR and DR pellets; details of the formulation can be found in the JZP385 IB.  
b The dose strength of JZP385 is based on the active moiety in the drug product. 
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Amendment 04 
 
 
 
 
 
6.2. 
Preparation/Handling/Storage/Accountability 
Further guidance and information for the final disposition of unused study interventions are 
provided to the sites. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study interventions received, and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention, and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All participants who sign the informed consent form (ICF) will receive a participant number 
assigned by interactive response technology (IRT) at screening. The participant number 
identifies the participant for all study procedures that occur throughout the study. This number is 
unique and once assigned, cannot be reassigned to another study participant.  
Treatment allocation/randomization for this study will occur centrally through the use of an IRT. 
Participants eligible for the study will be randomized in a 1:1:1:1 ratio to receive once daily 
doses of 10, 20, or 30 mg JZP385 or placebo. Randomization will be stratified by the TETRAS 
composite outcome score (≤ 17 or > 17) and the use of concomitant antitremor medication (Yes 
or No), as assessed at the Baseline Visit. 
A double-blind approach will be used throughout the 12-week treatment period. During the study 
(including the titration period), the number of capsules taken each day will be the same for 
patients randomized to each treatment. JZP385 and placebo capsules will look and feel identical. 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a participant’s 
intervention assignment unless this could delay emergency treatment of the participant.  
If a participant’s intervention assignment is unblinded, the sponsor must be notified within 
24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and IRT system, as applicable. The participant’s treatment 
assignment may be unblinded for regulatory reporting purposes. Notification of the treatment 
assignment is only made known to those who require it for safety reporting and submission 
processes. All other individuals involved in the study, including the investigator, will remain 
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Amendment 04 
 
 
 
 
 
blinded to treatment assignment. Participants for whom the blind is broken for this reason will 
not be withdrawn from the study.  
Sponsor safety staff may unblind the intervention assignment for any participant with an SAE. If 
the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, 
a copy of the report, identifying the participant’s intervention assignment, may be sent to 
investigators in accordance with local regulations and/or sponsor policy.  
6.4. 
Study Intervention/Treatment Compliance 
When participants administer study intervention in the clinic (ie, at Week 1, Week 4, Week 8, 
and Week 12 visits), they will take the last dose from the kit dispensed at the previous visit, 
under medical supervision. The date and time of each dose administered in the clinic will be 
recorded in the source documents.  
Participants will take the first dose of study intervention at home in the morning on the day 
following the Baseline Visit (or Day 1). When participants self-administer study intervention at 
home, compliance with study intervention will be assessed at each clinic visit. Compliance will 
be assessed by counting returned capsules during the site visits and documented in the source 
documents Deviation(s) from the prescribed dosage regimen should be recorded. 
A record of the quantity of JZP385 or placebo capsules dispensed to and administered by each 
participant must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates should also be recorded. 
6.5. 
Dose Modification 
No dose adjustments or modifications will be allowed. Participants who cannot tolerate their 
assigned fixed dose of JZP385 will be discontinued from the study intervention (see Section 7.1). 
Every effort should be made to have the participant attend an Early Discontinuation Visit (see 
Section 1.3). 
6.6. 
Continued Access to Study Intervention After the End of the Study 
There is no continued access to study intervention upon completion of the study. Participants 
should follow-up with their healthcare provider regarding the resumption of any medications that 
were discontinued prior to study participation. 
6.7. 
Treatment of Overdose 
Any dose greater than the assigned dose that a participant receives in a 24-hour time period will 
be considered an overdose. In a case of an acute overdose, it is recommended that the stomach is 
emptied and that oral gavage with activated charcoal is used to reduce absorption of JZP385. See 
the JZP385 IB for further details. 
In the event of an overdose, the investigator should: 
• Contact the medical monitor immediately. 
• Evaluate the participant to determine, in consultation with the medical monitor, 
whether study intervention should be interrupted or discontinued. 
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• Report any AE/SAE or laboratory abnormalities associated with the overdose. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
6.8. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Concomitant treatment with some medications/therapies is not permitted during the study (see 
Exclusion Criteria 11 to 17 in Section 5.2). A full list of prohibited medications is provided in 
the Investigator Trial Site Binder. 
JZP385 has a potential to inhibit P-glycoprotein (P-gp) and breast cancer resistance protein 
(BCRP) in the intestine at the studied doses. Therefore, medicines that are known sensitive 
substrates of P-gp and BCRP should be administered approximately 12 hours apart from study 
intervention. In vitro data indicate JZP385 is a weak inducer of CYP3A4 and CYP2B6. 
Therefore, medicines that are sensitive substrates of CYP3A4 and CYP2B6 that are taken 
concomitantly with JZP385 should be monitored for potential decrease in pharmacological 
effect. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
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Amendment 04 
 
 
 
 
 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Discontinuation from study intervention does not represent withdrawal from the study 
(Section 7.2). Participants may discontinue from study intervention at any time for any reason, or 
at the discretion of the investigator. In addition, a participant may be dropped from study 
intervention by the investigator or sponsor for safety, behavioral, compliance and/or 
administrative reasons.  
For participants who discontinue study intervention, all effort should be made to complete the 
procedures listed in the Early Discontinuation Visit (Section 1.3). Participants should be asked to 
return 2 weeks later for the EoS/Safety Follow-up Visit. If the Early Discontinuation Visit occurs 
2 or more weeks after the last dose of study intervention, an additional safety follow-up visit is 
not required. 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will not remain in 
the study. See the SoA for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed. 
A participant must be discontinued from study intervention for any of the following reasons: 
• The participant or participant’s legal representative requests to discontinue study 
intervention. 
• The participant has an AE that may compromise the participant’s continued 
participation. 
• The participant has a suicide risk reported or assessed by the Columbia Suicide 
Severity Rating Scale (C-SSRS; see Section 8.3.6). 
• The participant has a positive serum pregnancy test or becomes pregnant during the 
study (see Appendix 5 and Section 8.3.5). 
• The participant is noncompliant with study intervention or procedures. 
• Sponsor decides to terminate the study prior to completion.  
7.1.1. 
Positive Alcohol or Urine Drug Screens 
The investigator may discontinue study intervention for any participant with a positive alcohol or 
urine drug screen. However, if the investigator believes discontinuation of study intervention is 
not necessary despite a positive alcohol or urine drug screen result, approval from the medical 
monitor is required in order to retain the participant in the study. 
7.1.2. 
Temporary Discontinuation/Study Intervention Interruption 
If a participant must temporarily interrupt study intervention for any reason, the sponsor’s 
medical monitor should be consulted to determine whether the participant will continue in the 
study.  
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Jazz Pharmaceuticals, Inc. 
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Amendment 04 
 
 
 
 
 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or compliance 
reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an Early Discontinuation Visit should be 
conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected at the time of 
study discontinuation and follow-up, and for any further evaluations that need to be completed. 
The participant will be permanently discontinued both from the study intervention and from the 
study at that time. 
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 study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
7.3. 
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 study site. The following actions must be 
taken if a participant fails to return to the clinic for a required study visit: 
• 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 study. 
• 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 study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Study and Site 
Start and Closure Section 10.1.9. 
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Amendment 04 
 
 
 
 
 
8.1. 
General Administrative Procedures 
8.1.1. 
Informed Consent 
The investigator or medically qualified designee (consistent with local requirements) must obtain 
documented consent from each potential participant/legal representative prior to participation in 
this study. No study procedures, including washout of prior medications, may be undertaken 
before signing the ICF. A signed copy of the ICF should be given to the participant and the 
original should be placed in the participant’s medical records.  
8.1.2. 
Assignment of Participant Number 
Each participant who signs the ICF will be assigned a unique number that will identify the 
participant throughout the study. Once a number has been assigned, it cannot be reassigned to 
another study participant. 
8.1.3. 
Medical History 
A medical history will be obtained by the investigator or a medically qualified designee 
(consistent with local regulations). All active conditions should be recorded and any condition 
diagnosed within the participant’s lifetime that the investigator deems clinically significant. The 
information will include, but is not limited to, symptoms of ET (current and past, including 
symptoms experienced prior to any ET treatment); history and treatment (if any) of 
cardiovascular, pulmonary, gastrointestinal, hepatic, renal, immunologic, neurologic, or 
psychiatric disease; reproductive status; current contraceptive method (if appropriate); and 
confirmation of relevant inclusion and exclusion criteria. 
8.1.4. 
Medication Review (Prior and Concomitant Medications) 
The investigator or medically qualified designee should review the participant’s prior medication 
use within 30 days (any medication(s) taken for ET should be reviewed within the prior 
6 weeks). Medication that is required to be washed out prior to the study should also be recorded. 
All medications currently being taken by the participant should be recorded.  
Additional information related to any medications taken for the treatment of ET since diagnosis 
(eg, treatment duration, satisfaction) should be collected.  
8.1.5. 
Inclusion and Exclusion Criteria Review 
All inclusion and exclusion criteria should be reviewed by the investigator to ensure the 
participant qualifies for the study. A research diagnostic verification form will be completed by 
the site within 2 days of completion of the TETRAS-PS assessment, which will be video-
recorded at Screening Visit 1 or Screening Visit 2, as applicable (see Section 1.3), and rated by a 
trained blinded rater on site. To support selection of the appropriate patient population in the 
study, the video recording of the TETRAS-PS conducted at Screening will undergo central 
review by an independent expert rater from the EAC to confirm a correct diagnosis of ET. 
Results of this review will be available in the electronic clinical outcome assessment provider’s 
portal. Screening results from all participants meeting the eligibility requirements will be further 
assessed for final approval of inclusion in the study. Details of the eligibility review by the EAC 
will be provided in the EAC Charter.  
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Amendment 04 
 
 
 
 
 
8.1.6. 
Timing of Study Intervention Dosing 
Participants will be requested to take study intervention in the morning on an empty stomach 
upon awakening (and no more than 1 hour after awakening). After the Baseline Visit, on days 
when participants come into the clinic, study intervention will be administered on site on an 
empty stomach. When participants administer study intervention in the clinic (ie, at the Week 1, 
Week 4, Week 8, and Week 12 visits), they will take the last dose from the kit dispensed at the 
previous visit, under medical supervision. 
8.1.7. 
Montreal Cognitive Assessment 
The Montreal Cognitive Assessment (MoCA) is designed as a rapid screening instrument to 
detect mild cognitive dysfunction. The MoCA test was validated in 2000 and revalidated in 2004 
(Nasreddine, 2005). The assessment comprises a 30-question test that can be completed in 
approximately 10 minutes. The MoCA assesses different cognitive domains, including attention 
and concentration, executive functions, memory, language, visuoconstructional skills, conceptual 
thinking, calculations, and orientation. The total possible score is 30 points; a score of < 20 is 
considered exclusionary in the current study. According to the DSM-V criteria, people with 
major neurocognitive disorders typically have scores on cognitive scales that fall at least 2 SD 
below the mean of a normative sample. The eligibility cutoff of < 20 represents 2 SD below the 
mean for the highest age group (75 to 85 years) and lowest education level (elementary school or 
lower) in a rigorously selected normal cognitive population in Sweden (N = 758) 
(Borland, 2017). In the largest population-based US sample (N = 2,653) where cognitive 
impairment was not rigorously screened out, the eligibility cut-off of < 20 represents 1 SD below 
the mean (Rossetti, 2011), lending additional support for this cut-off in a different sample. 
A sample MoCA can be found in the Investigator Trial Site Binder. 
8.2. 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Tremor Research Group Essential Tremor Rating Assessment Scale – Activities 
of Daily Living 
The Tremor Research Group first published TETRAS in 2008 (Elble, 2008). TETRAS consists 
of a 12-item activities of daily living (ADL) subscale, and a 9-item performance subscale (PS). 
TETRAS was developed as a rapid clinical assessment of ET that requires no equipment other 
than pen and paper.  
The ADL subscale includes many of the items assessed in previously developed scales for the 
evaluation of tremor (Fahn, 1993; Louis, 2000; Bain, 1993), including eating and drinking, 
dressing and personal hygiene, carrying items and finer motor skills. Each item in the 
TETRAS-ADL subscale is rated on a 0 to 4 scale, with 0 representing normal activity and 4 
representing severe abnormality. The sum of the individual scores provides the overall score, 
ranging from 0 to 48. The TETRAS-ADL subscale has face validity, has preliminarily 
demonstrated test-retest reliability, and is highly correlated with the TETRAS-PS (Elble, 2012; 
Elble, 2016). It has also demonstrated sensitivity to change with JZP385 treatment in the 
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T-CALM study. Items 1 to 11 of the TETRAS-ADL subscale assess the impact of tremor on 
day-to-day functioning, while item 12 assesses the social impact of tremor. 
A sample TETRAS-ADL subscale can be found in the Investigator Trial Site Binder. 
During the study, the TETRAS-ADL will be administered and scored by a trained rater at the 
site. 
8.2.2. 
Tremor Research Group Essential Tremor Rating Assessment Scale – 
Performance Subscale 
The TETRAS-PS quantifies tremor in the head, face, voice, limbs, and trunk. Each item on the 
TETRAS-PS is rated on a 0 to 4 rating scale, with scoring of upper limb tremor allowing for 
0.5-point increments. Specific amplitude ranges (measured in centimeters) define the tremor 
rating. Raters first estimate the maximum amplitude of tremor and then assign the corresponding 
rating. The sum of the individual rating scores provides the overall performance score, ranging 
from 0 to 64. Administration of the TETRAS-PS takes approximately 10 minutes. The 
TETRAS-PS has demonstrated both test-retest reliability and sensitivity to change (Elble, 2012; 
Study CX-8998-CLN2-001 [T-CALM] – see IB for details) and was given a “recommended” 
rating as a tremor severity scale by the MDS (Elble, 2013). 
TETRAS-PS items 6 and 7 are the Archimedes spiral and handwriting assessments, respectively. 
Both are rated on a 0 (normal) to 4 (severe) rating scale. The Archimedes spiral is tested in both 
the right and the left hands, while the handwriting is assessed with the dominant hand only. The 
sum of the TETRAS-PS items 6 and 7 provides a score ranging from 0 to 12. The Archimedes 
spiral and handwriting tasks have been integral in the routine examination of patients with tremor 
for decades, heavily utilized in tremor rating scales beyond the TETRAS (Bain, 1993; Fahn, 
1993; Louis, 2001), and have demonstrated sensitivity to change with treatment (Calzetti, 1982; 
Haubenberger, 2011; Hopfner, 2015; Koller, 1986; Shill, 2004; Tolosa and Loewenson, 1975). 
A sample TETRAS-PS can be found in the Investigator Trial Site Binder.  
During the study, the TETRAS-PS assessment will be administered and scored by a blinded 
trained rater at the site throughout the study and conducted as detailed in Table 5. 
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Table 5: 
TETRAS-PS Assessments 
Visit 
Description of Assessment 
Screening Visit 1 
A blinded rater will assess TETRAS-PS if participant does not need to washout 
of a medication that impacts tremor. 
Video record this assessment. 
Participants who will undergo washout of medications that impact tremor (eg, 
primidone) are assessed at Screening Visit 2 only. 
Screening Visit 2 
(if applicable) 
A blinded rater will assess TETRAS-PS if participant needs to washout of a 
medication that impacted tremor reported at Screening Visit 1. 
Video record this assessment. 
Baseline 
A blinded rater will assess TETRAS-PS (assess at same time of day as the 
anticipated 1-hour postdose assessment at post-baseline visits) 
[Optional] Assess items 6 and 7 of the TETRAS-PS serially across the day at 
6 time points: initial assessment, 1 (use assessment from full TETRAS-PS for 
this time point), 2, 4, 6, and 8 hours after initial assessment 
Week 4 
A blinded rater will assess TETRAS-PS 1-hour postdose. 
Week 8 
A blinded rater will assess TETRAS-PS 1-hour postdose. 
[Optional] Assess items 6 and 7 of the TETRAS-PS serially across the day at 
6 time points: predose, 1 (use assessment from full TETRAS-PS for this time 
point), 2, 4, 6, and 8 hours postdose (time points should correspond to the same 
time of day as Baseline assessments).  
Week 12 
A blinded rater will assess TETRAS-PS 1-hour postdose. 
E/D Visit 
A blinded rater will assess TETRAS-PS 1-hour postdose (assess at same time of 
day as 1-hour postdose assessment at post-baseline visits). 
Abbreviations: EAC = Eligibility Adjudication Committee; ET = essential tremor; TETRAS-PS = The Essential 
Tremor Rating Assessment Scale - Performance Subscale. 
Note: Potential participants screened an additional time (rescreened) who had previously met the inclusion criterion 
relative to ET diagnosis confirmed by the central EAC (Inclusion Criterion #2) will not have to complete the 
TETRAS-PS assessment and subsequent central review by the EAC at Screening Visit 1 or 2, as applicable. 
8.2.3. 
Clinical Global Impression of Severity 
The CGI-S will be assessed by qualified medical personnel (ie, a clinician) to assess the severity 
of participants’ ET. The severity assessment will rate the participants’ ability to function due to 
their ET. 
The CGI-S is a 5-point Likert-type rating scale and a widely used assessment in clinical 
psychopharmacology trials to assess severity of illness. The responses to this clinician-completed 
scale range from 1 (no limitations) to 5 (severe). The clinician will rate his/her impression of the 
severity of the participant’s current ability to function due to their ET relative to his/her 
experience with this patient population. 
A sample CGI-S can be found in the Investigator Trial Site Binder. 
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8.2.4. 
Quality of Life in Essential Tremor Questionnaire 
The Quality of life in Essential Tremor Questionnaire (QUEST) was developed to specifically 
assess the impact of ET on health-related quality of life (Tröster, 2005). The QUEST is a 30-item 
questionnaire comprising 5 subscales (physical, psychosocial, communication, hobbies/leisure, 
and work/finance) and a total score, plus 3 additional items relating to sexual function and 
satisfaction with tremor control and medication side effects. Initial reports provide preliminary 
support of its reliability and validity. The internal consistency was very good to excellent for 4 of 
the subscales and the total score, and moderately high for the Work/Finance subscale 
(Tröster, 2005). The QUEST has also demonstrated sensitivity to change with deep brain 
stimulation for ET (Sandvik, 2012). 
A sample QUEST questionnaire can be found in the Investigator Trial Site Binder. 
8.2.5. 
Clinical Global Impression of Change 
The CGI-C will be assessed by qualified medical personnel (ie, a clinician) to assess the change 
in the participants’ ability to function due to ET. 
The CGI-C is a 5-point Likert-type rating scale and a widely used assessment to assess efficacy 
in clinical drug trials. Clinicians will rate their impression of any change in the severity of the 
participant’s condition since Baseline on a 5-point scale ranging from 1 (much improved) to 5 
(much worse). Clinicians’ rating will focus on the participants’ change in their ability to function 
due to ET. 
A sample CGI-C can be found in the Investigator Trial Site Binder. 
8.2.6. 
Patient Global Impression of Change 
The PGI-C is a 5-point Likert-type rating scale and a widely used assessment to assess efficacy 
in clinical drug trials. Participants will rate the change in their condition since Baseline on a 
5-point scale ranging from 1 (much improved) to 5 (much worse). Participants’ rating will focus
on the change in their ability to function due to ET.
A sample PGI-C can be found in the Investigator Trial Site Binder. 
8.2.7. 
36-item Short Form Health Survey Version 2
The 36-item Short Form Health Survey Version 2 (SF-36v2) is a multi-purpose, short form 
health survey with 36 questions. It yields an 8-scale profile of functional health and well-being 
scores as well as psychometrically-based physical and mental health summary measures and a 
preference-based health utility index (Hays and Stewart, 1992; Ware and Sherbourne, 1992). 
A sample SF-36v2 can be found in the Investigator Trial Site Binder.  
8.2.8. 
Essential Tremor Embarrassment Assessment 
The Essential Tremor Embarrassment Assessment (ETEA) is a patient-rated questionnaire 
administered by a health care provider or researcher that contains 14-items assessing 
embarrassment related to tremor. Participants provide a simple response (disagree or agree) to 
each of the 14-items, the sum of which yields an initial score (Score A, range = 0 to 14). 
Participants then provide a more nuanced response to each question on a 0-to-5-point Likert 
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scale ranging from disagree (0) to agree strongly (5). The sum of the nuanced responses yields a 
second score (Score B, range = 0 to 70). Higher scores on both the simple and nuanced responses 
indicate greater embarrassment. The ETEA was developed based on input from both tremor 
experts and patients and was subsequently validated in 75 patients with ET where it 
demonstrated high internal consistency (Traub, 2010). The ETEA has also demonstrated 
sensitivity to change with treatment in patients with ET (Kreisler, 2019). 
A sample ETEA questionnaire can be found in the Investigator Trial Site Binder. 
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.3.1. 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, and neurological systems; a genitourinary exam is excluded. Height 
and weight (in ordinary indoor clothes without shoes) will also be measured and recorded as 
indicated in the SoA in Section 1.3.  
Any abnormalities identified at the screening physical exam should be recorded as medical 
history.  
8.3.2. 
Vital Signs 
Vital signs (to be taken before blood collection, when applicable), including body temperature, 
respiratory rate, and orthostatic blood pressure, and pulse rate will be assessed at each clinic 
visit, as indicated in the SoA (Section 1.3). 
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
Orthostatic blood pressure (systolic and diastolic) and pulse rate will be obtained after the 
participant has been in a supine position for at least 5 minutes, and again after the participant has 
been standing for 2 minutes. Baseline and Screening orthostatic assessments will be taken in 
triplicate (at 15 to 30-minute intervals), and a single orthostatic assessment will be performed at 
all other visits. 
Respiratory rate and body temperature will be assessed after the participant has been resting and 
seated (or supine) for at least 5 minutes. 
8.3.3. 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected 
QT (QTc) intervals. 
Electrocardiograms will be reviewed, initially interpreted, signed, and dated by the investigator 
or a designated physician after each ECG collection. All ECGs (with the exception of ECGs for 
participants who are screen failures) will be transmitted to a designated central ECG laboratory. 
A cardiologist at the central ECG laboratory will conduct a full over-read. A report based on data 
from this over-read will be issued to the site.  
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8.3.4. 
Clinical Safety Laboratory Assessments 
See Appendix 3 for the list of clinical laboratory tests to be performed and the SoA (Section 1.3) 
for the timing and frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
All laboratory tests with abnormal values considered clinically significant during participation in 
the study and considered related to study intervention should be repeated until the values return 
to normal or baseline or are no longer considered clinically significant by the investigator or 
medical monitor. 
•
If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified, and the 
sponsor notified.
•
All protocol-required laboratory tests, as defined in Appendix 3, must be conducted in 
accordance with the laboratory manual and the SoA (Section 1.3).
8.3.5. 
Pregnancy Testing 
Refer to Section 5.1 for pregnancy testing entry criteria. 
Pregnancy testing (urine or serum as required by local regulations) should be conducted as 
specified in the SoA (Section 1.3). Additional serum or urine pregnancy tests may be performed, 
as determined necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the study. 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring 
JZP385 is considered to be a central nervous system-active study intervention. Participants being 
treated with JZP385 should be monitored appropriately and observed closely for suicidal ideation 
and behavior or any other unusual changes in behavior, especially at the beginning and end of 
the course of study intervention, or at the time of dose changes, either increases or decreases. 
Participants who experience signs of suicidal ideation or behavior, should undergo a risk 
assessment. All factors contributing to suicidal ideation or behavior should be evaluated and 
consideration should be given to discontinuation of the study intervention.  
Baseline assessment of suicidal ideation and behavior/ intervention emergent suicidal ideation 
and behavior will be monitored using the C-SSRS. At the Screening Visit, the 
Baseline/Screening Version of the C-SSRS will be administered to participants to exclude any 
individuals with active suicidal ideation or behavior. 
The Since Last Visit Version of the C-SSRS will be administered to participants at every clinic 
visit after their Screening visit, including the Baseline and Follow-up visits. At the Baseline 
Visit, any participant who reports active suicidal ideation (eg, a positive response to Question 4 
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or 5 on the C-SSRS) or behavior (eg, a positive response to any suicidal behavior question on the 
C-SSRS) will be excluded. At post-baseline visits, active suicidal ideation or behavior must be
recorded as an AE and reported to the sponsor or designee within 24 hours of first knowledge of
the event by study personnel. Please refer to Appendix 4 for details on reporting other reportable
experiences (OREs).
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Appendix 4. 
Adverse events 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 all AEs. 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 4. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the start of study intervention until the follow-up visit 
at the time points specified in the SoA (Section 1.3). 
All SAEs will be recorded and reported to the sponsor or designee immediately and within 
24 hours of first knowledge of the event by study personnel, as indicated in Appendix 4. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.  
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded as medical history/current medical conditions, not as AEs. All SAEs 
that occur after the consent form is signed but before study intervention/treatment must be 
reported by the investigator if they cause the participant to be excluded from the study, or are the 
result of a protocol-specified study intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment, or a procedure. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading 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 will be followed until resolution, stabilization, the event 
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is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix 4. 
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 
intervention 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 intervention 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. 
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. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
The Reference Safety Information for the determination of expectedness of JZP385 can be found 
in the IB. 
8.4.5. 
Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until 30 days after last study 
intervention. 
If a pregnancy is reported, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the female participant or female 
partner of male participant (after obtaining the necessary signed informed consent from the 
female partner) pregnancy. 
While pregnancy itself is not considered an AE or SAE, any pregnancy complications or elective 
termination of a pregnancy for medical reasons will be reported as an AE or SAE. Abnormal 
pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs and will be reported as such. 
The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. After obtaining the necessary signed informed consent, the investigator will collect 
follow-up information on the participant/pregnant female partner and the neonate and the 
information will be forwarded to the sponsor. Neonates will be followed for 6 months following 
birth. 
Any post-study pregnancy-related SAE considered reasonably related to the study intervention 
by the investigator will be reported to the sponsor as described in Section 8.4.5. While the 
investigator is not obligated to actively seek this information in former study participants/ 
pregnant female partners, he or she may learn of an SAE through spontaneous reporting. 
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8.8. 
Immunogenicity Assessments 
Immunogenicity assessments are not being conducted in this study. 
8.9. 
Health Economics 
Health economics are not being assessed in this study. 
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The null and alternative hypotheses for analysis of the primary estimand variable are: 
H0: u JZP385 = u Placebo 
H1: u JZP385 ≠ u Placebo 
Specifically, the null hypothesis states that there is no difference in the mean change on the 
TETRAS composite outcome score from Baseline to Week 12 between each dose of JZP385 and 
the placebo control group. The alternative hypothesis is that the mean change on the TETRAS 
composite outcome score from Baseline to Week 12 is not equal between each dose of JZP385 
and the placebo control group.  
The null and alternative hypotheses for analysis of the key secondary estimand variable are: 
H0: p JZP385 = p Placebo 
H1: p JZP385 ≠ p Placebo 
Specifically, the null hypothesis states that there is no difference in the proportion of participants 
who improved by ≥ 1 point on the CGI-S from Baseline to Week 12 between each dose of 
JZP385 and the placebo control group. The alternative hypothesis is that the proportion of 
participants who improved by ≥ 1 point on the CGI-S from Baseline to Week 12 is not equal 
between each dose of JZP385 and the placebo control group. 
Each JZP385 treatment group will be compared individually to placebo. The remaining 
secondary and exploratory endpoints will not be controlled within the formal hypothesis test for 
type Ⅰ error. All safety analyses will be descriptive; no formal statistical testing will be 
performed. 
9.2. 
Sample Size Determination 
A sample size of 80 evaluable participants per treatment group will provide 90% power to detect 
a difference of 3.1 points for the change from Baseline to Week 12 on the TETRAS composite 
outcome score between JZP385 and placebo, with a common SD of 6.0 points. This sample size 
will also provide 91.7% power to detect a 26% between-treatment (assuming JZP385 at 66% 
versus placebo at 40%) difference in proportion of participants who improved by at least 1 point 
on the CGI-S from Baseline to Week 12. Assuming a 20% dropout rate, a total of 
400 participants (100 participants per treatment group) will be randomized. The sample size 
calculation for the TETRAS composite outcome score is based on t-test and the CGI-S sample 
size calculation is based on chi-square test, both tests are 2-sided at the significance level of 0.05. 
For the TETRAS composite outcome score, at least 80% power is still achieved if there is a 
reduction of 0.4 points from the assumption in the difference in mean change from baseline 
(assuming a constant common standard deviation) or an increase in common standard deviation 
by 1 point, (assuming a constant difference in means). 
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hierarchical testing sequence will be employed. The testing procedure will stop when a p-value 
exceeds 2-sided significance level of 0.05 (see below). 
Statistical hypotheses to be tested (in sequential order): 
1. Change in the TETRAS composite outcome score from Baseline to Week 12, 30 mg/day
versus placebo.
2. Difference in proportion of participants who improved ≥ 1 point on the CGI-S from Baseline
to Week 12, 30 mg/day versus placebo.
3. Change in the TETRAS composite outcome score from Baseline to Week 12, 20 mg/day
versus placebo.
4. Difference in proportion of participants who improved ≥ 1 point on the CGI-S from Baseline
to Week 12, 20 mg/day versus placebo.
5. Change in the TETRAS composite outcome score from Baseline to Week 12, 10 mg/day
versus placebo.
6. Difference in proportion of participants who improved ≥ 1 point on the CGI-S from Baseline
to Week 12, 10 mg/day versus placebo.
9.4.1.2. 
Intercurrent Event Strategies 
Discontinuation of study intervention, as specified in Section 7.1, will be considered as 
intercurrent events.  
For the primary and key secondary estimands, the following 2 types of intercurrent events will be 
considered: 
•
Discontinuation of treatment due to an AE, for lack of efficacy, or any other reason.
Participants who experience this type of intercurrent event will be treated as if they
did not experience an intercurrent event (hypothetical strategy). The hypothetical
strategy used is defined as the pharmacologic effect of JZP385 compared to placebo
assuming the intercurrent event did not happen with continuation of study
intervention for the duration of the study. Analyses will be conducted using data
collected at time points obtained at or prior to participants’ discontinuation of study
intervention and combined with imputed values for post-discontinuation time points
for which the underlying assumptions are considered appropriate.
•
Any change to concomitant antitremor medication use after the initiation of study
intervention, including but not limited to the following: 1) starting a new antitremor
medication, 2) stopping a concomitant antitremor medication, and 3) a dose or
regimen change to current antitremor medication. This type of intercurrent event will
be disregarded, and measurements obtained subsequently will be reported and
analyzed (treatment policy). Treatment policy is defined as the effect of randomized
treatment over the study period regardless of the occurrence of the intercurrent event.
In accordance with treatment policy, data collected after this type of intercurrent
event will be reported and included in analyses.
If a participant experiences a combination of both types of ICE (eg, change the use of anti-tremor 
medication and discontinue the study intervention afterwards), each ICE should be treated 
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independently. Data collected after the change of antitremor medication but on or before the 
study intervention discontinuation will be included in analyses per treatment policy, the 
postdiscontinuation data will be handled by hypothetical strategy.  
9.4.1.3. 
Pooling of Investigational Centers 
Data from all investigational centers will be pooled for presentation of the main results (eg, 
demographics, safety, PK, and efficacy). Data may be pooled by region or country as appropriate 
for exploratory analyses of the primary and key secondary endpoints. 
9.4.1.4. 
Dropouts and Missing Data 
The TETRAS composite outcome score will be derived as the sum of items 1 to 11 of the ADL 
section of TETRAS plus the sum of items 6 (left and right) and 7 of the PS section of the 
TETRAS (for a total of 14 items on the composite primary outcome). If ≤ 3 items of the 
TETRAS composite outcome score are missing at a specific time point, the mean of the 
remaining non-missing TETRAS composite outcome score item scores at that point will be used 
to impute the missing TETRAS composite outcome score item value. The TETRAS composite 
outcome score will then be calculated as the sum of the observed and imputed item scores. If ≥ 4 
items of the composite primary outcome are missing, the TETRAS composite outcome score will 
not be calculated.  
For the analysis of the TETRAS composite outcome score, the primary analysis will rely on 
MMRM, assuming participants who early discontinue the study intervention (defined as an 
intercurrent event) or missed the assessments due to other reasons would have efficacy outcomes 
like other participants in their treatment group, randomization stratum, and initial trajectory who 
completed the study. Sensitivity analyses will adopt control-based drop-out imputation methods 
to assess the impact on the treatment effect of JZP385 when underlying missing at random 
(MAR) assumption on the primary MMRM analysis shifted accordingly. A tipping point analysis 
will further assess the robustness of the primary analysis method.  
For the analysis of CGI-S, the primary analysis will adopt a 2-step multiple imputation method 
and assume data to be missing at random. A tipping point analysis will be conducted as 
sensitivity analysis to assess the robustness of the primary analysis method.  
The details will be further described in the SAP. 
9.4.2. 
Primary Estimand 
The primary estimand is a composite outcome score of the sum of modified items 1 to 11 of the 
TETRAS-ADL and modified items 6 and 7 of the TETRAS-PS. For the primary estimand, the 
scoring of each of the items 1 to 11 of the TETRAS-ADL subscale as well as items 6 and 7 of 
the TETRAS-PS will be modified. For TETRAS-ADL, each item will be modified from 5 
response items to 4 response items by collapsing options 0 and 1 together and for TETRAS-PS, 
each item will be modified from 9 response items (due to 0.5 scoring increments) to 4 response 
items. Each item has a maximum score of 3. As item 6 of the TETRAS-PS includes assessments 
for both hands, there are a total of 3 items from the TETRAS-PS and 11 items from the 
TETRAS-ADL that contribute to a 14-item TETRAS composite outcome score. The total range 
of the TETRAS composite outcome score that will be used for the primary analysis will 
therefore be 0 to 42.  
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The attributes of the primary estimand are listed below: 
•
Treatment: 10, 20, and 30 mg/day JZP385 and placebo.
•
Population: Adults with moderate to severe ET.
•
Variable: Change from Baseline to Week 12 on the TETRAS composite outcome
score.
•
Intercurrent Events:
−Discontinuation of study intervention due to an AE, for lack of efficacy, or any
other reason. Participants who experience this type of intercurrent event will be
addressed by hypothetical strategy.
−Any change to concomitant antitremor medication use after the initiation of study
intervention (refer to Section 9.4.1.2). Participants who experience this type of
intercurrent event will be addressed by treatment policy.
•
Summary: Difference in the mean TETRAS composite outcome score from Baseline
to Week 12 between each dose of JZP385 and placebo.
For the main estimator analysis, a MMRM will be used to include the difference in the TETRAS 
composite outcome score from the Baseline Visit to Weeks 4, 8, and 12. The model will include 
fixed effects for treatment group, week, treatment group by week interaction, baseline TETRAS 
composite outcome score stratification (≤ 17 or > 17), baseline concomitant antitremor 
medication stratification (Yes or No), baseline TETRAS composite outcome score by week 
interaction, baseline TETRAS composite outcome score as a continuous covariate, and week 
repeated within each participant as a repeated effect. An unstructured variance-covariance matrix 
will be used to model the correlation among repeated measurements. 
For sensitivity analyses, a control-based Pattern Mixture Model (PMM) will be used to explore 
the possibility of data being missing not at random (MNAR). A supplementary analysis will be 
conducted with only those participants who have Week 12 TETRAS composite outcome scores. 
Additional details on sensitivity and supplementary analyses will be provided in the SAP. 
Subgroup analyses by randomization stratum, sex, age, and region will be conducted as 
applicable. Further details will be provided in the SAP. 
9.4.3. 
Secondary Estimands and Endpoints 
9.4.3.1. 
Key Secondary Estimand 
The attributes of the key secondary estimand are listed below: 
•
Treatment: 10, 20, and 30 mg/day JZP385 and placebo.
•
Population: Adults with moderate to severe ET.
•
Variable: Proportion of participants who improved (≥ 1 point improvement) from
Baseline to Week 12 on the CGI-S.
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• Intercurrent Events:  
− Discontinuation of study intervention due to an AE, for lack of efficacy, or any
other reason. Participants who experience this type of intercurrent event will be 
addressed by hypothetical strategy. 
− Any change to concomitant antitremor medication use after the initiation of study
intervention (refer to Section 9.4.1.2). Participants who experience this type of 
intercurrent event will be addressed by treatment policy. 
• Summary: Difference in the proportion of participants who improved (≥ 1 point
improvement) from Baseline to Week 12 on the CGI-S between each dose of JZP385 
and placebo. 
The main estimator will be analyzed using the CMH test adjusting for the stratification factors at 
randomization (baseline TETRAS composite outcome score [≤ 17 or > 17] and the use of 
concomitant antitremor medication [Yes or No]). The 2-sided p-values from the CMH test, the 
adjusted treatment difference in proportion using the weighted average of the treatment 
differences across the strata with the CMH weights, and the associated 2-sided 95% CIs using a 
normal approximation to the weighted average will be provided. 
For the intercurrent event of discontinuation of study intervention due to an AE, for lack of 
efficacy, or any other reason, under the hypothetical strategy, the primary analysis will adopt a 
2-step multiple imputation approach, with MCMC to impute non-monotone intermittent missing
followed by a predictive mean matching method to impute the rest monotone missing outcomes. 
Sensitivity analysis will be conducted through the tipping point analysis, with further details 
provided in the SAP. 
Supplementary analyses will be performed using the Non-responder Imputation (NRI) method as 
well as completers analysis with only participants who have Week 12 CGI-S assessment. 
9.4.3.2. 
Secondary Endpoints 
For the analysis of CGI-C and PGI-C at Week 12, the CMH test stratified by the randomization 
stratum will be used for the comparison between each dose of JZP385 and placebo. 
For the analysis of change from Baseline to Week 12 on the TETRAS-ADL, TETRAS-PS, 
TETRAS-PS upper limb score (item 4), and TETRAS total score, the same MMRM models used 
for the primary estimand will be used. 
For the analysis of change of QUEST score from Baseline to Week 12, an analysis of covariance 
(ANCOVA) model will be used. The model will include treatment group, randomization stratum, 
and corresponding baseline value as fixed effects. 
For the analysis of change of ETEA score from Baseline to Week 12, an ANCOVA model will 
be used. The model will include treatment group, randomization stratum, and corresponding 
baseline value as fixed effects. 
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9.4.4. 
Tertiary/Exploratory Endpoints 
For the analysis of change from Baseline to Weeks 4 and 8 on the TETRAS composite outcome 
score, TETRAS-ADL, TETRAS-PS, TETRAS upper limb score (item 4), TETRAS total score, 
the analyses results will be derived from the MMRM used in the Week 12 analysis on the 
primary estimand and the secondary endpoints. 
For the analysis of change from Baseline to Week 12 on modified items 6 and 7 of the 
TETRAS-PS (where each item is modified from 9 response items [due to 0.5 scoring increments] 
to 4 response items), the sum of modified items 1 to 11 of the TETRAS-ADL subscale (where 
each item is modified from 5 response items to 4 response items), and TETRAS total score, the 
analyses results will be derived from a similar MMRM used in the Week 12 analysis on the 
primary estimand endpoint.  
For the analyses of proportion of participants who improved ≥ 1 point from Baseline to Weeks 4 
and 8 on the CGI-S, the CMH test stratified by the randomization stratum will be used for the 
comparison between each dose of JZP385 and placebo. For the analyses of PGI-C and CGI-C at 
Weeks 4 and 8, the CMH test stratified by the randomization stratum will be used for the 
comparison between each dose of JZP385 and placebo.  
For the analysis of change in SF-36v2 score from Baseline to Week 12, a descriptive summary at 
each scheduled visit along with change from Baseline to Week 12 will be tabulated and listed. 
The time course efficacy analysis using the sum of modified items 6 and 7 of the TETRAS-PS 
will be performed with a mixed model. The model will include treatment group, time points, 
treatment group by time point interaction and the randomization stratum as fixed effects, and 
participant as a random effect. 
9.4.5. 
Safety Analysis 
All safety analyses will be performed on the Safety Population. Safety analyses will be 
descriptive; no formal statistical testing will be performed. 
Adverse Event Analyses: 
Adverse events will be mapped to system organ classes and preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). The participant incidence of AEs, AEs related 
to study intervention, SAEs, AEs leading to discontinuation, and fatal AEs will be summarized. 
This overall summary will also provide AEs by maximum severity. 
The participant incidence of AEs, AEs related to study intervention, AEs, and AEs leading to 
discontinuation will also be presented by SOC and preferred term. Preferred term summaries 
may also be provided. 
The participant incidence of an AE will be summarized; if a participant has multiple events with 
the same PT occurring in different periods, the event will be reported for each of those periods. 
Multiple increases in severity will only be counted as one AE. 
Vital Signs: 
For each vital sign parameter, summary statistics will be provided for observed and change from 
baseline values by scheduled visit. 
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Physical Examinations 
Observed and change from baseline values for weight will be summarized descriptively by 
scheduled visit. 
12-lead ECG
Observed and change from baseline values for ECG intervals will be summarized descriptively. 
QT abnormalities will be assessed; the number and percent of participants with values or change 
from baseline values exceeding certain thresholds will be tabulated. 
Laboratory Evaluations 
Observed and change from baseline laboratory evaluations will be summarized descriptively. 
C-SSRS
Columbia Suicide Severity Rating Scale parameters will be summarized by scheduled visit.
9.4.6. 
Pharmacokinetic Analysis 
Plasma concentrations of JZP385 and its metabolites will be listed and summarized by visit and 
dose. 
Pharmacokinetics parameters (eg, Cmax, Tmax, t½, Ctau, AUC) of JZP385 and its metabolites, if 
applicable, will be estimated using a population PK model and will be presented separately from 
the study data.  
Population exposure-response analysis for JZP385 and its metabolites, if applicable will be 
performed and will be presented separately from the study data. 
9.5. 
Interim Analysis 
No formal interim analysis will be performed. 
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Amendment 04 
 
 
 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the 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 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 study is initiated. 
• Protocols and any amendments to the protocol will require IRB/IEC and national
regulatory authority approval (as applicable) prior to initiation, except for changes 
necessary to eliminate an immediate hazard to study participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study 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 study at the site and adherence to
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
EU Regulation 536/2014 for clinical studies (when applicable) or EU Directive 
2001/20/EC (if still in force), EU Medical Device Regulation 2017/745 for clinical 
device research (if applicable), and all other applicable local regulations. 
10.1.2. 
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 study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the participant 
and answer all questions regarding the study. 
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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 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study 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 study. 
A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
Establishing a Data Monitoring Committee is not planned for this study. The sponsor recognizes 
the importance of ongoing review of the accumulating safety data and will perform periodic data 
monitoring regularly by data listing review. In addition, safety data from the study will be 
reviewed on an ongoing basis as part of routine pharmacovigilance and safety surveillance 
activities. Reports of safety findings (from either single events or based on aggregate review) 
that suggest a significant risk to humans will be distributed to all participating investigators and 
to the relevant regulatory authorities and IRBs/IECs. 
Eligibility Adjudication Committee: 
Select eligibility criteria will be centrally reviewed by an independent expert from the EAC. 
Details can be found in the EAC Charter. 
10.1.6. 
Dissemination of Clinical Study Data 
As the sponsor of the study, Jazz Pharmaceuticals is solely responsible for disclosing results on 
ClinicalTrials.gov, EudraCT, and other public registries in accordance with applicable global 
laws and regulations. By signing this protocol, the investigator acknowledges that all posting 
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requirements are solely the responsibility of the sponsor and agrees not to submit any 
information about the study or its results. 
10.1.7. 
Data Quality Assurance 
Investigators and site staff will be trained on protocol procedures and electronic case report form 
(eCRF) completion prior to enrolling participants in the study  
All participant data relating to the study will be recorded on printed or eCRF 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). 
Guidance on completion of CRFs will be provided in the CRF completion guidelines. 
The investigator must permit study-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 study including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator, or institution/study site, as applicable, for the period of time 
established in the clinical study agreement entered into by the investigator’s study site unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period or thereafter without the written approval of the sponsor 
and must be managed and retained in accordance with the terms of the clinical study agreement. 
No records may be transferred to another location or party without written notification to the 
sponsor. 
10.1.8. 
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 
study. Also, current medical records must be available. 
A definition of what constitutes source data can be found in the Monitoring Plan and/or CRF 
completion guidelines. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
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Study 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 study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the first participant has the first visit. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The investigator may initiate study 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 study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
•
Discontinuation of further study intervention development
For site termination: 
•
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 or no recruitment (evaluated after a reasonable amount of time) of
participants by the investigator
•
Total number of participants included earlier than expected
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should 
ensure appropriate participant therapy and/or follow-up.  
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APPENDIX 1. ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
AEOSI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BCRP 
Breast cancer resistance protein 
BID 
Twice daily 
CaV3 
T-type calcium channel
CBD 
Cannabidiol 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
Cmax 
Maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form 
C-SSRS
Columbia Suicide Severity Rating Scale 
Ctau 
Concentration at trough 
DR 
Delayed release 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
EAC 
Eligibility Adjudication Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EoS 
End of study 
ET 
Essential tremor 
ETEA 
Essential Tremor Embarrassment Assessment 
EU 
European Union 
FDA 
Food and Drug Administration 
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Abbreviation 
Definition 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
H2RA 
Histamine-2 receptor antagonists 
HRT 
Hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IR 
Immediate release 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
MAR 
Missing at random 
MDRD 
Modification of Diet in Renal Disease 
MDS 
Movement Disorder Society 
MMRM 
Mixed-effect model with repeated measures 
MNAR 
Missing not at random 
MoCA 
Montreal Cognitive Assessment 
OREs 
Other reportable experiences 
PGI-C 
Patient Global Impression of Change 
PK 
Pharmacokinetics 
PK/PD 
Pharamacokinetic/ Pharmacodynamic 
PMM 
Pattern Mixture Model 
PRN 
As needed 
PS 
Performance Subscale 
QUEST 
Quality of life in Essential Tremor Questionnaire 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SF-36v2 
36-item Short Form Health Survey Version 2
SoA 
Schedule of activities 
SOC 
System Organ Class 
SV 
Screening Visit 
T-CALM
Phase 2 proof‑of‑concept study CX-8998-CLN02-001 
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Abbreviation 
Definition 
TEAE 
Treatment-emergent adverse event 
TETRAS 
Tremor Research Group Essential Tremor Rating Assessment Scale 
TETRAS-ADL 
The Essential Tremor Rating Assessment Scale – Activities of Daily Living 
TETRAS-PS 
The Essential Tremor Rating Assessment Scale – Performance Subscale 
Tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
US 
United States 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of non-childbearing potential 
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APPENDIX 2. REFERENCES 
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Neurosurgery and Psychiatry. 1993;56(8):868-73. 
Bermejo PE, Ruiz-Huete C, Dorado R, et al. Zonisamida en el temblor esencial refractario. 
Revista de neurología. 2008;46(3):139-42. 
Bhatia KP, Bain P, Bajaj N, et al. 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. Movement 
Disorders. 2018;33(1):75-87. 
Borland E, Nägga K, Nilsson PM, et al. The Montreal Cognitive Assessment: Normative data 
from a large Swedish population-based cohort. J Alzheimer’s Disease. 2017;59:891-901.  
Busner J, Targum SD. The Clinical Global Impressions Scale: Applying a clinical research tool 
in clinical practice. Psychiatry. 2007;July:28-37. 
Calzetti S, Findley LJ, Perucca E, et al. Controlled study of metoprolol and propranolol during 
prolonged administration in patients with essential tremor. Journal of Neurology, Neurosurgery 
and Psychiatry. 1982;45(10):893-7. 
Chang KH, Wang SH, Chi CC. Efficacy and safety of topiramate for essential tremor: a meta-
analysis of randomized controlled trials. Medicine. 2015;94(43). 
Diaz NL and Louis ED. Survey of medication usage patterns among essential tremor patients: 
movement disorder specialists vs. general neurologists. Parkinsonism and Related Disorders. 
2010;16(9):604-7. 
Elble R, Comella C, Fahn S, et al. The essential tremor rating assessment scale (TETRAS): 1094. 
Movement Disorders. 2008;23:S1. 
Elble R, Comella C, Fahn S, et al. Reliability of a new scale for essential tremor. Movement 
Disorders. 2012;27(12):1567-9. 
Elble R, Bain P, João Forjaz M, et al. Task force report: scales for screening and evaluating 
tremor: critique and recommendations. Movement Disorders. 2013;28(13):1793-800. 
Elble RJ, Hellriegel H, Raethjen J, et al. The essential tremor rating assessment scale. Journal of 
Neurology Neuromedicine. 2016;1(4):34-8. 
Fahn S, Tolosa E, Marin C. Parkinson’s Disease and Movement Disorders. Clinical Rating Scale 
for Tremor, 2nd ed. New York: Williams & Wilkins. 1993:225-234. 
Ferreira JJ, Mestre TA, Lyons KE, et al., MDS Task Force on Tremor and the MDS Evidence 
Based Medicine Committee. MDS evidence‐based review of treatments for essential tremor. 
Movement Disorders. 2019;34(7):950-8. 
Gironell A and Kulisevsky J. Diagnosis and management of essential tremor and dystonic 
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Amendment 04 
Handforth A, Homanics GE, Covey DF, et al. T-type calcium channel antagonists suppress 
tremor in two mouse models of essential tremor. Neuropharmacology. 2010;59(6):380-7. 
Haubenberger D, Kalowitz D, Nahab FB, et al. Validation of digital spiral analysis as outcome 
parameter for clinical trials in essential tremor. Movement Disorders. 2011;26(11):2073-80. 
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Ware (eds.), Measuring functioning and well-being: The Medical Outcomes Study approach. 
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Hedera P, Cibulčík F, Davis TL. Pharmacotherapy of essential tremor. Journal of Central 
Nervous System Disease. 2013;5:JCNSD-S6561. 
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large cohort with essential tremor. Parkinsonism & Related Disorders. 2015;21(8):848-51. 
Koller W, Biary N, Cone S. Disability in essential tremor: effect of treatment. Neurology. 
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activities of daily living and quality of life in patients with upper limb tremor. Tremor and Other 
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Protocol JZP385-201-04 
Amendment 04 
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Parkinsonism & Related Disorders. 2008;14(1):33-6. 
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Shipe WD, Barrow JC, Yang ZQ, et al. Design, synthesis, and evaluation of a novel 4-
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Amendment 04 
Song P, Zhang Y, Zha M, Yang Q, et al. The global prevalence of essential tremor, with 
emphasis on age and sex: A meta-analysis. Journal of Global Health. 2021;11:04029. 
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Conceptual framework and item selection. Medical Care. 1992(30):473-83. 
Zesiewicz TA, Chari A, Jahan I, et al. Overview of essential tremor. Neuropsychiatric Disease 
and Treatment. 2010;6:401.  
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
APPENDIX 5. CONTRACEPTIVE AND BARRIER GUIDANCE 
Definitions 
Woman of Non-childbearing Potential 
Women in the following categories are considered women of non-childbearing potential 
(WONCBP): 
1. Premenopausal female with permanent infertility due to one of the following:
2. Documented hysterectomy
3. Documented bilateral salpingectomy
4. Documented bilateral oophorectomy
5. For individuals with permanent infertility due to an alternate medical cause other than the
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
6. Postmenopausal female
7. A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause.
8. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be
used to confirm a postmenopausal state in women not using hormonal contraception or
hormonal replacement therapy (HRT). However, in the absence of 12 months of
amenorrhea, confirmation with more than one FSH measurement is required.
9. Females on HRT and whose menopausal status is in doubt must discontinue HRT to
allow confirmation of postmenopausal status before study enrollment.
Woman of Childbearing Potential 
Women in the following categories are considered women of childbearing potential (WOCBP; 
fertile): 
10. Following menarche
11. From the time of menarche until becoming post-menopausal unless permanently sterile
(see below)
•
A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause.
•
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be
used to confirm a postmenopausal state in women not using hormonal contraception
or HRT. However, in the absence of 12 months of amenorrhea, confirmation with
more than one FSH measurement is required.
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
•
Females on HRT and whose menopausal status is in doubt will be required to use one
of the non-estrogen hormonal highly effective contraception methods if they wish to
continue their HRT during the study. Otherwise, they must discontinue HRT to allow
confirmation of postmenopausal status before study enrollment.
•
Permanent sterilization methods (for the purpose of this study) include:
•
Documented hysterectomy
•
Documented bilateral salpingectomy
•
Documented bilateral oophorectomy
•
For individuals with permanent infertility due to an alternate medical cause other than
the above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis),
investigator discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
•
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle
cannot be confirmed before first dose of study intervention, additional evaluation
should be considered.
Contraception Guidance: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when 
used consistently and correctly. 
•
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS)c
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or due to a medical cause)
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. Spermatogenesis cycle is 
approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review 
of the participant’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulationc 
•
oral
•
intravaginal
•
transdermal
•
injectable
Progestogen-only hormone contraception associated with inhibition of ovulationc 
•
oral
•
injectable
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
b Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with Clinical 
Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together due to risk of failure from friction. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
APPENDIX 6. GENETICS 
Use/Analysis of DNA 
•
Genetic variation may impact a participant’s response to study intervention,
susceptibility to, and severity and progression of disease. Variable response to study
intervention may be due to genetic determinants that impact intervention absorption,
distribution, metabolism, and excretion; mechanism of action of the intervention;
disease etiology; and/or molecular subtype of the disease being treated. Therefore,
where local regulations and IRB/IEC allow, a blood sample will be collected for
DNA analysis from consenting participants.
•
DNA samples will be used for research related to JZP385 and related diseases. They
may also be used to develop tests/assays including diagnostic tests related to JZP385.
Genetic research may consist of the analysis of one or more candidate genes or the
analysis of genetic markers throughout the genome (as appropriate).
•
DNA samples will be analyzed for polymorphisms in calcium channel genes.
Additional analyses may be conducted if it is hypothesized that this may help further
understand the clinical data.
•
The samples may be analyzed as part of a multi-study assessment of genetic factors
involved in the response to JZP385 or study interventions of this class to understand
study disease or related conditions.
•
The results of genetic analyses may be reported in the clinical study report or in a
separate study summary.
•
The sponsor will store the DNA samples in a secure storage space with adequate
measures to protect confidentiality.
•
The samples will be retained while research on JZP385 continues but no longer than
15 years from the date of sample collection or other period as per local requirements.
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
APPENDIX 7. CRITERIA FOR DIAGNOSIS OF ESSENTIAL TREMOR 
Movement Disorder Society (MDS) Consensus Statement on the Classification of Tremors 
from the Task Force on Tremor of the International Parkinson’s and Movement Disorder 
Society (Bhatia, 2018)  
Essential Tremor 
•
Isolated tremor syndrome of bilateral upper limb action tremor
•
At least 3 years’ duration
•
With or without tremor in other locations (eg, head, voice, or lower limbs)
•
Absence of other neurological signs, such as dystonia, ataxia, or parkinsonism
Essential Tremor Plus 
Tremor with the characteristics of ET and additional neurological signs of uncertain significance 
such as impaired tandem gait, questionable dystonic posturing, memory impairment, or other 
mild neurologic signs of unknown significance that do not suffice to make an additional 
syndrome classification or diagnosis. ET with tremor at rest should be classified here. 
Exclusion Criteria for Essential Tremor and Essential Tremor Plus 
•
Isolated focal tremors (voice, head)
•
Orthostatic tremor with a frequency > 12 Hz
•
Task- and position-specific tremors
•
Sudden onset and step-wise deterioration
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
APPENDIX 8. PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
Amendment 01 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
This amendment is being implemented to align with feedback received from the United States 
Food and Drug Administration (FDA) regarding study endpoints, to correct an error in the 
hepatic and renal values necessary for participant exclusion, and to add general clarifications 
throughout the protocol.  
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis;  
3 Objectives, 
Estimands and 
Endpoints;  
4.2 Scientific 
Rationale for Study 
Design;  
8.2 Efficacy 
Assessments;  
9.1 Statistical 
Hypotheses;  
9.2 Sample Size 
Determination;  
9.3 Analysis Sets;  
9.4 Statistical 
Analyses 
The primary endpoint was 
changed from the Essential 
Tremor Rating Assessment 
Scale – Activities of Daily 
Living (TETRAS-ADL) to a 
composite primary endpoint 
that includes the sum of items 1 
to 11 on the TETRAS-ADL 
subscale and items 6 and 7 of 
the Essential Tremor Rating 
Assessment Scale – 
Performance Subscale 
(TETRAS-PS). 
To align with feedback received from 
the FDA. 
1.1 Synopsis;  
3 Objectives, 
Estimands and 
Endpoints;  
4.2 Scientific 
Rationale for Study 
Design;  
8.2 Efficacy 
Assessments;  
9.4 Statistical 
Analyses 
The first key secondary 
endpoint was changed from the 
Clinical Global Impression of 
Change (CGI-C) to the Clinical 
Global Impression of Severity 
(CGI-S). 
The second key secondary 
endpoint (items 6 and 7 of the 
TETRAS-PS) was removed. 
To align with feedback received from 
the FDA. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis;  
3 Objectives, 
Estimands and 
Endpoints;  
9.4.4 
Tertiary/Exploratory 
Endpoint(s) 
The following endpoints were 
added under exploratory 
endpoints: 
• Items 6 and 7 of the
TETRAS-PS, with a
change to the analysis to
modify from 5 response
items to 4 response items
• The sum of modified items
1 to 11 of the
TETRAS-ADL subscale
To provide clarification regarding the 
use of original and modified scales. 
9.2 Sample Size 
Determination;  
9.3 Analysis Sets; 
9.4 Statistical 
Analyses 
New effect sizes for study 
sample size were calculated, 
text regarding the impact to 
power with shifts in 
assumptions were added, and 
multiplicity adjustments were 
revised to reflect the changes to 
the endpoints. 
As a result of changes to the primary 
endpoint, new effect sizes were 
calculated. The sample size 
assumptions and power were also 
provided for the key secondary 
endpoint. Changes to the number of 
key secondary endpoints led to a new 
multiplicity testing sequence. 
1.1 Synopsis;  
4.1 Overall Design;  
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
The randomization stratum was 
changed from the 
TETRAS-ADL subscale to 
select modified items from the 
TETRAS-ADL subscale and 
TETRAS-PS (ie, TETRAS 
composite outcome score). 
To align the randomization 
stratification with the primary 
endpoint. 
1.3 Schedule of 
Activities;  
8.2.2 Tremor 
Research Group 
Essential Tremor 
Rating Assessment 
Scale – Performance 
Subscale;  
9.4.4 
Tertiary/Exploratory 
Endpoint(s) 
The efficacy assessments and 
breath alcohol test were 
removed from the Week 1 
clinic visit. 
The 5 mg dose that is administered to 
participants randomized to active 
treatment arms during the first study 
week serves as a titration dose only 
and is not being evaluated for 
efficacy. 
1.3 Schedule of 
Activities 
The CGI-S was added as an 
assessment at Weeks 4 and 8. 
To enable assessment of this new key 
secondary endpoint at each clinic 
visit.  
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities; 
Language was added regarding 
the timing of collection of 
adverse events (AEs) and 
serious adverse events (SAEs). 
To provide clarification regarding the 
collection of AEs/SAEs. 
1.1 Synopsis;  
3 Objectives, 
Estimands and 
Endpoints;  
9.4 Statistical 
Analyses 
The following endpoints were 
added under secondary 
endpoints: 
• CGI-C
• TETRAS-ADL subscale
As a result of changes to the primary 
and key secondary endpoints, other 
endpoints were rearranged 
accordingly. 
1.1 Synopsis;  
3 Objectives, 
Estimands and 
Endpoints;  
9.4.3 Secondary 
Estimands and 
Endpoints 
Analysis of CGI-C and Patient 
Global Impression of Change 
(PGI-C) was changed to only 
include participants with 
“much improvement.” 
To align with feedback received from 
the FDA. 
2.3.2 Benefit 
Assessment 
Participation in long-term study 
was removed. 
To not imply a benefit to participants 
for such a study, which is not part of 
this protocol. 
5.1 Inclusion 
Criteria 
Inclusion criterion #4 was 
revised to add clarification 
from Appendix 5 about barrier 
contraception for male partners 
of female participants. 
To clarify the contraception 
requirements for female participants 
with male partners. 
5.2 Exclusion 
Criteria  
Exclusion criterion #6 was 
updated to add estimated 
glomerular filtration rate 
(eGFR) exclusionary values 
and to move the bilirubin 
exclusionary values into the 
parenthesis with other values 
addressing hepatic function.  
To clarify the level of renal disease 
that is considered exclusionary and 
correct an error on the placement of 
the exclusionary bilirubin values.  
6.8 Concomitant 
Therapy 
Added clarification regarding 
timing of administration for 
concomitant medications that 
are known sensitive substrates 
of P-glycoprotein (P-gp) and 
To align with feedback received from 
the FDA. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
Section # and 
Name 
Description of Change 
Brief Rationale 
breast cancer resistance protein 
(BCRP). 
8.4.5 Pregnancy 
The term “participant” was 
added into the language 
regarding follow-up of 
pregnancy outcome and it was 
specified that the neonate will 
be followed for 6 months 
following birth. 
To clarify that in addition to the 
participant’s pregnant female partner, 
the participant herself who may 
become pregnant needs to be 
appropriately followed for the 
pregnancy outcome. 
8.3.3 ECGs  
Corrected text to indicate that 
electrocardiograms (ECGs) 
measurements will be taken in 
triplicate not as single 
measurements  
To align with the Schedule of 
Activities (SoA) and clarify that ECG 
measurements should be taken in 
triplicate. 
Appendix 3; Table 6 The description “fasted state 
required at Screening only” 
was removed for glucose 
testing.  
All labs will be fasted (8 hours) prior 
to visit, as study drug is taken in the 
fasted state. Therefore, it is redundant 
to indicate that glucose should be 
taken in the fasted state. 
Appendix 3; Table 6 The eGFR assessment added to 
Clinical Chemistry. 
To clarify the method of eGFR 
assessment. 
Appendix 3; Table 6 Removed “drug” from the list 
of exceptions for study-
required laboratory tests 
performed by a central 
laboratory. Also added the 
clarification that urine 
pregnancy tests are not 
performed at the central lab.  
To correct an error and clarify the 
following text in Appendix 3: “The 
tests detailed in Table 6 will be 
performed by the central laboratory, 
with the exception of urine pregnancy 
and breath alcohol tests, which will 
be performed locally.” 
Throughout 
The molecule name was 
changed from CX-8998 to 
JZP385. 
To reference the current molecule 
name and link it to interchangeable 
names of CX-8998, suvecaltamide, 
and MK-8998 and to ensure 
consistency across JZP385 studies. 
Throughout 
Minor editorial and document 
formatting revisions 
Minor, therefore have not been 
summarized 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Amendment 02 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
This amendment is being implemented to revise text regarding participant rollover into a 
separate long-term study, remove CYP2C9 inducers from the exclusion criteria, and to make 
other minor edits.  
Section # and Name 
Description of Change 
Brief Rationale 
Table 3 Overall Study 
Design; 
1.3 Schedule of 
Activities; 
6.6 Continued Access 
to Study Intervention 
After the End of the 
Study 
Deleted language regarding 
direct rollover into a 
long-term study. 
The timing of a long-term extension 
study is yet to be determined and 
therefore participants will not have 
the opportunity to directly roll over 
into the long-term study after 
completing the current study. 
Table 1 Primary and 
Key Secondary 
Objectives and 
Estimands (footnote); 
Table 2 Secondary and 
Exploratory 
Objectives and 
Endpoints (footnote); 
3 Objectives, 
Estimands and 
Endpoints (footnote); 
9.4.2 Primary 
Estimand; 
9.4.4 
Tertiary/Exploratory 
Endpoints 
Revised language regarding 
the TETRAS composite 
outcome score. 
To clarify language around 
modification of the response items 
for the TETRAS-ADL and 
TETRAS-PS subscales. 
1.2 Schema 
Study intervention name was 
changes from “CX-8998” to 
“JZP385.” 
To ensure consistent nomenclature 
of study intervention. 
2 Introduction 
Appendix 2 
References 
Added more recent (2021) ET 
prevalence data, 
To ensure that background 
information is current. 
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
Table 2 Secondary and 
Exploratory 
Objectives and 
Endpoints; 
3 Objectives, 
Estimands and 
Endpoints 
Added the following items to 
the list of exploratory 
objectives and endpoints: 
•
Change from Baseline to
Weeks 4 and 8 on the
TETRAS composite
outcome score, PGI-C,
CGI-S, TETRAS-ADL,
TETRAS-PS, TETRAS
upper limb score (item 4),
and total TETRAS score.
• Change from Baseline to
Week 12 on the 36-item
Short Form Health Survey
(SF-36) as summarized by
each dose of JZP385 and
placebo.
•
Time course analysis on
the sum of modified items
6 and 7 of the TETRAS-
PS as summarized by each
dose of JZP385 and
placebo.
These endpoints were inadvertently 
omitted from the list of exploratory 
objectives and endpoints. 
Table 2 Secondary and 
Exploratory 
Objectives and 
Endpoints; 
3 Objectives, 
Estimands and 
Endpoints; 
8.5 Pharmacokinetics; 
9.4.6 Pharmacokinetic 
Analysis 
Pharmacokinetic (PK) 
endpoints and analysis were 
revised. 
To provide clarification. 
1.3 Schedule of 
Activities, Footnote e 
Added “or local requirements” 
to the footnote regarding the 
change from telephone to 
in-clinic visits. 
To allow flexibility for study sites. 
5.2 Exclusion Criteria, 
#14 and #15 
Removed CYP2C9 inducers 
from the exclusion criteria and 
provided additional details. 
Definitive in vitro drug-drug 
interaction studies indicate that 
JZP385 is predominantly 
CONFIDENTIAL
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
metabolized by CYP3A4 and other 
enzymes play a minor role. 
Table 4 Study 
Treatment/Intervention 
Added footnote to clarify that 
the dose strength of JZP385 is 
based on the active moiety in 
the drug product. 
To clarify dosage strength of study 
intervention. 
6.4 Study 
Intervention/Treatment 
Compliance 
Added “clinic” in front of the 
term “visit” to the sentence 
regarding at which visits 
compliance with study 
intervention will be assessed.  
To clarify that compliance with 
study intervention is only assessed 
at clinic visits and not at phone 
visits. 
8.1.5  Inclusion and 
Exclusion Criteria 
Review 
Changed “Study Operations 
Manual” to “EAC Charter.” 
To correct the location of details for 
the participant eligibility review. 
8.4.6  Adverse Events 
of Special Interest  
Section heading changed to 
“8.4.6 Adverse Events of 
Special Interest and Other 
Reportable Experiences” and 
details were added regarding 
the definition of other 
reportable experiences 
(OREs). 
To provide clarification about 
adverse events of special interest 
(AEOSIs) and OREs. 
Appendix 4 Adverse 
Events and Serious 
Adverse Events: 
Definitions and 
Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting 
Corrected the reporting period 
for OREs and AEOSIs from 
within 72 hours to within 
24 hours from the time of 
site’s knowledge of the event. 
To indicate that OREs and AEOSIs 
should be reported within 24 hours. 
Appendix 3 Clinical 
Laboratory Tests 
Added that breathalyzers and 
urine pregnancy tests will be 
provided by the central 
laboratory. 
Specified that serum 
pregnancy testing is 
mandatory at screening, and 
urine is collected thereafter. 
To provide clarification 
Appendix 3 Clinical 
Laboratory Tests, 
Footnote b 
Deleted footnote b regarding 
fractionating for alkaline 
phosphatase sampling. 
Clarification since additional tests 
may be performed at any time 
during the study as determined 
CONFIDENTIAL
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
necessary by the investigator or 
required by local regulations. 
Appendix 8 
Moved Amendment 1 
Summary of Changes to 
Appendix 8. 
For clarity. 
Throughout 
Changed the nomenclature of 
the primary endpoint from 
“composite primary endpoint” 
to “TETRAS composite 
outcome score.” 
To ensure that consistent 
nomenclature is used for the 
primary endpoint. 
Throughout 
Minor editorial and document 
formatting revisions 
Minor, therefore have not been 
summarized 
CONFIDENTIAL
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Amendment 03 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The overall rationale for this amendment is to broaden the eligibility criteria and reduce study 
burden.  
Section # and Name 
Description of Change 
Brief Rationale 
Table 1 Primary and Key 
Secondary Objectives and 
Estimands; 
3 Objectives, Estimands and 
Endpoints; 
9.1 Statistical Hypotheses; 
9.2 Sample Size 
Determination 
9.4.1.1 Multiplicity 
Adjustments; 
9.4.3.1 Key Secondary 
Estimand 
Changed analysis of CGI-S 
endpoint from a continuous 
analysis to categorical 
analysis (ie, a 1-point 
change). 
Revised statistical details 
regarding the key secondary 
estimand variable. 
Revised statistical power 
calculations. 
To improve interpretability of the 
results and ensure that any 
statistically significant finding will 
also be meaningful (ie, represent a 
category change on this ordinal 
scale).  
Statistical section updated to reflect 
the change on key secondary 
estimand variable CGI-S, along with 
updated categorical analysis methods 
and additional revisions to improve 
interpretability of the results. The 
statistical power calculations were 
also revised, accordingly. 
Table 1 Primary and Key 
Secondary Objectives and 
Estimands; 
Table 2 Secondary and 
Exploratory Objectives and 
Endpoints; 
3 Objectives, Estimands and 
Endpoints; 
9.4.2 Primary Estimand; 
9.4.4 Tertiary/Exploratory 
Endpoints 
Clarified language around the 
primary and key secondary 
estimands. 
Added separate bullet points 
for the following exploratory 
endpoints: 
Proportion of participants 
who improved (≥ 1-point 
improvement) from Baseline 
to Weeks 4 and 8 on the 
CGI-S. 
Proportion of participants 
reported as much improved 
on the PGI-C and CGI-C at 
Weeks 4 and 8. 
To better distinguish the difference 
in the primary and key secondary 
objectives. 
To separate categorical endpoints 
CGI-S, PGI-C, and CGI-C from 
continuous endpoints and further 
define them under 
Tertiary/Exploratory Endpoints 
1.3 Schedule of Activities 
Specified that the blood 
sample for genetic testing is 
optional. 
To provide clarification 
CONFIDENTIAL
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
Specified that serum 
pregnancy tests can be 
conducted at additional visits 
to confirm positive urine tests. 
1.2 Schema; 
1.3 Schedule of Activities; 
Table 3 Overall Study Design; 
2.3.1 Risk Assessment 
4.1 Overall Design 
Shortened standard screening 
period to 35 days. Added a 
footnote to indicate that an 
additional 28 days are 
permitted for participants who 
require longer washout of 
primidone and reordered the 
other footnotes accordingly 
Screening period has been shortened 
to avoid an unnecessarily long 
screening period for most 
participants. A provision permitting 
a longer screening period to allow 
for safe washout of the excluded 
antitremor medication, primidone, 
has been added. 
1.3 Schedule of Activities; 
8.2.2 Tremor Research Group 
Essential Tremor Rating 
Assessment Scale – 
Performance Subscale; 
Table 5 TETRAS-PS 
Assessments 
Specified serial TETRAS-PS 
items 6 and 7 are optional and 
5 to 8-hour postdose PK 
sample at Week 8 is optional. 
Indicated that a light lunch is 
only provided to those 
participants who are doing the 
optional assessments. 
Clarified in Table 5 that 
TETRAS-PS assessments are 
administered by a blinded 
rater and need to be video 
recorded at Screening Visit 1 
and 2. 
Revised the nomenclature in 
Table 5 for the serial item 6 
and 7 TETRAS-PS Baseline 
assessments. 
To improve the operational 
execution and reduce study 
complexity by making these 
exploratory endpoints that drive long 
clinic visit days optional.  
To clarify that the TETRAS-PS 
should be performed at the time of 
the anticipated 1-hour postdose at 
future visits, and to clarify that 
participants do not dose at the 
Baseline visit. 
Table 3 Overall Study Design 
Added footnote to define the 
TETRAS composite outcome 
score. 
To provide clarification 
2.3.1 Risk Assessment 
2.3.3 Overall Benefit: Risk 
Summary 
Added additional detail on the 
risk-benefit of JZP385. 
To provide more specificity in the 
protocol regarding the risk-benefit in 
the patient population under study as 
opposed to referring to the IB. 
CONFIDENTIAL
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria #3 
Removed Inclusion 3b (Score 
of > 5 on the sum of items 6 
and 7 of the TETRAS-PS). 
Inclusion 3a (TETRAS-ADL score 
≥ 22) and 3c (CGI-S rating of at least 
moderate for participants’ ability to 
function) are considered sufficient to 
enroll a moderate to severe ET 
population.  
5.1 Inclusion Criteria #4b; 
Table 6 Protocol-required 
Safety Laboratory Tests 
Revised Inclusion 4b to 
clarify when serum vs urine 
pregnancy tests are required 
for WOCBP. 
To provide clarification. 
5.2 Exclusion Criteria #4; 
8.1.7 Montreal Cognitive 
Assessment 
Revised Exclusion #4 to 
lower MoCA eligibility 
threshold to < 20 and added 
clarification that the 
investigator should ensure 
participants are able to 
accurately self-report on study 
questionnaires. 
To better assess and exclude 
participants with severe cognitive 
impairment based on more rigorous 
data on the use of the MoCA and the 
judgment of the investigator on the 
individual participant.  
The original cut-off of < 23 was 
developed based on a limited study 
in a convenience sample of 
participants with Parkinson’s disease 
(N = 114) and healthy controls 
(N = 47) at a single non-US center. 
However, a more thorough literature 
review showed that in a normal 
cognitive population, MoCA average 
scores fell within this range, which 
suggested that the original criteria 
(< 23) had low specificity to detect 
severe cognitive impairment.  
5.2 Exclusion Criteria #6 
Revised Exclusion 6 to 
remove specified threshold of 
the eGFR to define renal 
disease and to add severe 
renal impairment or end-stage 
renal disease. 
Based on the finding that JZP385 is 
primarily cleared via metabolism, 
and that, previously, patients with 
creatinine clearance ≥ 39 mL/min 
were allowed in the T-CALM study 
with no safety concerns, the specific 
eGFR threshold to define renal 
disease will be removed from the 
protocol. The eGFR will still be 
calculated for each participant as part 
of the laboratory assessment.  
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities; 
5.2 Exclusion Criteria #7f; 
8.3.2 Vital Signs 
Added triplicate assessments 
of orthostatic vital signs at 
Screening Visit and added 
that Exclusion 7f applies to 
Screening Visit as well as 
Baseline. 
To clarify criteria should be met at 
the Screening Visit as well as 
Baseline. 
5.2 Exclusion Criteria #10 
Clarified that tobacco and 
cannabis use disorder are 
excluded and that a substance 
abuse disorder should be 
diagnosed. 
To provide clarification. 
5.2 Exclusion Criteria #11 
Revised Exclusion 11 to 
clarify that MR-guided 
focused ultrasound is a 
thalamotomy. 
To provide clarification. 
5.2 Exclusion Criteria #12 
Revised Exclusion 12 to 
specify botulinum toxin (ie, 
Botox) for the treatment of 
upper limb tremor is 
exclusionary. 
JZP385 is targeting treatment of the 
core symptom of ET, which is upper 
limb tremor. Thus, the use of 
botulinum toxin for other reasons 
(eg, cosmetic, head tremor, etc.) will 
not confound this assessment. 
5.2 Exclusion Criteria #13b 
Revised Exclusion 13b to 
clarify that PRN use of 
medications that impact 
tremor is not permitted. 
To provide clarification. 
5.2 Exclusion Criteria #16 
Revised Exclusion 16 to 
allow the use of histamine-2 
receptor antagonists under the 
condition they are taken at 
least 4 hours after and 
12 hours before study 
intervention. 
Administering a dose of H2RA at 
least 12 hours before JZP385 will 
ensure that H2RA effect has washed 
out before JZP385 administration. 
Administration of H2RA 4-hours 
post-JZP385 dose will ensure that 
JZP385 has been absorbed or passed 
through the stomach to the intestine. 
5.2 Exclusion Criteria #22 
Revised Exclusion 22 to 
clarify that a positive urine 
drug screen at Screening that 
is attributed to a medication 
To provide clarification. 
CONFIDENTIAL
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
that is being washed out is not 
exclusionary. 
6.3 Measures to Minimize 
Bias: Randomization and 
Binding 
Specified that IRT assigns the 
participant number at 
Screening. 
To provide clarification. 
6.8 Concomitant Therapy 
Revised the timing of 
administration for 
concomitant medications that 
are known sensitive substrates 
of P-glycoprotein (P-gp) and 
breast cancer resistance 
protein (BCRP) relative to 
study drug administration.  
To better align with the known PK 
profile of the ER formulation of 
JZP385 used in the current study 
whereby -there is no JZP385 left 
12 hours postdose in the intestine to 
elicit transporter inhibition, 
permitting safe administration of 
P-gp/BCRP substrates at that time.
7.1.2 Temporary 
Discontinuation/Study 
Intervention Interruption 
Specified that the sponsor’s 
medical monitor must be 
consulted if a participant 
temporarily interrupts study 
intervention. 
To provide clarification. 
8 Study Assessments and 
Procedures 
Specified that Principal 
Investigators should not serve 
as blinded raters, except when 
approved by the sponsor. 
To provide clarification. 
8.2.3 Clinical Global 
Impression of Severity 
8.2.5 Clinical Global 
Impression of Change 
Revised text to clarify the 
CGI assessments are rated by 
qualified medical personnel 
(ie, a clinician). 
To provide clarification. 
8.3.2 Vital Signs 
Oral temperature was changed 
to body temperature. 
To provide clarification. 
8.4.6 Adverse Events of 
Special Interest 
Revised text regarding 
AEOSIs. 
Updated to reflect the most relevant 
and accurate information based on 
clinical studies with JZP385. 
8.4.7 Overdose, Medication 
Errors, and Misuse 
Renamed section title to 
include OREs. 
Updated to reflect the most relevant 
and accurate information based on 
clinical studies with JZP385. 
CONFIDENTIAL
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Jazz Pharmaceuticals, Inc. 
JZP385 
Protocol JZP385-201-04 
Amendment 04 
 
Section # and Name 
Description of Change 
Brief Rationale 
9.4.1.2 Intercurrent Event 
Strategies  
Revised current text. 
Added text to further clarify the 
intercurrent event handling strategy 
(hypothetical) and removed 
redundant text covered in Sections 
9.4.2 and 9.4.3.  
9.4.1.4 Dropouts and Missing 
Data 
Updated analysis methods. 
Updated primary and sensitivity 
analysis methods related to CGI-S. 
Also clarified the primary and 
sensitivity analysis approach on the 
TETRAS composite outcome score. 
9.4.2 Primary Estimand 
Revised text on sensitivity 
and supplemental analysis. 
Text revised to align with the 
mixed model components. 
Updated language to further clarify 
on sensitivity analysis and 
supplemental analysis approaches. 
10.1.1 Regulatory and Ethical 
Considerations 
Text regarding IRB/IEC and 
national regulatory authority 
approval combined into 
1 bullet, instead of 2. 
To align with the protocol template. 
Appendix 4 
Revised text regarding 
AEOSI and ORE reporting. 
For clarification and to align with the 
protocol template. 
Appendix 8 
Moved Amendment 2 
Summary of Changes to 
Appendix 8. 
For clarity. 
Throughout 
Revised formulation language 
throughout to change from 
“delayed release” to 
“extended-release.”  
To improve accuracy of formulation 
description. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor; therefore, have not been 
summarized 
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SAP_001.pdf: 
Jazz Pharmaceuticals 
 
 
Statistical Analysis Plan - Protocol JZP385-201  
 
 
1 
 
 
  
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Version: 1.0 
Date: 31-May-2024 
 
 
STUDY DRUG: 
JZP385 
Protocol/STUDY Number: 
JZP385-201 Amendment 4.0 (10-Feb-2023) 
 
STUDY TITLE: 
A Phase 2b, 12-week, Double-blind, Placebo-controlled, Randomized, Parallel-group, 
Multicenter Study of the Safety and Efficacy of JZP385 in the Treatment of Adults with Moderate 
to Severe Essential Tremor 
Sponsor: 
Cavion, Inc., a subsidiary of Jazz Pharmaceuticals, Inc. 
3170 Porter Dr, Palo Alto, CA 94304 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
DocuSign Envelope ID: 0414D087-8407-4F04-A861-BA42008FC1BD


Jazz Pharmaceuticals 
 
 
Statistical Analysis Plan - Protocol JZP385-201  
 
 
2 
 
 
  
 
SIGNATURE PAGE 
 
 
This document has been prepared by: 
 
MA, MS 
 
 
 
 
Associate Director, Biostatistics 
Jazz Pharmaceuticals  
 
 
 
Date 
 
 
 
 
 
This document has been reviewed and approved by: 
 
 MSc 
 
 
 
 
Senior Director, Biostatistics 
Jazz Pharmaceuticals  
 
 
 
Date 
 MD, PhD 
 
 
 
 
Senior Director, Clinical Development   
Jazz Pharmaceuticals 
 
 
 
Date 
 
 
DocuSign Envelope ID: 0414D087-8407-4F04-A861-BA42008FC1BD
May-31-2024 | 11:04 AM PDT
May-31-2024 | 10:25 AM PDT
May-31-2024 | 10:26 AM PDT


Jazz Pharmaceuticals 
 
 
Statistical Analysis Plan - Protocol JZP385-201  
 
 
3 
 
 
  
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
1. 
LIST OF ABBREVIATIONS.......................................................................................6 
2. 
MODIFICATION HISTORY .......................................................................................8 
3. 
INTRODUCTION ........................................................................................................9 
4. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................10 
4.1. 
Study Objectives .........................................................................................................10 
4.1.1. 
Primary Objective .......................................................................................................10 
4.1.2. 
Key Secondary Objective ...........................................................................................10 
4.1.3. 
Secondary Objectives .................................................................................................10 
4.1.4. 
Exploratory Objectives ...............................................................................................10 
4.2. 
Study Estimands and Endpoints .................................................................................10 
4.2.1. 
Primary Estimand .......................................................................................................10 
4.2.2. 
Key Secondary Estimand ............................................................................................11 
4.2.3. 
Other Secondary Endpoints ........................................................................................12 
4.2.4. 
Exploratory Endpoints ................................................................................................12 
5. 
STUDY DESIGN .......................................................................................................14 
5.1. 
Summary of Study Design ..........................................................................................14 
5.2. 
Study Intervention ......................................................................................................15 
5.3. 
Power and Sample Size Calculations .........................................................................16 
5.4. 
Randomization and Blinding ......................................................................................16 
5.5. 
Interim Analysis ..........................................................................................................17 
6. 
ANALYSIS SETS ......................................................................................................18 
7. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ........................................19 
7.1. 
General Methods .........................................................................................................19 
7.2. 
Baseline and Study Day Definitions ...........................................................................19 
7.2.1. 
Baseline .......................................................................................................................19 
7.2.2. 
Study Day ...................................................................................................................19 
7.2.3. 
Visit Windows ............................................................................................................19 
7.2.4. 
Visit and Assessment Changes Due to COVID-19 ....................................................21 
7.2.5. 
Missing and Partial Data .............................................................................................21 
7.3. 
Hypotheses Testing .....................................................................................................22 
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Statistical Analysis Plan - Protocol JZP385-201  
 
 
4 
 
 
  
 
7.4. 
Level of Significance & Multiplicity Adjustment ......................................................23 
7.5. 
Subgroups and Subgroup Analyses ............................................................................23 
7.6. 
Changes to Planned Analyses .....................................................................................24 
8. 
STUDY POPULATION SUMMARIES ....................................................................25 
8.1. 
Enrollment ..................................................................................................................25 
8.2. 
Subject Disposition .....................................................................................................25 
8.3. 
Demographic and Baseline Characteristics ................................................................25 
8.4. 
Medical/Surgical History ............................................................................................25 
8.5. 
Prior and Concomitant Medications ...........................................................................25 
8.6. 
Protocol Deviations ....................................................................................................26 
9. 
EFFICACY .................................................................................................................27 
9.1. 
Primary Efficacy Estimand and Analysis ...................................................................27 
9.1.1. 
Primary Estimand .......................................................................................................27 
9.1.2. 
Primary Analyses ........................................................................................................27 
9.1.3. 
Sensitivity Analyses ....................................................................................................28 
9.1.4. 
Completers Analysis (Data as Observed) ...................................................................30 
9.1.5. 
Subgroup Analyses .....................................................................................................30 
9.2. 
Secondary Efficacy Estimand, Endpoints and Analyses ............................................30 
9.2.1. 
Key Secondary Efficacy Estimand .............................................................................30 
9.2.2. 
Primary Analysis ........................................................................................................31 
9.2.3. 
Sensitivity Analyses ....................................................................................................32 
9.2.4. 
Completers Analysis (Data as Observed) ...................................................................33 
9.2.5. 
Subgroup Analyses .....................................................................................................33 
9.2.6. 
Other Secondary Endpoints and Analyses ..................................................................33 
9.3. 
Exploratory Endpoints ................................................................................................35 
9.3.1. 
Analysis of Exploratory Efficacy Continuous Endpoints ...........................................35 
9.3.2. 
Analysis of Exploratory Dichotomous Endpoints ......................................................35 
9.3.3. 
Time course efficacy analysis .....................................................................................35 
10. 
SAFETY .....................................................................................................................37 
10.1. 
Exposure .....................................................................................................................37 
10.1.1. 
Extent of Exposure .....................................................................................................37 
10.1.2. 
Treatment Compliance ................................................................................................37 
10.2. 
Adverse Events ...........................................................................................................37 
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Jazz Pharmaceuticals 
 
 
Statistical Analysis Plan - Protocol JZP385-201  
 
 
5 
 
 
  
 
10.2.1. 
Adverse Events of Special Interest .............................................................................39 
10.3. 
Laboratory Assessments .............................................................................................39 
10.3.1. 
Laboratory Specific Derivation ..................................................................................40 
10.3.2. 
Laboratory Normal Reference Ranges .......................................................................40 
10.4. 
Vital Signs ..................................................................................................................40 
10.4.1. 
Vital Signs Markedly Abnormal Criteria ...................................................................41 
10.5. 
ECG ............................................................................................................................41 
10.5.1. 
ECG Abnormal Criteria ..............................................................................................42 
10.6. 
Other Safety Endpoints ...............................................................................................42 
10.6.1. 
Columbia-Suicide Severity Rating Scale ....................................................................42 
10.6.2. 
Safety and COVID-19 Considerations .......................................................................43 
11. 
PHARMACOKINETIC ANALYSES ........................................................................44 
11.1. 
Pharmacokinetic Concentrations ................................................................................44 
12. 
PHARMACODYNAMIC ANALYSES .....................................................................45 
13. 
REFERENCES ...........................................................................................................46 
APPENDIX 1: DATE IMPUTATION RULES ............................................................................47 
 
List of Tables 
Table 1: 
List of Abbreviations ....................................................................................................6 
Table 2 
Version History for SAP ...............................................................................................8 
Table 3 
Study Intervention ......................................................................................................15 
Table 4 
Analysis Sets ...............................................................................................................18 
Table 5 
Visit Windows for Assessments or Measurements ....................................................20 
Table 6 
Vital Signs Predefined Markedly Abnormal Criteria .................................................41 
 
List of Figures 
Figure 1 
Study Schema .............................................................................................................15 
Figure 2 
MAR vs CBI ...............................................................................................................29 
 
 
 
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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
Cmax 
Maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
COVID 
Coronavirus disease 2019 
CBI 
Control-based Imputation 
CRF 
Case report form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Ration Scale 
Ctau 
Concentration at trough 
DBP 
Diastolic blood pressure 
DR 
Delayed release 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ET 
Essential tremor 
ETEA 
Essential Tremor Embarrassment Assessment 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IR 
Immediate release 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
MAR 
Missing at Random 
MCMC 
Markov chain Monte Carlo 
MDS 
Movement Disorder Society 
MI 
Multiple Imputation 
MMRM 
Mixed-effect model with repeated measures 
MNAR  
Missing not at Random 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
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PI 
Prescribing Information 
PK 
Pharmacokinetics 
PMM 
Predictive mean matching 
QD 
Once daily 
QTcB 
Bazett’s Corrected QT interval 
QTcF 
Fridericia’s corrected QT interval 
QUEST 
Quality of Life in Essential Tremor Questionnaire 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SF-36v2 
36-item Short Form Health Survey Version 2 
SOC 
System Organ Class 
t1/2 
Terminal half-life 
T-CALM 
Phase 2 proof of concept study CX-8998-CLN02-001 
TEAE 
Treatment-emergent adverse event 
TETRAS-ADL 
The Essential Tremor Rating Assessment Scale – Activities of Daily Living 
TETRAS-PS 
The Essential Tremor Rating Assessment Scale – Performance Subscale 
Tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
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2. 
MODIFICATION HISTORY 
Table 2 
Version History for SAP 
Version 
Date 
Description  
Version 1.0 
31 May 2024 
Final 
 
 
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3. 
INTRODUCTION 
The purpose of this SAP is to describe in detail the statistical methodology and planned analyses 
to be conducted for Protocol JZP385-201 for inclusion in the CSR. The current version is based 
on Protocol Amendment 04 dated 10 February 2023. Any additional analyses or deviation from 
the analyses outlined in this plan will be documented with rationale in the final CSR. 
 
 
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4. 
STUDY OBJECTIVES AND ENDPOINTS 
4.1. 
Study Objectives 
4.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of JZP385 to improve functional 
and performance-based impairment due to tremor when administered once daily for up to 12 
weeks at fixed doses of 10, 20, and 30 mg/day. 
4.1.2. 
Key Secondary Objective 
The key secondary objective of the study is to evaluate the efficacy of JZP385 to improve 
functional impairment due to tremor when administered once daily for up to 12 weeks at fixed 
doses of 10, 20, and 30 mg/day. 
4.1.3. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the efficacy of JZP385 to improve overall ET when administered once daily 
for up to 12 weeks at fixed doses of 10, 20, and 30 mg/day. 
• To evaluate the safety and tolerability of JZP385 administered once daily for up to 
12 weeks at fixed doses of 10, 20, and 30 mg/day in the treatment of adult participants 
with ET. 
4.1.4. 
Exploratory Objectives 
The exploratory objectives of the study are:  
• To characterize the PK and exposure-response of JZP385 in adult participants with ET 
using sparse PK sampling. 
• To evaluate the efficacy of JZP385 to improve overall ET when administered once daily 
for up to 12 weeks at fixed doses of 10, 20, and 30 mg/day. 
4.2. 
Study Estimands and Endpoints 
4.2.1. 
Primary Estimand 
The primary estimand of the study is defined as: 
• Treatment: 10, 20, and 30 mg/day JZP385 and placebo. 
• Population: Adults with moderate to severe ET. 
• Variable: Change from Baseline to Week 12 on the TETRAS composite outcome score*. 
• Intercurrent events:  
o Discontinuation of treatment due to an AE, for lack of efficacy, or any other 
reason. Participants who experience any intercurrent event will be included as if 
they did not experience the intercurrent event (hypothetical strategy). 
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o Any change to concomitant anti-tremor medication use after the initiation of study 
intervention, including but not limited to the following: 1) starting a new 
antitremor medication, 2) stopping a concomitant antitremor medication, and 3) a 
dose or regimen change to current antitremor medication. This type of intercurrent 
event will be disregarded, and measurements obtained subsequently will be 
reported and analyzed (treatment policy).+ 
• Summary: Difference in the mean TETRAS composite outcome score from Baseline to 
Week 12 between each dose of JZP385 and placebo. 
* The TETRAS composite outcome score is the sum of modified items 1 to 11 of the TETRAS-ADL subscale and 
modified items 6 and 7 of the TETRAS-PS. For TETRAS-ADL, each item is modified from 5 response items to 4 
response items by collapsing options 0 and 1 together and for TETRAS-PS, each item is modified from 9 response 
items (due to 0.5 scoring increments) to 4 response items. As such, the range of possible scores at each visit is 0 to 
42. 
+ A blinded review of all concomitant medications and therapies will be performed prior to database lock to 
determine the occurrence of this intercurrent event.  
4.2.2. 
Key Secondary Estimand 
The key secondary estimand is defined as: 
• Treatment: 10, 20, and 30 mg/day JZP385 and placebo. 
• Population: Adults with moderate to severe ET. 
• Variable: Proportion of participants who improved (≥ 1 point decrease) from Baseline to 
Week 12 on the CGI-S*. 
• Intercurrent events:  
o Discontinuation of treatment due to an AE, for lack of efficacy, or any other 
reason. Participants who experience any intercurrent event will be included as if 
they did not experience the intercurrent event (hypothetical strategy). 
o Any change to concomitant antitremor medication use after the initiation of study 
intervention, including but not limited to the following: 1) starting a new 
antitremor medication, 2) stopping a concomitant antitremor medication, and 3) a 
dose or regimen change to current antitremor medication. This type of intercurrent 
event will be disregarded, and measurements obtained subsequently will be 
reported and analyzed (treatment policy).+ 
• Summary: Difference in the proportion of participants who improved (≥ 1 point decrease) 
from Baseline to Week 12 on the CGI-S between each dose of JZP385 and placebo. 
* The CGI-S is converted to a numerical scale of 1 to5. 
+ A blinded review of all concomitant medications and therapies will be performed prior to database lock to 
determine the occurrence of this intercurrent event.  
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4.2.3. 
Other Secondary Endpoints 
• Secondary efficacy endpoints include the following: 
o Proportion of participants reported as much improved on the CGI-C at Week 12. 
o Proportion of participants reported as much improved on the PGI-C at Week 12. 
o Change from Baseline to Week 12 on the TETRAS-ADL subscale as summarized 
by each dose of JZP385and placebo. 
o Change from Baseline to Week 12 on the TETRAS-PS as summarized by each 
dose of JZP385 and placebo. 
o Change from Baseline to Week 12 on the upper limb score (item 4) of the 
TETRAS-PS as summarized by each dose of JZP385 and placebo. 
o Change from Baseline to Week 12 on the TETRAS total score, as summarized by 
each dose of JZP385 and placebo. 
o Change from Baseline to Week 12 on the QUEST as summarized by each dose of 
JZP385 and placebo. 
o Change from Baseline to Week 12 on the ETEA as summarized by each dose of 
JZP385 and placebo. 
• Secondary safety and tolerability endpoint is: 
o Incidence and severity of TEAEs, evaluation of safety laboratory assessments, 
vital signs, ECG results, C-SSRS results. 
4.2.4. 
Exploratory Endpoints  
• The exploratory PK endpoints include: 
o Plasma concentrations of JZP385 and its metabolites, if applicable, will be listed 
and summarized. 
o PK parameters (e.g., Cmax, Tmax, t½, Ctau, AUC) of JZP385 and its metabolites, 
if applicable, will be estimated using population PK model and will be presented 
separately from the study data. 
o Population exposure-response analysis for JZP385 and its metabolites, if 
applicable, will be performed and will be presented separately from the study 
data. 
• Exploratory efficacy endpoints include: 
o Change from Baseline to Week 12 on the sum of modified items 6 and 7 of the 
TETRAS-PS as summarized by each dose of JZP385 and placebo. 
o Change from Baseline to Week 12 on the sum of modified items 1 to 11 of the 
TETRAS-ADL subscale as summarized by each dose of JZP385 and placebo. 
o Proportion of participants who improved (≥ 1 point decrease) from Baseline to 
Weeks 4 and 8 on the CGI-S. 
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o Change from Baseline to Weeks 4 and 8 on the TETRAS composite outcome 
score, TETRAS-ADL, TETRAS-PS, TETRAS upper limb score (item 4), and 
TETRAS total score. 
o Proportion of participants reported as much improved on the PGI-C and CGI-C at 
Weeks 4 and 8. 
o Change from Baseline to Week 12 on the 36-item Short Form Health Survey (SF-
36) as summarized by each dose of JZP385 and placebo. 
o Time course analysis on the sum of modified items 6 and 7 of the TETRAS-PS as 
summarized by each dose of JZP385 and placebo. 
 
 
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5. 
STUDY DESIGN 
5.1. 
Summary of Study Design 
This is a 12-week, double-blind, placebo-controlled, randomized, parallel-group, multicenter 
study of the safety and efficacy of JZP385 in the treatment of adult participants with moderate to 
severe ET. 
The total duration of the study for each participant will be approximately 19 weeks. During the 
Screening Period, which will occur over a period of up to 35 days (an additional 28 days are 
permitted for participants who require washout of primidone), all participants will be evaluated 
for eligibility and will washout any prohibited medications. Participants eligible for the study 
will be randomized in a 1:1:1:1 ratio to receive once daily doses of 10, 20, or 30 mg JZP385 or 
placebo during a 12-week Double-blind Treatment Period. Randomization will be stratified by 
the TETRAS composite outcome score (≤ 17 or > 17) and the use of concomitant antitremor 
medication (Yes or No), as assessed at the Baseline Visit. JZP385 will be administered orally 
(PO) once daily in the morning on an empty stomach for 12 weeks. Dosing will be titrated as 
follows:  
• Participants randomized to the 10 mg/day dose will initially receive 5 mg/day from Day 1 
through Day 7, and 10 mg/day starting on Day 8.  
• Participants randomized to the 20 mg/day dose will initially receive 5 mg/day from Day 1 
through Day 7, 10 mg/day from Day 8 through Day 14, and 20 mg/day starting on Day 
15.  
• Participants randomized to the 30 mg/day dose will initially receive 5 mg/day from Day 1 
through Day 7, 10 mg/day from Day 8 through Day 14, 20 mg/day from Day 15 through 
Day 21, and 30 mg/day starting on Day 22.  
Once participants reach their assigned fixed dose, they will continue on that dose for the 
remainder of the planned 12-week treatment period. No dose adjustments will be allowed. 
Participants who cannot tolerate their assigned fixed dose of JZP385 will be withdrawn from the 
study. 
The schema of study is shown in Figure 1.  
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Figure 1 
Study Schema 
 
5.2. 
Study Intervention 
The study intervention planned for use in this study are described in table below.  
Table 3 
Study Intervention 
Treatment 
Arm 
Intervention 
Namea 
Formulation 
Unit Dose Strength(s)b 
Dosage Level(s) 
Route of 
Administration 
1 
Placebo 
Capsule 
Placebo 
3 x placebo QD 
Oral 
2 
JZP385 
(DR2) 
Capsule 
Baseline Visit:  
5 mg JZP385 
1 x 5 mg QD + 2 x 
placebo QD 
Oral 
Weeks 2-12: 
10 mg JZP385 
1 x 10 mg QD + 2 x 
placebo QD 
3 
JZP385 
(DR2) 
Capsule 
Baseline Visit:  
5 mg JZP385 
1 x 5 mg QD + 2 x 
placebo QD 
Oral 
Week 2:  
10 mg JZP385 
1 x 10 mg QD + 2 x 
placebo QD 
Weeks 3-12: 20 mg 
JZP385 
2 x 10 mg QD + 1 x 
placebo QD 
4 
JZP385 
(DR2) 
Capsule 
Baseline Visit:  
5 mg JZP385 
1 x 5 mg QD + 2 x 
placebo QD 
Oral 
Week 2:  
10 mg JZP385 
1 x 10 mg QD+ 2 x 
placebo QD 
Week 3: 
20 mg JZP385 
2 x 10 mg QD+ 1 x 
placebo QD 
Weeks 4-12: 30 mg 
JZP385 
3 x 10 mg QD 
Abbreviations: mg = milligram; QD = once daily; DR2 = delayed release formulation 2. 
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a The JZP385 DR2 formulation is delayed release formulation 2; details of the formulation can be found in the 
JZP385 IB.  
b The dose strength of JZP385 is based on the active moiety in the drug product. 
5.3. 
Power and Sample Size Calculations  
A sample size of 80 evaluable participants per treatment group will provide 90% power to detect 
a difference of 3.1 points for the change from Baseline to Week 12 on the TETRAS composite 
outcome between JZP385 and placebo, with a common SD of 6.0 points. This sample size will 
also provide 91.7% power to detect a 26% between-treatment (assuming JZP385 at 66% versus 
placebo at 40%) difference in proportion of participants who improved by at least 1 point on the 
CGI-S from Baseline to Week 12. Assuming a 20% dropout rate, a total of 400 participants (100 
participants per treatment group) will be randomized. The sample size calculation for the 
TETRAS composite outcome score is based on t-test and the CGI-S sample size calculation is 
based on chi-square test, both tests are 2-sided at the significance level of 0.05.  
For the TETRAS composite outcome, at least 80% power is still achieved if there is a reduction 
of 0.4 points from the assumption in the difference in mean change from baseline (assuming a 
constant common standard deviation) or an increase in common standard deviation by 1 point, 
(assuming a constant difference in means). For the key secondary endpoint, at least 80% power 
is still achieved with comparable shifts in the assumptions. 
The assumptions for these sample sizes were supported by the results from the Phase 2 study in 
Essential Tremor (Study CX-8998-CLN2-001 [T-CALM]), where the TETRAS ADL and PS 
were assessed. Using the same derived TETRAS composite outcome score, as defined in this 
SAP, and assessing the change from baseline to Day 28 in T-CALM, there was a difference in 
means between JZP385 and placebo of 3.04 and a difference in LS Means of 3.27. The standard 
deviation for the change from baseline was 5.86 in JZP385 and 5.47 in placebo. It is 
hypothesized that the treatment improvement will remain consistent over the longer study 
duration of JZP385-201, with a small increase in variability, thus supporting the above 
assumptions.  
5.4. 
Randomization and Blinding 
Treatment allocation/randomization for this study will occur centrally through the use of an 
interactive response technology (IRT). Participants eligible for the study will be randomized in a 
1:1:1:1 ratio to receive once daily doses of 10, 20, or 30 mg JZP385 or placebo. Randomization 
will be stratified by the TETRAS composite outcome score (≤ 17 and > 17), as assessed at the 
Baseline. 
A double-blind approach will be used throughout the 12-week treatment period. During the study 
(including the titration period), the number of capsules taken each day will be the same for 
patients randomized to each treatment. JZP385 and placebo capsules will look and feel identical. 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participants’ 
intervention assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. If the investigator decides that unblinding is warranted, the 
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investigator should make every effort to contact the sponsor prior to unblinding a participant’s 
intervention assignment unless this could delay emergency treatment of the participant. 
If a participant’s intervention assignment is unblinded, the sponsor must be notified within 
24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and IRT system, as applicable. The participant’s treatment 
assignment may be unblinded for regulatory reporting purposes. Notification of the treatment 
assignment is only made known to those who require it for safety reporting and submission 
processes. All other individuals involved in the study, including the investigator, will remain 
blinded to treatment assignment. Participants for whom the blind is broken for this reason will 
not be withdrawn from the study.  
Sponsor safety staff may unblind the intervention assignment for any participant with an SAE. If 
the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, 
a copy of the report, identifying the participant’s intervention assignment, may be sent to 
investigators in accordance with local regulations and/or sponsor policy. 
5.5. 
Interim Analysis 
No interim analysis is planned. 
 
 
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6. 
ANALYSIS SETS 
For purposes of analysis, the following populations are defined: 
Table 4 
Analysis Sets 
Analysis Set 
Description 
Enrolled  
The Enrolled Analysis Set will include all participants who 
provide informed consent for this study.  
This set will be used to summarize participants’ screening, and 
inclusion/exclusion from each analysis set as well as reasons for 
exclusion. Summaries will be presented overall and by the 
randomization group for those randomized.  
Intent-to-treat (ITT) 
The ITT Analysis Set will include all participants who are 
randomized regardless of taking the study intervention (JZP385 or 
placebo). This set will be used for standard, baseline 
characteristics and demographic summaries, as well to be used for 
efficacy analyses, and participants should be summarized 
according to the randomized treatment arm.  
Safety  
The Safety Analysis Set will include all participants who are 
randomized and receive at least 1 dose of study intervention 
(JZP385 or placebo). This set will be used for standard, baseline 
characteristics and demographic summaries, as well to be used for 
safety analyses, and participants should be summarized according 
to actual received treatment arm. 
PK  
The PK Analysis Set will include all participants who are 
randomized and receive at least 1 dose of JZP385 and have at least 
1 post-dose evaluable PK concentration. All PK analyses and 
summaries will be based on the PK Analysis Set.  
 
 
 
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7. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
The statistical principles applied in the design and planned analyses of this study are consistent 
with International Conference on Harmonization (ICH) E9 guidelines (ICH 1998). 
7.1. 
General Methods 
In general, results will be summarized by treatment group. Categorical variables will be reported 
as frequency and percent. Continuous variables will be reported as the number of participants, 
mean, SD, or SE, median, minimum, and maximum. All summaries, statistical analyses, and 
individual participant data listings described below will be completed using Version 9.4 or later 
of the SAS Statistical Analysis System (SAS Institute, Inc. Cary, NC). 
7.2. 
Baseline and Study Day Definitions 
7.2.1. 
Baseline 
In general, the Baseline measurement for a variable is defined as the last non-missing value from 
the baseline visit measured prior to the first dose of the study intervention. If a participant has 
repeated measurements from the baseline visit, then the last repeated non-missing value will be 
used. If there is not a value from the scheduled baseline visit, the last non-missing value from 
other screening or unscheduled visits measured prior to the first dose of study intervention will 
be used. If a participant who early discontinued without taking the study intervention, the 
Baseline visit or the latest Screening Visit will be used. 
7.2.2. 
Study Day 
A study day will be assigned as follows: 
• 
The first dose of study intervention is designated as Day 1. Participants self-administer 
the first dose study intervention at home the day after the Baseline Visit.  
• 
For visit days after Day 1, study day = visit date - Day 1 date + 1. 
• 
For visit days prior to Day 1, study day = visit date - Day 1 date. Thus, study days for 
screening visit are negative numbers. There is no “Day 0”. 
• 
The end date of treatment for each subject is the subject’s last dose date in the study. 
• 
The end date of the study for each subject is defined as the date of the subject’s last 
assessment including the safety follow-up in the study. 
7.2.3. 
Visit Windows  
All scheduled, unscheduled, and early termination assessments will be summarized by derived 
analysis visit per the Table 5, regardless of whether the visit was performed on-site or remotely. 
Visit dates will be mapped based on the scheduled Period of each visit, with adjusted analysis-
defined visit windows as specified in Table 5. 
 
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Table 5 
Visit Windows for Assessments or Measurements 
Study Period 
Scheduled Visit 
Scheduled 
Study Day 
TETRAS-ADL, 
TETRAS-PS, 
CGIs 
CGIc and PGIc 
QUEST, SF-36v2, 
ETEA 
C-SSRSb, Clinical 
Laboratoryc, e, Urinalysise, 
Weight, Vital Signs, Breath 
Alcohold, e, ECG, Urine 
Pregnancy test 
Screening 
Visit 1/Visit 2a 
-49 to -8 
Any Day up to -2 
na 
n/a 
Any Day up to -2 
Baselinef 
Baseline Visit 
-1 
Closest prior to 
dosing 
na 
Closest prior to dosing 
Closest prior to dosing 
Double-Blind 
Treatment  
Week 1 
7 (-1, +2) 
na 
na 
na 
2 - 14 
Week 4 
28±3 
2 - 42 
2 - 42 
na 
15 - 42 
Week 8 
56± 3 
43 - 70 
43 - 70 
na 
43 - 70 
Week 12 
84± 3 
71 - 98 
71 – 98 
2 - max 
71 - max 
Safety 
Follow-up 
End of Study 
 
98± 3 
na 
na 
2 - max 
2 – max f  
 
a Screening Visit 2 is only for participants who need to wash out of any medications that impact tremor (e.g., anti-tremor medications) prior to Baseline; 
b At screening visit 1, C-SSRS screening/baseline version, at screening visit 2, C-SSRS since last visit version; 
c Clinical laboratory includes hematology and chemistry labs; 
d Breath Alcohol is not collected at W1; 
e Not collected at Safety Follow-up. 
f For participants who randomized without taking the study intervention, the Baseline Visit or latest Screening Visit (if Baseline Visit is not available) will be 
mapped. 
 
 
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If multiple assessments or measurements are recorded within a single visit window (including 
scheduled, unscheduled, repeated, and retest assessments or measurements as well as early 
discontinuation data), the following rules will be applied to determine the result from which 
assessment will be used for the summaries for that analysis visit.  
• The priority will always be given to the scheduled visit within the corresponding visit 
window (e.g., scheduled W4 visit corresponds to Week 4 visit window) regardless of the 
relative distance to the scheduled Visit Day.  
• If there are 2 or more observations within the same visit window, then the non-missing 
one closest to the scheduled Visit Day will be used in the analysis.  
• If 2 or more observations are equidistant from the scheduled Visit Day, then the non-
missing observation with the earliest collection date will be used in the analysis.  
• If 2 or more observations are collected on the same day and this day is the closest to the 
scheduled Visit Day, then the non-missing observation with the earliest collection time 
will be included in the analysis.  
Screening Visit 1 and Visit 2 will be treated as two visits. Observations from the two visits will 
be summarized separately, as applicable.  
If a visit window does not contain any observations, then the data will remain missing for the 
analysis visit.  
Listings will include scheduled, unscheduled, repeated, retest, and early termination data per 
nominal visits. 
7.2.4. 
Visit and Assessment Changes Due to COVID-19  
Changes in scheduled visits and corresponding assessments due to COVID-19 restrictions will be 
captured as in the eCRF. In the eCRF completion guidelines, sites were provided instructions for 
capturing visits that were missed (not performed) or performed remotely. The following visit and 
assessment changes will be included in submission datasets:  
• All on-site visits that were converted to remote visits for any reason will be flagged. This 
information will be captured in the eCRF and protocol deviation log.  
• 
Missed visits are flagged if the “not done” field is indicated and the reason for “not done” 
is indicated as “Covid-19 restriction” or “Participant acquired Covid-19” from the 
dropdown list.  
7.2.5. 
Missing and Partial Data 
Missing or partially missing start and stop dates for concomitant medications and AEs will be 
imputed as described in Appendix 1: Date Imputation Rules. However, imputed dates will NOT 
be presented in the listings as their sole purpose will be for the classification of the medications 
as past, concomitant or post (refer to Section 8.5). 
Missing data will be handled as described below: 
• 
Missing safety data will not be imputed except for the start and stop dates for AEs and 
concomitant medication. 
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• 
Missing data for primary estimand and key secondary estimand will be handled as 
described in Section 9.1 and 9.2. 
• 
Missing data for other secondary endpoints, and exploratory endpoints will be managed 
as described in Section 9.2 and 9.3. 
• 
To manage the partial missing scales on TETRAS composite outcome score (derived 
using TETRAS-ADL and TETRAS-PS items as described in Section 9.1.1), the 
imputation of missing ADL and PS scores will be handled separately. For the purposes of 
this imputation, only ADL items 1 to 11 and PS items 6 and 7 are considered. 
Additionally, item 6 of the PS includes 2 separate scores (for the left- and right-hand 
responses).  
o If ≤ 3 ADL item scores are missing at a specific time point, the mean of the 
remaining nonmissing ADL item scores at that time point will be used to impute 
the missing ADL item score value. The TETRAS composite outcome score will 
then be calculated as the sum of the observed and imputed item scores. If ≥ 4 
ADL item scores are missing, the composite outcome score will not be calculated. 
o If 1 PS item score is missing at a specific time point, the mean of the remaining 
non-missing PS item scores at that time point will be used to impute the missing 
PS item score value. The TETRAS composite outcome score will then be 
calculated as the sum of the observed and imputed item scores. If ≥ 2 PS item 
scores are missing, the composite outcome score will not be calculated. 
7.3. 
Hypotheses Testing 
The null and alternative hypotheses for analysis of the primary estimand are:  
H1_0: μ (JZP385) = μ (Placebo) (i.e., there is no difference in the mean change on the TETRAS 
composite outcome score from Baseline to Week 12 between each JZP385 dose group and the 
placebo group). 
H1_A: μ(JZP385) ≠ μ (Placebo) (i.e., the mean change on the TETRAS composite outcome score 
from Baseline to Week 12 is not equal between each JZP385 dose group and the placebo group). 
The null and alternative hypotheses for analysis of key secondary estimand are: 
H2_0: π (JZP385) = π (Placebo) (i.e., there is no difference in the proportion of participants who 
improved [≥ 1 point decrease] on the CGI-S from Baseline to Week 12 between each JZP385 
dose group and the placebo group. 
H2_A: π  (JZP385) ≠ π  (Placebo) (i.e., there is a difference in the proportion of participants who 
improved [≥ 1 point decrease] on the CGI-S from Baseline to Week 12 between each JZP385 
dose group and the placebo group). 
Each JZP385 treatment group will be compared individually to the placebo group in the order 
specified in Section 7.4. 
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7.4. 
Level of Significance & Multiplicity Adjustment 
To evaluate the efficacy of JZP385 at doses of 10, 20, and 30 mg/day compared with placebo, 
pairwise treatment difference between each of the 3 doses and placebo will be tested at the end 
of Week 12 for the primary and key secondary endpoints.  
The family-wise Type I error rate will be controlled at a 2-sided significance level of 0.05. To 
address the multiplicity issue due to the multiple efficacy endpoints and doses, a fixed 
hierarchical testing sequence will be employed. The testing procedure will stop when a p-value 
exceeds 2-sided significance level of 0.05 (see below). 
Statistical hypotheses to be tested (in sequential order): 
1. Change in the TETRAS composite outcome score from Baseline to Week 12, 30 mg/day 
versus placebo. 
2. Difference in proportion of participants who improved (≥ 1 point decrease) on the CGI-S 
from Baseline to Week 12, 30 mg/day versus placebo. 
3. Change in the TETRAS composite outcome score from Baseline to Week 12, 20 mg/day 
versus placebo. 
4. Difference in proportion of participants who improved (≥ 1 point decrease) on the CGI-S 
from Baseline to Week 12, 20 mg/day versus placebo. 
5. Change in the TETRAS composite outcome score from Baseline to Week 12, 10 mg/day 
versus placebo. 
6. Difference in proportion of participants who improved (≥ 1 point decrease) on the CGI-S 
from Baseline to Week 12, 10 mg/day versus placebo. 
7.5. 
Subgroups and Subgroup Analyses 
Subgroup analyses will be conducted on the primary and key secondary efficacy endpoints for 
the following: 
• 
Sex at birth (Female, Male) 
• 
Region (North America, Europe) 
• 
High enrolling sites, based on the number randomized (≥ 20 randomized, < 20 
randomized) 
• 
Randomization stratum: TETRAS composite outcome score (≤ 17, > 17)  
• 
Randomization stratum: antitremor medication (No, Yes) 
• 
Age (< 65, ≥ 65) 
• 
Diagnosis (ET, ET plus) 
• 
Family history of ET (No, Yes) 
The output for estimating the treatment difference within subgroup will not be provided (least 
square means, standard error, LS Mean Difference (95% CI) or proportion difference (95% CI) 
and p-value) if the data are too sparse.  
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It should be noted that the study was not designed to detect treatment differences with high 
statistical power within any subgroups. 
7.6. 
Changes to Planned Analyses 
Section 9.4.1.4 of the Protocol outlines the approach to imputation of missing item scores, as part 
of the TETRAS composite outcome score. Based on these rules, it was possible for a participant 
to have a missing TETRAS PS score at a visit and still have a valid composite outcome score. 
The rules have been amended to change the imputation of missing item scores to be managed 
within the individual subscale scores (ADL or PS) before the composite outcome score is 
calculated. The details of the new calculation are specified in Section 7.2.5. 
The mITT Analysis Set defined in the Protocol Section 9.3 has been updated to ITT, to include 
all randomized participants for the primary efficacy analyses. 
For Adverse Events of Special Interests defined in Protocol Section 8.4.6, presyncope was 
removed in the formal definition of AEOSI in Section 10.2.1. 
 
 
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8. 
STUDY POPULATION SUMMARIES 
8.1. 
Enrollment 
The total number and percentage of participants for each Analysis Set defined in Section 6 will 
be summarized by treatment group, also by country and study site/Investigator. 
8.2. 
Subject Disposition 
All participants who provide informed consent will be accounted for in this study. The number 
and percentages of screen failure participants will be presented by overall among the Enrolled 
Analysis Set. The number and percentages of participants who received at least one dose, 
completed, are still ongoing and withdrew, including reasons for withdrawal, will be presented 
overall and by randomized treatment group. 
Note that the disposition listing will capture the reason for withdrawal including any subject who 
discontinues from the study due to COVID-19 related AE, or COVID-19 related. 
8.3. 
Demographic and Baseline Characteristics 
Demographics and other baseline characteristics data including age, age group (<65, ≥65), race, 
ethnicity, sex at birth, weight, height at screening, body mass index, childbearing potential 
(female only), region, wash out of ET medications prior to Baseline, randomization stratification 
factors, baseline TETRAS-ADL (items 1-12), TETRAS-PS (items 1-9) and CGI-S will be 
summarized by treatment group for Safety, ITT, and PK analysis sets. Categorical variables will 
be summarized by frequency and percentage of participants. The denominators for calculating 
the percentages will be the number of participants in each analysis set. Continuous variables will 
be summarized using descriptive statistics including the number of participants, mean, median, 
standard deviation (SD), minimum and maximum. 
8.4. 
Medical/Surgical History 
Surgical and medical history are defined as those medical conditions/ diseases which started 
prior to or on the date first study dose.  
The surgical and medical history data will be summarized based on the Safety Analysis Set and 
ITT Analysis Set. 
8.5. 
Prior and Concomitant Medications 
Medications will be coded to the anatomical therapeutic class (ATC) level 4 and preferred drug 
name using the WHODrug Global-B3, March 2024, and will be classified as follows:  
• 
Prior medications are defined as any medications which started prior to the first dose of 
study intervention. 
• 
Concomitant medications are defined as any medications which started prior to, on or 
after the first dose of study intervention up to the last dose of study intervention and 
continued during the study intervention.  
• 
Post medications are defined as any medications which started after the last dose of 
study intervention.  
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See Appendix 1: Date Imputation Rules for handling of partial dates for medications. 
Medications will be summarized by ATC level 4 and preferred drug name.  
Summaries will include all prior medications under ITT and Safety Analysis Set, as well as 
concomitant medications under the Safety Analysis Set. Additionally, prior and concomitant ET 
medications will be summarized and listed.  
8.6. 
Protocol Deviations 
Protocol deviations as classified in the CTMS (type of deviation and severity) will be 
summarized using the ITT as well as Safety Analysis Set. All protocol deviations will also be 
provided in a listing.  
Changes to study conduct due to COVID-19 restrictions will be reported as protocol deviations. 
These deviations will be summarized separately by the classification type in CTMS and included 
in a listing. 
Any IMP dispensing errors will be reported as protocol deviations. For outputs summarized 
under ITT Analysis Set, participants will be analyzed according to the randomized treatment 
arm. For outputs summarized under the Safety Analysis Set, actual treatment arm will be mapped 
according to the planned arm based on randomization schedule, to handle potential drug 
dispensation error(s) when unblinding, the most frequent dispensed dose (10, 20 or 30 mg)  on or 
after Week 4 will be used, in case the drug dispensation error(s) occurred prior to Week 4, the 
last dispensed kit upon early discontinuation will be used, for participant who early discontinued 
on or prior to Day 7 on a 5 mg blister card, 10mg will be assigned as the actual treatment arm. 
 
 
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9. 
EFFICACY  
Unless otherwise described, efficacy data will be primarily presented by randomized treatment 
groups using ITT, and treatment comparison will be between the randomized treatment groups. 
9.1. 
Primary Efficacy Estimand and Analysis 
9.1.1. 
Primary Estimand 
The attributes of the primary estimand are listed in Section 4.2.1. 
The primary estimand is a composite outcome of the sum of modified items 1 to 11 of the 
TETRAS-ADL and modified items 6 and 7 of the TETRAS-PS. The scoring of each of the items 
1 to 11 of the TETRAS-ADL subscale will be modified from 5 response options to 4 response 
options by using the following rules: 
• A score of 0 or 1 will be modified to a score of 0 
• A score of 2 will be modified to a score of 1 
• A score of 3 will be modified to a score of 2 
• A score of 4 will be modified to a score of 3 
• A missing score will remain missing 
The scoring of each of the items 6 and 7 of the TETRAS-PS will be modified from 9 options to 4 
response options by using the following rules: 
• A score of 0, 0.5, or 1 will be modified to a score of 0 
• A score of 1.5 or 2 will be modified to a score of 1 
• A score of 2.5 or 3 will be modified to a score of 2 
• A score of 3.5 or 4 will be modified to a score of 3 
• A missing score will remain missing 
There are a total of 14 items that contribute to the TETRAS composite outcome score (11 items 
from the TETRAS-ADL with a total possible score of 33, TETRAS-PS item 6 with a total 
possible score of 6 as this item includes assessments for both hands, and TETRAS-PS item 7 
with a total possible score of 3). Therefore, the total range of the TETRAS composite outcome 
score that will be used for the primary analysis is 0 to 42. 
9.1.2. 
Primary Analyses 
For the main analysis of the primary efficacy endpoint, a MMRM will be used to include the 
change in the TETRAS composite outcome score from Baseline to Weeks 4, 8, and 12.  
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑖𝑖𝑖𝑖= 𝛼𝛼𝑖𝑖+ 𝛽𝛽1 ∗𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑖𝑖 + 𝛽𝛽2 ∗𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑗𝑗+ 𝛽𝛽3 ∗𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑖𝑖  + 𝛽𝛽4 ∗𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑖𝑖∗ 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑗𝑗 +  
𝛽𝛽5 ∗𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑖𝑖∗ 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑗𝑗 + 𝛽𝛽6 ∗𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑡𝑡𝑢𝑢𝑢𝑢𝑖𝑖  + 𝜀𝜀𝑖𝑖𝑖𝑖 
The model will include treatment group (𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑖𝑖  ), baseline TETRAS composite outcome 
score (𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑖𝑖), week (as a discrete factor, 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑗𝑗), treatment group by week interaction 
(𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑘𝑘∗ 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑗𝑗 ), week by baseline interaction (𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑗𝑗∗ 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑖𝑖), and randomization 
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stratum (𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑖𝑖  ) as fixed effects, and week repeated within each participant as a repeated 
effect (𝛼𝛼𝑖𝑖). For the purposes of this model, “week” refers to the treatment visit, as determined 
using the windows specified in Section 7.2.3. An unstructured variance-covariance matrix will 
be used to model the correlation among repeated measurements. If the model fails to converge on 
the Newton-Raphson Algorithm, the alternative Fisher scoring algorithm should be explored 
before considering other variance-covariance structures. Kenward-Roger’s degrees of freedom 
will be used. 
Least squares mean and standard error for Week 12 will be provided for each treatment group. 
The difference between the LS means of JZP385 and placebo for Week 12, along with the SE of 
the difference, 95% CI and associated p-value corresponding to testing the hypothesis of no 
difference between the treatment groups will also be provided.  
The assumption of normality will be examined by obtaining a histogram and a QQ-plot on 
studentized residuals. Based on these plots, if there exists evidence to suggest the departure from 
the normality assumption, a non-parametric MMRM with the covariate and response variables 
replaced by their ranks will be used for the primary analysis. 
The following is an example of SAS code for linear mixed model analysis: 
PROC MIXED; 
CLASS PATIENT TRT WEEK STRATUM; 
MODEL CHG = BASELINE TRT WEEK STRATUM TRT*WEEK BASELINE*WEEK / 
RESIDUAL OUTP=RESIDUAL DDFM=KR; 
REPEATED WEEK/TYPE=UN SUB=PATIENT; 
LSMEANS TRT*WEEK / CL DIFF ALPHA=0.05; 
RUN; 
9.1.3. 
Sensitivity Analyses 
Sensitivity analyses for the primary estimand will be conducted under the hypothetical strategy 
framework using the ITT Analysis Set. These sensitivity analyses will only be needed where the 
JZP385 group demonstrates a statistically significant improvement over the placebo group, based 
on the criteria outlined in Section 7.3. 
Under the hypothetical strategy, the MAR assumption is being followed for the primary analysis, 
which supports the justification for using an MMRM model. This is supplemented by the 
possibility of data being MNAR, assessed under the sensitivity and supplemental analyses. 
9.1.3.1. 
Pattern Mixture Model  
A control-based Pattern Mixture Model will be used to explore the possibility of data being 
MNAR for participants who discontinued early from study due to either lack of efficacy or an 
adverse event. For participants who early discontinued due to other reasons, missing data will be 
imputed assuming MAR. Control-based Imputation (CBI) method assumes a mean and variance 
based on the control group for participants who withdrew from the JZP385 group at the time of 
withdrawal to the imputed timepoint, with the observed values prior to withdrawal still 
considered, thus a slow decay back toward the control group mean eventually. (Carpenter JR, 
2013) This method assumes that from withdrawal onwards, participants in the active treatment 
group will progress back to the participants in the control group.  
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Figure 2 illustrates MAR estimates versus the estimates derived from CBI (assuming study 
participants withdraw at Visit 2 and a lower response indicates improvement).  
Figure 2 
MAR vs CBI 
 
The control-based imputation will be implemented through steps below: 
Treatment dropouts and missing observations at Weeks 4, 8 and 12 will be imputed using the 
multiple imputation method. MI procedure in SAS will be used to impute the missing TETRAS 
composite outcome score at the missed visit to create 20 complete datasets.  
The missing data pattern will be checked. If any non-monotone missing data pattern is observed, 
2 separate steps will be followed to complete the imputation, starting with Step 1. If a monotone 
missing data pattern is observed, skip to Step 2 directly (set imputation number to 20 instead).   
Step 1: the Markov Chain Monte Carlo (MCMC) method will be used with a single chain to 
impute TETRAS composite outcome score by treatment, baseline stratification group as well as 
baseline TETRAS composite outcome score to create 20 imputed datasets with monotone 
missing patterns. Set the seed as 8715942. Imputed scores should be rounded to nearest integer, 
with the minimum and maximum possible score set to 0 and 42 respectively, which corresponds 
to the range of possible TETRAS composite outcome score.  
Step 2: the predictive mean matching (PMM) method will be used to impute the remaining 
missing scores for the 20 imputed datasets with monotone missing patterns. The imputation 
procedure will use monotone statement to create 1 compete dataset for each of the monotone 
datasets from Step 1, with model variables to include treatment, baseline stratification group, as 
well as TETRAS composite outcome score at scheduled visits from Baseline to Weeks 4, 8 and 
12. Set the seed as 4985135 and number of closest observations to 2.  
For participants who discontinued the study early due to either lack of efficacy or an adverse 
event, the post-discontinuation values imputed through Steps 1 and 2 will be set to missing and 
rederived using CBI method (MNAR).  
The imputed datasets with a mixture of MAR and MNAR imputations will be analyzed 
separately using the MMRM model specified in 9.1.2, then final inference will be pooled using 
the MIANALYZE procedure and reported.  
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9.1.3.2. 
Tipping Point Analyses 
Tipping point analyses will be used to investigate the robustness of the primary analysis method. 
The delta adjusting approach (O’Kelly & Ratitch, 2014) will be used to find the tipping point, at 
which JZP385 is no longer statistically significant. This analysis will only be performed where a 
JZP385 treatment group shows a statistically significant improvement against placebo, based on 
the criteria outlined in Section 7.4.  
The marginal delta approach will be used for tipping point analyses by following Steps 1 and 2 
specified above (Section 9.1.3.1) and then followed by: 
Step 3: For participants in a JZP385 treatment group, make the imputed value worse by an 
increment of delta, with the initial delta value set at 0, which is equivalent to the MAR estimate, 
and increases delta value by 10% of the maximum observed treatment difference among all dose 
groups at each time, until the tipping point is detected. 
The primary analysis will be reperformed, using the MMRM model specified in Section 9.1.2, 
for each imputed dataset, at each delta. The results from the datasets, at each delta, will be 
pooled, using the MIANALYZE procedure.  
The delta identified at which the results are no longer statistically significant will be the tipping 
point. After the tipping point is determined, clinical judgement will be applied to the plausibility 
of the assumptions underlying this tipping point. 
9.1.4. 
Completers Analysis (Data as Observed) 
The primary analysis in Section 9.1.2 will only include the participants who have the TETRAS 
composite outcome score at Weeks 4, 8 and 12. This constitutes a Completers Analysis. 
Normality assumptions will not be reassessed. The corresponding parametric or nonparametric 
analysis will be used from the primary analysis. 
9.1.5. 
Subgroup Analyses 
Subgroup analyses for groups specified in Section 7.5 will be performed for the primary efficacy 
estimand using the ITT Analysis Set. The primary analysis in Section 9.1.2 will be used for the 
subgroup analyses. However, the randomization stratification factor will be removed from the 
model for the analysis by subgroups of participants by randomization strata. The corresponding 
parametric analysis used for the overall sample will be applied to each subgroup. A forest plot 
summarizing the treatment difference and 95% CI will be provided for each subgroup with 
sufficient sample size. 
9.2. 
Secondary Efficacy Estimand, Endpoints and Analyses 
9.2.1. 
Key Secondary Efficacy Estimand  
The attributes of the key secondary estimand are listed in Section 4.1.2.  
The CGI-S is a 5-point Likert-type ordinal scale. The responses to this investigator-completed 
scale range from 1 to 5 and correspond to the following categories: 
• No limitations (1) 
• Mild (2) 
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• Moderate (3) 
• Marked (4) 
• Severe (5) 
For analysis purposes, CGI-S will be treated as a dichotomous variable where a response is 
defined as a ≥ 1-point decrease (improvement) from Baseline to Weeks 4, 8 and 12. For the 
estimator, the proportion of participants who have achieved the response at Week 12 will be 
compared between JZP385 and placebo groups.  
9.2.2. 
Primary Analysis  
The main estimator of the key secondary estimands will be analyzed using the CMH test 
adjusting for the stratification factor at randomization (Baseline TETRAS composite score: ≤ 17 
or > 17 and antitremor medication use at Baseline: Yes or No). Number of responders in each 
group, proportion as well as 95% CI (Wilson score method) will be reported at Week 12. The 2-
sided p-values from the CMH test, the unadjusted treatment difference as well as the adjusted 
treatment difference in proportion using the weighted average of the treatment differences across 
strata with CMH weights, and the associated 2-sided 95% CI using a normal approximation to 
the weighted average will be derived and reported at Week 12.  
Treatment dropouts and missing observations for the main analytic approach will be handled 
through multiple imputation (MI), a method that relies on observed values from similar 
participants who remained in the study to bridge information to deduce missing observations. 
Missing values at Weeks 4, 8 and 12 for CGI-S will be imputed using the MI method. The MI 
procedure in SAS will be used to impute a missing CGI-S score at the scheduled visit to create 
20 complete datasets.  
The missing data pattern will be checked at Baseline, Weeks 4, 8 and 12. If any non-monotone 
missing pattern is observed, 2 separate steps will be followed to complete the imputation, starting 
with Step 1. If a monotone missing pattern is observed, skip to Step 2 (setting imputation number 
to 20) 
Step 1: the Markov Chain Monte Carlo (MCMC) method will be used with a single chain to 
impute missing CGI-S scores by treatment, baseline stratification group as well as baseline CGI-
S score to create 20 imputed datasets with monotone missing patterns. Set the seed as 8715942. 
Imputed scores should be rounded to nearest integer, set minimum and maximum possible score 
to 1 and 5 respectively, which corresponds to the range of CGI-S.  
Step 2: the predictive mean matching (PMM) method will be used to impute the remaining 
missing CGI-S scores for the 20 imputed datasets with monotone missing patterns. The 
imputation procedure will use monotone statement to create 1 compete dataset for each of the 
monotone datasets from Step 1, with model variables include treatment, baseline stratification 
group, as well as CGI-S score at scheduled visits from Baseline to Weeks 4, 8 and 12. Set the 
seed as 4985135 and number of closest observations to 2.  
The imputed datasets will be analyzed using CMH test, and the final inference will be pooled 
using SAS procedure MIANALYZE. 
The following is an example SAS code for CMH analysis: 
PROC SORT DATA = CGIS; 
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BY IMPUTESEQ VISIT TRT STRATUM DECENDING RESPONSE; 
RUN; 
 
PROC SQL; 
CREATE TABLE ADDIN AS 
SELECT DISTINCT IMPUTESEQ, VISIT, TRT, STRATUM, 1 AS RESPONSE 
FROM CGIS; 
QUIT; 
 
DATA CMH; 
MERGE CGIS (IN=A) ADDIN (IN=B); 
BY IMPUTESEQ VISIT TRT STRATUM DECENDING RESPONSE; 
IF B AND NOT A THEN WGT = 0; 
ELSE WGT = 1; 
RUN; 
 
*Adjusted (Stratified) Difference and CMH TEST; 
PROC FREQ DATA=CMH; 
BY IMPUTESEQ AVISITN; 
TABLES STRATUM*TRT*RESPONSE/RISKDIFF (COMMON CL=(NEWCOMBE)) CMH; 
WEIGHT WGT/ZEROS; 
RUN; 
 
*Unadjusted (Unstratified) Difference; 
PROC FREQ DATA=CMH; 
BY IMPUTESEQ AVISITN; 
TABLES TRT*RESPONSE/RISKDIFF CMH; 
WEIGHT WGT/ZEROS; 
RUN; 
9.2.3. 
Sensitivity Analyses 
Sensitivity analyses will be conducted to account for missing data using NRI (Non-responder 
Imputation) method and 2-dimensional tipping point analyses.  
For NRI, participants who have insufficient data (due to missingness) for response determination 
will be considered as non-responder (< 1 point change from Baseline) for Week 12. Then a 
similar stratified/unstratified CMH test will be conducted, and results will be reported.  
For the 2-dimensional tipping point analyses, let M1 and M2 be the total number of participants 
with missing CGI-S data in the JZP385 and Placebo groups, respectively. There will be a total of 
(M1+1)*(M2+1) possible ways end up with imputing missing values to a result of responder or 
non-responder in each of the 2 groups. For each of the (M1+1)*(M2+1) imputation patterns, a 
Chi-square test will be conducted to test the statistical significance, and the output will be 
displayed in a rectangle shape. The staircase region that separates significant and non-significant 
outcomes forms the tipping-point boundary. 
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9.2.4. 
Completers Analysis (Data as Observed) 
The primary analysis in Section 9.2.2 will be conducted to only include the participants who 
have the CGI-S at Week 12. This constitutes a Completers Analysis. The corresponding CMH 
analysis will be used from the primary analysis. 
9.2.5. 
Subgroup Analyses 
Subgroup analyses for groups specified in Section 7.5 will be performed for the key secondary 
efficacy estimand using ITT. The analysis in Section 9.2.2 will be used for the subgroup 
analyses. However, the randomization stratification factor will be removed from the model for 
the analysis by subgroups of participants by randomization strata.  
9.2.6. 
Other Secondary Endpoints and Analyses 
9.2.6.1. 
CGI-C and PGI-C at Week 12 
The secondary efficacy endpoint of CGI-C is defined as the proportion of investigators reporting 
improvement of symptoms (“much improved”) on CGI-C at Week 12. The CGI-C is a 5-point 
Likert-type rating scale. Investigators will rate their impression of any change in severity of the 
subject’s condition on a 5-point scale ranging from 1 = “much improved” to 5 = “much worse” 
since Baseline. Clinicians’ rating will focus on the change in the patients’ ability to function due 
to ET. 
The proportion of participants reporting improvement of symptoms on CGI-C will be compared 
between treatment groups using the Cochran-Mantel-Haenszel (CMH) test stratified by 
randomization stratum. The point estimate and continuity corrected Wilson’s 95% CI (as 
modified by Newcombe) for the difference of the proportion will also be provided. 
Similarly, the secondary efficacy endpoint of PGI-C is defined as the proportion of participants 
reporting improvement of symptoms (“much improved”) on PGI-C at Week 12. The PGI-C is a 
5-point Likert-type rating scale. Participants will rate the change in their condition since Baseline 
on a 5-point scale ranging from 1 = “much improved” to 5 = “much worse”. Participants’ rating 
will focus on the change in their ability to function due to ET.  
The proportion of participants reporting improvement of symptoms on PGI-C will be compared 
between treatment groups using the Cochran-Mantel-Haenszel (CMH) test stratified by 
randomization stratum. The point estimate and continuity corrected Wilson’s 95% CI (as 
modified by Newcombe) for the difference of the proportion will also be provided. 
Treatment dropouts and missing observations will be handled by multiple imputation (MI) as 
stated in Section 9.2.2. No sensitivity analyses or supplemental analysis planned. 
9.2.6.2. 
Change from Baseline to Week 12 on the TETRAS-ADL, TETRAS-PS, 
TETRAS-PS upper limb score (item 4), and TETRAS total score 
The secondary efficacy endpoints of change from Baseline to Week 12 on: 
• TETRAS-ADL (sum of 12 items, each rated 0, 1, 2, 3 or 4. The maximum total score is 
48)  
• TETRAS-PS (sum of 9 items rated from 0-4 with half points and a maximum total score 
of 64)  
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• TETRAS-PS upper limb score (item 4) 
• TETRAS total score (sum of the TETRAS-ADL and TETRAS-PS) 
will be analyzed similarly with MMRM. The MMRM will include the difference from Baseline 
to Weeks 4, 8, and 12. The model will include treatment group, corresponding baseline, week (as 
a discrete factor), treatment group by week interaction, and randomization stratum as fixed 
effects, and participant as a random effect. If the model fails to converge on the Newton-
Raphson Algorithm, the alternative Fisher scoring algorithm should be explored before 
considering other variance-covariance structures. The first alternative variance-covariance matrix 
will be autoregressive. Kenward-Roger’s degrees of freedom will be used. 
LS mean and SE for Week 12 will be provided for each treatment group. The difference between 
the LS means of JZP385 and placebo for Week 12, along with the SE of the difference, 95% CI 
and associated p-value corresponding to the testing hypothesis of no difference between the 
treatment groups will also be provided.  
The assumption of normality will be examined by obtaining a histogram and a QQ-plot on 
studentized residuals. Based on these plots, if there is evidence to suggest the departure from the 
normality assumption, a non-parametric MMRM with the covariate and response variables 
replaced by their ranks will be used.  
9.2.6.3. 
Change from Baseline to Week 12 of QUEST score 
The Quality of Life in Essential Tremor Questionnaire (QUEST) was developed to specifically 
assess the impact of ET on health-related quality of life (Tröster 2005). The QUEST is a 30-item 
questionnaire comprising 5 subscales (physical, psychosocial, communication, hobbies/leisure, 
and work/finance), besides participants also provided assessments on overall health status, 
overall quality of life, tremor self assessment plus 4 additional items under general information 
relating to sexual function, satisfaction with tremor control, medication side effects and work 
status.  
For the analysis of change of QUEST score from Baseline to Week 12, an analysis of covariance 
(ANCOVA) model will be used for related items on a continuous scale. The model will include 
treatment group, randomization stratum, and corresponding baseline value as covariates. For 
items on categorical scale, shift tables will be provided to detect change from Baseline to Week 
12. No participant level imputation will be conducted to missing data or data after intercurrent 
events. 
9.2.6.4. 
Change from Baseline to Week 12 of ETEA score 
The Essential Tremor Embarrassment Assessment (ETEA) is a patient-rated questionnaire 
administered by a health care provider or researcher that contains 14-items assessing 
embarrassment related to tremor. Participants provide a simple response (disagree or agree) to 
each of the 14-items, the sum of which yields an initial score (Score A, range = 0 to 14). 
Participants then provide a more nuanced response to each question on a 0 to 5 point Likert scale 
ranging from disagree (0) to agree strongly (5). The sum of the nuanced responses yields a 
second score (Score B, range = 0 to 70). Higher scores on both the simple and nuanced responses 
indicate greater embarrassment.  
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For the analysis of change of ETEA score from Baseline to Week 12, an ANCOVA model will 
be performed using the PROC MIXED SAS procedure. The model will include treatment group, 
randomization stratum, and corresponding baseline value as covariates. No participant level 
imputation will be conducted to missing data or data after intercurrent events. 
9.3. 
Exploratory Endpoints 
9.3.1. 
Analysis of Exploratory Efficacy Continuous Endpoints 
The continuous exploratory endpoints include the change from Baseline to Weeks 4 and 8 on:  
• 
The TETRAS composite outcome score 
• 
TETRAS-ADL 
• 
TETRAS-PS 
• 
TETRAS upper limb score (item 4)  
• 
TETRAS total score 
The analyses results will be derived from the MMRM models for the Week 12 analysis used in 
the primary estimand (Section 9.1.2), key secondary estimand (Section 9.2.2), and secondary 
endpoints (Section 9.2.3). 
For the analyses of exploratory endpoints: 
• 
The change from baseline to Week 12 on the modified items 6 and 7 of the TETRAS-PS 
(where each item is modified from 9 response items to 4 response items as specified in 
Section 9.1.1).  
• 
The change from baseline to Week 12 on the sum of modified items 1 to 11 of the 
TETRAS-ADL subscale (where each item is modified from 5 response items to 4 response 
items by collapsing options 0 and 1 together).  
MMRM models similar to the one used in analysis for primary estimand (Section 9.1.2) will be 
used.  
For the analysis of change in SF-36v2 score from Baseline to Week 12, a descriptive summary at 
each scheduled visit along with change from Baseline to Week 12 will be summarized and listed. 
9.3.2. 
Analysis of Exploratory Dichotomous Endpoints 
For the analyses of proportion of participants reported as much improved on the PGI-C and CGI-
C at Weeks 4 and 8, as well as proportion of participants improved (≥ 1 point decrease) from 
Baseline to Weeks 4 and 8, the similar analysis to Section 9.2.2 will be conducted. Week 4 and 
Week 8 data will be analyzed separately. CMH test stratified by the randomization stratum will 
be used for the comparison between each dose of JZP385 and placebo. Study dropouts and 
missing observations will be handled by multiple imputation (MI) as stated in Section 9.2.2. No 
sensitivity analyses or supplemental analysis are planned. 
9.3.3. 
Time course efficacy analysis 
The time course efficacy analysis uses the sum of modified items 6 and 7 of the TETRAS-PS. At 
Baseline: items 6 and 7 of the TETRAS-PS will be assessed serially across the day at 6 time 
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points: predose, 1, 2, 4, 6, and 8 hours post-dose. At Week 8 visit, items 6 and 7 of the TETRAS-
PS will be assessed serially at the same 6 time points: predose, 1, 2, 4, 6, and 8 hours post-dose 
(time matched at Baseline). The 1 hour post-dose assessment at Baseline as well as Week 8 
should be taken from the full TETRAS-PS assessment.  
The time course efficacy analysis will be performed with a mixed model with repeated 
measurements (MMRM). The time-matched change on items 6 and 7 of the TETRAS-PS will be 
the dependent variable in the model. The model will include time-matched baseline TETRAS-PS 
item 6 and 7, treatment group, time points, treatment group by time point interaction and 
randomization stratum as fixed effects, and participant as a random effect. 
 
 
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10. 
SAFETY  
All safety analyses, summaries, listings and figures will use the Safety Analysis Set unless 
otherwise specified.  
10.1. 
Exposure 
10.1.1. 
Extent of Exposure 
The duration of exposure will be derived as date of last dose of study intervention – date of first 
dose of study intervention + 1. Dosing Interruptions are not taken into account for the duration of 
exposure. The duration of exposure will be summarized using descriptive statistics.  by treatment 
groups. Exposure summaries are based on data collected by the study intervention administration 
eCRF and data collected in IRT. 
10.1.2. 
Treatment Compliance 
Summary statistics for compliance to study intervention will be presented using descriptive 
statistics as well as counts and percentages, as appropriate, based on the Safety Analysis Set 
overall and by treatment group. Compliance will also be summarized by category (<75%, 75-
125% and >125%). A listing of compliance will also be presented. 
Compliance will be calculated as the number of capsules taken (i.e. total dispensed – total 
returned) divided by the number of capsules that should have been taken by the subject during 
that study period, expressed as a percentage i.e. 
𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐(%) = 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑢𝑢𝑙𝑙𝑙𝑙𝑙𝑙 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
 
10.2. 
Adverse Events 
Adverse events (AEs) occurring from the first dose until the final study visit will be reported. If 
the Investigator becomes aware of a SAE within 14 days after the last dose of study intervention, 
the event must also be reported. In addition, any SAE assessed as related to study intervention or 
procedure by the Investigator must be reported regardless of time after study termination.  
AEs will be coded to system organ class (SOC) and preferred term using the Medical Dictionary 
for Regulatory Activities (MedDRA), Version 27.0. The investigator will assess the relationship 
of each AE to study intervention. AE with a missing relationship to study intervention will be 
reported as related in the summaries. Severity, as determined by the Investigator, will be classed 
as mild, moderate, severe, life-threatening or fatal. AE with missing severity will be reported as 
missing in the summaries.  
Note that participants who acquire COVID-19 or report AEs due to the COVID-19 public health 
emergency (e.g., anxiety) while on study will be coded accordingly and included in the adverse 
event summaries. 
A treatment-emergent adverse event (TEAE) is defined as any event with onset date on or after 
the first dose of study intervention, including adverse events that occur until 14 days after the last 
dose date. For the purpose of calculating treatment emergence, incomplete onset dates will be 
imputed as detailed in Appendix 1: Date Imputation Rules.  
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Time of first onset of AE is calculated as: TEAE start date – First dose date + 1 and is 
categorized as: 
• Week 1 (1 ≤ day of first onset of AE ≤ 7) 
• Week 2 (8 ≤ day of first onset of AE ≤ 14) 
• Week 3 (15 ≤ day of first onset of AE ≤ 21) 
• Week 4 (22 ≤ day of first onset of AE ≤ 28) 
• Weeks 5 to 8 (29 ≤ day of first onset of AE ≤ 56) 
• Weeks 9 to 12 (57 ≤ day of first onset of AE ≤ 84) 
• 
After Week 12 (84 < day of first onset of AE) 
Only TEAEs are included in summary tables unless otherwise specified. If a subject has multiple 
episodes of events coded to the same SOC or PT, then the subject will be counted just once in the 
summaries for that term. Subject incidence of TEAEs by SOC and PT tables are sorted by SOCs 
(alphabetical order) and then by PTs (descending order) within each SOC for the overall 
frequency. For summaries by PT only, PTs will be sorted in descending order of overall 
frequency. 
Each TEAE will be summarized by treatment group.  
A general overall summary of TEAEs with the number and percent of participants who 
experienced the following types of events will be provided: 
• Participants with any TEAE  
• Participants with any related TEAE  
• Participants with any serious TEAE  
• Participants with TEAE by severity  
• Participants with an AE outcome as death  
• Participants with any TEAE leading to study intervention discontinuation  
• Any TEAE leading to study intervention dose reduction  
• Any TEAE leading to study intervention dose interruption  
• Any TEAE not recovered  
Subject incidence of TEAEs tables will be summarized by the following:  
• SOC and PT  
• TEAE reported ≥5% in any treatment group by SOC and PT  
• PT only  
• TEAE reported >=5% in any treatment group by PT 
• Maximum severity by SOC and PT  
• Treatment-related by SOC and PT  
• TEAEs of special interest by category (defined in Section 10.2.1) and PT  
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• TEAEs leading to permanent withdrawal of study intervention by SOC and PT  
• TEAEs leading to dose reduction of study intervention by SOC and PT  
• TEAEs leading to dose interruption of study intervention by SOC and PT  
• TEAE by Time of First Onset, SOC, and PT 
• Serious TEAE by Time of First Onset, SOC, and PT 
• 
Serious treatment related TEAE by Time of First Onset, SOC, and PT 
Separate adverse event listings will be provided including the following:  
• All adverse events  
• Adverse events with an outcome of death  
• Adverse events leading to permanent withdrawal of study intervention 
• Serious adverse events  
• 
Adverse events of special interest, defined in defined in Section 10.2.1 
10.2.1. 
Adverse Events of Special Interest  
TEAEs of special interest will be summarized and may include the terms or categories noted 
below.  
• Hallucinations of any type 
• Syncope 
10.3. 
Laboratory Assessments 
The continuous clinical laboratory assessments (hematology, chemistry, and urinalysis) will be 
summarized at each visit using descriptive statistics. The change from Baseline will be provided 
at the Week 12.  
Shift tables will summarize changes in clinical laboratory assessments at each of the post-
baseline visit with respect to baseline. Lab values are categorized into L1, low, normal, high, or 
H1 based on the lab reference range. L1 and H1 values are predefined per the lab vendor alert 
ranges and correspond to the extreme abnormal lower and higher ranges, respectively. 
Abnormal laboratory assessments deemed clinically significant by the investigator will be 
reported as an adverse event.  
A listing of Participants with abnormal value(s) according to the following criteria will be 
summarized using Safety Analysis Set:  
• Any laboratory value that falls into the pre-defined low or high panic ranges (L1 or 
H1) per the Q2 Laboratory Range Chart.  
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 × Upper 
Limit of Normal (ULN) and total bilirubin > 2 × ULN, inclusive (Hy’s Law).   
• AST or ALT ≥ 5 × ULN,  
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• Creatinine ≥ 1.5 × ULN  
• Participants positive for alcohol, urine drug screen or pregnancy assessments  
All laboratory results, including pregnancy test, drug screen, and alcohol screen, will also be 
presented in subject data listings. 
10.3.1. 
Laboratory Specific Derivation  
• Multiple of upper limit of normal (ULN) = result / ULN  
10.3.2. 
Laboratory Normal Reference Ranges 
Quantitative laboratory measurements will be compared with the relevant laboratory reference 
ranges in SI units and categorized as:  
• L1: result less than the low alert (L1)  
• Low: result within the low alert (L1) and lower limit of normal (LLN) (L1 and LLN 
limit included)  
• Normal: result within the laboratory normal reference range (LLN and ULN limit 
included)  
• High: result within the ULN and high alert (H1) (ULN and H1 limit included)  
• 
H1: result greater than the high alert (H1)  
10.4. 
Vital Signs 
The following vital signs measurements will be reported for this study. 
• Supine and standing systolic blood pressure (SBP), (millimeter of mercury [mmHg]) 
• Supine and standing diastolic blood pressure (DBP) (mmHg) 
• Supine and standing pulse rate (beats per minutes [bpm]) 
• Sitting or supine respiratory rate (breaths/min) 
• Body Temperature (°C) 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) [derived] 
The orthostatic vital signs will be derived as the difference found by subtracting the supine 
measurement from the standing measurements. The orthostatic measurement will be summarized 
with the supine and standard measurements. 
These vital signs (with the exception of the BMI which will be calculated programmatically) will 
be measured during the screening visit and each in-clinic scheduled visit. Height (cm) will be 
obtained at screening visit only.  
The following summaries will be provided for vital signs data: 
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• Observed and change from baseline by visit  
• Incidence of markedly abnormal criteria by visit  
10.4.1. 
Vital Signs Markedly Abnormal Criteria  
Markedly abnormal quantitative vital signs measurements will be identified in accordance with 
the following predefined markedly abnormal criteria as specified in Table 6. 
Table 6 
Vital Signs Predefined Markedly Abnormal Criteria 
Variable (unit) 
Low 
High 
SBP (mmHg) 
≤ 90 mmHg AND  
change from baseline ≤ -20 mmHg 
≥ 180 mmHg AND 
change from baseline ≥ 20 mmHg 
DBP (mmHg) 
≤ 50 mmHg AND 
change from ≤ -15 mmHg 
≥ 110 mmHg AND 
change from baseline ≥ 15 mmHg 
Orthostatic SBP 
(mmHg) 
≥ 20 mmHg drop with posture change from supine to standing 
Orthostatic DBP 
(mmHg) 
≥ 10 mmHg drop with posture change from supine to standing 
Pulse rate (bpm) 
≤ 50 bpm AND 
change from baseline ≤ -15 bpm 
≥ 120 bpm AND 
change from baseline ≥ 15 bpm 
Orthostatic pulse rate 
(bpm) 
≥ 30 bpm increase with posture change from supine to standing 
Weight (kg) 
percentage change from baseline ≤  
-10.0% 
percentage change from baseline ≥ 
10.0 % 
Temperature (ºC) 
≤ 35.0 ºC 
≥ 39.0 ºC 
Note: bpm: Beats per minute. DBP: Diastolic Blood Pressure. kg: kilogram. mmHg: Millimeter of mercury. SBP: 
Systolic Blood Pressure 
10.5. 
ECG 
A standard 12-Lead ECG will be recorded with the subject resting in supine for at least 5 
minutes. ECGs will be performed during the Screening visit, Baseline visit, in-clinic scheduled 
visit or early termination visit. Results from the central ECG core lab will be included in the 
reporting of this study. The following ECG parameters will be reported: 
• PR Interval (msec)  
• RR Interval (msec)  
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• QRS Interval (msec)  
• QT Interval (msec)  
• QT Bazett’s correction (QTcB) Interval (msec) [derived]  
• QT Fridericia’s correction (QTcF) Interval (msec) [derived]  
• Mean HR (bpm)  
• Overall assessment of ECG:  
o Normal  
o Abnormal  
The following summaries will be provided for ECG data across the study:  
• Observed and change from baseline by visit (for quantitative measurements)  
• ECG parameters results will be listed over time 
10.5.1. 
ECG Abnormal Criteria 
Abnormal quantitative ECG measurements will be identified in accordance with the following 
predefined markedly abnormal criteria: 
Observed values for QT interval, QTcB interval and QTcF will be classified as follows at each 
time point: 
• > 450 msec 
• > 480 msec 
• > 500 msec 
Change from baseline for QT interval, QTcB interval and QTcF will be classified as follows: 
• >30 msec increase from baseline 
• >60 msec increase from baseline 
A listing of participants meeting markedly abnormal criteria as well as a listing of participants 
with abnormal ECG overall assessment will also be provided based on the Safety Analysis Set. 
10.6. 
Other Safety Endpoints 
10.6.1. 
Columbia-Suicide Severity Rating Scale  
The Screening/Baseline version of the C-SSRS will be administered to participants at screening 
visit. 
The Since Last Visit version of the C-SSRS will be administered to participants at every 
scheduled in-clinic after the screening visit 2 up to the Safety Follow-up visit or early 
discontinuation visit. 
The following summaries will be provided for the C-SSRS data by visit and by treatment group: 
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• Number and percentage of participants with any suicidal ideation (i.e., having responded 
yes to any of the 5 types of suicide ideation) as well as broken down by type of suicidal 
ideation 
• Number and percentage of participants with any suicidal behavior (i.e., having responded 
yes to any of the 4 or 5 types of suicidal behavior, as applicable) as well as broken down 
by type of suicidal behavior 
• Number and percentage of participants with any suicidal behavior or any suicidal ideation; 
a subject having reported both suicidal behavior and suicidal ideation will be counted 
only once 
• Number and percentage of participants with self-injurious behavior without suicidal 
intent  
Missing data will not be imputed. All C-SSRS parameters will be presented in the subject data 
listing. 
10.6.2. 
Safety and COVID-19 Considerations 
10.6.2.1. Alternative methods for safety assessments  
For remote visits, the Investigator will remain in contact with the subject via telephone to discuss 
adverse events, as well as to evaluate efficacy and tolerability of the prescribed dose of study 
intervention. Note that all protocol deviations due to changes in how assessments are collected 
will be recorded and labeled as related to COVID-19 mitigations. 
10.6.2.2. Assessment of safety due to COVID-19 considerations 
Safety summaries will combine data that is collected on-site and remotely (e.g., exposure, 
adverse event, and CSSR-S). A total number of assessments not done due to COVID-19 
restrictions will be provided. A summary table of all protocol deviations relating to COVID-19 
restrictions will be included. 
 
 
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11. 
PHARMACOKINETIC ANALYSES  
The dosing regimen during the PK evaluation will be the subject’s currently assigned treatment 
regimen. Participants will take their dose at similar conditions to those normally followed at 
home. Blood samples will be collected at 0 (pre-dose), and 1 sample between 0.5 to 3 hours post-
dose for Weeks 1, 4 and 12 visits; and pre-dose, 1 sample between 0.5 to 3 hours postdose, and 1 
sample anytime between 5 to 8 hours postdose for Week 8 visit. In the event a shorter clinic visit 
is needed because of the COVID-19 pandemic, the 5 to 8 hour postdose sample at W8 may be 
omitted with approval from the Sponsor’s Medical Monitor. 
11.1. 
Pharmacokinetic Concentrations 
The plasma concentrations data for each analyte will be listed by participant and listing will 
include visit, nominal timepoint, and actual time postdose.  
The plasma concentration data will be used as part of population PK and population exposure-
response analysis that will be described in separate SAP(s) and its results will be presented 
separately from the study data. 
The plasma concentration data will be used as part of population PK and population exposure-
response analysis that will be described in separate SAP(s) and will be presented separately from 
the study data. 
 
 
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12. 
PHARMACODYNAMIC ANALYSES  
Not applicable 
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13. 
REFERENCES 
Carpenter JR, Roger JH, Kenward MG. Analysis of Longitudinal Trials with Protocol Deviation: 
A Framework for Relevant, Accessible Assumptions, and Inference via Multiple Imputation 
(2013) J Biopharm Stat. 2013;23(6):1352-71. 
O’Kelly M, Ratitch B (2014) Clinical Trials with Missing Data A Guide for Practitioners, John 
Wiley & Sons. 
Tröster AI, Pahwa R, Fields JA, et al. Quality of life in Essential Tremor Questionnaire 
(QUEST): development and initial validation. Parkinsonism & Related Disorders. 
2005;11(6):367-73. 
 
 
DocuSign Envelope ID: 0414D087-8407-4F04-A861-BA42008FC1BD


Jazz Pharmaceuticals 
 
 
Statistical Analysis Plan - Protocol JZP385-201  
 
 
47 
 
 
  
 
APPENDIX 1: DATE IMPUTATION RULES 
Incomplete Adverse Event Onset Date 
If year is missing (or completely missing): set to the date of first dose. 
If (year is present and month and day are missing) or (year and day are present and month 
is missing): 
 
If year = year of first dose: set the date to the first dose date. 
 
If year < year of first dose: set month and day to December 31st. 
 
If year > year of first dose: set month and day to January 1st. 
If month and year are present and day is missing: 
 
If year = year of first dose, and: 
If month = month of first dose: set day to day of first dose. 
 
 
If month < month of first dose: set day to last day of month. 
 
 
If month > month of first dose: set day to 1st day of month. 
 
If year < year of first dose: set day to last day of month. 
 
If year > year of first dose: set day to 1st day of month. 
             For all other cases: set to date of first dose. 
 
Incomplete Concomitant Medication Start Date 
If year is missing (or completely missing): do not impute. 
If (year is present and month and day are missing) or (year and day are present and month 
is missing): 
Set month and day to January 1st. 
If year and month are present and day is missing: 
Set day to 1st day of month. 
 
Incomplete Concomitant Medication End Date 
Do not impute if Ongoing Flag is checked. 
If year is missing (or completely missing): do not impute. 
If (year is present and month and day are missing) or (year and day are present and month 
is missing): 
Set month and day to December 31st. 
If year and month are present and day is missing: 
Set day to last day of the month.  
DocuSign Envelope ID: 0414D087-8407-4F04-A861-BA42008FC1BD


Jazz Pharmaceuticals 
 
 
Statistical Analysis Plan - Protocol JZP385-201  
 
 
48 
 
 
  
 
 
NOTE: If PD/Relapse date is available and after date of last dose, replace last dose of study 
intervention with PD/Relapse date for imputation algorithm given in this section. 
 
DocuSign Envelope ID: 0414D087-8407-4F04-A861-BA42008FC1BD


Certificate Of Completion
Envelope Id: 0414D08784074F04A861BA42008FC1BD
Status: Completed
Subject: Complete with Docusign: JZP385-201 SAP v1.0.pdf
Source Envelope: 
Document Pages: 48
Signatures: 3
Envelope Originator: 
Certificate Pages: 5
Initials: 0
AutoNav: Enabled
EnvelopeId Stamping: Enabled
Time Zone: (UTC-08:00) Pacific Time (US & Canada)
3180 Porter Dr.
Palo Alto, CA  94304
IP Address: 163.116.248.73 
Record Tracking
Status: Original
             5/31/2024 10:23:11 AM
Holder  
 
             
Location: DocuSign
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Sr Dir, Clinical Development
Jazz Pharmaceuticals
Security Level: Email, Account Authentication 
(Required)
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7C8C69DA-74B8-4EB1-9DE1-9C553A1C31BE
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Signed: 5/31/2024 11:04:45 AM
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Associate Director, Biostatistics
Jazz Pharmaceuticals
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(Required), Login with SSO
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FE9E8018-58C0-4A8B-B742-49EF5003ECDF
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Signed: 5/31/2024 10:25:55 AM
Electronic Record and Signature Disclosure: 
      Accepted: 1/25/2023 9:10:40 AM
      ID: 660e5bac-0ba6-446c-845c-100738fbfea5
      Company Name: Jazz Pharmaceuticals


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Sr Director, Biostatistics
Jazz Pharmaceuticals
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F1EAA5F5-10C6-46C0-B57E-23057E8C651E
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Sent: 5/31/2024 10:25:20 AM
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Signed: 5/31/2024 10:26:32 AM
Electronic Record and Signature Disclosure: 
      Accepted: 2/14/2020 1:06:36 PM
      ID: 67a3fd0d-7db0-46ed-b3b7-b7eb941ac397
      Company Name: Jazz Pharmaceuticals
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Electronic Record and Signature Disclosure


ELECTRONIC RECORD AND SIGNATURE DISCLOSURE 
From time to time, Jazz Pharmaceuticals (we, us or Company) may be required by law to provide 
to you certain written notices or disclosures. Described below are the terms and conditions for 
providing to you such notices and disclosures electronically through the DocuSign system. 
Please read the information below carefully and thoroughly, and if you can access this 
information electronically to your satisfaction and agree to this Electronic Record and Signature 
Disclosure (ERSD), please confirm your agreement by selecting the check-box next to ‘I agree to 
use electronic records and signatures’ before clicking ‘CONTINUE’ within the DocuSign 
system. 
 
Getting paper copies 
At any time, you may request from us a paper copy of any record provided or made available 
electronically to you by us. You will have the ability to download and print documents we send 
to you through the DocuSign system during and immediately after the signing session and, if you 
elect to create a DocuSign account, you may access the documents for a limited period of time 
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to 
send you paper copies of any such documents from our office to you, you will be charged a 
$5.00 per-page, with a minimum of $100 per-document fee. You may request delivery of such 
paper copies from us by following the procedure described below. 
 
Withdrawing your consent 
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
 
Consequences of changing your mind 
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to 
receive required notices and consents electronically from us or to sign electronically documents 
from us. 
 
All notices and disclosures will be sent to you electronically 
Electronic Record and Signature Disclosure created on: 8/8/2019 10:59:54 AM
Parties agreed to  
 
 
 
 


Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact Jazz Pharmaceuticals: 
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to: 
 
To advise Jazz Pharmaceuticals of your new email address 
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at 
jazz_notices@jazzpharma.com and in the body of such request you must state: your previous 
email address, your new email address. 
If you created a DocuSign account, you may update it with your new email address through your 
account preferences. 
 
To request paper copies from Jazz Pharmaceuticals 
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to jazz_notices@jazzpharma.com and in 
the body of such request you must state your email address, full name, mailing address, and 
telephone number.  
 
To withdraw your consent with Jazz Pharmaceuticals 
To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 


i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to
 nd in the body of such request you must state 
your email, full name, mailing address, and telephone number. 
 
Required hardware and software 
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements. 
 
Acknowledging your access and consent to receive and sign documents electronically 
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
 
You can access and read this Electronic Record and Signature Disclosure; and 
 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
 
Until or unless you notify Jazz Pharmaceuticals as described above, you consent to 
receive exclusively through electronic means all notices, disclosures, authorizations, 
acknowledgements, and other documents that are required to be provided or made 
available to you by Jazz Pharmaceuticals during the course of your relationship with Jazz 
Pharmaceuticals. 
 
You are the user identified and that you are applying to use electronic signatures at Jazz 
Pharmaceuticals. Your first and last names and assigned user name are correct. You 
hereby agree to use the combination of my assigned user name and associated private 
password as my electronic signature to review and approve documents that require my 
signature. You further agree that this electronic signature shall be the legally binding 
equivalent of my handwritten signature. You understand that you are accountable and 
responsible for any actions on documents that you initiate under your electronic 
signature.