A 17-week, Phase 2, Randomized, Double-blind, Placebo-controlled, Flexible-dosing, Parallel-group, Multicenter Study of the Efficacy and Safety of Suvecaltamide in the Treatment of Moderate to Severe Residual Tremor in Participants With Parkinson's Disease
Phase: PHASE2
Conditions: Parkinson Disease, Tremor
Sponsor: Jazz Pharmaceuticals

Jazz Pharmaceuticals 
 
Protocol JZP385-202-01 
JZP385 
 
Amendment 01 
 
 
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Page 1 
TITLE PAGE 
Protocol Title: 
A 17-week, Phase 2, Randomized, Double-blind, Placebo-controlled, Flexible-dosing, 
Parallel-group, Multicenter Study of the Efficacy and Safety of Suvecaltamide in the Treatment 
of Moderate to Severe Residual Tremor in Participants with Parkinson’s Disease 
Study Number: JZP385-202 
Protocol and Amendment Number: JZP385-202-01 
Amendment Scope: Global 
Compound: Suvecaltamide (JZP385, formerly CX-8998 and MK-8998) 
Brief Title: A Study of Suvecaltamide in Adults with Moderate to Severe Residual Tremor in 
Parkinson’s Disease 
Study Phase: Phase 2 
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: 
 
 
 
 
 
 
 
EU Clinical Trial Number: 2022-001063-27 
 
Refer to the final page of this protocol for electronic signature and date of approval. 
 
 

Jazz Pharmaceuticals 
 
Protocol JZP385-202-01 
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Amendment 01 
 
 
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Sponsor Signatory: 
 
 
 
{Please see appended electronic signature page} 
 MD, PhD 
Sr. Director Clinical Development, Neuroscience 
 
Date 
 
Investigator Signatory: 
 
 
 
[Name] 
[Title] 
 
Date 
 
 
Medical Monitor name and contact information can be found in the Trial Site Binder (or 
equivalent).  
 
 

Jazz Pharmaceuticals 
 
Protocol JZP385-202-01 
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Amendment 01 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
DOCUMENT HISTORY  
Document  
Date  
Amendment 01  
Please see appended electronic signature page. 
Original Protocol  
16-May-2022  
Amendment 01 (Date: Please see appended electronic signature page) 
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 and 
EU Regulation No 5136/2014. 
Overall Rationale for the Amendment:  
The overall rationale for this amendment is to facilitate participant enrollment by modifying 
eligibility criteria, including the removal of the TETRAS-PS inclusion criterion and expansion of 
participant’s upper age limit to 85 years. 
Section # and Name 
Description of Change 
Brief Rationale 
Signature Page 
Updated the name of the 
Medical Monitor. 
To account for change in study 
personnel. 
1.3 Schedule of Activities 
(Table 4) 
Removed the requirement for 
urinalysis at Week 1. 
To reduce burden to the participants 
and sites. No other safety laboratory 
assessments are being conducted at 
this visit. 
1.3 Schedule of Activities 
(Table 4) 
Added a reminder to the 
comments in Table 4 regarding 
Week 5 for the “Provide 
instructions for titration” 
activity. 
To provide a reminder regarding 
titrating to reach an efficacious and 
tolerable dose. 
3 Objectives, Estimands, and 
Endpoints (Table 6); also 
updated in 1.1 Synopsis 
(Table 2) 
Changed the order of 
secondary efficacy endpoints 
so that TETRAS-PS comes 
after the PGI-C, PGI-S, and 
CGI-C endpoints. 
Correction to align with the planned 
order of analysis in the SAP. 
 
Removed ‘physical 
examination findings’ from 
safety secondary endpoint. 
Physical examination findings will be 
reported as medical history prior to 
the first dose of study intervention 
and as AEs after the first dose of 
study intervention. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
For clarification. 

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Section # and Name 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
4.1 Overall Design; 5.4 
Screen Failures 
Specified that ‘Medical 
Monitor’ is the ‘Sponsor 
Medical Monitor’ for 
rescreening purposes. 
For clarification. 
4.1 Overall Design; also 
updated in 1.1 Synopsis 
Added text about optimization 
to Dose Titration and 
Optimization Period bullet. 
For clarification. 
4.1 Overall Design; 6.5 Dose 
Modification; also updated 
in 1.1 Synopsis 
Changed ‘continued study 
participation’ to ‘continuation 
of study intervention’ for 
Maintenance Period bullet. 
For clarification. 
5.1 Inclusion Criteria; also 
updated in 1.1 Synopsis 
(Table 3) 
Inclusion Criterion #1 – 
changed the upper age limit 
from ‘80 years’ to ‘85 years’. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
Participant safety will be managed by 
exclusion criteria for comorbid 
conditions, and the flexible dosing 
design will allow participants to be 
titrated to an optimal dose based on 
efficacy and tolerability. 
5.1 Inclusion Criteria; also 
updated in 1.1 Synopsis 
(Table 3) 
Inclusion Criterion #3 – 
changed ‘idiopathic PD’ to 
‘PD’ and removed the 
requirement for this diagnosis 
to occur ‘within the past 
5 years’. 
The term idiopathic was removed to 
align with the terminology in the 
MDS 2015 criteria and the past 
5 years was removed to correct the 
timing. 
5.1 Inclusion Criteria 
Inclusion Criterion #7b – 
removed criterion for 
TETRAS-PS score. 
Inclusion #7a (TETRAS-ADL score 
≥ 22) and #7c (CGI-S rating of at 
least moderate for participants’ 
ability to function) are considered 
sufficient to enroll a PD participant 
with moderate to severe residual 
tremor. 

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Section # and Name 
Description of Change 
Brief Rationale 
 
Inclusion Criterion #8a – 
removed the bullet for 
abstinence from heterosexual 
intercourse and revised other 
bullets. 
To align with sponsor’s standard 
procedures. 
 
Inclusion Criterion #8b –
updated the note 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. 
For clarification and to align with 
sponsor’s standard procedures. 
5.2 Exclusion Criteria 
Exclusion Criterion #2 – added 
example medical conditions 
and a note regarding prior 
essential tremor diagnosis to 
criterion. 
For clarification. 
 
Exclusion Criterion #9 – 
clarified language to align with 
intent and added note to 
explain when remote history of 
cancer may be allowed. 
For clarification. 
 
Exclusion Criterion #10 – 
added text regarding Gilbert’s 
syndrome, combined criteria 
#10 and #11, and removed the 
eGFR threshold. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion Criterion #17 –
modified to clarify that 
participants should refrain 
from using PRN 
medication(s)/substance(s) that 
For clarification. 

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Section # and Name 
Description of Change 
Brief Rationale 
may produce tremor or 
interfere with the evaluation of 
tremor prior to discharge on 
study visit days. Also, 
provided clarification 
regarding PRN sleep 
medications and regular 
benzodiazepine use. 
 
Exclusion Criterion #19 – 
replaced ‘PD medications or 
other anti-tremor medications’ 
with ‘medications to treat 
tremor’ and added a note 
regarding PRN use of 
dopaminergic rescue 
medications. 
Use of PRN dopaminergic 
medications can be standard of care 
for other motor symptoms (eg, 
rigidity or bradykinesia); therefore, 
PRN use of dopaminergic 
medications is allowed for the 
treatment of non-tremor PD 
symptoms (rigidity and 
bradykinesia). PRN use of 
medications to treat tremor is 
prohibited. 
 
Exclusion Criterion #21 – 
added text regarding 
permissible uses of botulinum 
toxin. 
For clarification. Suvecaltamide is 
targeting treatment of tremor in PD. 
Thus, the use of botulinum toxin for 
other reasons (eg, cosmetic, excessive 
salivation, dystonia) will not 
confound this assessment as long as 
the location of use is anatomically 
distinct from the region with tremor. 
 
Exclusion Criterion #22 – 
added examples of dopamine 
receptor antagonists and 
dopamine depleting 
medications. 
For clarification. 
 
Exclusion Criterion #28 – 
revised criterion to include 
‘known use of recreational 
drugs’. 
Added a note regarding opioid 
use at stable doses. 
For clarification and to align with 
sponsor’s standard procedures. 
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding; 8.1.2 Assignment 
of Participant Number  
Updated first paragraph to 
specify that a participant 
number will be assigned by 
IRT at Screening. 
Updated second paragraph of 
Section 6.3 for clarification.  
For clarification. 

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Section # and Name 
Description of Change 
Brief Rationale 
6.8 Concomitant Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
For clarification. 
7.1.2 Positive Alcohol or 
Urine Drug Screens; 8 Study 
Assessments and Procedures 
Changed ‘Medical Monitor’ to 
‘Sponsor Medical Monitor’. 
For clarification. 
7.1.2 Positive Alcohol or 
Urine Drug Screens 
Added text to clarify that the 
urine sample will be sent to the 
central laboratory. 
For clarification. 
8 Study Assessments and 
Procedures 
Removed protocol waiver list 
item. 
Protocol waivers are discussed in 
Section 5. 
8.1.1 Informed Consent  
Replaced ‘medically qualified 
designee” with ‘qualified 
designee’. 
For clarification (qualified designee 
does not need a medical degree if 
consistent with local regulations). 
8.1.3 Medical History; 
Appendix 5 Contraceptive 
and Barrier Guidance 
Removed text related to sexual 
abstinence. 
To align with the inclusion criterion 
changes and the sponsor’s standard 
procedures. 
8.1.5 Inclusion and 
Exclusion Criteria Review  
Revised text to clarify that 
approval of eligibility to attend 
the Baseline Visit will be 
obtained from the Medical 
Monitor. Also, added text to 
clarify that the sites must 
re-confirm eligibility at the 
Baseline Visit prior to 
randomization. 
For clarification and to align with the 
sponsor’s standard procedure. 
8.3.2 Vital Signs 
Revised text to clarify that 
vital signs will be taken prior 
to blood collection when 
possible. 
For clarification. 
9.4.1.2 Definition of Study 
Periods for Analysis 
Removed Section 9.4.1.2 from 
the protocol. 
The analysis period definition resides 
within the contexts of the SAP. 
Section 9.4.1.3 Intercurrent 
Event Strategies (formerly 
Section 9.4.1.4) 
Replaced ‘taking rescue 
medications’ with ‘PRN use of 
medications to treat tremor’. 
To align with updated Exclusion 
Criterion #19. 
Section 9.4.1.5 Dropouts and 
Missing Data (formerly 
Section 9.4.1.6) 
Updated the Dropouts and 
Missing Data section. Updated 
Figure 1. 
For clarification. 
9.4.2 Primary Estimand 
Updated MMRM model 
components. 
For clarification. 

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Section # and Name 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
10.1.6 Dissemination of 
Clinical Study Data  
Removed ‘EudraCT’. 
Correction. 
Appendix 3 Clinical 
Laboratory Tests (Table 9) 
Added text to clarify that LDL 
is calculated and added HDL. 
Revised text so prothrombin 
time INR is specified 
separately. 
To clarify that both a lipid panel and 
coagulation parameters will be 
collected. 
Throughout 
Minor editorial changes were 
made throughout the protocol. 
For clarification and consistency. 
Abbreviations: AEs = adverse events; BID = twice a day; CGI-C = Clinical Global Impression of Change; 
CGI-S = Clinical Global Impression of Severity; eGFR = estimated glomerular filtration rate; EudraCT = European 
Union Drug Regulating Authorities Clinical Trials Database; HDL = high density lipoprotein; IRT = interactive 
response technology; LDL = low density lipoprotein; MDS = Movement Disorder Society; MMRM = mixed effect 
model with repeated measures; PD = Parkinson’s disease; PGI-C = Patient’s Global Impression of Change; 
PGI-S = Patient’s Global Impression of Severity; 
 
PRN = as 
needed; SAP = Statistical Analysis Plan; TETRAS-ADL = The Essential Tremor Assessment Rating Scale, 
Activities of Daily Living; TETRAS-PS = The Essential Tremor Assessment Rating Scale, Performance Subscale; 
WOCBP = woman of childbearing potential. 

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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................3 
TABLE OF CONTENTS .................................................................................................................9 
LIST OF TABLES .........................................................................................................................14 
LIST OF FIGURES .......................................................................................................................15 
1. 
PROTOCOL SUMMARY ..........................................................................................16 
1.1. 
Synopsis ......................................................................................................................16 
1.2. 
Schema ........................................................................................................................22 
1.3. 
Schedule of Activities .................................................................................................23 
2. 
INTRODUCTION ......................................................................................................29 
2.1. 
Study Rationale ...........................................................................................................29 
2.2. 
Background .................................................................................................................30 
2.2.1. 
Parkinson’s Disease ....................................................................................................30 
2.2.2. 
Suvecaltamide .............................................................................................................30 
2.3. 
Benefit/Risk Assessment ............................................................................................31 
2.3.1. 
Risk Assessment .........................................................................................................31 
2.3.2. 
Benefit Assessment .....................................................................................................32 
2.3.3. 
Overall Benefit:Risk Summary ...................................................................................32 
3. 
OBJECTIVES, ESTIMANDS, AND ENDPOINTS ..................................................33 
4. 
STUDY DESIGN .......................................................................................................37 
4.1. 
Overall Design ............................................................................................................37 
4.2. 
Scientific Rationale for Study Design ........................................................................38 
4.3. 
Justification for Dose ..................................................................................................39 
4.4. 
End of Study Definition ..............................................................................................40 
5. 
STUDY POPULATION .............................................................................................41 
5.1. 
Inclusion Criteria ........................................................................................................41 
5.2. 
Exclusion Criteria .......................................................................................................43 
5.3. 
Lifestyle Considerations .............................................................................................47 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................47 
5.3.2. 
Caffeine, Alcohol, and Tobacco .................................................................................47 
5.4. 
Screen Failures ............................................................................................................47 

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5.5. 
Criteria for Temporarily Delaying Administration of Study Intervention .................47 
6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY...........................48 
6.1. 
Study Interventions Administered ..............................................................................48 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................51 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................51 
6.4. 
Study Intervention/Treatment Compliance .................................................................52 
6.5. 
Dose Modification ......................................................................................................52 
6.6. 
Continued Access to Study Intervention after the End of the Study ..........................52 
6.7. 
Treatment of Overdose, Medication Errors, or Misuse ..............................................53 
6.8. 
Concomitant Therapy .................................................................................................53 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................55 
7.1. 
Discontinuation of Study Intervention........................................................................55 
7.1.1. 
Participants Remaining in the Study After Study Intervention 
Discontinuation ...........................................................................................................55 
7.1.2. 
Positive Alcohol or Urine Drug Screens ....................................................................56 
7.1.3. 
Temporary Discontinuation/Study Intervention Interruption .....................................56 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................56 
7.3. 
Lost to Follow-up .......................................................................................................56 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................58 
8.1. 
General Administrative Procedures ............................................................................59 
8.1.1. 
Informed Consent .......................................................................................................59 
8.1.2. 
Assignment of Participant Number ............................................................................59 
8.1.3. 
Medical History ..........................................................................................................59 
8.1.4. 
Medication Review (Prior and Concomitant Medications) ........................................59 
8.1.5. 
Inclusion and Exclusion Criteria Review ...................................................................59 
8.1.6. 
Timing of Study Intervention Dosing .........................................................................60 
8.1.7. 
Montreal Cognitive Assessment .................................................................................60 
8.2. 
Efficacy Assessments .................................................................................................60 
8.2.1. 
Tremor Research Group Essential Tremor Rating Assessment Scale – 
Activities of Daily Living ...........................................................................................60 
8.2.2. 
Tremor Research Group Essential Tremor Rating Assessment Scale – 
Performance Subscale .................................................................................................61 
8.2.3. 
Clinical Global Impression of Severity ......................................................................61 

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8.2.4. 
Clinical Global Impression of Change .......................................................................61 
8.2.5. 
Patient Global Impression of Severity ........................................................................62 
8.2.6. 
Patient Global Impression of Change .........................................................................62 
8.2.7. 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale ...................62 
8.2.8. 
 
 
 
8.2.9. 
 
 
  
 
 
8.2.10. 
 
 
 
8.2.11. 
 
 
8.3. 
Safety Assessments .....................................................................................................63 
8.3.1. 
Physical Examinations ................................................................................................63 
8.3.2. 
Vital Signs ..................................................................................................................64 
8.3.3. 
Electrocardiograms .....................................................................................................64 
8.3.4. 
Clinical Safety Laboratory Assessments ....................................................................64 
8.3.5. 
Pregnancy Testing ......................................................................................................65 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................65 
8.3.7. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease 
Rating Scale ................................................................................................................66 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................66 
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................67 
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse Events ...........................67 
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events .......................................67 
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events .............................67 
8.4.5. 
Pregnancy ...................................................................................................................68 
8.4.6. 
Adverse Events of Special Interest .............................................................................68 
8.4.7. 
Other Reportable Experiences: Overdose, Medication Errors, and Misuse ...............68 
8.5. 
69 
8.6. 
69 
8.7. 
Biomarkers ..................................................................................................................69 
8.8. 
Immunogenicity Assessments ....................................................................................69 
8.9. 
Health Economics .......................................................................................................69 
9. 
STATISTICAL CONSIDERATIONS .......................................................................70 
9.1. 
Statistical Hypotheses .................................................................................................70 

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9.3. 
Analysis Sets ...............................................................................................................71 
9.4. 
Statistical Analyses .....................................................................................................71 
9.4.1. 
General Considerations ...............................................................................................71 
9.4.1.1. 
Multiplicity Adjustments ............................................................................................71 
9.4.1.2. 
Statistical Methods ......................................................................................................72 
9.4.1.3. 
Intercurrent Event Strategies ......................................................................................72 
9.4.1.4. 
Pooling of Investigational Centers ..............................................................................73 
9.4.1.5. 
Dropouts and Missing Data ........................................................................................73 
9.4.2. 
Primary Estimand .......................................................................................................74 
9.4.3. 
Secondary Estimand and Endpoints ...........................................................................74 
9.4.3.1. 
Key Secondary Estimand ............................................................................................74 
9.4.3.2. 
Secondary Endpoints ..................................................................................................75 
9.4.4. 
Exploratory Endpoints ................................................................................................75 
9.4.5. 
Safety Analyses ..........................................................................................................76 
9.4.6. 
Other Analyses ............................................................................................................77 
9.5. 
Interim Analysis ..........................................................................................................77 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................78 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................78 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................78 
10.1.2. 
Financial Disclosure ...................................................................................................78 
10.1.3. 
Informed Consent Process ..........................................................................................78 
10.1.4. 
Data Protection ...........................................................................................................79 
10.1.5. 
Committee Structure ...................................................................................................79 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................79 
10.1.7. 
Data Quality Assurance ..............................................................................................80 
10.1.8. 
Source Documents ......................................................................................................80 
10.1.9. 
Study and Site Start and Closure ................................................................................81 
10.1.9.1. 
First Act of Recruitment .............................................................................................81 
10.1.9.2. 
Study/Site Termination ...............................................................................................81 
APPENDIX 1. ABBREVIATIONS AND DEFINITIONS ........................................................82 
APPENDIX 2. REFERENCES ...................................................................................................86 

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APPENDIX 3. CLINICAL LABORATORY TESTS ................................................................90 
APPENDIX 4. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ...............................................92 
APPENDIX 5. CONTRACEPTIVE AND BARRIER GUIDANCE .........................................97 
APPENDIX 6. 
 
 
 

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LIST OF TABLES 
Table 1: 
Primary and Key Secondary Objectives and Estimands .............................................17 
Table 2: 
Secondary and Exploratory Objectives and Endpoints ..............................................18 
Table 3: 
Overall Study Design ..................................................................................................21 
Table 4: 
Schedule of Activities .................................................................................................23 
Table 5: 
Primary and Key Secondary Objectives and Estimands .............................................33 
Table 6: 
Secondary and Exploratory Objectives and Endpoints ..............................................35 
Table 7: 
Study Interventions .....................................................................................................49 
Table 8: 
Analysis Sets ...............................................................................................................71 
Table 9: 
Protocol-Required Safety Laboratory Tests ...............................................................90 
 
 
 

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LIST OF FIGURES 
Figure 1: 
Handling of Missing Data Due to Early Discontinuation for the Primary and 
Key Secondary Efficacy Endpoints ............................................................................73 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
A 17-week, Phase 2, Randomized, Double-blind, Placebo-controlled, Flexible-dosing, 
Parallel-group, Multicenter Study of the Efficacy and Safety of Suvecaltamide in the Treatment 
of Moderate to Severe Residual Tremor in Participants with Parkinson’s Disease 
Brief Title:  
A Study of Suvecaltamide in Adults with Moderate to Severe Residual Tremor in Parkinson’s 
Disease 
Rationale:  
Tremor negatively impacts the ability to perform ADL and negatively impacts psychosocial 
functioning for patients with Parkinson’s disease (PD) throughout the disease course. There are 
currently no pharmacotherapies specifically approved for treatment of tremor in PD. 
Dopaminergic therapies (eg, levodopa/carbidopa) are considered the gold standard treatment for 
motor symptoms (including bradykinesia, rigidity, and tremor). However, tremor response to 
these pharmacotherapies is highly variable among patients with PD, and tremor often remains 
inadequately controlled at tolerable doses. This suggests that the underlying pathophysiology for 
tremor in PD is multifactorial and likely differs from the other motor symptoms of PD. The 
challenge of adequately treating tremor in PD with the available pharmacotherapies coupled with 
the significant impact on patient quality of life highlights the considerable need for novel 
pharmacotherapeutic options for the treatment of tremor in patients with PD.  
Suvecaltamide (JZP385, formerly CX-8998 and MK-8998) is a highly selective negative 
modulator of CaV3 channels that shows low nM potency against all 3 CaV3 isoforms. CaV3 
channels are low-voltage-activated T-type calcium channels that are thought to modulate 
neuronal cell firing and are highly expressed in brain areas that are hypothesized to be important 
in PD, particularly the subthalamic nucleus, ventrolateral thalamus, and the cerebellar-thalamic-
cortical circuit. Numerous lines of evidence suggest that the increased activation of CaV3 
channels and excessive rhythmicity play a key role in neurological disorders such as tremor in 
PD. Given that CaV3 channels are distributed in regions implicated in the pathophysiology of 
tremor and have been a pharmacological target in PD, selective targeting of these channels may 
offer an efficacious and well-tolerated treatment option.  
The current study is designed to evaluate the efficacy and safety of suvecaltamide for the 
treatment of moderate to severe residual tremor in adults with PD that is not adequately 
controlled by PD medication and that interferes with their ADL and/or with their performance of 
tasks. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 Representative of the real-
world setting, a flexible-dosing regimen based on investigator assessment of clinical response 
and tolerability will be used. The flexible-dosing regimen further provides a conservative 
approach for the first larger study in the older PD population who may have other comorbidities 
and who are also taking PD medications, by starting suvecaltamide in patients at a lower dose 
and gradually titrating based on clinical response and tolerability. 

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Objectives, Estimands, and Endpoints: 
Table 1: 
Primary and Key Secondary Objectives and Estimands 
Objectives 
Estimands and Attributes 
Primary 
 
To evaluate the efficacy of suvecaltamide 
administered once daily for 17 weeks to improve 
functional and performance-based impairment 
due to tremor. 
Treatments: Suvecaltamide and placebo. 
Population: Participants with PD who are 
experiencing moderate to severe residual tremor 
despite being optimally treated on a stable 
regimen of PD medication(s). 
Variable: Change from Baseline to Week 17 on 
the TETRAS composite outcome score.a 
Intercurrent events: Alternative/additional 
therapy as well as discontinuation of treatment 
due to lack of efficacy, an AE, or any other 
reason. Definitions for all intercurrent events are 
provided in Section 9.4.1.3. Participants who 
experience any intercurrent event will be included 
in the analysis regardless (treatment policy). 
Summary: Difference in the mean change in the 
TETRAS composite outcome scorea from 
Baseline to Week 17 between suvecaltamide and 
placebo. 
Key Secondary 
 
To evaluate the efficacy of suvecaltamide 
administered once daily for 17 weeks to improve 
functional impairment due to tremor.  
Treatments: Suvecaltamide and placebo. 
Population: Participants with PD who are 
experiencing moderate to severe residual tremor 
despite being optimally treated and on a stable 
regimen of PD medication(s). 
Variable: Proportion of participants who 
improved (≥ 1-point improvement) from Baseline 
to Week 17 on the CGI-S.  
Intercurrent events: Alternative/additional 
therapy as well as discontinuation of treatment 
due to lack of efficacy, an AE, or any other 
reason. Definitions for all intercurrent events are 
provided in Section 9.4.1.3. Participants who 
experience any intercurrent event will be included 
in the analysis regardless (treatment policy). 
Summary: Difference in the proportion of 
participants who improved (≥ 1-point 
improvement) from Baseline to Week 17 in CGI-S 
scores between suvecaltamide and placebo. 
Abbreviations: AE = adverse event; CGI-S = Clinical Global Impression of Severity; PD = Parkinson’s disease; 
TETRAS-ADL = The Essential Tremor Rating Scale, Activities of Daily Living Subscale; TETRAS-PS = The 
Essential Tremor Rating Scale, Performance Subscale. 

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a The TETRAS composite outcome score is the sum of modified items 1 to 11 of the TETRAS-ADL and items 6 (6a 
and 6b) 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. For TETRAS-PS, each item is modified from 9 response items (due 
to 0.5 scoring increments) to 4 response items. 
Table 2: 
Secondary and Exploratory Objectives and Endpoints  
Objectives 
Endpoints 
Secondary 
 
To evaluate the efficacy of suvecaltamide 
administered once daily for 17 weeks to 
improve tremor and the functional 
impairment due to tremor. 
• Change from Baseline to Week 17 on 
TETRAS-ADL.a 
• Change from Baseline to Week 17 on TETRAS total 
score (TETRAS-ADL + TETRAS-PS).a 
• Proportion of participants who improved (≥ 1 point) 
from Baseline to Week 17 on the PGI-S. 
• Proportion of participants who were much improved 
on the PGI-C at Week 17. 
• Proportion of participants who were much improved 
on the CGI-C at Week 17. 
• Change from Baseline to Week 17 on TETRAS-PS.a 
• Change from Baseline to Week 17 on the 
MDS-UPDRS tremor score (items 2.10, 3.15, 3.16, 
3.17, and 3.18). 
To evaluate the safety and tolerability of 
suvecaltamide administered once daily for 
17 weeks. 
Incidence and severity of AEs as well as evaluation of 
safety laboratory assessments, vital signs, ECG results, 
C-SSRS, and QUIP-RS. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Objectives 
Endpoints 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AUC = area under the plasma concentration-time curve; CGI-C = Clinician’s Global Impression of 
Change; C-SSRS = Columbia Suicide Severity Rating Scale; Cmax = concentration at peak; Ctau = concentration at 
trough; ECG = electrocardiogram; 
 
 
 
 
MDS-UPDRS = Movement Disorder Society Unified Parkinson’s Disease Rating Scale; PD = Parkinson’s disease; 
 
 
 
 PGI-C = Patient’s Global Impression of Change; 
PGI-S = Patient’s Global Impression of Severity; 
 
 
 
 
 
 QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating Scale; 
 
 
 
 
 
 
 
 t½ = terminal half-life; 
TETRAS-ADL = The Essential Tremor Rating Scale, Activities of Daily Living Subscale; TETRAS-PS = The 
Essential Tremor Rating Scale, Performance Subscale; Tmax = time to maximum concentration. 
a This endpoint uses the unmodified or raw TETRAS score. 
b For the modified items 1-11 of the TETRAS ADL, each item is modified from 5 response items to 4 by collapsing 
options 0 and 1 together. 
c For the modified items 6 (6a and 6b) and 7 of the TETRAS-PS, each item is modified from 9 response items (due 
to scoring in 0.5 increments) to 4 response items. 
Brief Summary: 
This is a 17-week double-blind, placebo-controlled, randomized, flexible-dosing, parallel-group, 
multicenter study of the efficacy and safety of suvecaltamide in the treatment of moderate to 
severe residual tremor in adult participants with PD. 
 
 
 
  
 
 
 
 
 
 
  
 
 
The maximum total duration of the study for each participant will be 23 weeks, with a maximum 
treatment duration of 17 weeks. For each participant, the study consists of a Screening Period (up 
to 4 weeks), a 5-week Dose Titration and Optimization Period, a 12-week Maintenance Period, 

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and a 2-week Safety Follow-up Period. There is no continued access to study intervention upon 
completion of the study. 
Participants eligible for the study will be randomized 1:1 to receive suvecaltamide or placebo 
and stratified by TETRAS composite outcome score (≤ 17 or > 17) as assessed at Baseline. 
Suvecaltamide (or matching placebo) will be administered orally 
 
  
 
 
  
 
. Each participant’s optimal dose (10, 20, or 30 mg suvecaltamide 
or matching placebo) will be determined by the investigator during the Dose Titration and 
Optimization Period, and the participant will receive this optimal dose throughout the 
Maintenance Period as follows: 
• Dose Titration and Optimization Period: study intervention will be titrated by the 
investigator in collaboration with the participant to individually optimize efficacy and 
tolerability. Every effort should be made by the investigator to ensure that the 
maintenance dose is optimized for efficacy and tolerability. Investigators should 
thoroughly assess whether tremor symptoms have been optimally treated and consider 
up-titration if therapeutic benefit has not yet been achieved. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Maintenance Period: participants will continue to take study intervention of 1, 2, or 
3 capsules of either suvecaltamide (10 mg per capsule) or matching placebo at the 
optimal dose determined by the investigator at the end of the Dose Titration and 
Optimization Period (see Table 7). No dose adjustment should occur during the 
Maintenance Period. If the investigator determines a dose adjustment is indicated for 
safety reasons, the Medical Monitor should be consulted regarding continuation of 
study intervention.  
A 2-week Safety Follow-up Period (with visit planned at the end of the 2-week period) will be 
required for participants who either discontinue early or fully complete the Maintenance Period. 
Assessments of efficacy, safety, 
 
 will be conducted throughout the study period.  

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Overall Design: 
Table 3: 
Overall Study Design 
Overall Design 
Study Phase 
2 
Clinical Indication 
Suvecaltamide for treatment of moderate to severe residual tremor in 
participants with PD 
Study Type 
Interventional 
Type of Design 
Randomized, placebo-controlled, flexible-dosing, parallel-group, 
multicenter study. Participants will be stratified by the TETRAS 
composite outcome score (≤ 17 or > 17) as assessed at Baseline. 
Type of Control 
Placebo  
Study Blinding 
Double-blind 
Population 
Male and female participants ages 40 to 85 years inclusive with a 
diagnosis of clinically probable or clinically established PD meeting 
the MDS 2015 criteria (Postuma, 2015) with moderate to severe 
residual tremor despite treatment with PD medication(s). 
Number of Participants  
Approximately 160 participants will be randomized (80 to each 
treatment arm) to achieve 128 participants to complete Week 17 
assessments assuming a 20% drop-out rate (see Section 9). 
Duration of Participation 
The study comprises 4 periods: an up to 4-week Screening Period, a 
5-week Dose Titration and Optimization Period, a 12-week 
Maintenance Period, and a 2-week Safety Follow-up Period. The 
maximum treatment duration for each participant will be 17 weeks. 
The maximum total study duration for each participant is 23 weeks. 
Number of Treatment Arms 
2 
Treatment Groups 
1. Placebo 
2. Suvecaltamide (titrated to optimal once-daily oral dose of 10, 
20, or 30 mg) 
Data Monitoring Committee 
Not applicable. 
Abbreviations: MDS = Movement Disorder Society; PD = Parkinson’s disease; TETRAS = The Essential Tremor 
Rating Scale. 

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1.3. 
Schedule of Activities 
Table 4: 
Schedule of Activities  
Screening 
(up to 
28 days) 
BL 
Dose Titration and 
Optimization Period 
Maintenance Period 
Efficacy 
FU Visita 
E/D 
Visitb 
Safety 
FU 
Period 
Comments 
SV 
BL 
W1, 
W2 
W3, 
W4 
W5 
W6, 
W7, 
W8 
W9 
W10, 
W11, 
W12 
W13 
W14, 
W15, 
W16 
W17 
 
 
W19 
See Section 7 
regarding d/c of study 
intervention and 
participant d/c or 
withdrawal. 
Clinic Visitsc 
X 
X 
Xd 
Xd 
Xd 
 
Xd 
 
X 
Xd 
X 
Xb, d 
Phone Visitsc 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Day 
-28 to -3 
-1 
7, 14 
21, 28 
35 
42, 49, 
56 
63 
70, 77, 
84 
91 
98, 105, 
112 
119 
 
 
133 
(-1, +2) 
(-3, +2) 
 
 
 
Visit windows 
ICF 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 5. 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
See Section 8.1.3 and 
Section 8.4.1. 
Complete 
physical exam 
X 
 
 
 
X 
 
X 
X 
See Section 8.3.1. 
Height 
X 
 
 
 
 
 
See Section 8.3.1. 
Weight 
X 
X 
 
 
 
X 
 
X 
X 
See Section 8.3.1. 
Serum or urine 
pregnancy test 
X 
 
 
 
 
 
See Section 8.3.5. 
Urine pregnancy 
testc 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
See Section 8.3.5 
Urine drug 
screen 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
See Section 7.1.2 and 
Appendix 3.  

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Screening 
(up to 
28 days) 
BL 
Dose Titration and 
Optimization Period 
Maintenance Period 
Efficacy 
FU Visita 
E/D 
Visitb 
Safety 
FU 
Period 
Comments 
 
SV 
BL 
W1, 
W2 
W3, 
W4 
W5 
W6, 
W7, 
W8 
W9 
W10, 
W11, 
W12 
W13 
W14, 
W15, 
W16 
W17 
 
 
W19 
See Section 7 
regarding d/c of study 
intervention and 
participant d/c or 
withdrawal. 
Clinic Visitsc 
X 
X 
Xd 
Xd 
Xd 
 
Xd 
 
X 
Xd 
X 
Xb, d 
Phone Visitsc 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Day 
-28 to -3 
-1 
7, 14 
21, 28 
35 
42, 49, 
56 
63 
70, 77, 
84 
91 
98, 105, 
112 
119 
 
 
133 
(-1, +2) 
(-3, +2) 
 
 
 
Visit windows 
Breath alcohol 
test 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
See Section 7.1.2. 
Laboratory 
assessments 
(chemistry, 
hematology) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
See Section 8.3.4 and 
Appendix 3.  
Orthostatic 
blood pressure 
and pulse 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
See Section 8.3.2.  
Urinalysis 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
See Section 8.3.4 and 
Appendix 3. 
Temperature 
and respiratory 
rate 
X 
X 
W1 
only 
X 
 
X 
 
X 
 
X 
 
X 
X 
See Section 8.3.2. 
12-lead ECG 
X 
X 
W1 
only 
 
X 
 
 
X 
 
X 
X 
See Section 8.3.3.  
C-SSRS 
Screening/ 
Baseline 
Version 
X 
 
 
 
 
 
See Section 8.3.6.  
C-SSRS Since 
Last Visit 
Version 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
See Section 8.3.6. 

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Screening 
(up to 
28 days) 
BL 
Dose Titration and 
Optimization Period 
Maintenance Period 
Efficacy 
FU Visita 
E/D 
Visitb 
Safety 
FU 
Period 
Comments 
 
SV 
BL 
W1, 
W2 
W3, 
W4 
W5 
W6, 
W7, 
W8 
W9 
W10, 
W11, 
W12 
W13 
W14, 
W15, 
W16 
W17 
 
 
W19 
See Section 7 
regarding d/c of study 
intervention and 
participant d/c or 
withdrawal. 
Clinic Visitsc 
X 
X 
Xd 
Xd 
Xd 
 
Xd 
 
X 
Xd 
X 
Xb, d 
Phone Visitsc 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Day 
-28 to -3 
-1 
7, 14 
21, 28 
35 
42, 49, 
56 
63 
70, 77, 
84 
91 
98, 105, 
112 
119 
 
 
133 
(-1, +2) 
(-3, +2) 
 
 
 
Visit windows 
QUIP-RS 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
See Section 8.3.7.  
MoCA 
X 
 
 
 
 
 
 
See Section 8.1.7.  
Instruction on 
medication 
washout 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 5.2 and 
Section 6.8.  
TETRAS-ADL 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
See Section 8.2.1.  
TETRAS-PS 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
See Section 8.2.2. 
CGI-S 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
See Section 8.2.3. 
CGI-C 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
See Section 8.2.4.  
PGI-S 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
See Section 8.2.5.  
PGI-C 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
See Section 8.2.6.  
MDS-UPDRS I-
IV 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
See Section 8.2.7.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.8.  
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.9.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.10.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.11.  

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Screening 
(up to 
28 days) 
BL 
Dose Titration and 
Optimization Period 
Maintenance Period 
Efficacy 
FU Visita 
E/D 
Visitb 
Safety 
FU 
Period 
Comments 
 
SV 
BL 
W1, 
W2 
W3, 
W4 
W5 
W6, 
W7, 
W8 
W9 
W10, 
W11, 
W12 
W13 
W14, 
W15, 
W16 
W17 
 
 
W19 
See Section 7 
regarding d/c of study 
intervention and 
participant d/c or 
withdrawal. 
Clinic Visitsc 
X 
X 
Xd 
Xd 
Xd 
 
Xd 
 
X 
Xd 
X 
Xb, d 
Phone Visitsc 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Day 
-28 to -3 
-1 
7, 14 
21, 28 
35 
42, 49, 
56 
63 
70, 77, 
84 
91 
98, 105, 
112 
119 
 
 
133 
(-1, +2) 
(-3, +2) 
 
 
 
Visit windows 
Light breakfast, 
lunch, or snack 
as needed 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Participants will be 
asked to fast for their 
Screening Visit only. 
 
 
 
 
  
 
Dispense study 
intervention 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Participants should 
begin taking study 
intervention at home on 
Day 1 (the day 
following the Baseline 
Visit). Remind 
participants not to take 
study intervention prior 
to clinic visits for 
Weeks 1, 9, 13, and 17. 
Provide 
instructions for 
titration 
 
X 
X 
X 
X 
 
 
 
 
 
 
For Week 5 Visit, 
confirm that participant 
has reached an 
efficacious and tolerable 
dose and provide 
instructions to 
participant to maintain 
dose for remainder of 
study. 

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Screening 
(up to 
28 days) 
BL 
Dose Titration and 
Optimization Period 
Maintenance Period 
Efficacy 
FU Visita 
E/D 
Visitb 
Safety 
FU 
Period 
Comments 
 
SV 
BL 
W1, 
W2 
W3, 
W4 
W5 
W6, 
W7, 
W8 
W9 
W10, 
W11, 
W12 
W13 
W14, 
W15, 
W16 
W17 
 
 
W19 
See Section 7 
regarding d/c of study 
intervention and 
participant d/c or 
withdrawal. 
Clinic Visitsc 
X 
X 
Xd 
Xd 
Xd 
 
Xd 
 
X 
Xd 
X 
Xb, d 
Phone Visitsc 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Day 
-28 to -3 
-1 
7, 14 
21, 28 
35 
42, 49, 
56 
63 
70, 77, 
84 
91 
98, 105, 
112 
119 
 
 
133 
(-1, +2) 
(-3, +2) 
 
 
 
Visit windows 
Collect study 
intervention/ 
assess 
compliance 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
If participants do not 
return study intervention 
at the Week 17 or E/D 
visit, they should be 
asked to return unused 
study intervention at the 
Safety FU Visit or 
Efficacy FU Visit. See 
Section 6.4  
Administer 
study 
intervention on 
site 
 
 
W1 
only 
 
 
 
X 
 
X 
 
X 
 
 
 
See Section 8.1.6.  
Blood draws for 
genetic testing 
 
 
W1 
only 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.6.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.5.  
AEs 
 
 
 
 
X 
X 
See Section 8.4 and 
Appendix 4.  
Prior/ 
concomitant 
medications 
 
X 
X 
X 
See Section 6.8 and 
Section 8.1.4. 

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Screening 
(up to 
28 days) 
BL 
Dose Titration and 
Optimization Period 
Maintenance Period 
Efficacy 
FU Visita 
E/D 
Visitb 
Safety 
FU 
Period 
Comments 
 
SV 
BL 
W1, 
W2 
W3, 
W4 
W5 
W6, 
W7, 
W8 
W9 
W10, 
W11, 
W12 
W13 
W14, 
W15, 
W16 
W17 
 
 
W19 
See Section 7 
regarding d/c of study 
intervention and 
participant d/c or 
withdrawal. 
Clinic Visitsc 
X 
X 
Xd 
Xd 
Xd 
 
Xd 
 
X 
Xd 
X 
Xb, d 
Phone Visitsc 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Day 
-28 to -3 
-1 
7, 14 
21, 28 
35 
42, 49, 
56 
63 
70, 77, 
84 
91 
98, 105, 
112 
119 
 
 
133 
(-1, +2) 
(-3, +2) 
 
 
 
Visit windows 
Schedule next 
visit and/or 
phone contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tentatively schedule all 
study visits at 
Screening. Confirm 
visits at each subsequent 
visit. 
Abbreviations: AEs = adverse events; BL = baseline; CGI-C = Clinical Global Impression of Change; CGI-S = Clinical Global Impression of Severity; 
C-SSRS = Columbia Suicide Severity Rating Scale; d/c = discontinuation; ECG = electrocardiogram; E/D = early discontinuation; 
 
 
 
 FU = follow-up; ICF = Informed Consent Form; I/E = inclusion/exclusion; MDS-UPDRS = Movement Disorder Society Unified 
Parkinson’s Disease Rating Scale; MoCA = Montreal Cognitive Assessment; 
 
 
 
 PGI-C = Patient 
Global Impression of Change; PGI-S = Patient Global Impression of Severity; 
 
 
 
 
 
 
 
QUIP-RS = Questionnaire for Impulsive Control Disorders in PD Rating Scale; 
 
 
  
 
 
 
 
 
 
 
 SV = Screening Visit; TETRAS-ADL = The Essential Tremor Rating Scale, Activities of Daily Living Subscale; TETRAS-PS = The Essential 
Tremor Rating Scale, Performance Subscale; W = week; WOCBP = women of childbearing potential.  
a Discontinuation from study intervention does not represent discontinuation from the study. For participants who discontinue study intervention early, every 
effort should be made to attend Efficacy Follow-up Visits through 17 weeks after the first dose. See Section 7 for additional guidance. 
b If participant discontinues study intervention early (regardless of whether or not he/she continues in the study), he/she will require an E/D Visit and a Safety FU 
Visit. The E/D Visit should occur as soon as possible following early discontinuation of study intervention. The Safety FU Visit should occur 2 weeks after the 
E/D visit.  
c Additional onsite clinic visits may be scheduled at any time, including in place of scheduled phone contacts, if required due to local requirements (eg, for study 
intervention dispensation). If performed in-clinic, urine pregnancy testing should be completed for WOCBP.  
d Clinic visits at Week 1, Week 2, Week 5, Week 9, Week 13, E/D, and Safety FU may be conducted remotely, if required due to the coronavirus 2019 pandemic, 
and with approval from the Sponsor Medical Monitor. The TETRAS-PS and MDS-UPDRS will not be performed during remote visits  
 
 
 
 
. 

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2. 
INTRODUCTION 
Suvecaltamide (JZP385, formerly CX-8998 and MK-8998) is a potent, highly selective, 
state-dependent, negative modulator of low-voltage-activated T-type calcium channels (also 
known as CaV3 channels) that is being developed for once-daily treatment of moderate to severe 
residual tremor in PD. 
2.1. 
Study Rationale 
Tremor negatively impacts the ability to perform ADL and negatively impacts psychosocial 
functioning for patients with Parkinson’s disease (PD) throughout the disease course. There are 
currently no pharmacotherapies specifically approved for treatment of tremor in PD. 
Dopaminergic therapies (eg, levodopa/carbidopa) are considered the gold standard treatment for 
motor symptoms; however, tremor response to these pharmacotherapies is highly variable among 
patients with PD and often tremor remains inadequately controlled at tolerable doses. This 
suggests that the underlying pathophysiology for tremor in PD is multifactorial and likely differs 
from the other motor symptoms of PD. The challenge of adequately treating tremor in PD with 
the available pharmacotherapies coupled with the significant impact on patient quality of life 
highlights the considerable need for novel pharmacotherapeutic options for the treatment of 
tremor in patients with PD.  
Suvecaltamide is a highly selective negative modulator of CaV3 channels that shows low nM 
potency against all 3 CaV3 isoforms. CaV3 channels are low-voltage-activated T-type calcium 
channels that are thought to modulate neuronal cell firing and are highly expressed in brain areas 
that are hypothesized to be important in PD, particularly the subthalamic nucleus, ventrolateral 
thalamus, and the cerebellar-thalamic-cortical circuit. Numerous lines of evidence suggest that 
the increased activation of CaV3 channels and excessive rhythmicity play a key role in 
neurological disorders such as tremor in PD. Given that CaV3 channels are distributed in regions 
implicated in the pathophysiology of tremor and have been a pharmacological target in PD, 
selective targeting of these channels may offer an efficacious and well-tolerated treatment 
option.  
The current study is designed to evaluate the efficacy and safety of suvecaltamide for the 
treatment of moderate to severe residual tremor in adults with PD that is not adequately 
controlled by PD medications and that interferes with their ADL and/or with their performance 
of tasks. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 Representative of the real-
world setting, a flexible-dosing regimen based on investigator assessment of clinical response 
and tolerability will be used. The flexible-dosing regimen further provides a conservative 
approach for the first larger study in the older PD population who may have other comorbidities 
and who are also taking PD medications, by starting suvecaltamide in patients at a lower dose 
and gradually titrating based on clinical response and tolerability. 

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2.2. 
Background 
2.2.1. 
Parkinson’s Disease 
Parkinson’s disease is a neurodegenerative disease affecting over 1 million patients in the United 
States, 1.2 million in Europe, and 6.3 million worldwide (Dorsey, 2018). The prevalence of PD 
is approximately 1% for individuals over 65 years of age, increasing to 3% for octogenarians 
(Nussbaum and Ellis, 2003).  
PD is characterized early on by the classic motor symptom triad of resting tremor, bradykinesia, 
and rigidity (Postuma, 2015). Tremor is one of the most prominent and visible features of PD 
and is often the first symptom noticed by patients (Jankovic, 2008). Approximately 75% of 
patients with PD experience tremor at some point during the disease course (Hughes, 1993; 
Gupta, 2020). While rest tremor is commonly observed, the majority of patients also experience 
action and postural tremors (Pasquini, 2018; Gupta, 2020). 
In addition to being one of the most visual symptoms of PD, tremor is also ranked as one of the 
5 most troubling symptoms by both early and advanced stage patients (Politis, 2010), interfering 
with the ability to perform ADL and negatively impacting psychosocial functioning, including 
personal and social relationships, self-image, and overall sense of well-being 
(Heusinkveld, 2018).  
There are currently no pharmacotherapies specifically approved for the treatment of tremor in 
patients with PD. Unlike other motor symptoms of PD, tremor often does not resolve for many 
patients despite treatment with standard PD medications including dopaminergic therapies 
(Yahr, 1969; Helmich, 2018). In addition, higher doses of these therapies are generally needed to 
address tremor symptoms. As a result, the dose-limiting side effects of nausea, vomiting, 
dyskinesia, or psychosis can lead to the undertreatment of tremor symptoms (Nonnekes, 2016). 
Taken together, the pharmacological treatment of tremor in patients with PD remains challenging 
and coupled with the significant impact on patient quality of life, there is a high unmet need for 
novel therapeutic options for the treatment of tremor in patients with PD.  
2.2.2. 
Suvecaltamide 
Suvecaltamide, a highly selective negative modulator of low-voltage-activated CaV3 channels, 
shows low nM potency against all 3 CaV3 isoforms. All 3 isoforms of CaV3 are expressed 
throughout the CNS and the peripheral nervous system. In particular, CaV3 channels are highly 
expressed in thalamocortical circuitry and tremor network regions, where they mediate 
subthreshold oscillations and excessive rhythmicity in pathophysiologic states found in 
movement disorders, such as essential tremor (ET) and PD, neuropathic pain, and epilepsy 
(Handforth, 2005; Llinás, 2007; Park, 2013). For example, CaV3 is highly expressed in brain 
areas that are hypothesized to be important in tremor in PD, particularly the STN, ventrolateral 
thalamus, and the cerebellar-thalamic-cortical circuit (Park, 2013). Consistent with these 
findings, pharmacological inhibition of CaV3 channels in the STN rescues locomotor deficits in 
rat models of PD (Tai, 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 PD. 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; Chang, 2015). Given that CaV3 channels 

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are distributed in regions implicated in the pathophysiology of tremor and have been a 
pharmacological target in PD, selective targeting of these channels may offer a more efficacious 
and better-tolerated treatment option.  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A detailed description of the chemistry, pharmacology, efficacy, and safety of suvecaltamide is 
provided in the IB. 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
Participants with tremor in PD who enroll in this study may encounter the following potential 
risks:  
• The potential risks from treatment with suvecaltamide in participants with PD are 
expected to be consistent with the known pharmacology and safety profile of 
suvecaltamide in clinical studies conducted to date. In general, AE profiles were 
consistent across populations studied (eg, ET, schizophrenia, healthy volunteers). 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Generally, the most commonly reported AEs were in 
the SOCs of Nervous System Disorders and Psychiatric Disorders and included 
dizziness, euphoric mood, headache, 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 with PD will be managed and mitigated by the use 
of exclusion criteria in this clinical study protocol, which will preclude participants 
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 
studies. In addition, a flexible-dosing regimen and titration schedule will be 
implemented such that participants will start at a lower dose and titrate up to an 
individually optimized dose based on tolerability and efficacy. This will help mitigate 
the potential risk associated with pharmacodynamic interaction between 
suvecaltamide and concomitant PD medication. Extensive monitoring of AEs, ECGs, 
orthostatic hypotension, and suicidal ideation and behavior will occur at frequent 
clinic visits throughout the study. These measures are intended to mitigate potential 
risks and to more fully assess the risks of using suvecaltamide for this indication.  

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• For participants who are randomized to receive placebo, the risks may be similar to 
the risks associated with uncontrolled or inadequately controlled tremor in PD, 
however, these risks are not worse than the risks faced by the PD population treated 
according to standard of care. The consequences of inadequately controlling tremor in 
PD include decreased work productivity, increase psychosocial burden, as well as 
functional limitations resulting from motor impairment (eg, the inability to attend to 
personal needs and perform personal hygiene activities), all of which contribute to an 
overall reduction in quality of life.  
• Study procedure-related risks, including risks and/or discomfort associated with blood 
collection, ECGs, physical examinations, and completion of questionnaires and other 
assessments (see Section 8 for details of study assessments). 
2.3.2. 
Benefit Assessment 
Participants with tremor in PD who enroll in this study may experience the following benefits: 
• Treatment with suvecaltamide for the study duration may alleviate the significant 
symptom burden associated with tremor in PD. 
• Irrespective of which treatment a participant receives in the study, all participants will 
contribute to the process of developing new therapies in tremor in PD. 
• Participants will receive comprehensive clinical exams and clinical monitoring 
associated with the study for up to 23 weeks. 
2.3.3. 
Overall Benefit:Risk Summary 
Benefits to participants include the potential to receive therapy which may alleviate symptoms of 
tremor in PD, contribute to the development of new therapeutics in tremor in PD, as well as 
receiving comprehensive physical examination, clinical safety assessments, and laboratory 
testing. 
Risks to participants include those related to suvecaltamide, the potential to be treated with 
placebo for the study duration, potential pharmacodynamic interactions between suvecaltamide 
and concomitant PD medications, and risks related to the study procedures including blood 
collection. The remaining risks associated with treatment with suvecaltamide are expected to be 
like those seen in previous clinical studies (see Section 2.3.1). 
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of suvecaltamide may be found in the IB and Development Safety Update 
Report. 

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3. 
OBJECTIVES, ESTIMANDS, AND ENDPOINTS 
Table 5: 
Primary and Key Secondary Objectives and Estimands 
Objectives 
Estimands and Attributes 
Primary 
 
To evaluate the efficacy of suvecaltamide 
administered once daily for 17 weeks to improve 
functional and performance-based impairment 
due to tremor. 
Treatments: Suvecaltamide and placebo. 
Population: Participants with PD who are 
experiencing moderate to severe residual tremor 
despite being optimally treated on a stable 
regimen of PD medication(s). 
Variable: Change from Baseline to Week 17 on 
the TETRAS composite outcome score.a 
Intercurrent events: Alternative/additional 
therapy as well as discontinuation of treatment 
due to lack of efficacy, an AE, or any other 
reason. Definitions for all intercurrent events are 
provided in Section 9.4.1.3. Participants who 
experience any intercurrent event will be included 
in the analysis regardless (treatment policy). 
Summary: Difference in the mean change in the 
TETRAS composite outcome scorea from 
Baseline to Week 17 between suvecaltamide and 
placebo. 
Key Secondary 
 
To evaluate the efficacy of suvecaltamide 
administered once daily for 17 weeks to improve 
functional impairment due to tremor.  
Treatments: Suvecaltamide and placebo. 
Population: Participants with PD who are 
experiencing moderate to severe residual tremor 
despite being optimally treated and on a stable 
regimen of PD medication(s). 
Variable: Proportion of participants who 
improved (≥ 1-point improvement) from Baseline 
to Week 17 on the CGI-S.  
Intercurrent events: Alternative/additional 
therapy as well as discontinuation of treatment 
due to lack of efficacy, an AE, or any other 
reason. Definitions for all intercurrent events are 
provided in Section 9.4.1.3. Participants who 
experience any intercurrent event will be included 
in the analysis regardless (treatment policy). 
Summary: Difference in the proportion of 
participants who improved (≥ 1-point 
improvement) from Baseline to Week 17 in CGI-S 
scores between suvecaltamide and placebo. 
Abbreviations: AE = adverse event; CGI-S = Clinical Global Impression of Severity; PD = Parkinson’s disease; 
TETRAS-ADL = The Essential Tremor Rating Scale, Activities of Daily Living Subscale; TETRAS-PS = The 
Essential Tremor Rating Scale, Performance Subscale. 

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a The TETRAS composite outcome score is the sum of modified items 1 to 11 of the TETRAS-ADL and items 6 (6a 
and 6b) 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. 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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Table 6: 
Secondary and Exploratory Objectives and Endpoints 
Objectives 
Endpoints 
Secondary 
 
To evaluate the efficacy of suvecaltamide 
administered once daily for 17 weeks to 
improve tremor and the functional 
impairment due to tremor. 
• Change from Baseline to Week 17 on 
TETRAS-ADL.a 
• Change from Baseline to Week 17 on TETRAS total 
score (TETRAS-ADL + TETRAS-PS).a 
• Proportion of participants who improved (≥ 1 point) 
from Baseline to Week 17 on the PGI-S. 
• Proportion of participants who were much improved 
on the PGI-C at Week 17. 
• Proportion of participants who were much improved 
on the CGI-C at Week 17. 
• Change from Baseline to Week 17 on TETRAS-PS.a 
• Change from Baseline to Week 17 on the 
MDS-UPDRS tremor score (items 2.10, 3.15, 3.16, 
3.17, and 3.18). 
To evaluate the safety and tolerability of 
suvecaltamide administered once daily for 
17 weeks. 
Incidence and severity of AEs as well as evaluation of 
safety laboratory assessments, vital signs, ECG results, 
C-SSRS, and QUIP-RS. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
  

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Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AUC = area under the plasma concentration-time curve; CGI-C = Clinician’s Global Impression of 
Change; C-SSRS = Columbia Suicide Severity Rating Scale; Cmax = concentration at peak; Ctau = concentration at 
trough; ECG = electrocardiogram; 
 
 
 
 
MDS-UPDRS = Movement Disorder Society Unified Parkinson’s Disease Rating Scale; PD = Parkinson’s disease; 
 
 
 
 PGI-C = Patient’s Global Impression of Change; 
PGI-S = Patient’s Global Impression of Severity; 
 
 
 
 
 
 QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating Scale; 
 
 
 
 
 
 
 
 t½ = terminal half-life; 
TETRAS-ADL = The Essential Tremor Rating Scale, Activities of Daily Living Subscale; TETRAS-PS = The 
Essential Tremor Rating Scale, Performance Subscale; Tmax = time to maximum concentration. 
a This endpoint uses the unmodified or raw TETRAS score. 
b For the modified items 1-11 of the TETRAS ADL, each item is modified from 5 response items to 4 by collapsing 
options 0 and 1 together. 
c For the modified items 6 (6a and 6b) and 7 of the TETRAS PS, each item is modified from 9 response items (due 
to scoring in 0.5 increments) to 4 response items. 
 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a 17-week double-blind, placebo-controlled, randomized, flexible-dosing, parallel-group, 
multicenter study of the efficacy and safety of suvecaltamide in the treatment of moderate to 
severe residual tremor in adult participants with PD. 
 
 
 
  
 
 
 
 
 
 
  
 
 
The maximum total duration of the study for each participant will be 23 weeks, with a maximum 
treatment duration of 17 weeks. For each participant, the study consists of a Screening Period (up 
to 4 weeks), a 5-week Dose Titration and Optimization Period, a 12-week Maintenance Period, 
and a 2-week Safety Follow-up Period. There is no continued access to study intervention upon 
completion of the study. 
During the Screening Period, all participants will be evaluated for eligibility (including an 
assessment of their concomitant PD medication use) and will washout any prohibited 
medications. Participants may be allowed to rescreen once if the rescreening is approved by the 
Sponsor Medical Monitor.  
Participants eligible for the study will be randomized 1:1 to receive suvecaltamide or placebo 
and stratified by TETRAS composite outcome score (≤ 17 or > 17) as assessed at Baseline. 
Suvecaltamide (or matching placebo) will be administered orally 
 
  
 
 
  
 
. Each participant’s optimal dose (10, 20, or 30 mg suvecaltamide 
or matching placebo) will be determined by the investigator during the Dose Titration and 
Optimization Period, and the participant will receive this optimal dose throughout the 
Maintenance Period as follows: 
• Dose Titration and Optimization Period: study intervention will be titrated by the 
investigator in collaboration with the participant to individually optimize efficacy and 
tolerability. Every effort should be made by the investigator to ensure that the 
maintenance dose is optimized for efficacy and tolerability. Investigators should 
thoroughly assess whether tremor symptoms have been optimally treated and consider 
up-titration if therapeutic benefit has not yet been achieved. The starting dose is 
5 mg suvecaltamide or 1 matching placebo capsule once daily. After 7 to 14 days, the 
dose of study intervention will be increased to 10 mg suvecaltamide (or 1 matching 
placebo capsule) 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
. If needed, 
participants will be able to titrate down to a minimum of 10 mg suvecaltamide (or a 
minimum of 1 matching placebo capsule) per day at any time following consultation 
with the investigator. Participants not tolerating a once-daily dose of 
5 mg suvecaltamide after 2 weeks of treatment will be discontinued from the study. 
• Maintenance Period: participants will continue to take study intervention of 1, 2, or 
3 capsules of either suvecaltamide (10 mg per capsule) or matching placebo at the 
optimal dose determined by the investigator at the end of the Dose Titration and 

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Optimization Period (see Table 7). No dose adjustment should occur during the 
Maintenance Period. If the investigator determines a dose adjustment is indicated for 
safety reasons, the Medical Monitor should be consulted regarding continuation of 
study intervention.  
A 2-week Safety Follow-up Period (with visit planned at the end of the 2-week period) will be 
required for participants who either discontinue early or fully complete the Maintenance Period. 
Assessments of efficacy, safety, 
 
 will be conducted as described in Section 8.2, 
Sections 8.3/8.4, and Section 8.5, respectively, and as described in the SoA (Section 1.3). Note 
that to ensure study intervention is taken in the morning, clinic visits should take place in the 
morning.  
4.2. 
Scientific Rationale for Study Design 
This study was designed to be consistent with the US FDA Guidance for Industry on Providing 
Clinical Evidence of Effectiveness for Human Drug and Biological Products, the ICH E1A and 
E8 Guidance, and with the ethical principles in these guidances that originate in the Declaration 
of Helsinki. 
The target patient population for this study is adults with moderate to severe residual tremor in 
PD that interferes with their ADL and/or function. This represents a subset of the overall 
population of patients with PD-related tremor. Approximately 75% of the patients with 
PD-related tremor are anticipated to have a tremor that would impact their ADL (Pasquini, 2018; 
Gupta, 2020); the majority of these patients are expected to have residual tremor that is not 
adequately controlled by PD medications (Raethjen, 2005; Sung, 2008; Zach, 2020).  
The severity of the functional impact of tremor in PD will be defined by eligibility criteria on 
patient interview (TETRAS-ADL), clinician-rated (CGI-S), and objective measures of disability 
(TETRAS-PS items 6 [6a and 6b] and 7). The inclusion of a placebo control group in this study 
is necessary to determine the efficacy and safety of suvecaltamide. 
The 17-week treatment duration (5-week Dose Titration and Optimization Period and 12-week 
Maintenance Period) is to ensure adequate duration to evaluate efficacy and safety of 
suvecaltamide in this phase 2 study.  
Tremor may have a pathophysiology different from other motor symptoms (Helmich, 2012). 
First, tremor does not progress as quickly as bradykinesia, rigidity, gait, and balance 
(Louis, 1999). Second, tremor severity does not correlate with the severity of other motor 
symptoms (Louis, 2001). Third, tremor can occasionally impact the body contralateral to the 
otherwise most affected side, ie, where bradykinesia and rigidity are most prominent. Finally, 
tremor responds less well to dopaminergic treatment than bradykinesia and rigidity 
(Koller, 1994; Fishman, 2008). While the clinical presentation of tremor can be different, there is 
evidence to suggest that the underlying pathophysiology of ET and tremor in PD is similar 
(Filip, 2022). As a result, the proof-of-concept findings from a phase 2, randomized, 
double-blind, multicenter, placebo‑controlled, dose titration study of suvecaltamide in adults 
with ET (Study CX-8998-CLN2-001 [T-CALM]), provide some support for the study of tremor 
in PD. The results of the 4-week T-CALM demonstrated that reduction in tremor with daily 
doses of 16 and 20 mg suvecaltamide is observed within several weeks, although the durability 
of the effect is unknown. In the T-CALM study, doses were titrated for the first 2 weeks and the 

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final target dose was maintained for 2 additional weeks; efficacy assessments were taken at the 
end of Weeks 2 and 4. Despite not meeting statistical significance on the primary endpoint 
(TETRAS-PS, as rated by independent video raters), numerical improvements favoring 
suvecaltamide over placebo were observed on TETRAS-PS as rated by the investigators at both 
timepoints. Numerical improvements were also observed on the TETRAS-ADL subscale at both 
timepoints. The 12-week Maintenance Period in the present study is of sufficient duration to 
permit assessment of the durability of efficacy of suvecaltamide for the treatment of moderate to 
severe residual tremor in PD. 
From a safety perspective, AEs in the T-CALM study were primarily reported during the first 
week of treatment. Most of the commonly reported AEs resolved within a week of treatment 
initiation despite continued dosing with suvecaltamide. The 17-week treatment duration of the 
present study, with multiple clinic visits to assess safety as well as phone visits for AE reporting, 
will allow for adequate assessment of safety.  
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 (6a and 6b) and 7 of the TETRAS-PS 
(ie, TETRAS composite outcome score). The TETRAS-ADL subscale is a scale that assesses the 
impact of tremor on day-to-day functioning that is administered by a trained interviewer. It 
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 suvecaltamide in the 
T-CALM study (see the suvecaltamide IB). 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 (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 clinician-rated and objective measures of the 
functional impact of tremor. 
The key secondary endpoint is the CGI-S. The clinician-rated CGI-S will complement the 
primary endpoint and specifically evaluate the clinician’s assessment of the participants’ ability 
to function due to tremor in PD. In the T-CALM study, a numerically higher percentage of 
clinicians reported participant improvement on the CGI-C when treated with 16 and 20 mg 
suvecaltamide per 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 suvecaltamide. 
4.3. 
Justification for Dose 
Since this is a flexible-dose study, during the Dose Titration and Optimization period, 
participants will be titrated to their optimally effective and tolerable dosing regimen of 10, 20, or 
30 mg suvecaltamide administered 
 
  
 
 
  
 
 (see 
Section 4.1). Participants will enter the Maintenance Period on their optimized dose and will 
remain on their optimal dose until the end of treatment. 

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The flexible-dosing regimen is the optimal design to adequately detect efficacy and minimize the 
potential for issues related to safety and tolerability in the PD population. Flexible dosing based 
on clinical response has been used in the registrational studies used to support the approval of 
pharmacotherapies for PD as well as in clinical studies of PD tremor therapies (Pogarell, 2002). 
Likewise, optimizing dose based on clinical response using a titration schedule (starting 
participants at a low dose and titrating up slowly as needed) is consistent with clinical practice. 
Thus, the approach is representative of how a patient with PD would be treated with 
suvecaltamide in a real-world setting. 
In the T-CALM study, daily doses of 16 and 20 mg suvecaltamide per day (administered as the 
 
 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 well 
tolerated. 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
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 (Section 1.3). 
The end of the study is defined as the date of the last visit of the last participant in the study.  

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and eligibility criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Inclusion and exclusion criteria must be evaluated during the Screening Period and rechecked 
before randomization and/or first dose of study intervention. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Male and female participants ages 40 to 85 years inclusive, at time of signing the ICF. 
2. Body mass index from 17 to 45 kg/m2 (inclusive) at Screening. 
3. Diagnosis of clinically probable or clinically established PD meeting the MDS 2015 
criteria (Postuma, 2015). 
4. Participants must be individually optimized on PD medications for the treatment of other 
cardinal signs of PD (bradykinesia, rigidity) per the judgement of the investigator. 
Optimized treatment is defined as the maximum therapeutic effect obtained with PD 
medications when no further improvement is expected regardless of any additional 
adjustments to these medications or when the PD medications or adjustments to these 
medications are anticipated to result in intolerable side effects. This will be based on the 
investigator’s clinical judgement. 
5. Participants must be on a stable dosing regimen of their permitted PD and/or other tremor 
(eg, propranolol) medications for the treatment of motor symptoms for at least 6 weeks 
prior to Screening and do not anticipate the need to make any changes for the duration of 
the study. A lack of use of medications used to treat motor symptoms also must be stable 
for 6 weeks prior to Screening and remain stable for the duration of the study 
(eg, participants who tried PD medications and are no longer taking them must be off of 
these medications and stable for 6 weeks prior to Screening). 
6. For participants who experience motor fluctuations, tremor must also be present during 
“ON” periods and participants should be able to have tremor symptoms evaluated during 
“ON” periods, as determined by the investigator, in relation to the participant’s PD 
medications. If necessary, participants may take their PD medications in the clinic during 
visits where tremor symptoms are evaluated (timing of PD medications relative to tremor 
evaluations can be determined by the investigator). 
7. Participants have moderate to severe impairment associated with tremor at both the 
Screening and Baseline Visits, as determined by all the following:  
a. A score of > 21 on the TETRAS-ADL subscale; and  
b. This criterion has been removed.  
c. CGI-S rating of tremor severity of > 2 (at least moderate for participants ability to 
function). 

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8. Contraception:  
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 
• Use contraception/barrier as follows: 
o 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 WOCBP who is not 
currently pregnant.  
o 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 
1 of the following conditions applies: 
• Is a 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% per year, preferably with low user dependency, as described 
in Appendix 5, during the study intervention period and for at least 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. 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. 
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum 
as required by local regulations) at Screening and at the Baseline Visit before the 
first dose of study intervention (see Section 8.3.5). 
o 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 described 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. 
9. Capable of giving signed informed consent as described in Section 10.1.3 which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 

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10. Willing and able to comply with the study design schedule and other requirements. 
 
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, 
including, but not limited to: psychogenic tremor; myoclonus or ataxia; cerebellar 
disease; traumatic brain injury; alcohol abuse or withdrawal; mercury poisoning; 
hyperthyroidism; pheochromocytoma; multiple sclerosis; clinically significant 
polyneuropathy in the opinion of the investigator; or family history or diagnosis of 
Fragile X syndrome.  
Note: Participants with a history of essential tremor are eligible. 
3. Hoehn & Yahr stage 5 (confinement to bed or wheelchair unless aided). 
4. Participants who only experience tremor during their “OFF” periods. 
5. Severity of motor fluctuations or medication-induced dyskinesia that would interfere 
with the assessment of tremor and/or “ON”/“OFF” periods that are unpredictable per 
the opinion of the investigator.  
6. Clinically significant symptomatic orthostatic hypotension in the opinion of the 
investigator. 
7. Has evidence at Screening of cognitive impairment as defined by a MoCA score < 22 
or has cognitive impairment that in the opinion of the investigator would prevent 
completion of study procedures or the ability to provide informed consent. 
8. Received any study intervention in a previous suvecaltamide (JZP385, formerly 
CX8998 and MK-8998) clinical study.  
9. Presence of any unstable medical or surgical history that could affect the safety of the 
participant or interfere with study efficacy, safety
; or the ability of 
the participant to complete the study per the judgment of the investigator. Examples of 
this may include, but are not limited to, untreated or currently treated malignancy or 
chronic infection, including human immunodeficiency virus. Note: Participants with a 
remote history of cancer may be eligible if the cancer has resolved and is not expected 
to impact safety, efficacy
. 
10. History or presence of gastrointestinal disease (including prior bariatric bypass 
surgery), hepatic (including ALT or AST ≥ 2 × 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 the absorption, distribution, metabolism, 

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or excretion of suvecaltamide. 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. 
11. This criterion has been combined with the criterion above. 
12. Presence of significant cardiovascular disease at Screening including but not limited to 
the following:  
a. Myocardial infarction within the past year;  
b. Revascularization procedure(s) within the past year; 
c. Unstable angina pectoris;  
d. Symptomatic congestive heart failure (American College of Cardiology/American 
Heart Association Stage C or D);  
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 or Baseline);  
g. Markedly abnormal ECG per the Investigator assessment, or QTcF > 450 msec for 
men and > 470 msec for women, based on the average of triplicate assessments at 
Screening or Baseline. 
13. History or presence of bipolar and related mood disorders, schizophrenia, 
schizophrenia spectrum disorders, or other psychotic disorders according to DSM-5 
criteria. 
14. 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; the participant’s antidepressant treatment must be stable for at least 
6 months prior to Screening and expected to remain stable for the duration of the study. 
15. History (within past 2 years at Screening) or presence of substance use disorder 
(including alcohol) according to DSM-5 criteria, known drug dependence, or seeking 
treatment for alcohol or substance abuse related disorder. Nicotine use disorder would 
not be exclusionary if it does not impact tremor per the judgement of the investigator. 

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Prior/Concomitant Therapy 
16. Treatment-naïve patients (ie, those who have never tried PD medication) are excluded 
from participating in the study.  
17. Use of PRN medication/substance(s) that might produce 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, alcohol, or caffeine. Participants 
who consume caffeine or use tobacco should take their regular amount of caffeine or 
tobacco on the clinic days.  
Note: Use of PRN sleep medications is permitted (including the night before a study 
visit day) if it does not impact tremor per the judgement of the investigator. Regular 
use of sleep medications or anxiolytics (eg, benzodiazepines) to improve sleep or 
anxiety is also permitted provided it will continue to be used at stable dosages 
throughout the study. 
18. Prior or planned surgical intervention to treat PD, including but not limited to magnetic 
resonance-guided focused ultrasound thalamotomy, deep brain stimulation, ablative 
thalamotomy, and gamma knife thalamotomy. A history of implantation of an infusion 
pump for delivery of PD medications, or percutaneous endoscopic gastrojejunostomy 
for delivery of PD medications including levodopa-carbidopa intestinal gel would not 
be exclusionary if these medication delivery systems are no longer being utilized. 
19. Use of PRN medications to treat tremor or continuous infusion of PD medications.  
Note: Use of dopaminergic rescue medications (eg, PRN use of carbidopa/levodopa, 
including levodopa inhalation powder) for non-tremor PD symptoms (eg, rigidity or 
bradykinesia) is permitted. 
20. Inability to refrain from using a mechanical device for the management of tremor 
(eg, weighted bracelet) during the study. 
21. Botulinum toxin injection for the treatment of tremor in the 6 months before Screening 
or planned use at any time during the study. Note: Use of botulinum toxin for other 
reasons (eg, cosmetic, excessive salivation, dystonia) is permitted as long as the 
location of use is anatomically distinct from the region with tremor.  
22. Currently taking dopamine antagonists or depleting medications including 
antipsychotics such as clozapine, olanzapine, risperidone, or inhibitors of vesicular 
monoamine transporter 2 such as tetrabenazine, deutetrabenazine, and valbenazine, and 
other adrenergic reuptake inhibitors such as reserpine. 
23. Use of prescription or nonprescription drugs or other products (eg, St. John’s Wort) 
known to be inducers of CYP3A4 (cause > 30% reduction of sensitive substrates 
AUC), which cannot be discontinued at least 4 weeks before Baseline, or planned use 
at any time during the study. 
24. Use of prescription or nonprescription drugs or other products (eg, grapefruit) known 
to be strong or moderate inhibitors of CYP3A4, which 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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25. Use of proton pump inhibitors, which cannot be discontinued at least 2 weeks before 
Baseline, or planned use at any time during the study. (Occasional use of antacids or 
H2 receptor antagonists will be permitted, but antacids should be taken at least 4 hours 
apart from study intervention; and H2 receptor antagonists should be taken at least 
4 hours after and/or 12 hours before study intervention). 
Prior/Concurrent Clinical Study Experience 
26. Received an investigational drug in the past 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. 
Diagnostic Assessments 
27. Laboratory value(s) at Screening outside the laboratory reference range that is/are 
considered markedly abnormal by the investigator (clinical chemistry, hematology, and 
urinalysis).  
Note: Screening laboratory tests may be repeated once. 
28. Known use of recreational drugs, inclusive of the following: phencyclidine, cocaine, 
opioids, barbiturates, amphetamines, or 3,4-methylenedioxymethamphetamine 
[ecstasy]. 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.  
Note: Opioid use at stable doses, either regularly or PRN, for pain management, as 
prescribed, is permitted. Use of cannabinoids (including cannabidiol) is permitted if 
there is no impact to tremor symptoms per the judgement of the investigator.  
Other Exclusions 
29. Daily or near-daily use of more than 2 units of alcohol per day. 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). 
30. Regular consumption of > 600 mg caffeine per day or > 6 cups of coffee per day. 
31. Allergy or sensitivity to any ingredients in the study intervention formulation or 
placebo. 
32. Any other condition and/or situation that causes the investigator or Medical Monitor to 
deem a participant unsuitable for the study. 

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5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
• Refrain from consumption of Seville oranges, grapefruit, or grapefruit juice from 
2 weeks before the start of study intervention until after the final dose. 
• Participants will be instructed to take a single oral daily dose of study intervention  
 
 
  
 
. At clinic visits, a light breakfast, lunch, or 
snack will be provided as needed. See Section 8.1.6 for a description of timing of 
study intervention dosing. 
• Participants will be asked to fast for their Screening Visit only. 
• Note that per exclusion criterion 25, occasional use of antacids or H2 receptor 
antagonists will be permitted, but antacids should be taken at least 4 hours apart from 
study intervention and H2 receptor antagonists should be taken at least 4 hours after 
and/or 12 hours before study intervention. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
As noted in exclusion criteria 29 and 30, respectively, daily or near-daily use of more than 
2 units of alcohol per day or regular consumption of > 600 mg of caffeine (or > 6 cups of coffee) 
per day is not permitted during the study. Participants must abstain from alcohol at least 12 hours 
prior to each clinic visit. 
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 randomly assigned to 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 publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any applicable SAE (see Section 8.4.1). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once if the rescreening is approved by the Sponsor Medical Monitor. 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 during the Maintenance Period. 
See Section 7.1.3 for details regarding temporary interruption of study intervention. 

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6. 
STUDY INTERVENTIONS 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 Interventions Administered 
The study interventions planned for use in this study are described in Table 7.

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Table 7: 
Study Interventions 
Treatment 
Arm 
Intervention/ 
Treatment 
Namea 
Formulation 
Unit Dose 
Strength(s)b 
Dosage 
Level(s) 
Route of 
Admin. 
Use 
Sourcing 
Package 
Labeling 
Storage 
Conditions 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

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Treatment 
Arm 
Intervention/ 
Treatment 
Namea 
Formulation 
Unit Dose 
Strength(s)b 
Dosage 
Level(s) 
Route of 
Admin. 
Use 
Sourcing 
Package 
Labeling 
Storage 
Conditions 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Abbreviations: admin = administration; 
 
 
 
 
 
 
 
 
 
 
 
QD = once daily. 
 
 
 
 
 
 
  
 
b The dose strength of suvecaltamide is based on the active moiety in the drug product. 

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6.2. 
Preparation/Handling/Storage/Accountability 
1. Further guidance and information for the final disposition of unused study intervention 
are provided in the Trial Site Binder. 
2. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
3. Only participants enrolled in the study may dose with study intervention.  
4. At clinic visits, only authorized site staff may dispense or administer study intervention.  
5. 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. 
6. 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). Refer to the Pharmacy Manual 
for details.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All participants who sign the ICF will receive a participant number by 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 ratio to receive once-daily doses of 
suvecaltamide or placebo. Randomization will be stratified by the TETRAS composite outcome 
score (≤ 17 or > 17) as assessed at Baseline. A double-blind approach will be used throughout 
the 17-week treatment period (ie, during the Dose Titration and Optimization Period as well as 
the Maintenance Period). During the Dose Titration and Optimization Period the number of 
capsules of suvecaltamide or placebo taken each day will be titrated based on efficacy response 
and tolerability. Participants will enter the Maintenance Period on 1, 2, or 3 capsules of either 
suvecaltamide (10 mg per capsule) or placebo. Suvecaltamide and placebo capsules will appear 
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 
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 

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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. 
6.4. 
Study Intervention/Treatment Compliance 
For clinic visits where participants are dosed at the site (ie, during Weeks 1, 9, 13, and 17), 
participants will receive study intervention directly from the investigator or designee, under 
medical supervision. The date and time of each dose of study intervention administered in the 
clinic will be recorded in the source documents. In addition, the time of last meal and last dose of 
study intervention taken prior to the clinic dose will be recorded in the source documents. The 
dose of study intervention and study participant identification should be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention. Study site staff will examine each participant’s mouth to ensure that the study 
intervention was ingested. 
For clinic visits where participants dose at home (ie, during Weeks 2, and 5), participants will 
self-administer study intervention at home and compliance with study intervention will be 
assessed at each clinic visit. The date and time of the dose of study intervention on the day of the 
clinic visit will be recorded in the source documents. Compliance will be assessed by direct 
questioning and counting returned capsules during the clinic visits and documented in the source 
documents. Deviation(s) from the prescribed dosage regimen should be recorded. 
A record of the quantity of suvecaltamide (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, including dates for intervention delays (see 
Section 7.1.3) should also be recorded as applicable. 
6.5. 
Dose Modification 
Titration and optimization of study intervention dose during the Dose Titration and Optimization 
Period will occur as outlined in Section 4.1. During the Maintenance Period, participants will 
take suvecaltamide or placebo at the optimal dose determined by the investigator at the end of 
the Dose Titration and Optimization Period (10, 20, or 30 mg once daily). No dose adjustment 
should occur during the Maintenance Period. If the investigator determines a dose adjustment is 
indicated for safety reasons, the Medical Monitor should be consulted regarding continuation of 
study intervention. 
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 PD medications following study 
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6.7. 
Treatment of Overdose, Medication Errors, or Misuse 
For this study, any dose of suvecaltamide (or placebo) greater than the assigned dose that a given 
participant takes within a 24-hour period will be considered an overdose. In 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 suvecaltamide. Attendant signs and symptoms should be 
managed expectantly. See the IB for 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. 
• Closely monitor the participant for any AE/SAE and/or laboratory abnormality.  
• 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; and 
• Dosage information including dose and frequency. 
Concomitant treatment with certain medications/therapies is not permitted during the study (see 
Section 5.2).  
Participants will continue their permitted PD medication(s) at the same stable dose(s) and 
regimen(s) as in the 6 weeks immediately prior to the study and will remain on the same dose(s) 
and regimen(s) of these medication(s) until the end of the study. On clinic visit days, site staff 
will record the time of the last dose(s) of PD medication(s) prior to the efficacy assessments. For 
all participants, efficacy assessments should occur during “ON” periods, as determined by the 
investigator, in relation to the participant’s PD medication(s). 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
Refer to the permitted, prohibited, and cautionary list of medications in the Trial Site Binder. 

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The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 

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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In some instances, it may be necessary for a participant to permanently discontinue study 
intervention. 
A participant must be discontinued from study intervention for any of the following reasons: 
• The participant or their legally authorized 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 C-SSRS (see 
Section 8.3.6). 
• The participant has a positive serum pregnancy test (Appendix 5 and Section 8.4.5). 
• The participant is noncompliant with study intervention or procedures. 
• The sponsor decides to terminate the study prior to completion.  
• The investigator determines the participant should not continue study intervention. 
7.1.1. 
Participants Remaining in the Study After Study Intervention Discontinuation 
Discontinuation from study intervention does not represent discontinuation from the study. For 
participants who discontinue study intervention early, every effort should be made to attend 
Efficacy Follow-up Visits through 17 weeks after the first dose of study intervention. After 
completing the E/D visit, if the participant is willing to attend Efficacy Follow-up Visits after the 
study intervention is discontinued, the guidelines for scheduling efficacy visits are as follows: 
• For participants who discontinue study intervention prior to the Week 9 Visit, it is 
encouraged to schedule 3 additional Efficacy Follow-up Visits at 9, 13, and 17 weeks 
after first dose. 
• For participants who discontinue study intervention after the Week 9 Visit but prior to 
the Week 13 visit, it is encouraged to schedule 2 additional Efficacy Follow-up Visits 
at 13 and 17 weeks after first dose. 
• For participants who discontinue study intervention after the Week 13 Visit but prior 
to the Week 17 Visit, it is encouraged to schedule an additional Efficacy Follow-up 
Visit at 17 weeks after first dose. 
• Participants should be scheduled for the Safety Follow-up Visit 2 weeks after the last 
dose of study intervention. However, 1 of the Efficacy Follow-up Visits can be 
combined with the participant’s Safety Follow-up Visit if the Efficacy Follow-up 
Visit is scheduled to occur within 2 weeks after the participant’s last dose of study 
intervention. 

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7.1.2. 
Positive Alcohol or Urine Drug Screens 
Participants must abstain from alcohol at least 12 hours prior to each clinic visit. 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 Sponsor 
Medical Monitor is required to retain the participant in the study. If the investigator suspects a 
false positive urine drug screen, he/she is encouraged to send a portion of the same urine sample 
to the central laboratory for confirmatory testing (eg, GCMS). 
7.1.3. 
Temporary Discontinuation/Study Intervention Interruption 
If a participant must temporarily interrupt study intervention for any reason, the Medical Monitor 
should be consulted to determine whether the participant will resume study intervention. 
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.  
• At the time of discontinuing from the study, an E/D Visit should be conducted. In 
addition, a Safety Follow-up Visit should be conducted as shown in the SoA 
(Section 1.3). See the SoA for data to be collected at the time of study discontinuation 
and at the Safety Follow-up Visit 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. 
• The site must 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. 

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• 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). After trying to contact the participant, the 
investigator should reach out to the contact provided by the participant. 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 and lost to follow-up.  
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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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Section 1.3).  
• For clinic visits, participants should be admitted to the study site in the morning. The 
investigator may opt to have the participant attend an unscheduled visit, if deemed 
necessary, at any time during the study. Some clinic visits may be conducted 
remotely, if required due to the coronavirus 2019 pandemic, and with approval from 
the Sponsor Medical Monitor, as noted in the SoA.  
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All Screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator should maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
• After Screening procedures have been completed and eligibility criteria have been 
confirmed, the investigator should provide eligible participants with instructions on 
how to discontinue any excluded medication(s). Document that the investigator has 
determined that discontinuation is safe and medically appropriate, and the 
discontinuation is medically supervised. The Sponsor Medical Monitor should be 
contacted if there are any questions regarding discontinuation of excluded 
medication(s). 
• 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
• The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
125 mL (see Laboratory Manual). Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with samples. 
• For clinical outcome assessment measures that are rated by specially qualified and 
trained interviewers/raters, the same person should perform each assessment for the 
same participant throughout the duration of the study, whenever possible. 
• The TETRAS-PS assessment will be administered and scored by a blinded trained 
rater at the site throughout the study. Blinded raters are defined as clinical site 
personnel who have undergone the required training in administration and scoring of 
the TETRAS-PS. The blinded rater who rates the TETRAS-PS for a participant may 
not rate/administer other scales for that participant nor be involved in other 
procedures for that participant. Blinded raters must not share any information they 
collect about participants with other site staff, except when required to ensure 
participant safety. Appropriate training for rating scales will be provided by the rater 

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training vendor. Documentation of how and when data are filed, stored, and 
transmitted to or from the study site will be provided in the Trial Site Binder.  
8.1. 
General Administrative Procedures 
8.1.1. 
Informed Consent 
The investigator or qualified designee (consistent with local requirements) must obtain 
documented consent from each potential participant/legal representative prior to participation in 
this study. 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 by IRT at Screening 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) during the Screening Period and updated at the Baseline Visit. 
All active conditions should be recorded as well as any condition diagnosed within the 
participant’s lifetime that the investigator deems clinically significant. 
Medical history information will include, but is not limited to, symptoms of PD (current and 
past, including symptoms experienced prior to any PD treatment); history and treatment (if any) 
of cardiovascular, pulmonary, gastrointestinal, hepatic, renal, immunologic, neurologic, or 
psychiatric disease; reproductive status; current contraceptive method; confirmation of relevant 
inclusion and exclusion criteria; and any events that occur during the Screening Period and prior 
to the participant’s first dose of study intervention (see Appendix 4).  
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. Medication that is required to be washed out prior to the study should also be 
recorded. All medication(s) currently taken by the participant, as well as all concomitant 
medication(s) taken during the study, should be recorded (see Section 6.8). 
Additional information related to any medications taken for the treatment of PD and/or other 
treatments specific for tremor (eg, propranolol, primidone) since diagnosis should also 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 Participant Eligibility Form will be completed for all participants considered by the 
investigator to meet the eligibility requirements at Screening. The site will submit the form to the 
Medical Monitor for review. The Medical Monitor will provide approval of eligibility to proceed 

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to the Baseline Visit. Some inclusion and exclusion criteria must be re-assessed at the Baseline 
Visit by the investigator or designated study site staff to confirm eligibility prior to 
randomization (see Section 5). 
8.1.6. 
Timing of Study Intervention Dosing 
Participants will be instructed to take a single oral daily dose of study intervention  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
. Participants should also take their daily dose of PD medication(s) at the 
clinic, if necessary, to ensure assessments of efficacy can occur during “ON” periods (as 
determined by the investigator). 
At clinic visits, a light breakfast, lunch, or snack will be provided as needed. Participants will be 
asked to fast for their Screening Visit only. 
8.1.7. 
Montreal Cognitive Assessment 
The 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 26 or above is considered normal. 
A sample MoCA can be found in the Trial Site Binder. 
8.2. 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
On clinic visit days, site staff will record the time of the participant’s dose of study intervention 
as well as the time of the last dose(s) of PD medication(s) prior to the efficacy assessments. For 
all participants, assessment of efficacy should occur during “ON” periods, as determined by the 
investigator, in relation to the participant’s PD medication(s). 
Note that the primary endpoint is the TETRAS composite outcome score. First published in 2008 
and designed as a 10-minute clinical assessment of tremor (Elble, 2008; Elble, 2012), the 
TETRAS consists of a 12-item ADL subscale and a 9-item PS. The TETRAS composite score 
utilized in the present study is comprised of the sum of modified items 1 to 11 of the 
TETRAS-ADL subscale (see Section 8.2.1) and modified items 6 (6a and 6b) and 7 of the 
TETRAS-PS (see Section 8.2.2). While the TETRAS has not been validated in a PD population, 
many of the ADL and functional tasks assessed by the composite outcome score have been 
shown to be impacted by tremor in PD (Elble, 2016; Louis and Machado, 2015). 
8.2.1. 
Tremor Research Group Essential Tremor Rating Assessment Scale – Activities 
of Daily Living 
The TETRAS-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 

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TETRAS-ADL subscale is rated on a 0 (normal activity) to 4 (severe abnormality) scale. 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 in the ET population (Elble, 2012; Elble, 2016). It 
has also demonstrated sensitivity to change with suvecaltamide treatment in the T-CALM study 
in participants with ET. 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 Trial Site Binder. 
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. Blinded 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. The TETRAS-PS has demonstrated both test-retest reliability and 
sensitivity to change in the ET population (Elble, 2012; suvecaltamide IB T-CALM study) and 
was given a “recommended” rating as a tremor severity scale by the MDS for ET (Elble, 2013). 
TETRAS-PS items 6 (6a and 6b) 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 (ie, item 6a) and the left (ie, item 6b) hands, while the handwriting is assessed with the 
dominant hand only. The sum of the TETRAS-PS items 6 (6a and 6b) 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 in the ET population (Calzetti, 1982; Haubenberger, 2011; Hopfner, 2015; 
Koller, 1986; Shill, 2004; Tolosa and Loewenson, 1975). 
A sample TETRAS-PS can be found in the Trial Site Binder. 
8.2.3. 
Clinical Global Impression of Severity 
The CGI-S will be assessed by qualified personnel to assess the severity of the impact of tremor 
in PD on the participants’ ability to function. The CGI-S is a 5-point Likert-type rating scale and 
is widely used in clinical psychopharmacology trials to assess severity of illness. The responses 
to this investigator-completed scale range from 1 (no limitations) to 5 (severe). The investigator 
will rate his/her impression of the severity of the impact of tremor in PD on the participant’s 
current ability to function relative to his/her experience with this patient population. 
A sample CGI-S can be found in the Trial Site Binder. 
8.2.4. 
Clinical Global Impression of Change 
The CGI-C is a 5-point Likert-type rating scale widely used to assess efficacy in clinical drug 
trials. Investigators as trained raters will rate their impression of any change in the severity of the 

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participant’s condition since Baseline on a 5-point scale ranging from 1 (much improved) to 
5 (much worse). Investigators’ rating will focus on the participants’ change in their ability to 
function due to tremor in PD. 
A sample CGI-C can be found in the Trial Site Binder. 
8.2.5. 
Patient Global Impression of Severity 
The PGI-S is a 5-point Likert-type rating scale, with response options ranging from 1 (no 
limitations) to 5 (severe). The participant will rate his/her impression of the severity of the 
impact of their tremor in PD on their current ability to function. 
A sample PGI-S can be found in the 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 tremor in PD. 
A sample PGI-C can be found in the Trial Site Binder. 
8.2.7. 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale  
The MDS-UPDRS is the most widely used clinical rating scale for tracking PD progression 
(Goetz, 2008; Ramaker, 2002). The scale takes approximately 30 minutes to complete and 
consists of 4 parts: 
• Part I: non-motor aspects of experiences of daily living; 
• Part II: motor aspects of experiences of daily living; 
• Part III: motor examination; and 
• Part IV: motor complications (dyskinesias and motor fluctuations including “OFF” 
state dystonia). 
Note that the Part I, II, III, and IV scores, total score, and the tremor score (items 2.10, 3.15, 
3.16, 3.17, and 3.18) will be calculated (see other secondary endpoints, Section 3).  
A sample MDS-UPDRS can be found in the Trial Site Binder.  
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

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8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
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. 

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• Investigators should pay special attention to clinical signs related to previous 
clinically significant or serious illnesses. 
− Any abnormalities identified at the Screening Visit physical exam should be 
recorded as medical history. 
8.3.2. 
Vital Signs 
• Vital signs (to be taken prior to blood collection, when possible) including oral 
temperature, pulse rate, respiratory rate, and orthostatic blood pressure (systolic and 
diastolic) will be assessed at each clinic visit as indicated in the SoA. 
• 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 the supine position for at least 5 minutes, and again in the 
standing position after the participant has been standing for 2 minutes. At Screening 
and Baseline, orthostatic assessments will be taken in triplicate (at intervals of 15 to 
30 minutes). All 3 measurements should be recorded. The average of the 
3 measurements will be automatically calculated. At all other visits, orthostatic blood 
pressure and pulse assessments will consist of a single post-dose measurement. 
• 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 
• 
 
 will be obtained as outlined in the SoA using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
corrected QT (ie, QTc), QTcF intervals. 
• 
 
 
  
 
  
 
 
 
 
 
 
• Each ECG will be reviewed, initially interpreted, signed, and dated by the 
investigator or a designated physician after collection. All ECGs (except for 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. 
• Additional ECGs may be obtained at any time per the investigator’s judgement. 
8.3.4. 
Clinical Safety Laboratory Assessments 
• See Appendix 3 for the list of clinical laboratory tests to be performed and to the SoA 
for the timing and frequency. 
− Screening laboratory assessments should be conducted under fasting conditions. 
Record if the participant was fasting or non-fasting.  

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− Screening laboratory assessments (including urinalysis) should be repeated at the 
Baseline Visit if the visit occurs outside of the Screening Period. 
• The investigator must review the laboratory report, document this review, and record 
any markedly abnormal changes occurring during the study as an AE. Laboratory 
reports must be filed with the source documents. Note: any markedly abnormal 
laboratory findings or other abnormal safety assessments that are associated with a 
specific diagnosis would not be reported as an AE. (The specific diagnosis would be 
reported as an AE if the event occurred after the participant received his/her first dose 
of study intervention; see Appendix 4.) 
• Laboratory findings associated with the underlying disease are not considered 
markedly abnormal unless judged by the investigator to be more severe than expected 
for the participant’s condition. 
• All laboratory tests with markedly abnormal values during participation in the study 
and considered by the investigator to be related to study intervention should be 
repeated until the values return to normal or baseline or are no longer considered 
markedly abnormal by the investigator or Medical Monitor. 
− If markedly abnormal values do not return to normal/baseline within a period 
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. 
8.3.5. 
Pregnancy Testing 
Pregnancy testing is applicable only for WOCBP.  
• Refer to Section 5.1 for pregnancy testing entry criteria. 
• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted as outlined in the SoA.  
− In the event of a positive urine pregnancy test, confirmatory serum pregnancy test 
must be conducted. 
• Additional serum or urine pregnancy tests may be performed, as determined by the 
investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the participant’s participation in the study, and in addition to 
laboratory testing, the investigator must take appropriate steps to confirm, evaluate, 
and manage the potential pregnancy, including referral, when indicated. 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring 
Suvecaltamide is considered a CNS-active study intervention. Participants being treated with 
suvecaltamide 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 intervention, or at the time of dose changes (increases or decreases). Participants who 
experience signs of suicidal ideation or behavior should undergo a risk assessment. All factors 

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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 during the study using the C SSRS administered by a qualified 
and appropriately trained rater. At the Screening Visit, the Screening/Baseline Version of the C 
SSRS will be administered to participants to exclude any individual 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 Visit. At the Baseline Visit, any 
participant who reports active suicidal ideation (eg, a positive response to Question 4 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 postbaseline visits, active suicidal ideation (eg, a positive response to 
Question 4 or 5 on the C-SSRS) or behavior (eg, a positive response to any suicidal behavior 
question on the C-SSRS) 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. 
8.3.7. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease 
Rating Scale 
The QUIP-RS is a rating scale designed to measure the severity of, and support a diagnosis of, 
impulse control and related disorders in PD. It can also be used to monitor changes in symptom 
severity over time (Weintraub, 2012).  
The QUIP-RS is a brief, self-rated questionnaire. It consists of 4 primary questions (pertaining to 
commonly reported thoughts, urges/desires, and behaviors associated with ICDs), each applied to 
the 4 ICDs (gambling, sex, buying, and eating) and 3 related disorders (hobbyism, punding, and 
medication use). It uses a 5-point Likert scale (scored 0 [never] to 4 [very often] for each 
question) to gauge the frequency of behaviors.  
A copy of the QUIP-RS is found in the Trial Site Binder. 
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 (see Section 8.4.3). 
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. 

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8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AEs and SAEs will be collected from the start of intervention until the Safety Follow-up 
Visit at the time points specified in the SoA (Section 1.3). 
Note: All SAEs that occur after the ICF 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 if they 
are the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment, or a procedure. 
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 will be recorded and reported to the sponsor or designee 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. 
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 should 
promptly notify the sponsor. 
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
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. However, after an occurrence is identified, more specific questions should be 
asked to obtain adequate information to ensure participant safety by providing proper diagnosis 
and treatment, and specific, accurate reporting of the event. 
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events 
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 
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 Serious Adverse Events 
• 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, IRB/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 

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review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
• Investigator safety reports will 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 suvecaltamide 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 to be an AE or SAE, any pregnancy 
complication 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. 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 8.4.4. While the investigator is not obligated to actively seek this information 
in former study participants/pregnant female partner, he or she may learn of an SAE 
through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
8.4.6. 
Adverse Events of Special Interest  
The AEOSIs defined for this study are 
 
 
. Additional information 
regarding reporting of AEOSIs is provided in Appendix 4.  
8.4.7. 
Other Reportable Experiences: Overdose, Medication Errors, and Misuse 
Overdose (defined as any dose administered or received that was higher than the intended dose), 
medication errors (defined as any unintentional error in the dispensing or administration of the 
study intervention), and misuse of the study intervention are considered OREs. The method for 

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completing and transmitting reports of these OREs are provided in Appendix 4. Guidelines for 
the treatment of overdose are provided in Section 6.7. 
If any overdose, medication error, or misuse of the study intervention results in an AE, this must 
be recorded. If the AE is serious, it must also be reported as described in Appendix 4. 
Decisions regarding dose interruptions will be made by the investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the participant. 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
8.7. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Immunogenicity assessments are not evaluated in this study. 
8.9. 
Health Economics 
Health economics are not evaluated in this study. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The null and alternative hypotheses for the primary estimand variable are: 
H0: msuvecaltamide = mcontrol 
H1: msuvecaltamide ≠ mcontrol  
Specifically, the null hypothesis states that there is no difference in the mean change on the 
TETRAS composite outcome score (primary estimand) from Baseline to Week 17 between the 
suvecaltamide and control (placebo) groups. The alternative hypothesis is that the mean change 
on the TETRAS composite outcome score from Baseline to Week 17 is not equal between the 
suvecaltamide and control (placebo) groups.  
The null and alternative hypotheses for the key secondary estimand variable are: 
H0: psuvecaltamide = pcontrol 
H1: psuvecaltamide ≠ pcontrol  
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 17 between the suvecaltamide 
and control (placebo) groups. The alternative hypothesis is that the proportion of participants 
who improved by ≥ 1 point on the CGI-S from Baseline to Week 17 is not equal between the 
suvecaltamide and control (placebo) groups. 
There are no hypotheses to be tested for the remaining secondary or exploratory endpoints. All 
safety analyses will be descriptive; no formal statistical testing will be performed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
  
 
 

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9.3. 
Analysis Sets 
For the purposes of analysis, the analysis sets are defined as shown in Table 8. 
Table 8: 
Analysis Sets 
Participant Analysis Set 
Description 
Enrolled Analysis Set 
All participants who sign the ICF. 
Full Analysis Set 
All participants who are randomized. Participants will be analyzed 
according to randomized treatment. 
Safety Analysis Set 
All participants who are randomized and receive at least 1 dose of 
study intervention. This analysis set will be used for safety 
analyses and participants should be summarized according to 
actual treatment. 
Modified ITT Analysis Set 
All participants who are randomized, receive at least 1 dose of 
study intervention, and have baseline and at least 1 non missing 
evaluable postbaseline TETRAS composite outcome score. 
Participants will be analyzed according to randomized treatment. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Abbreviations: ICF = Informed Consent Form; ITT = intention to treat; 
 TETRAS = The 
Essential Tremor Assessment Rating Scale. 
9.4. 
Statistical Analyses 
The SAP will be finalized prior to database lock and will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints, including primary and key 
secondary endpoints. 
9.4.1. 
General Considerations 
In general, results will be summarized by treatment group. Categorical variables will be reported 
as frequency and proportion. 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 will be completed using Version 9.4 or later of the SAS 
Statistical Analysis System (SAS Institute, Inc. Cary, NC). 
9.4.1.1. 
Multiplicity Adjustments 
A fixed sequence hierarchical testing strategy will be implemented to preserve the family-wise 
type 1 error rate at the significance level of 0.05. Testing will begin with the comparison of 
suvecaltamide versus placebo for the primary efficacy variable followed by sequential testing of 

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the key secondary efficacy variable. 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 TETRAS composite outcome score from Baseline to Week 17, suvecaltamide 
versus placebo. 
2. Proportion of participants who improved by ≥ 1 point on the CGI-S from Baseline to 
Week 17, suvecaltamide versus placebo. 
For the secondary and exploratory endpoints, there will be no control for multiple comparisons. 
9.4.1.2. 
Statistical Methods 
Refer to the SAP for a detailed description of statistical methods. 
9.4.1.3. 
Intercurrent Event Strategies 
For the primary and key secondary estimands, the following ICEs should be considered:  
• Treatment discontinuation due to lack of efficacy or AE; and any other reason 
including study intervention noncompliance, and other significant protocol 
deviations.  
• Additional/alternative therapies including PRN use of medications to treat tremor, 
changing background PD treatments, and switching PD treatments.  
The ICEs will be handled using 2 approaches: 
• As the main approach, treatment policy will be used to address the ICEs. Treatment 
policy is defined as the effect of the randomized treatment over the study period 
regardless of whether randomized treatment is continued. Per the treatment policy, 
data collected (during Efficacy Follow-up Visits) after participants experience a 
treatment discontinuation ICE will be included for analysis.  
• As a supplemental approach, additional analyses of the primary and key secondary 
estimands will use the hypothetical strategy to address the ICEs. This strategy is 
defined as the pharmacologic effect of suvecaltamide compared to placebo assuming 
the intercurrent event did not happen with continuation of randomized treatments for 
the duration of the study. Analyses will be conducted using data collected at time 
points that are obtained at or prior to participants discontinuing from randomized 
treatment and combined with modeled values for post-discontinuation timepoints 
where the underlying assumptions are considered as appropriate.  
In summary, ICEs will be addressed using the treatment policy estimand for the main analysis of 
the primary and key secondary endpoints and using the hypothetical strategy estimand for 
supplemental analyses. 

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9.4.1.4. 
Pooling of Investigational Centers 
Data from all investigational centers will be pooled for presentation of the main results 
(eg, demographics, efficacy, safety, 
 
). Data may be pooled by region or country as 
appropriate for exploratory analyses of the primary and key secondary endpoints. 
9.4.1.5. 
Dropouts and Missing Data 
Every effort will be made to limit premature discontinuation of the study and ascertain 
completeness of the data collection. Efficacy Follow-up Visits at Weeks 9, 13, and 17 will be 
conducted as needed for participants who discontinue study intervention but remain in the study 
to complete scheduled efficacy assessments (see Section 1.3).  
However, missing data caused by reasons defined outside the scope of intercurrent events can 
still occur (eg, intermittent missing data due to noncompliance). In that case, the MAR 
assumption will be considered appropriate and missing data will be handled accordingly by 
MMRM or MI.  
Figure 1 provides a flowchart depicting how missing data due to early discontinuation will be 
addressed for the main analyses of the primary and key secondary efficacy estimands. 
Figure 1: 
Handling of Missing Data Due to Early Discontinuation for the Primary and 
Key Secondary Efficacy Endpoints 
 
Abbreviations: AE = adverse event; LOE = lack of efficacy; MAR = missing at random; MI = multiple imputation; 
MMRM = mixed-effect model with repeated measures; MNAR = missing not at random; NRI = non-responder 
imputation. 
Under the main analytical approach, missing data will be assumed to be MAR for participants 
who do not complete the Efficacy Follow-up Visit(s). The MMRM (for the TETRAS composite 
outcome score) and MI (for CGI-S response) assume participants with missing data would have 
efficacy outcomes similar to those participants in their respective study intervention group, 
randomization stratum, and initial trajectory who completed the study. The MMRM produces an 
estimate of the treatment effect via restricted maximum likelihood estimation, and a 2-step MI 
method produces a group of statistical estimates and will be pooled using Rubin’s rule.  

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Under the sensitivity analyses, control-based imputations (for TETRAS composite outcome 
score) and NRI (for CGI-S response) will be used to treat missing data among participants 
discontinued due to an AE or lack of efficacy. Tipping-point analyses will be further conducted 
to assess the robustness of the underlying MAR assumption used in MMRM and MI. 
9.4.2. 
Primary Estimand 
The attributes of the primary estimand are listed in Section 3. 
For the main estimator analysis, a MMRM will be used to include the change in the TETRAS 
composite outcome score from Baseline to Weeks 5, 9, 13, and 17. The model will include 
treatment group, visit, treatment-by-visit interaction, baseline-by-visit interaction, and 
randomization stratum as fixed effects; baseline TETRAS composite outcome scores as a 
covariate; and week repeated within each participant as repeated effect. An unstructured 
variance-covariance matrix will be used to model the correlation among repeated measurements. 
The Kenward-Roger adjustment of degrees of freedom along with REML will be used to make 
proper statistical inference. Within-group LS means and the associated 2-sided 95% CIs, 
treatment difference in LS means and associated 2-sided 95% CIs and p-values will be reported. 
Per the treatment policy, the main analyses will include data collected during the Efficacy 
Follow-up Visits for participants who experience ICEs. However, for participants who 
experience ICEs and do not attend Efficacy Follow-up Visit(s), missing data will be handled per 
Section 9.4.1.5.  
For sensitivity analysis, control-based imputation methods (Roger, 2012) will be used to handle 
missing observations in addition to treatment policy. Details will be further defined in SAP.  
For supplementary analysis, a hypothetical strategy will be used to include data points up to the 
timepoint when a participant experiences an ICE into the MMRM specified above. This will 
serve as complementary analysis and will ignore observations collected after an ICE.  
9.4.3. 
Secondary Estimand and Endpoints 
9.4.3.1. 
Key Secondary Estimand 
The attributes of the secondary estimand are listed in Section 3. 
The main estimator will be analyzed using the CMH test adjusting for the stratification factor at 
randomization (Baseline TETRAS composite score ≤ 17 or > 17). 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. 
Per the treatment policy, the main analyses will include data collected during the Efficacy 
Follow-up Visits for participants who experience ICEs. However, for participants who 
experience ICEs and do not attend Efficacy Follow-up Visit(s), missing data for CGI-S will be 
imputed using a 2-step MI method based on similar participants who remained in the study. 
Further details will be provided in the SAP.  
Sensitivity analyses will be conducted to account for missing data using the NRI method and the 
tipping point analysis, with further details provided in the SAP. 

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For supplementary analysis, a hypothetical strategy will be used to include data points up to the 
timepoint when a participant experiences an ICE into the CMH test specified above. This will 
serve as a complementary analysis and will ignore observations collected after an ICE; the 
missing observations will be further imputed using 2-step MI.  
9.4.3.2. 
Secondary Endpoints 
Refer to Section 3 for a complete list of other secondary endpoints.  
Unless otherwise specified, continuous efficacy endpoints will be analyzed using a MMRM as 
the primary method. The model will include treatment group, visit, treatment-by-visit interaction, 
and randomization stratum as fixed effects, and Baseline as a covariate, and participant as a 
random effect. An unstructured variance-covariance matrix will be used to model the correlation 
among repeated measurements. The Kenward-Roger adjustment of degrees of freedom along 
with REML will be used to make proper statistical inference. Within-group LS means and the 
associated 2-sided 95% CIs, treatment difference in LS means and associated 2sided 95% CIs, 
and nominal p-values will be reported. 
Binary efficacy endpoints will be analyzed using the CMH test adjusting for the stratification 
factor at randomization (Baseline TETRAS composite score ≤ 17 or > 17). 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, along with the associated 
2-sided 95% CIs using a normal approximation to the weighted average will be provided. 
Per the treatment policy, the main analyses will include data collected during the Efficacy 
Follow-up Visit(s) for participants who experience ICEs. However, for participants who 
experience ICEs and do not attend Efficacy Follow-up Visit(s), missing data will be handled per 
Section 9.4.1.5. No additional sensitivity or supplementary analyses are planned for these 
secondary endpoints. 
For safety endpoints, please refer to Section 9.4.5. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ho 

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9.4.5. 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. Safety analyses will be 
descriptive; no formal statistical testing will be performed. These analyses will be performed as 
outlined below, with further details provided in the SAP. 
Adverse events: 
All AEs will be mapped to SOC and PT using the MedDRA classification system. 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. Note summaries will be provided by treatment group, study period, and 
time of onset. 
The participant incidence of AEs, AEs related to study intervention, and AEs leading to 
discontinuation will also be presented by SOC and PT. Preferred term summaries may also be 
provided. 
If a participant has multiple events with the same PT occurring in different study periods, the 
event will be reported for each of those periods. Multiple increases in severity will be counted as 
1 AE. 
Vital signs: 
For each vital sign parameter, summary statistics will be provided for observed and change from 
Baseline values by scheduled visit. 
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 proportion 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. 
Markedly abnormal laboratory findings will be summarized separately.  
C-SSRS and QUIP-RS: 
The CSSRS parameters and QUIP-RS scores will be summarized descriptively by scheduled 
visit. 

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9.4.6. 
Other Analyses 
Subgroup analyses and additional analyses of secondary and exploratory endpoints will be 
further described in the SAP. 
9.5. 
Interim Analysis 
No interim analysis will be performed. 

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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 International Ethical Guidelines; 
− Applicable ICH Good Clinical Practice (GCP) Guidelines; and 
− 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 and national regulatory authority (as applicable) 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; and 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, EU regulation 536/2014 
for clinical studies, 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 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 (as 
applicable) of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act requirements, General Data Protection Regulation, 
and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was 
obtained before any study activities were performed unless otherwise allowed by 
protocol criteria, and must also include 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 that 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. 
Committee Structure 
Establishing a Data Monitoring Committee is not planned for this trial. 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. 
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 and other public registries in accordance with applicable global laws and 
regulations. By signing this protocol, the investigator acknowledges that all posting requirements 

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are solely the responsibility of the sponsor, and he/she 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 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 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/site as applicable, for the 
period 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. 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. 
• Definition of what constitutes source data can be found in the Monitoring Plan and/or 
CRF completion guidelines. 

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• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• 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 
10.1.9.1. First Act of Recruitment 
The study start date is the date on which the first participant has the first visit. 
10.1.9.2. 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; and/or 
• 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 assure 
appropriate participant therapy and/or follow-up. 
 

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APPENDIX 1. ABBREVIATIONS AND DEFINITIONS 
Abbreviation or Term 
Definition/Explanation 
ADL 
Activities of daily living 
Admin. 
Administration 
AE 
Adverse event 
AEOSI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC  
Area under the plasma concentration-time curve 
 
 
BID 
Twice a day 
BL 
Baseline 
BUN 
Blood urea nitrogen 
CaV3 
T-type calcium channel 
CFR 
Code of Federal Regulations 
CGI-C 
Clinician Global Impression of Change 
CGI-S 
Clinician Global Impression of Severity 
CI 
Confidence interval 
Cmax 
Concentration at peak 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CRF 
Case report form 
C-SSRS  
Columbia Suicide Severity Rating Scale 
Ctau  
Concentration at trough  
CYP 
Cytochrome 
d/c 
Discontinuation 
DNA 
Deoxyribonucleic acid 
 
 
 
 
 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 

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Abbreviation or Term 
Definition/Explanation 
ECG 
Electrocardiogram 
E/D  
Early Discontinuation 
eGFR 
Estimated glomerular filtration rate 
ER 
Extended release 
ET 
Essential tremor 
 
 
 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
GCMS 
Gas chromatography-mass spectrometry 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transferase 
H2 
Histamine receptor type 2 
hCG 
Human chorionic gonadotropin 
HDL 
High density lipoprotein 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
ICE 
Intercurrent event 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
I/E 
Inclusion/exclusion 
IEC 
Independent Ethics Committee 
IND 
Investigational new drug 
INR 
International normalized ratio 
 
 
IRB 
Independent Review Board 
IRT 
Interactive response technology 
ITT 
Intention to treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 

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Abbreviation or Term 
Definition/Explanation 
LDL 
Low density lipoprotein 
LOCF 
Last observation carried forward 
LOE 
Lack of efficacy 
LS 
Least squares 
MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 
MCMC 
Markov chain Monte Carlo 
MCV 
Mean corpuscular volume 
MDMA 
3,4,-methylenedioxymethamphetamine 
MDS 
Movement Disorder Society 
MDS-UPDRS 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale 
MedDRA 
The Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MI 
Multiple imputation 
MMRM 
Mixed-effect model with repeated measures 
MNAR 
Missing not at random 
MoCA 
Montreal Cognitive Assessment 
NA 
Not applicable 
NRI 
Non-responder imputation 
ORE 
Other reportable experience 
PCP 
Phenylcyclidine 
PD  
Parkinson’s disease 
 
 
 
 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
 
 
 
 
PRN 
As needed 
PT 
Preferred term 
QD 
Once daily 
 
 
 
 
 

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Abbreviation or Term 
Definition/Explanation 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease 
Rating Scale 
RBC 
Red blood cell 
REML 
Restricted maximum likelihood 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SE 
Standard error 
 
 
 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SoA 
Schedule of activities 
SOC 
System organ class 
STN 
Subthalamic nucleus 
t½  
Terminal half-life 
TETRAS 
The Essential Tremor Assessment Rating Scale 
TETRAS-ADL 
The Essential Tremor Assessment Rating Scale, Activities of Daily Living 
TETRAS-PS 
The Essential Tremor Assessment Rating Scale, Performance Subscale 
Tmax 
Time to maximum concentration. 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Woman of nonchildbearing potential 
 

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Sandvik U, Hariz GM, Blomstedt P. Quality of life following DBS in the caudal zona incerta in 
patients with essential tremor. Acta Neurochir. 2012;154(3):495-9. 
Shill HA, Bushara KO, Mari Z, et al. Open-label dose-escalation study of oral 1-octanol in 
patients with essential tremor. Neurology. 2004;62(12):2320-2. 
Sung YH, Chung SJ, Kim SR, et al. Factors predicting response to dopaminergic treatment for 
resting tremor of Parkinson’s disease. Mov Disord. 2008;23:137-40. 
Tai CH, Yang YC, Pan MK, Huang CS, Kuo CD. Modulation of subthalamic T-type Ca2+ 
channels remedies locomotor deficits in a rat model of Parkinson disease. J Clin Invest. 
2011;121:3289-305. 
Tolosa ES and Loewenson RB. Essential tremor: treatment with propranolol. Neurology. 
1975;25(11):1041-4. 

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Traub RE, Gerbin M, Mullaney MM, et al. Development of an essential tremor embarrassment 
assessment. Parkinsonism Relat Disord. 2010;16(10):661-5. 
Tröster AI, Pahwa R, Fields JA, et al. Quality of life in Essential Tremor Questionnaire 
(QUEST): development and initial validation. Parkinsonism Relat Disord. 2005;11(6):367-73. 
Ware Jr JE and Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. 
Conceptual framework and item selection. Med Care. 1992(30):473-83. 
Weintraub D, Mamikonyan E, Papay K, et al. Questionnaire for Impulsive-Compulsive 
Disorders in Parkinson’s Disease-Rating Scale. Mov Disord. 2012;27(2):242-7. 
Yahr MD, Duvoisin RC, Schear MJ, et al. Treatment of Parkinsonism with levodopa. Arch 
Neurol. 1969;21(4):343-54.  
Zach H, Dirkx MF, Roth D, et al. Dopamine-responsive and dopamine-resistant resting tremor in 
Parkinson disease. Neurology. 2020;95:e1461-70. 

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APPENDIX 3. CLINICAL LABORATORY TESTS 
• The tests detailed in Table 9 will be performed by the central laboratory, except for 
urine pregnancy and breath alcohol tests, which will be performed locally. 
Breathalyzers and urine pregnancy tests will be provided by the central laboratory. 
• Laboratory assessments at Screening should be conducted under fasting conditions. 
Record if the participant was fasting or non-fasting. Repeat laboratory assessments at 
the Baseline Visit if the visit occurs outside of the screening window. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
• All events of ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN (> 35% direct 
bilirubin) or ALT or AST ≥ 3 × ULN and INR > 1.5 which may indicate severe liver 
injury (possible Hy’s Law), must be reported to the sponsor in an expedited manner. 
Table 9: 
Protocol-Required Safety Laboratory Tests 
Laboratory 
Test(s) 
Parameters 
Hematology 
Platelet count  
RBC indices: 
MCV 
MCH 
% Reticulocytes 
WBC count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC count 
Hemoglobin 
Hematocrit 
Clinical 
chemistry 
Albumin 
ALP 
ALT/SGPT 
AST/SGOT 
BUN 
Calcium 
CO2 
Chloride 
Creatinine 
eGFRa 
GGT 
Glucose 
Lactate dehydrogenase 
Phosphorus 
Potassium 
Prolactin 
Sodium 
Total and direct 
bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
HDL 
LDL (calculated) 
Prothrombin time INR 
Routine 
urinalysis 
Appearance, color 
Specific gravity 
pH, glucose, protein, occult blood, ketones, bilirubin, urobilinogen, nitrite, and leukocytes by 
dipstick 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
testing 
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)b 
Serum pregnancy testing is mandatory at Screening; urine is collected thereafter 

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Laboratory 
Test(s) 
Parameters 
Other 
Screening 
tests 
Urine drug screen (to include at minimum: amphetamines, methadone, MDMA, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, and PCP) 
Breath alcohol test 
FSH to evaluate postmenopausal status (female participants only; see Appendix 5) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CO2 = carbon dioxide; eGFR = estimated glomerular filtration rate; 
FSH = follicle-stimulating hormone; GGT = gamma-glutamyl transferase; hCG = human chorionic gonadotropin; 
HDL = high density lipoprotein; IEC = Independent Ethics Committee; IRB = Independent Review Board; 
INR = international normalized ratio; LDL = low density lipoprotein; MCH = mean corpuscular hemoglobin; MCV 
= mean corpuscular volume; MDMA = 3,4,-methylenedioxymethamphetamine; PCP = phenylcyclidine; RBC = red 
blood cell; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; 
ULN = upper limit of normal; WBC = white blood cell; WOCBP = women of childbearing potential. 
a Calculated via central laboratory using the Modification of Diet in Renal Disease method. 
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. Serum pregnancy testing for confirmation of positive urine test, as well as locally or IRB/IEC required 
serum testing will be performed at the central laboratory. Serum pregnancy testing is mandatory at screening, and 
urine is collected thereafter. 

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APPENDIX 4. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention. 
 
Events Meeting the AE Definition 
• 
Any laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that 
worsen from baseline, considered markedly abnormal in the medical and scientific judgment of 
the investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent preexisting condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should 
be reported regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as an 
AE or SAE if they fulfil the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition 
• 
Any markedly abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more severe 
than expected for the participant’s condition. 
• 
Any markedly abnormal laboratory findings or other abnormal safety assessments that are 
associated with a specific diagnosis. (The specific diagnosis would be reported as an AE if it 
occurred during the study.) 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 

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Events NOT Meeting the AE Definition 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence SAE that, at any dose: 
Results in death 
Is life-threatening 
• 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been admitted (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE. 
Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) that may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Is a suspected transmission of any infectious agent via an authorized medicinal product 
Other situations: 
Medical or scientific judgment should be exercised by the investigator in deciding whether SAE 
reporting is appropriate in other situations, such as significant medical events that may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other outcomes listed 
in the above definition. These events should usually be considered serious. 

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An SAE is defined as any untoward medical occurrence SAE that, at any dose: 
Examples of such events include invasive or malignant cancers, intensive treatment for allergic 
bronchospasm, blood dyscrasias, convulsions, or development of intervention dependency or 
intervention abuse. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) related 
to the event. 
• 
The investigator will then record all relevant AE/SAE information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical records 
to the sponsor or designee in lieu of completion of the required form. 
• 
There may be instances when copies of medical records for certain cases are requested by 
sponsor or designee. In this case, all participant identifiers, except for the participant number, 
will be redacted on the copies of the medical records before submission to the sponsor or 
designee. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
• 
The investigator will assess intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories*:  
o Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
o Moderate: minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. 
o Severe: severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL. An AE/SAE that is assessed as severe should not be confused with a SAE. 
Severe is a category utilized for rating the intensity of an event; and both AEs and 
SAEs can be assessed as severe. 
o Life-threatening: life-threatening consequences; urgent intervention indicated. 
o 
Fatal: death related to AE 
* These categories are based on the National Cancer Institute Common Terminology Criteria 
for Adverse Events version 5.0 or higher. 
• 
When the severity of an AE increases over time, the increase in the severity will be recorded as 
a new AE and the original AE will stop when the new AE starts. 
• 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 

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Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship, cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration, will be 
considered and investigated. 
• 
The investigator will also consult the IB and/or Product Information, for marketed products, in 
his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor or designee. However, it is very 
important that the investigator always assess causality for every event before the initial 
transmission of the SAE data to the sponsor or designee. 
• 
The investigator may change his/her opinion of causality considering follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor (or 
designee) to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to the sponsor or designee within 24 hours 
of receipt of the information. 
Reporting of SAEs 
SAE Reporting to the sponsor or designee via an Electronic Data Collection Tool 
• 
SAEs must be reported to the sponsor (or designee) using an SAE Reporting Form within 
24 hours of first knowledge of the event by study personnel. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
The form, instructions on completion, and contact information can be found in the Trial Site 
Binder. 
• 
The SAE Reporting Form should be completed as much as possible before transmittal. 
• 
Contacts for SAE reporting can be found in the Trial Site Binder. 

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Reporting of AEOSIs and OREs 
Reporting of AEOSIs and OREs to the sponsor or designee 
• 
AEOSIs and OREs must be reported to the sponsor or its designee using an AEOSI/ORE 
Reporting Form within 24 hours of first knowledge of the event by study personnel. 
• 
The form, instructions on completion, and contact information can be found in the Trial Site 
Binder. 
• 
The AEOSI/ORE Reporting Form should be completed as much as possible before transmittal.  
• 
Contacts for AEOSI/ORE reporting can be found in the Trial Site Binder. 
 
 

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APPENDIX 5. CONTRACEPTIVE AND BARRIER GUIDANCE 
Definitions 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenopausal female with permanent infertility due to one of the following: 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
d. 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. 
2. Postmenopausal female 
a. 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 hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required. 
− 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 (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal 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 hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required.  
− 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 

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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  
• 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  
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
o oral 
o intravaginal 
o transdermal 
o injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulationc 
o oral 
o injectable 

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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 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 are not acceptable methods of contraception for this study. 
Male condom and female condom should not be used together (due to risk of failure from friction). 

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APPENDIX 6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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