Conditions: Parkinson Disease
Keywords: Parkinsonian Disorders Brain Diseases Central Nervous System Diseases Nervous System Diseases Movement Disorders Neurodegenerative Diseases
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 529
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the clinical efficacy, safety and pharmacokinetics (PK) of 2 fixed doses of tavapadon and placebo in participants with early PD.

Detailed description:

Arms:
arm 1: Participants will receive tavapadon tablet titrated up to 5 milligram (mg) once daily (QD) orally for 27 weeks. arm 2: Participants will receive tavapadon tablet titrated up to 15 milligram (mg) QD orally for 27 weeks. arm 3: Participants will receive placebo matching to tavapadon tablet QD orally for 27 weeks.

Interventions: intervention 1: Tavapadon intervention 2: Placebo intervention 3: Tavapadon
Intervention descriptions: intervention 1: Participants will be randomized to receive tavapadon 5mg tablet once daily orally for 27 weeks. intervention 2: Participants will receive placebo matching to tavapadon QD orally for 27 weeks. intervention 3: Participants will be randomized to receive tavapadon 15mg tablet once daily orally for 27 weeks.

Protocol document:
Prot_000.pdf: 
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CLINICAL PROTOCOL 
 
A PHASE 3, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, PARALLEL-GROUP, 27-WEEK TRIAL 
TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY 
OF TWO FIXED DOSES OF TAVAPADON IN EARLY 
PARKINSON’S DISEASE (TEMPO-1 TRIAL) 
Protocol Number: CVL-751-PD-001 
Compound: Tavapadon (CVL-751) 
Trial Phase: 3 
Short Title: Fixed-Dose Trial in Early Parkinson’s Disease 
Sponsor Name: Cerevel Therapeutics, LLC 
Legal Registered Address: 222 Jacobs Street, Suite 200, Cambridge, MA 02141 USA 
Regulatory Agency Identifier Number 
 
Regulatory Agency File 
Identifying # 
IND 
118,647 
EudraCT 
2019-002949-38 
Version 4.0: 06 Jul 2023 
Version 3.0: 03 Sep 2021 
Version 2.0: 29 Jun 2020 
Original Version 1.0: 07 Oct 2019 
MEDICAL MONITOR NAME AND CONTACT INFORMATION ARE PROVIDED 
IN THE TRIAL OPERATIONS MANUAL. 
 
 
NCT04201093




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PROTOCOL VERSION 4.0 SUMMARY OF CHANGES TABLE 
Document History 
Document:  
Date (Day-Month-Year) 
Version 4.0 
06 Jul 2023 
Version 3.0 
03 Sep 2021 
Version 2.0 
29 Jun 2020 
Original Protocol Version 1.0 
07 Oct 2019 
Amendment: Protocol Version 4.0 (06 Jul 2023) 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: The overall rationale for this amendment is to 
add eye examinations as an additional trial assessment to monitor for the new potential 
risk of increased intraocular pressure across the Phase 3 tavapadon protocols. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Assessments 
Added eye examination 
assessment   
Added footnotes “v” and “w” to 
clarify the assessment and 
follow-up frequency 
To monitor for increased 
intraocular pressure  
 
Removed footnote “b” allowing 
remote visits if the subject 
cannot attend the clinic visit in 
person due to restrictions related 
to COVID-19 
Note, footnote order has shifted 
as a result of these changes. 
Remote visits are no longer 
needed as COVID-19 
restrictions have ended 
7.3 Individual Subject 
Discontinuation 
Removed reference to in-home 
visits 
Remote visits are no longer 
needed as COVID-19 
restrictions have ended 
8.3.8 Eye Examinations 
Added new section for eye 
examinations and guidance for 
follow-up  
To monitor for increased 
intraocular pressure 
 


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TABLE OF CONTENTS 
 
PROTOCOL VERSION 4.0 SUMMARY OF CHANGES TABLE .............................3 
TABLE OF CONTENTS ..................................................................................................4 
TABLE OF TABLES .........................................................................................................7 
TABLE OF FIGURES .......................................................................................................7 
1 
PROTOCOL SUMMARY .........................................................................................8 
1.1 
Synopsis ...................................................................................................................8 
1.2 
Schema ..................................................................................................................12 
1.3 
Schedule of Assessments ......................................................................................12 
2 
INTRODUCTION ....................................................................................................17 
2.1 
Trial Rationale .....................................................................................................17 
2.2 
Background ..........................................................................................................17 
2.3 
Benefit/Risk Assessment ......................................................................................19 
3 
OBJECTIVES AND ENDPOINTS .........................................................................21 
4 
TRIAL DESIGN .......................................................................................................22 
4.1 
Overall Design ......................................................................................................22 
4.1.1 
Screening/Baseline Period .............................................................................22 
4.1.2 
Treatment Period ...........................................................................................23 
4.1.3 
Safety Follow-up Period ................................................................................24 
4.1.4 
Concentration-QT Substudy .........................................................................24 
4.2 
Scientific Rationale for Trial Design ..................................................................24 
4.3 
Justification for Dose ...........................................................................................25 
4.4 
Definition of Completed Subject.........................................................................26 
4.5 
End of Trial Definition ........................................................................................26 
5 
TRIAL POPULATION ............................................................................................26 
5.1 
Inclusion Criteria .................................................................................................26 
5.2 
Exclusion Criteria ................................................................................................27 
5.3 
Lifestyle Considerations ......................................................................................30 
5.4 
Screen Failures .....................................................................................................30 
6 
TRIAL TREATMENTS ...........................................................................................30 
6.1 
Trial Intervention(s) Administered ....................................................................30 
6.2 
Preparation/Handling/Storage/Accountability .................................................31 
6.3 
Measures to Minimize Bias: Randomization and Blinding..............................31 
6.3.1 
Subject Assignment to Treatment ................................................................31 
6.3.2 
Blinding ...........................................................................................................32 
6.4 
Trial Treatment Compliance ..............................................................................32 
6.5 
Concomitant Therapy ..........................................................................................33 
6.5.1 
Prior and Concomitant Medications ............................................................33 
6.5.2 
Prohibited Medications Before the Trial .....................................................33 
6.5.3 
Prohibited Medications During the Trial ....................................................34 
6.5.4 
Dose Modification ..........................................................................................36 
6.6 
Intervention after the End of the Trial ..............................................................36 
7 
DISCONTINUATION OF TRIAL INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ...............................................................37 
 


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7.1 
Discontinuation of Entire Trial...........................................................................37 
7.2 
Discontinuation of Individual Site ......................................................................37 
7.3 
Individual Subject Discontinuation ....................................................................37 
7.4 
Lost to Follow up ..................................................................................................38 
8 
TRIAL ASSESSMENTS AND PROCEDURES ....................................................39 
8.1 
Screening and Baseline Assessments ..................................................................39 
8.2 
Efficacy Assessments ...........................................................................................40 
8.2.1 
Movement Disorder Society-Unified Parkinson’s Disease Rating 
Scale .................................................................................................................40 
8.2.2 
Clinical Global Impression – Severity of Illness .........................................41 
8.2.3 
Clinical Global Impression – Improvement ................................................41 
8.2.4 
Patient Global Impression of Change ..........................................................41 
8.2.5 
39-Item Parkinson’s Disease Questionnaire ................................................41 
8.2.6 
Schwab and England Activities of Daily Living Scale ................................42 
8.2.7 
EuroQol 5 Dimension 5 Level .......................................................................42 
8.3 
Safety Assessments ...............................................................................................43 
8.3.1 
Epworth Sleepiness Scale ..............................................................................43 
8.3.2 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease-Rating Scale ......................................................................................44 
8.3.3 
Columbia-Suicide Severity Rating Scale .....................................................44 
8.3.4 
Physical and Neurological Examinations.....................................................45 
8.3.5 
Vital Signs .......................................................................................................45 
8.3.6 
Electrocardiograms........................................................................................46 
8.3.7 
Clinical Safety Laboratory Assessments ......................................................47 
8.3.8 
Eye Examinations...........................................................................................47 
8.4 
Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest .....................................................................................................48 
8.4.1 
Time Period and Frequency for Collecting AE and SAE/AESI 
Information .....................................................................................................48 
8.4.2 
Method of Detecting AEs and SAEs/AESI ..................................................49 
8.4.3 
Follow-up of AEs and SAEs/AESI................................................................49 
8.4.4 
Regulatory Reporting Requirements for SAEs/AESI ................................49 
8.4.5 
Pregnancy .......................................................................................................50 
8.4.6 
Adverse Events of Special Interest ...............................................................50 
8.5 
Treatment of Overdose ........................................................................................51 
8.6 
Pharmacokinetics .................................................................................................52 
8.7 
Pharmacodynamics ..............................................................................................52 
8.8 
Future Biospecimen Research ............................................................................52 
9 
STATISTICAL CONSIDERATIONS ....................................................................53 
9.1 
Statistical Hypotheses ..........................................................................................53 
9.2 
Sample Size Determination .................................................................................53 
9.3 
Populations for Analyses .....................................................................................53 
9.4 
Statistical Analyses...............................................................................................54 
9.4.1 
Efficacy Analyses ...........................................................................................54 
9.4.2 
Safety Analyses ...............................................................................................56 
9.4.3 
Other Analyses ...............................................................................................56 
 


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9.4.4 
Concentration-QT Analysis ..........................................................................57 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................57 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations .........57 
10.1.1 
Regulatory and Ethical Considerations .......................................................57 
10.1.2 
Financial Disclosure .......................................................................................58 
10.1.3 
Informed Consent Process ............................................................................58 
10.1.4 
Data Protection...............................................................................................58 
10.1.5 
Dissemination of Clinical Trial Data ............................................................59 
10.1.6 
Data Quality Assurance .................................................................................59 
10.1.7 
Source Documents ..........................................................................................60 
10.1.8 
Trial and Site Closure ....................................................................................60 
10.1.9 
Publication Policy...........................................................................................61 
10.2 
Appendix 2: Clinical Laboratory Tests..............................................................62 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ...........................................64 
10.3.1 
Definition of AE..............................................................................................64 
10.3.2 
Definition of SAE ...........................................................................................64 
10.3.3 
Recording and Follow-Up of AEs and/or SAEs/AESI ................................66 
10.3.4 
Reporting of SAEs/AESI ...............................................................................68 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ...........................................................................................................70 
10.4.1 
Definitions:......................................................................................................70 
10.4.2 
Collection of Pregnancy Information ...........................................................71 
10.5 
Appendix 5: Future Biospecimen Research ......................................................73 
10.6 
Appendix 6: Examples of Moderate and Strong Inducers and 
Inhibitors of Cytochrome P450 3a (CYP3A) .....................................................74 
10.7 
Appendix 7: US-Specific Substudy to Evaluate the Effect of 
Tavapadon on the QT Interval ...........................................................................76 
10.7.1 
Introduction ....................................................................................................76 
10.7.2 
Background and Rationale ...........................................................................76 
10.7.3 
Objective of C-QT Substudy .........................................................................76 
10.7.4 
Substudy Design .............................................................................................76 
10.7.5 
Subject Selection ............................................................................................77 
10.7.6 
Study Procedures ...........................................................................................77 
10.7.7 
Data Analysis ..................................................................................................77 
10.7.8 
Sample Size Determination ...........................................................................77 
10.8 
Appendix 8: Abbreviations .................................................................................78 
10.9 
Appendix 9: Protocol Amendment History .......................................................81 
11 REFERENCES .........................................................................................................89 
CLINICAL PROTOCOL PRINCIPAL INVESTIGATOR 
SIGNATURE PAGE ................................................................................................92 
 
 


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TABLE OF TABLES 
Table 1 
Objectives and Endpoints..........................................................................9 
Table 2 
Schedule of Assessments ..........................................................................13 
Table 3 
Objectives and Endpoints........................................................................21 
Table 4 
Tavapadon and Placebo Dosing Schedule .............................................23 
Table 5 
Investigational Medicinal Products Administered ...............................31 
Table 6 
List of Medications Prohibited Before the Trial ...................................34 
Table 7 
List of Medications Prohibited During the Trial ..................................35 
Table 8 
Populations for Analysis ..........................................................................54 
Table 9 
Efficacy Analysis ......................................................................................55 
Table 10 
Safety Analysis .........................................................................................56 
Table 11 
Protocol-Required Safety Laboratory Assessments .............................62 
Table 12 
Definition of AE........................................................................................64 
Table 13 
Events Meeting the AE Definition ..........................................................64 
Table 14 
Definition of SAE .....................................................................................65 
Table 15 
Recording of AEs and/or SAEs/AESI ....................................................66 
Table 16 
Follow-Up of AEs and SAEs/AESI .........................................................68 
Table 17 
SAE/AESI Reporting to the Sponsor or Designee via an Electronic 
Data Collection Tool ................................................................................68 
Table 18 
SAE/AESI Reporting to Sponsor or Designee via Paper CRF 
(If Needed) ................................................................................................69 
Table 19 
Examples of Moderate and Strong Inducers and Inhibitors of CYP3A
....................................................................................................................74 
 
TABLE OF FIGURES 
Figure 1 
Trial Schematic ........................................................................................12 
 
 
 


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1 PROTOCOL SUMMARY 
1.1 
Synopsis 
Sponsor Name: Cerevel Therapeutics, LLC 
Name of Investigational Medicinal Product: Tavapadon 
Protocol Title: A Phase 3, Double-Blind, Randomized, Placebo-Controlled, 
Parallel-Group, 27-Week Trial to Evaluate the Efficacy, Safety, and Tolerability of Two 
Fixed Doses of Tavapadon in Early Parkinson’s Disease (TEMPO-1 Trial) 
Short Title: Fixed-Dose Trial in Early Parkinson’s Disease 
IND Number: 118,647 
EudraCT Number: 2019-002949-38 
Trial Phase: 3 
Indication: Parkinson’s disease 
Rationale: Tavapadon (PF-06649751, CVL-751) is a partial agonist of the dopamine 
D1-like receptors (D1Rs), with high specificity for the D1 and D5 receptor subtypes 
(D1/D5), which is being developed as a treatment for Parkinson's disease (PD). The 
efficacy, safety, and tolerability of tavapadon in Phase 1b and 2 trials support its potential 
as the first partial agonist therapy in an important new dopamine receptor-selective 
mechanism for treatment of PD symptoms. By targeting the D1R subtype, tavapadon 
aims to improve motor control symptoms while minimizing adverse events (AEs) that 
may be mechanistically linked to D2/D3 dopamine receptor agonists (notably, 
dose-limiting hypotension, impulse control disorders, sleep disorders, and, potentially, 
some forms of hallucinations). This trial is designed to further define and confirm the 
magnitude of efficacy and the risk/benefit profile of tavapadon over the target dose range 
of 5 to 15 mg once daily (QD). 
Objectives and Endpoints:  
The objectives and efficacy, safety, and pharmacokinetic (PK) endpoints of the trial are 
summarized in Table 1. 
 


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Table 1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To assess the efficacy of 2 fixed 
doses of tavapadon in subjects with 
early PD 
Primary Efficacy Endpoint 
• 
Change from baseline to endpoint in the 
MDS-UPDRS Parts II and III combined score 
 
Key Secondary Efficacy Endpoints 
• 
Change from baseline to endpoint in the 
MDS-UPDRS Part II score  
• 
Percentage of responders at endpoint, defined as a 
score of “much improved” or “very much 
improved” on the PGIC 
 
Secondary Efficacy Endpoints (All Time Points) 
• 
Change from baseline in the MDS-UPDRS Parts II 
and III combined score 
• 
Change from baseline in the MDS-UPDRS Parts I, 
II, and III combined score 
• 
Change from baseline in the MDS-UPDRS Part I, 
Part II, and Part III individual scores 
• 
Change from baseline in the CGI-S score 
• 
CGI-I score 
• 
PGIC score 
 
Other Endpoints 
• 
Change from baseline in PDQ-39 score 
• 
Change from baseline in Schwab and England 
ADL score 
• 
Change from baseline in the EQ-5D-5L index and 
VAS scores 
Secondary 
 
• 
To assess the safety and tolerability 
of 2 fixed doses of tavapadon in 
subjects with early PD 
• 
ESS 
• 
QUIP-RS 
• 
C-SSRS 
• 
Nature, frequency, and temporality of TEAEs, 
including abuse-related AEs and AEs related to 
MHIs 
• 
Clinical laboratory evaluations 
• 
Vital signs 
• 
Physical and neurological examinations 
• 
ECGs 
Pharmacokinetic 
 
• 
To evaluate the PK of tavapadon in 
this population 
• 
Plasma concentrations of tavapadon and its major 
metabolite (if required) at baseline (Day 1) and 
Weeks 5, 11, 14, 22, and 27 
Abbreviations: ADL = activities of daily living, AE = adverse event, CGI-I = Clinical Global Impression – 
Improvement, CGI-S = Clinical Global Impression – Severity of Illness, C-SSRS = Columbia-Suicide Severity Rating 
Scale, ECG = electrocardiogram, EQ-5D-5L = EuroQol 5 Dimension 5 Level, ESS = Epworth Sleepiness Scale, 
MDS-UPDRS = Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, MHIs = medication handling 
irregularities, PD = Parkinson’s disease, PDQ-39 = 39-Item Parkinson’s Disease Rating Scale, PGIC = Patient Global 
Impression of Change, PK = pharmacokinetic, QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s Disease-Rating Scale, TEAE = treatment-emergent adverse event, VAS = visual analog scale. 
 


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Overall Design: 
This is a prospective, Phase 3, multicenter, multinational, randomized, double-blind, 
placebo-controlled, parallel-group, 27-week trial to evaluate the efficacy, safety, 
tolerability, and PK of 2 fixed doses of tavapadon (5 mg QD and 15 mg QD) in male and 
female subjects aged 40 to 80 years who have a diagnosis of PD (consistent with the UK 
Parkinson’s Disease Society Brain Bank diagnostic criteria); a modified Hoehn and Yahr 
stage of 1, 1.5, or 2; a Movement Disorder Society – Unified Parkinson’s Disease Rating 
Scale (MDS-UPDRS) Part II score ≥2 and Part III score ≥10; and are not receiving 
antiparkinsonian medication other than monoamine oxidase B (MAO-B) inhibitors. The 
trial will include a Screening Period (maximum of 4 weeks), a 27-week Treatment 
Period, and a 4-week Safety Follow-up Period.  
Each subject will participate in the trial for up to approximately 35 weeks, including 
screening (up to 4 weeks), treatment (27 weeks), and posttreatment safety follow-up 
(4 weeks). Subjects who complete through Week 27 of the trial may have the opportunity 
to enter an open-label extension trial (Protocol CVL-751-PD-004).  
A substudy to evaluate the effect of tavapadon on the QT interval using concentration-QT 
modelling is also included in this trial. Matched triplicate electrocardiograms (ECGs) and 
plasma tavapadon concentrations that are collected at preselected sites will be used to 
characterize the effects of tavapadon on the QT interval. 
Disclosure Statement: This is a parallel-group trial to evaluate the efficacy, safety, 
tolerability, and PK of 2 fixed doses of tavapadon (5 mg QD and 15 mg QD) and placebo 
in subjects with early PD. Treatment assignments will be blinded to the investigators and 
other trial site personnel, the subjects, and all sponsor personnel who are involved in the 
conduct of the trial (including trial monitoring, data management, and data analysis).  
Number of Subjects: A total of 522 subjects are planned to be randomized into 
3 treatment groups (174 subjects per treatment group). 
Key Entry Criteria: Male and female subjects aged 40 to 80 years who have a diagnosis 
of PD (consistent with the UK Parkinson’s Disease Society Brain Bank diagnostic 
criteria); a modified Hoehn and Yahr stage of 1, 1.5, or 2; an MDS-UPDRS Part II score 
≥2 and Part III score ≥10; and are not receiving antiparkinsonian medication other than 
MAO-B inhibitors will be enrolled.  
Intervention Groups, Trial Treatments, and Duration: Subjects will be randomized in 
a 1:1:1 ratio to receive tavapadon 5 mg QD, tavapadon 15 mg QD, or placebo QD. The 
dose of tavapadon will be titrated to a target dose using a fixed titration scheme. 
Randomization will be stratified by concurrent use of allowed PD medications (MAO-B 
inhibitors) during the Treatment Period. The planned duration of treatment is 27 weeks, 
including the Titration, Adjustment, and Maintenance Phases. The investigational 
medicinal products (IMPs) will be taken orally. 
 


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Statistical Methods 
Sample Size Estimation: A sample size of 174 subjects per group (total, 522 subjects) 
will provide at least 90% power to detect a change in the primary outcome measure 
(change from baseline in the MDS-UPDRS Parts II and III combined score) of 4 points, 
with a standard deviation of 9, 2-sided alpha level = 0.05, and assuming a 27% dropout 
rate. 
In the event of higher than anticipated early terminations due to COVID-19 or other 
reasons, Cerevel may extend enrollment in order to maintain the planned statistical 
power. 
Efficacy Analyses: The efficacy endpoints will be assessed for each of the 2 dose levels 
of tavapadon versus placebo. A hierarchical testing procedure with a prespecified order 
for the primary and key secondary endpoints will be used to control the Type I error rate 
at the 0.05 level (2-sided). Additional details will be provided in the statistical analysis 
plan.  
The primary efficacy endpoint (the change from baseline to endpoint in the 
MDS-UPDRS Parts II and III combined score) will be analyzed using a Mixed Model for 
Repeated Measures (MMRM). The change from baseline at each postbaseline timepoint 
will be included in the MMRM as repeated measures. The baseline score will be included 
as a covariate, and treatment group, visit, the interaction between treatment group and 
visit, and the stratification factor (concurrent use of MAO-B inhibitor; yes/no) will be 
included as fixed factors. An unstructured covariance structure will be utilized. The 
difference between each tavapadon dose level and placebo at endpoint will be estimated 
based on the least square means (LSMeans) from the MMRM. A hypothetical strategy 
will be used to address intercurrent events (ICEs) of potential death, treatment 
discontinuations, missed visits/assessments, and start of prohibited concomitant 
medications. The data after treatment discontinuations or after the start of prohibited 
concomitant medications will be censored under the hypothetical strategy. The missing 
values are assumed to be missing at random (MAR) in the primary analysis, including 
missing due to COVID-19 control measures. Sensitivity analyses will be performed to 
assess the impact of deviation from MAR assumptions on the analysis results. 
The key secondary endpoint of the change from baseline to endpoint in the MDS-UPDRS 
Part II score will be analyzed using an MMRM analysis similar to the analysis of the 
primary endpoint.  
The key secondary endpoint of the percentage of responders at endpoint, defined as a 
score of “much improved” or “very much improved” on the Patient Global Impression of 
Change (PGIC), will be analyzed using the SAS® GLIMMIX procedure for binomial data 
with logit link. This generalized linear mixed model analysis will include response data 
from each postbaseline visit as repeated measures with treatment group, visit, and 
interaction between treatment group and visit as fixed effects. An unstructured covariance 
structure will be used for the repeated measures. If the model fails to converge with the 
 




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Table 2 
Schedule of Assessments 
Trial Period: 
Screen 
Baseline 
Treatment 
Safety 
Follow-upa 
Trial Week: 
-4 to -1 
1 
2 
5 
8 
11 
14 
18 
22 
26 
27b 
31 
Trial Day: 
-31 to -1 
1 
14±3 
35±3 
56±3 
77±3 
98±3 
126±3 
154±3 
182±3 
189±3 
217±3 
Visit/Contact: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
(EOT/ET) 
Telephonec 
Entrance and History 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric historye  
-----------------→ 
 
 
 
 
 
 
 
 
 
 
Medical historye 
-----------------→ 
 
 
 
 
 
 
 
 
 
 
Alcohol/illicit drug use inquiry 
X 
 
 
 
 
 
 
 
 
 
 
 
Modified Hoehn and Yahr stage 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
MoCA 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Efficacy and Other Endpoint Assessments 
MDS-UPDRSf 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-S 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-Ig 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
PGICg 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
PDQ-39 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Schwab and England ADL 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
EQ-5D-5L 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
Safety Assessments 
ESS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
QUIP-RS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Table 2 
Schedule of Assessments 
Trial Period: 
Screen 
Baseline 
Treatment 
Safety 
Follow-upa 
Trial Week: 
-4 to -1 
1 
2 
5 
8 
11 
14 
18 
22 
26 
27b 
31 
Trial Day: 
-31 to -1 
1 
14±3 
35±3 
56±3 
77±3 
98±3 
126±3 
154±3 
182±3 
189±3 
217±3 
Visit/Contact: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
(EOT/ET) 
Telephonec 
C-SSRSh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical/neurological examinationi  
X 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Vital signsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECGs 
 
 
 
 
 
 
 
 
 
 
 
 
US sites 
 
 
 
 
 
 
 
 
 
 
 
 
Single ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
Three sets of triplicate ECGsk 
(-45, -30, and -15 min prior to 
first dose of IMP) 
 
X 
 
 
 
 
 
 
 
 
 
 
One set of triplicate ECGsk,l 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Non-US sites 
 
 
 
 
 
 
 
 
 
 
 
 
Single ECGl 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
One set of triplicate ECGsk,l 
prior to first dose of IMP 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xv 
 
 
 
 
Xw 
 
Prior/concomitant medications 
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
Adverse eventsm 
 
-------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
Laboratoryn 
Safety laboratory blood sample 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
Prolactin level 
 
Xu 
 
 
 
 
 
 
 
 
Xu 
 
Serology (HIV, HbsAg, and HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2 
Schedule of Assessments 
Trial Period: 
Screen 
Baseline 
Treatment 
Safety 
Follow-upa 
Trial Week: 
-4 to -1 
1 
2 
5 
8 
11 
14 
18 
22 
26 
27b 
31 
Trial Day: 
-31 to -1 
1 
14±3 
35±3 
56±3 
77±3 
98±3 
126±3 
154±3 
182±3 
189±3 
217±3 
Visit/Contact: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
(EOT/ET) 
Telephonec 
Dipstick urinalysiso 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
Serum pregnancy testp 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick pregnancy testp 
 
-------------------------------------------------------------------------------------------------------------------------------------→ 
 
Urine drug screenq 
X 
-------------------------------------------------------------------------------------------------------------------→ 
X 
 
Plasma PK sampler 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Future biospecimen research blood 
samples 
 
X 
 
 
 
 
 
 
 
 
 
 
IMP Administration and Compliancet 
Dispense IMP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assess IMP compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: ADL = activities of daily living, CGI-I = Clinical Global Impression – Improvement, CGI-S = Clinical Global Impression – Severity of Illness, 
C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, eCRF = electronic case report form, EQ-5D-5L = EuroQol 5 Dimension 5 Level, ESS = Epworth 
Sleepiness Scale, EOT = end of treatment, ET = early termination, HbsAg = hepatitis B surface antigen, HCV = hepatitis C virus, HIV = human immunodeficiency virus, 
IMP = investigational medicinal product, 
, MDS-UPDRS = Movement Disorder Society – Unified Parkinson’s Disease Rating Scale, MoCA = Montreal 
Cognitive Assessment, PDQ-39 = 39-Item Parkinson’s Disease Questionnaire, PGIC = Patient Global Impression of Change, PK = pharmacokinetic, QUIP-RS = Questionnaire for 
Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale. 
a. 
Subjects who prematurely discontinue from the trial or who are not eligible for or choose not to participate in the open-label extension trial (Protocol CVL-751-PD-004) are to 
participate in the 4-week Safety Follow-Up Period. Subjects who proceed into the open-label extension trial will go directly into that trial and will not complete the Safety 
Follow-Up Period. 
b. 
The assessments scheduled for the Week 27 visit are to be performed for any subject who prematurely discontinues from the trial. 
c. 
Contact with subjects via telephone call or other means of communication to check on their status. 
d. 
Informed consent must be obtained before any trial-related procedures are performed. 
e. 
Medical occurrences that begin before the start of IMP dosing but after obtaining informed consent will be recorded as medical and/or psychiatric history. 
f. 
MDS-UPDRS Parts I, II, and III will be conducted before the first dose of IMP at the Baseline Visit and at ~2 to ~6 hours after dosing (at home) at clinic visits during the 
Treatment Period. 
g. 
All responses will be relative to the subject’s condition at the Baseline Visit (Day 1) before the first dose of IMP. 
 


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h.
The “Baseline/Screening” C-SSRS form will be completed at the Screening Visit to determine eligibility. The “Since Last Visit” C-SSRS form will be completed at the
Baseline Visit to ensure that the subject continues to qualify for the trial and at all visits after the Baseline Visit.
i.
Full physical and neurological examinations should be completed at the Screening Visit and at Week 27. The physical examination should include height at the Screening
Visit only. Physical and/or neurological examinations can be done at any time point during the trial at the investigator's discretion.
j.
Duplicate measurements of blood pressure and heart rate will be obtained in supine (after 5 minutes of rest) and 1 measurement of blood pressure and heart rate will be
obtained on standing (2 minutes after rising from supine to standing).
k.
A triplicate set of ECGs is 3 consecutive ECGs collected 1 to 2 minutes apart over a 5-minute period.
l.
The postdose ECGs (triplicate set for US sites at all visits and single for non-US sites at all visits) will be obtained at ~1 hour after administration of the first dose of IMP at
the Baseline Visit just prior to the time of collection of the PK blood sample. ECGs at all postbaseline visits will be obtained just prior to the time of collection of the PK
blood sample.
m.
All adverse events that are observed by trial personnel or volunteered by the subject in response to open-ended questioning will be recorded from the first dose of IMP
through the end of the Safety Follow-up Period. Serious adverse events will be followed until resolution.
n.
Individual sites may require subjects to have COVID-19 testing done prior to randomization. COVID-19 testing may be performed after randomization per the principal
investigator’s discretion.
o.
Dipstick urinalysis results are not to be recorded on the eCRFs; any clinically significant abnormality should be captured as an adverse event.
p.
For women of childbearing potential only. All positive urine dipstick pregnancy tests must be confirmed by a serum test. Pregnancy tests can be performed at any time during
the trial at the discretion of the investigator. Female subjects with exclusively the same sex partners may not be required to have pregnancy tests per investigator discretion;
confirmation with the medical monitor is required.
q.
A urine drug screen is required at screening (see exclusion criteria for exclusions based on the urine drug screen) and may be obtained at other times, at investigator
discretion, if use of prohibited drugs is suspected.
r.
PK samples will be collected ~1 hour after administration of the first dose (Day 1) and at the clinic visits at the end of Weeks 5, 11, 14, 22, and 27 just after ECG acquisition
at each time point. The date and time of the most recent dose, the dose amount, and the time of the blood draw will be recorded.
s.
Future biospecimen research sample is optional and is to only be collected if signed consent is obtained from the subject.
t.
The first dose of IMP (at the Baseline Visit) will be taken in the clinic; all other doses will be taken on an outpatient basis. Subjects will be instructed to bring their IMP to
each clinic visit. Compliance will be assessed through self-reporting by the subject and by tablet count.
u.
Prolactin results will be blinded.
 


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2 INTRODUCTION 
2.1 
Trial Rationale 
Tavapadon (PF-06649751, CVL-751) is a partial agonist of the dopamine D1-like 
receptors (D1Rs), with high specificity for the D1 and D5 receptor subtypes (D1/D5), 
which is being developed as a treatment for Parkinson's disease (PD). Efforts to develop 
selective D1R agonists have been ongoing for decades, in part, because of their clear 
potential to produce robust efficacy through selective stimulation of the direct pathway. 
Mechanistic evidence also suggests that selective and partial activation of D1Rs may 
avoid some of the limiting side effects of the D2/3 agonist or dopamine replacement 
therapies. 
The efficacy, safety, and tolerability of tavapadon in Phase 1b and 2 trials support its 
potential as the first partial agonist therapy in an important new dopamine 
receptor-selective mechanism for treatment of PD symptoms. By targeting the D1R 
subtype, tavapadon aims to improve motor control symptoms while minimizing adverse 
events (AEs) that may be mechanistically linked to D2/D3 dopamine receptor agonists 
(notably, dose-limiting hypotension, impulse control disorders, sleep disorders, and, 
potentially, some forms of hallucinations). 
This prospective, Phase 3, multicenter, multinational, randomized, double-blind, 
placebo-controlled, parallel-group, 27-week trial will evaluate the efficacy, safety, 
tolerability and pharmacokinetics (PK) of 2 fixed doses of tavapadon (5 mg and 15 mg 
once daily [QD]) in subjects with early PD to further define and confirm the magnitude 
of efficacy and the risk/benefit profile of this specific target dose range. A substudy is 
also included in the main trial to characterize the relationship between tavapadon 
concentrations and the QT interval. 
2.2 
Background 
Parkinson’s disease is a chronic, progressive and disabling neurodegenerative disease. 
The number of individuals with PD aged 50 and older was between 4.1 and 4.6 million in 
2005 in the 10 most populous nations in the world* combined and is projected to double 
to between 8.7 and 9.3 million by 2030 (Dorsey et al, 2007). The incidence is 
approximately 20 per 100,000 persons per year, increases with advancing age (65 years 
and older) to up to >100 per 100,000 (Twelves et al, 2003), and is reported to be 1.4% at 
age 55 years and 4.3% at 85 years and older (de Rijk et al, 1995). 
The specific etiology of PD remains unclear, but there are continued advances in 
understanding the possible underlying mechanisms and causative factors. A more 
complete understanding of basal ganglia function, the neuropathologic and 
neurochemical abnormalities in PD, and genetic forms of parkinsonism provide hope that 
                                                 
* China, India, United States, Indonesia, Brazil, Pakistan, Bangladesh, Russia, Nigeria, and Japan. 
 


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disease-modifying therapeutic approaches can be identified. However, there remains 
significant current and future need for improved symptomatic therapies. 
It is generally recognized that the primary degeneration in PD involves basal ganglia and 
its projections. The underlying pathology indicates a loss of dopaminergic neurons in the 
substantia nigra, and neuronal loss in the locus coeruleus and the nucleus raphe. 
Dopamine acts on 5 receptor subtypes to facilitate controlled movement, and insufficient 
activation of these receptors is established as the primary cause of motor control deficits 
in PD. The dopamine receptor subtypes have distinct localization and primary signaling 
cascades and are commonly divided into 2 groups based on their function. The D1-like 
family includes the D1 and D5 subtypes, which are localized on a “direct” striatal motor 
control pathway and which stimulate cellular activity by increasing intracellular cyclic 
adenosine monophosphate (cAMP) levels. The D2-like family includes the D2, D3, and 
D4 subtypes, which are localized to an “indirect” motor control pathway and which 
decrease intracellular cAMP when activated. The degenerative character of the disease is 
accompanied by intracellular deposits of Lewy bodies and by microglia-activation. Basic 
research currently suggests that oxidative injury to specific neurons in the basal ganglia 
may be at least one of the underlying causes of “idiopathic parkinsonism,” apart from 
other factors, such as genetic changes. 
The major clinical diagnostic features of PD include tremor, rigidity of skeletal muscles, 
bradykinesia, impairment of postural reflexes (also referred to as parkinsonism), and gait 
disturbances. Additional symptoms include many other motor features and nonmotor 
features, including psychiatric, sensory, and autonomic changes. Patients may or may not 
require therapy in the early stages of PD, which typically presents with fewer and less 
severe symptoms, and may still be able to work. Unfortunately, disease progression is 
inevitable and, within 1 to 3 years of diagnosis, nearly all patients will require therapy. 
Continued disease progression, in conjunction with common medication-related side 
effects, usually leads to individualized optimization of therapy in an effort to manage the 
increasing symptoms and common medication-related side effects. Despite these efforts, 
a majority of patients experience significant worsening of symptoms and reduced quality 
of life and independence and will leave the workforce within 5 years of diagnosis 
(Jasinska-Myga et al, 2012). No proven disease-modifying treatments for PD are 
currently available. Management options for PD consist mainly of dopaminergic drugs 
and, in a limited number of patients, deep brain stimulation. 
Levodopa (L-Dopa, the metabolic precursor of dopamine) therapy provides increased 
dopamine levels in a transient and pulsatile fashion and affords rapid improvement of 
motor symptoms. However, prolonged use of L-Dopa leads to the development of motor 
complications in most patients. These include motor fluctuations, which are an 
alternation between “on” periods when motor symptoms are well controlled and “off” 
periods when motor symptoms are poorly controlled. An additional type of motor 
complication is the occurrence of dyskinesia or abnormal involuntary movements 
(Marconi et al, 1994; Vijayakumar and Jankovic, 2016). Troublesome motor 
complications from L-Dopa therapy can lead to substantial impairment, negative impacts 
on activities of daily living, and decreased quality of life. 
 


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Agents that preferentially activate the dopamine D2 and D3 receptor subtypes (D2/D3R), 
such as pramipexole, ropinirole, and rotigotine, are also approved for the symptomatic 
treatment of PD (Stocchi et al, 2016). These agents generally exhibit less frequent motor 
complications than L-Dopa but are not as effective for controlling motor symptoms 
(Connolly and Lang, 2014; Rizek et al, 2016; Dietrichs and Odin, 2017). 
D2/D3-preferring agonists are also associated with an increased incidence of specific 
adverse effects, including somnolence, hypotension, compulsive behaviors, and 
hallucinations, particularly in the elderly (Stowe et al, 2008). 
Selegiline, rasagiline, and safinamide are monoamine oxidase B (MAO-B) inhibitors, 
which block one pathway of dopamine degradation and improve motor symptoms of PD 
in some settings (Connolly and Lang, 2014; Binde et al, 2018). Of these, only rasagiline 
is approved in the United States and Europe as a monotherapy treatment, and available 
indirect evidence suggests that this class is less efficacious than D2/3 agonists (Stowe et 
al, 2008; Zhuo et al, 2017). 
Despite available treatment approaches, the chronic and progressive nature of PD 
continues to result in significant burden and impact on quality of life and day-to-day 
functioning for patients (Drutyte et al, 2014). There are significant unmet medical needs 
throughout the stages of PD, from improving motor control in patients with early-stage 
disease who have not yet begun dopamine replacement therapy, to increasing daily “on” 
time without troublesome dyskinesias while adequately controlling motor symptoms in 
patients with moderate-to-advanced disease who are receiving available therapies 
(patients with motor fluctuations). Patients and their families are anxious for testing of 
new therapeutic mechanisms that can provide strong and lasting control of the symptoms 
of PD and that can minimize some of the known side effects of existing therapeutic 
options, such as dose-limiting dyskinesias, daytime sleepiness, and impulsivity. 
Completed Phase 1b and 2 trials have demonstrated that tavapadon can provide improved 
control of motor symptoms in both early and more advanced stages of PD, with an 
acceptable safety profile. 
2.3 
Benefit/Risk Assessment 
In a Phase 1b trial in subjects with PD with motor fluctuations (Trial B7601009), 
increasing benefit on motor symptoms was observed with increased tavapadon dose, with 
magnitudes of change on the Movement Disorder Society – Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS) Part III scores well above the changes that are recognized 
as clinically meaningful (>3-point decrease from baseline; Horváth et al, 2015) and 
significantly better than for placebo. Sustained effects of tavapadon on tremor (as shown 
by the MDS-UPDRS Part III scores that were lower than at baseline for up to 12 hours 
after dosing) were also observed in a second Phase 1b trial in subjects with PD with 
motor fluctuations (Trial B7601005). 
In a Phase 2 trial of tavapadon in L-Dopa-treated subjects with PD who were 
experiencing motor fluctuations (Trial B7601003), analysis of the change from baseline 
in average daily “on” time without troublesome dyskinesia showed that the magnitude of 
 


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benefit of tavapadon 15 mg QD, relative to placebo, was approximately 1 hour at 
Week 10. Although the difference from placebo did not achieve statistical significance 
due to the small sample size, this difference is considered clinically meaningful (Hauser 
et al, 2011; Hauser et al, 2014).  
Motor symptoms were significantly more improved with tavapadon monotherapy than 
with placebo in a Phase 2, placebo-controlled, 15-week, flexible-dose trial in subjects 
with early PD (Trial B7601011), as assessed by the change from baseline to Week 15 in 
the MDS-UPDRS Part III total score (least square mean [LSMean] change from 
baseline = -9.0 for tavapadon and -4.3 for placebo; difference from placebo = -4.8; 
p=0.041). The difference between tavapadon and placebo in the change from baseline to 
Week 15 in the MDS-UPDRS Parts II and III combined score was also statistically 
significant (LSMean change from baseline = -11.2 for tavapadon and -5.4 for placebo; 
difference from placebo: -5.9; p=0.020). The magnitude of the placebo-adjusted 
treatment difference in improvement from baseline in the MDS-UPDRS Part III score 
met the threshold for a clinically meaningful change (>3-point decrease from baseline; 
Horváth et al, 2015), as did the magnitude of the placebo-adjusted treatment difference in 
improvement from baseline in the MDS-UPDRS Parts II and III combined score 
(>4.9-point decrease from baseline; Makkos et al, 2018). 
The safety results across all clinical trials demonstrate that tavapadon was generally 
well tolerated up to a titrated dose of 15 mg QD in subjects with PD, either as 
monotherapy (early PD) or as adjunctive treatment with a stable dose of L-Dopa 
(advanced PD). A dose-dependent increase in the frequencies of nausea and headache 
was observed across all trials. Nausea, vomiting, dyskinesia, fall, fatigue, sleep disorder, 
and tremors were the most common AEs leading to discontinuation of tavapadon. The 
appearance of nausea, orthostatic blood pressure changes, and fatigue is often related to 
the speed of titration with dopamine receptor agonists (historically with D2 agents) and 
may be mitigated by a slower titration method. 
No notable differences in laboratory abnormalities, electrocardiogram (ECG) parameters, 
or suicidality assessments were observed between tavapadon and placebo. Multidose 
cohorts in Phase 1 trials in healthy volunteers and subjects with PD (including subjects 
with PD who were treated at doses of up to 25 mg QD of tavapadon) did not suggest that 
tavapadon prolonged the QT interval corrected for heart rate by Fridericia’s formula 
(QTcF). Trials of longer treatment duration suggest a tavapadon dose-related decrease 
from baseline in systolic and/or diastolic parameters, with some cases of asymptomatic 
hypotension. This finding is common with dopamine D2 agonists and is prevalent in the 
population of patients with PD whether treatment naïve or treated with L-Dopa. 
Taken together, the current data suggest an appropriate benefit-risk ratio for further 
evaluation of tavapadon in Phase 3 clinical trials at doses up to 15 mg QD. Additional 
information about the known and expected benefits, risks, and AEs of tavapadon is 
provided in the Investigator’s Brochure. 
 


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In response to the COVID-19 pandemic, Cerevel has performed a risk assessment of this 
trial and the investigator of each individual trial site and has implemented measures 
throughout the protocol, which prioritizes trial participant safety and data validity. 
3 OBJECTIVES AND ENDPOINTS 
The trial objectives and endpoints are summarized in Table 3. 
Table 3 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
•
To assess the efficacy of 2 fixed
doses of tavapadon in subjects with
early PD
Primary Efficacy Endpoint 
•
Change from baseline to endpoint in the
MDS-UPDRS Parts II and III combined score
Key Secondary Efficacy Endpoints 
•
Change from baseline to endpoint in the
MDS-UPDRS Part II score
•
Percentage of responders at endpoint, defined as a
score of “much improved” or “very much
improved” on the PGIC
Secondary Efficacy Endpoints (All Time Points) 
•
Change from baseline in the MDS-UPDRS Parts II
and III combined score
•
Change from baseline in the MDS-UPDRS Parts I,
II, and III combined score
•
Change from baseline in the MDS-UPDRS Part I,
Part II, and Part III individual scores
•
Change from baseline in the CGI-S score
•
CGI-I score
•
PGIC score
Other Endpoints 
•
Change from baseline in PDQ-39 score
•
Change from baseline in Schwab and England
ADL score
•
Change from baseline in the EQ-5D-5L index and
VAS scores
Secondary 
•
To assess the safety and tolerability
of 2 fixed doses of tavapadon in
subjects with early PD
•
ESS
•
QUIP-RS
•
C-SSRS
•
Nature, frequency, and temporality of TEAEs,
including abuse-related AEs and AEs related to
MHIs
•
Clinical laboratory evaluations
•
Vital signs
•
Physical and neurological examinations
•
ECGs
 


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Table 3 
Objectives and Endpoints 
Objectives 
Endpoints 
Pharmacokinetic 
 
• 
To evaluate the PK of tavapadon in 
this population 
• 
Plasma concentrations of tavapadon and its major 
metabolite (if required) at baseline (Day 1) and 
Weeks 5, 11, 14, 22, and 27 
Abbreviations: ADL = activities of daily living, AE = adverse event, CGI-I = Clinical Global Impression – 
Improvement, CGI-S = Clinical Global Impression – Severity of Illness, C-SSRS = Columbia-Suicide Severity Rating 
Scale, ECG = electrocardiogram, EQ-5D-5L = EuroQol 5 Dimension 5 Level, ESS = Epworth Sleepiness Scale, 
MDS-UPDRS = Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, MHI = medication handling 
irregularities, PD = Parkinson’s disease, PDQ-39 = 39-Item Parkinson’s Disease Rating Scale, PGIC = Patient Global 
Impression of Change, PK = pharmacokinetic, QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s Disease-Rating Scale, TEAE = treatment-emergent adverse event, VAS = visual analog scale. 
4 TRIAL DESIGN 
4.1 
Overall Design 
This is prospective, Phase 3, multicenter, multinational, randomized, double-blind, 
placebo-controlled, parallel-group, 27-week trial to evaluate the efficacy, safety, 
tolerability, and PK of 2 fixed doses of tavapadon (5 mg QD and 15 mg QD) in male and 
female subjects aged 40 to 80 years who have a diagnosis of PD (consistent with the UK 
Parkinson’s Disease Society Brain Bank diagnostic criteria); a modified Hoehn and Yahr 
stage of 1, 1.5, or 2; an MDS-UPDRS Part II score ≥2 and a Part III score ≥10; and are 
not receiving antiparkinsonian medication other than MAO-B inhibitors. The trial will 
include a Screening Period (maximum of 4 weeks), a 27-week Treatment Period, and a 
4-week Safety Follow-up Period (Figure 1). Each subject will participate in the trial for 
up to approximately 35 weeks.  
4.1.1 
Screening/Baseline Period 
Subjects who provide written informed consent will be screened for eligibility during the 
maximum 4-week Screening Period. Subjects who are confirmed to be eligible for the 
trial will be scheduled for a Baseline Visit within approximately 4 weeks after the 
Screening Visit. Subjects who continue to meet the eligibility criteria at the Baseline Visit 
will be randomized in a 1:1:1 ratio to 3 treatment groups: 
• 
Tavapadon 5 mg QD 
• 
Tavapadon 15 mg QD 
• 
Placebo QD 
Randomization will be stratified by concurrent use of allowed PD medications (MAO-B 
inhibitors) during the Treatment Period. 
 


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4.1.2 
Treatment Period 
The dose of tavapadon will be titrated to either 5 mg QD or 15 mg QD and then 
maintained for the duration of the 27-week Treatment Period. The titration schedule, as 
shown in Table 4, will be used for all subjects who are randomized to receive tavapadon. 
Subjects will take 3 tablets of investigational medicinal product (IMP), either all 
tavapadon tablets, all placebo tablets, or a combination of tavapadon and placebo tablets, 
throughout the trial to maintain the trial blind. 
Table 4 
Tavapadon and Placebo Dosing Schedule 
Abbreviation: QD = once daily. 
This titration scheme will be used for all subjects who are randomized to tavapadon. 
Subjects who are randomized to the tavapadon 5 mg QD treatment group will receive this 
dose from Day 41 until Day 189 (end of Week 27). The dose of tavapadon will continue 
to be titrated for subjects who are randomized to the tavapadon 15 mg QD treatment 
group; these subjects will receive 10 mg QD of tavapadon from Day 57 through Day 72 
and then 15 mg QD of tavapadon from Day 73 until Day 189 (end of Week 27). 
No deviations in the titration schedule up through 
 will be allowed. Titration of 
tavapadon should be guided by absence of tolerability issues that are reported as AEs and 
that are of sufficient severity resulting in significant dysfunction or distress to the subject. 
Any questions regarding tolerability issues and titration should be directed to the medical 
monitor before adjustments are initiated. Subjects who cannot achieve or tolerate the dose 
at 
 (5 mg QD) or 
 (10 mg QD) must be discontinued from the trial.  
Starting on Day 74, subjects who achieve but do not tolerate the dose at 
 may go 
back to the dose at 
 Subjects may remain at the 
dose or will be permitted a 
one-time rechallenge back to the 
 dose if needed for symptomatic control. 
Subjects must receive the 
 dose for at least 7 days before a rechallenge to the 
 


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 dose is attempted. Subjects who are unable to tolerate the 
 dose upon 
rechallenge will be discontinued from the trial. 
The first dose of IMP will be taken at the trial site at the Baseline Visit; all other doses 
will be taken on an outpatient basis. Assessments will be conducted in the clinic, ~2 to 
~6 hours after the subjects have taken their daily dose of IMP (at home), at the end of 
Weeks 2, 5, 8, 11, 14, 18, 22, 26, and 27. Blood samples for PK will be collected after 
administration of the first dose on Day 1 (~1 hour after dosing) and at the Weeks 5, 11, 
14, 22, and 27 clinic visits. 
4.1.3 
Safety Follow-up Period 
Subjects who complete through Week 27 of the trial may have the opportunity to enter an 
open-label extension trial (Protocol CVL-751-PD-004). Subjects who are ineligible or 
elect not to enter the open label trial will be contacted by telephone at 4 weeks after 
discontinuation of IMP (either after completing the full 27-week Treatment Period or 
upon premature discontinuation from the trial). 
4.1.4 
Concentration-QT Substudy 
A substudy to evaluate the effect of tavapadon on the QT interval using C-QT modelling 
is also included in this trial. Matched triplicate ECGs and plasma tavapadon 
concentrations that are collected at preselected sites will be used to characterize the 
effects of tavapadon on the QT interval (see Section 10.7 [Appendix 7] for details). All 
other procedures will be the same as for the main trial. 
4.2 
Scientific Rationale for Trial Design 
The randomized, double-blind, placebo-controlled, parallel-group trial design is widely 
accepted as one that minimizes the risk of bias and that is appropriate for evaluating the 
effects of a trial treatment in indications in which use of a placebo is ethical (US FDA, 
2001). Randomization reduces bias in the assignment of subjects to a treatment group, the 
double-blind design prevents differential treatment and assessments, and the 
placebo-controlled design controls for all potential influences on the actual or apparent 
course of the disease other than those arising from the pharmacologic action of the drug. 
The MDS-UPDRS is a comprehensive assessment that is designed to monitor the burden 
and extent of PD across the longitudinal disease course and provides a clinical endpoint 
in therapy trials (Goetz et al, 2008). The primary endpoint, the change from baseline to 
endpoint in the MDS-UPDRS Parts II (motor aspects of experiences of daily living) and 
III (motor examination) combined score represents a clinically applicable outcome 
measure (Makkos et al, 2018). 
The key secondary efficacy endpoint of the percentage of responders at endpoint, defined 
as a score of “much improved” or “very much improved” on the Patient Global 
Impression of Change (PGIC), is an accepted measure of treatment response and is 
widely used in clinical trials as a patient-reported measurement of treatment success.  
 


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The safety endpoints, including physical and neurological examinations, vital signs, 
ECGs, laboratory evaluations, and AEs, are those commonly used to assess the safety and 
tolerability of trial treatments. The Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s Disease Rating Scale (QUIP-RS) is a global screening instrument that 
assesses impulsive control disorders (ICDs) and related disorders (punding, hobbyism, 
and dopamine dysregulation syndrome) in patients with PD (Weintraub et al, 2012), and 
the Epworth Sleepiness Scale (ESS) is a scale that is intended to measure daytime 
sleepiness (Johns, 1991). The Columbia-Suicide Severity Rating Scale (C-SSRS) is 
commonly used for stringent monitoring of suicidality in clinical trials of neurological 
compounds (Posner et al, 2011).  
4.3 
Justification for Dose 
Patients with PD prioritize robust motor control as a key attribute of a desirable 
symptomatic therapeutic. In the small, Phase 2, flexible-dose, 15-week trial of tavapadon 
in early PD (Trial B7601011), subjects gradually increased their dose of tavapadon at 
weekly intervals, as tolerated, during the initial 9-week dose optimization period until 
their parkinsonian symptoms were optimally controlled. The target dose range was 3 to 
15 mg QD; however, a maintenance dose of <3 mg may have been selected, based on 
clinical response. Of the 26 subjects who were randomized to tavapadon and who reached 
the 6-week maintenance dosing phase, 73% required doses of 5 to 15 mg QD to achieve 
optimized motor control based on clinical judgement. Reduction from baseline in motor 
symptoms of >10 points on the MDS-UPDRS Part III score primarily occurred in 
subjects who received doses of >5 mg QD of tavapadon, with robust separation from 
placebo treatment achieved at doses >7 mg QD (-6.9 placebo-adjusted treatment 
difference), whereas a dose of 3 mg QD consistently produced reductions of <10 points 
from baseline on the MDS-UPDRS Part III score. These data suggest that doses <5 mg 
QD are unlikely to deliver clinically meaningful benefit over placebo in motor symptom 
control to most patients with PD. 
In a Phase 1 multiple-dose trial in subjects with PD (Trial B7601005), tavapadon 
exposure increased with an increase in dose over the dose range of 5 to 15 mg; however, 
the increase in mean area under the plasma concentration-time curve over the dosing 
interval (24 hours; AUCtau) and in mean maximum observed plasma concentration (Cmax) 
was less than dose proportional between the 15 and 25 mg doses. This is consistent with 
the known moderate-to-low solubility of tavapadon at the pH of the gastrointestinal track 
(pH 6.5), which likely limited absorption. Therefore, doses >15 mg are not likely to 
provide meaningful increases in tavapadon exposure and may eventually lead to an 
exposure plateau. In this same trial, doses of 25 mg QD produced markedly greater rates 
of gastrointestinal AEs as compared with doses of 15 mg QD. Nausea and vomiting were 
reported in 8 of 19 and 4 of 19, respectively, of the subjects who received 25 mg QD 
doses of tavapadon, whereas nausea and vomiting were reported in 3 of 11 and 1 of 11, 
respectively, of the subjects who received 15 mg QD doses of tavapadon. The safety and 
pharmacokinetic data from this Phase 1 trial suggest that doses >15 mg QD are unlikely 
to have an optimal risk/benefit profile for patients with PD. 
 


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Taken together, these findings suggest that an optimal dose range of tavapadon for the 
treatment of PD may reasonably be between 5 and 15 mg QD for the individual patient, 
based on symptomatic needs and tolerability thresholds. 
4.4 
Definition of Completed Subject 
Subjects will be considered to have completed this trial once they complete the 
assessments that are scheduled at the Week 27 visit.  
4.5 
End of Trial Definition 
The end of the trial is defined as the date of the last visit (including phone contact) of the 
last subject in the trial globally. 
5 TRIAL POPULATION 
Prospective approval of protocol deviations to the recruitment and enrollment criteria, 
also known as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
General and Administrative 
1.  
Male and female subjects aged 40 to 80 years, inclusive, at the time of signing the ICF. 
2.  
Sexually active men or women of childbearing potential must agree to use acceptable (at 
minimum) or highly effective birth control, as defined in Section 10.4 (Appendix 4), or remain 
abstinent during the trial and for 4 weeks after the last dose of trial treatment.  
3.  
Subjects who are capable of giving signed informed consent as described in Section 10.1.3 
(Appendix 1), which includes compliance with the requirements and restrictions listed in the ICF 
and in this protocol. 
4.  
Subjects who are able, in the opinion of the investigator, to understand the nature of the trial and 
comply with protocol requirements, including the prescribed dosage regimens, scheduled visits, 
laboratory tests, and other trial procedures. 
Parkinson’s Disease Diagnosis 
5.  
Subjects with a diagnosis of PD that is consistent with the UK Parkinson’s Disease Society Brain 
Bank diagnostic criteria.  
Note: Subjects having more than one affected relative (Step 2 UK Parkinson’s Disease Society 
Brain Bank exclusion criterion) but meeting all other criteria consistent with the UK criteria will 
be considered to have met eligibility criteria for a diagnosis of PD (Litvan et al, 2003; Massano 
and Bhatia, 2012). 
Note: Motor asymmetry may or may not be present at the time of Screening, and is not an explicit 
requirement for inclusion, as long as the subject meets the UK Parkinson’s Disease Society Brain 
Bank diagnostic criteria based on medical history or physical examination. 
6.  
Subjects with modified Hoehn and Yahr stage 1, 1.5, or 2.  
 


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7.  
Subjects with disease duration (from time of diagnosis) of <3 years and disease progression in the 
3 years before signing the ICF. 
8.  
Subjects with an MDS-UPDRS Part II score ≥2 and Part III score ≥10 at the Screening Visit and 
at the Baseline Visit. 
9.  
Subjects with early PD who, in the opinion of the investigator, require pharmacologic 
intervention for disease management.  
Concomitant Parkinson’s Disease Medications 
10.  
Subjects who are treatment naïve or have a history of prior incidental treatment with 
dopaminergic agents (including L-Dopa and dopamine receptor agonist medications) for 
<3 months in total but not within 2 months of the Baseline Visit. Prior and concurrent use of 
MAO-B inhibitors is permitted if use was initiated >90 days before the Baseline Visit and the 
dosage will remain stable for the duration of the trial (ie, no change in the MAO-B inhibitor dose 
is permitted during the trial). 
11.  
Subjects who are willing and able to refrain from any PD medications that are not permitted by 
the protocol (including dopaminergic agents) throughout participation in the trial. 
Abbreviations: ICF = informed consent form, IMP = investigational medicinal product, L-Dopa = levodopa, 
MAO-B = monoamine oxidase B, MDS-UPDRS = Movement Disorder Society-Unified Parkinson’s Disease Rating 
Scale, PD = Parkinson’s disease. 
5.2 
Exclusion Criteria  
Subjects are excluded from the trial if any of the following criteria apply: 
Parkinson’s Disease Diagnosis 
1.  
Subjects with a history or clinical features consistent with essential tremor, atypical or secondary 
parkinsonian syndrome (including, but not limited to, progressive supranuclear palsy, multiple 
system atrophy, cortico-basal degeneration, or drug-induced or poststroke parkinsonism). 
2.  
Subjects with a history of nonresponse or insufficient response to L-Dopa or 2 or more other 
antiparkinsonian drugs at therapeutic dosages. 
3.  
Subjects who have had previous surgical intervention (eg, deep brain stimulation) for PD or for 
whom such a procedure is planned or anticipated during the trial period. 
Medical History 
4.  
Subjects with an acute or chronic, clinically significant medical or psychiatric condition, 
cognitive impairment, or laboratory abnormality that might increase the risk associated with trial 
participation or administration of trial treatment or interfere with the interpretation of the trial 
results or that, in the judgment of the investigator, would make the subject inappropriate for entry 
into this trial. 
Medical conditions that are minor or well controlled may be considered acceptable if the 
condition does not expose the subject to an undue risk of a significant AE or interfere with the 
assessments of safety or efficacy during the course of the trial. Subjects with symptoms of 
anxiety or depression that are not debilitating and that are stable or adequately controlled with 
non-prohibited medication are considered acceptable. The medical monitor should be contacted 
in any instance where the investigator is uncertain regarding the stability of a subject’s medical 
conditions(s) and the potential impact of the condition(s) on trial participation. 
5.  
Subjects with a history or current diagnosis of a clinically significant impulse control disorder 
(Disruptive, Impulse Control, and Conduct Disorder per DSM-5) (American Psychiatric 
Association, 2013). 
 


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6.  
Subjects with the presence of or history of brain tumor, hospitalization for severe head trauma, 
epilepsy (as defined by the International League Against Epilepsy), or seizures.  
7.  
Subjects with a history of psychosis or hallucinations within the previous 12 months based on 
medical records or subject/caregiver feedback. 
8.  
Subjects who answer “yes” on the C-SSRS Suicidal Ideation Item 4 or Item 5 (Active Suicidal 
Ideation with Some Intent to Act, Without Specific Plan, or Active Suicidal Ideation with 
Specific Plan and Intent) and whose most recent episode meeting the criteria for C-SSRS Item 4 
or Item 5 occurred within the last 6 months, OR 
Subjects who answer “yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, 
interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose most recent 
episode meeting the criteria for any of these 5 C-SSRS Suicidal Behavior Items occurred within 
the last 2 years, OR 
Subjects who, in the opinion of the investigator, present a serious risk of suicide. 
9.  
Subjects with substance abuse or dependence disorder, including alcohol, benzodiazepines, and 
opioids, but excluding nicotine, within the past 6 months (180 days). 
10.  
Subjects with dementia or cognitive impairment that, in the judgement of the investigator, would 
exclude the subject from understanding the ICF or participating in the trial. 
11.  
Subjects with any condition that could possibly affect drug absorption, including bowel 
resections, bariatric weight loss surgery, or gastrectomy (this does not include gastric banding). 
12.  
Subjects who have a positive result for HIV antibodies, HbsAg, or HCV antibodies at screening. 
Note: Subjects who were previously infected with hepatitis C but have been successfully treated 
(defined as a sustained virologic response or undetectable hepatitis C viral RNA levels at 12 or 
more weeks after the end of treatment) may be enrolled after discussion with the medical 
monitor. 
13.  
Subjects with a history of malignancy other than: 
• 
Non-metastatic basal or squamous cell carcinoma of the skin or carcinoma in situ that 
was surgically removed in total >1 year before signing the ICF and had not recurred 
• 
Another type of malignancy that had been in remission for ≥5 years before signing the 
ICF and had not recurred 
14.  
Subjects with a history of myocardial infarction with residual atrial, nodal, or ventricular 
arrhythmias that are not controlled with medical and/or surgical intervention; second- or 
third-degree atrioventricular block; sick sinus syndrome; severe or unstable angina; or congestive 
heart failure within the last 12 months. A recent (≤12 months) history of myocardial infarction 
with secondary arrhythmias is exclusionary regardless of the therapeutic control. 
15.  
Subjects with a history of neuroleptic malignant syndrome. 
16.  
Female subjects who are breastfeeding and/or who have a positive pregnancy test result prior to 
receiving IMP. 
Prior or Concomitant Medications 
17.  
Subjects who are currently receiving moderate or strong CYP3A4 inducers or CYP3A4 inhibitors 
(except for topical administration). 
18.  
Subjects with a positive urine drug screen for illicit drugs are excluded and may not be retested or 
rescreened. Subjects with a positive urine drug screen resulting from use of marijuana (any 
THC-containing product), prescription, or over-the-counter medications or products that, in the 
investigator’s documented opinion, do not signal a clinical condition that would impact the safety 
of the subject or interpretation of the trial results may continue evaluation for the trial following 
consultation and approval by the medical monitor. 
 


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19.  
Subjects who are using prohibited medications prior to randomization (as listed in Table 6) or 
who would be likely to require the use of prohibited concomitant medications during the trial (as 
listed in Table 7). 
Screening Assessments 
20.  
Subjects with a MoCA score <26. 
21.  
Subjects with a supine blood pressure ≥160 mmHg (systolic) or ≥100 mmHg (diastolic) at 
screening. The average of two supine measurements will be used to assess eligibility. 
22.  
Subjects with clinically significant orthostatic hypotension (eg, syncope). 
23.  
Subjects with a 12-lead ECG demonstrating a QTcF interval >450 msec  
At screening: 
• 
If the QTcF interval is >450 msec on the machine reading, the ECG should be repeated 
with 2 additional recordings. Based on the QTcF intervals that are reported by the 
central service, a subject will be excluded if the QTcF interval is >450 msec on 2 or 
more of the 3 ECG recordings, unless due to ventricular pacing.  
 
At baseline: 
• 
If the QTcF interval is >450 msec on the machine readings, consult the medical monitor 
to determine whether the subject remains eligible to be randomized while awaiting the 
readings from the central service. 
24.  
Subjects with moderate or severe renal impairment (creatinine clearance as estimated by 
Cockcroft-Gault formula <30 mL/min or on dialysis). 
25.  
Subjects with any of the following abnormalities in clinical laboratory tests at the Screening 
Visit, as assessed by the central laboratory and confirmed by a single repeat measurement, if 
deemed necessary: 
• 
AST or ALT ≥3 × ULN. 
• 
Total bilirubin ≥1.5 × ULN. Subjects with a history of Gilbert's syndrome may be 
eligible provided they have a value <ULN for direct bilirubin. 
26.  
Subjects with other abnormal laboratory test results, vital sign results, or ECG findings unless, in 
the judgment of the investigator, the findings are not medically significant and would not impact 
the safety of the subjects or the interpretation of the trial results. The medical monitor should be 
contacted to discuss individual cases, as needed. Tests with exclusionary results should be 
repeated to ensure reproducibility of the abnormality before excluding a subject based on the 
criteria provided in the protocol. For medically significant or exclusory abnormal ECGs results, 2 
additional ECG recordings should be collected, to ensure reproducibility of the abnormality, and 
the 3 ECG recordings read by the central service to confirm the abnormality before excluding a 
subject. 
Other 
27.  
Subjects who previously participated in any tavapadon trial, including this trial, and received 
IMP. 
28.  
Subjects who received treatment with any other investigational drug within 60 days before 
signing the ICF. 
29.  
Any subject who, in the opinion of the sponsor, investigator, or medical monitor, should not 
participate in the trial. 
Abbreviations: AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, 
C-SSRS = Columbia-Suicide Severity Rating Scale, CYP = cytochrome P450, DSM-5 = Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition, ECG = electrocardiogram, HbsAg = hepatitis B surface antigen, 
 


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HCV = hepatitis C virus, HIV = human immunodeficiency virus, ICF = informed consent form, IMP = investigational 
medicinal product, L-Dopa = levodopa, MoCA = Montreal Cognitive Assessment, PD = Parkinson’s disease, 
QTcF = QT interval as corrected for heart rate by Fridericia’s formula, THC = tetrahydrocannabinol, ULN = upper 
limit of normal. 
5.3 
Lifestyle Considerations 
Subjects should take the IMP at approximately the same time each day (in the morning at 
~24-hour intervals), with or without food. No lifestyle restrictions will be imposed. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
who are not subsequently randomized to treatment in the clinical trial. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
subjects to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, and eligibility criteria. 
Individuals who do not meet the criteria for participation in this trial (screen failure) at 
screening may be rescreened once at the discretion of the investigator and after 
consultation with the sponsor unless screen failure is due to a positive urine drug screen 
for illicit substances other than tetrahydrocannabinol (THC) (Section 5.2, exclusion 18). 
Subjects who have a positive urine drug screen for THC at screening may be rescreened 
once and randomized into the trial if the repeat urine drug screen is negative for THC, 
and the subject agrees to abstain from THC use throughout the duration of the trial. 
Rescreened subjects will be assigned a new subject number. 
6 TRIAL TREATMENTS 
Trial treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) that is intended to be administered to a trial subject 
according to the trial protocol. Investigational medicinal product (IMP) refers to a 
pharmaceutical form of any active substance or placebo that is being tested in this clinical 
trial. 
6.1 
Trial Intervention(s) Administered 
Tavapadon or matching placebo will be administered orally once daily for up to 27 weeks 
(Table 5). 
 


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Table 5 
Investigational Medicinal Products Administered 
ARM Name 
Tavapadon 5 mg QD 
Tavapadon 15 mg QD 
Placebo QD 
Type  
Drug 
Drug 
Matching drug 
Dose Formulation 
Tablet 
Tablet 
Matching tablet 
Unit Dose Strength(s) 
 
 
0 mg 
Dosage Level(s) 
5 mg 
15 mga 
0 mg 
Route of Administration 
Oral 
Oral 
Oral 
Sourcing 
Cerevel Therapeutics 
Cerevel Therapeutics 
Cerevel Therapeutics 
Packaging and Labeling 
Blister cards labeled 
according to local 
regulations 
Blister cards labeled 
according to local 
regulations 
Blister cards labeled 
according to local 
regulations 
Former Name(s) 
PF-06649751, 
CVL-751 
PF-06649751, 
CVL-751 
-- 
a. 
Subjects who achieve but do not tolerate a dose of 15 mg once daily (QD) may titrate down to a dose of 10 mg 
QD. Subjects may remain at 10 mg QD or will be permitted a one-time rechallenge back to 15 mg QD as needed 
for symptomatic control. Subjects must receive 10 mg QD for at least 7 days before a rechallenge to 15 mg QD is 
attempted.  
6.2 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit (original shipment and/or moving of IMP supply from one 
office or facility to another within the sites network) for all IMP received and any 
discrepancies are reported and resolved before use of the IMP. 
Only subjects who are enrolled in the trial may receive IMP and only authorized site staff 
may supply or administer IMP. All IMP must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions, with access limited to the investigator and authorized site staff. 
The investigator is responsible for IMP accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused IMPs are provided in 
the appropriate protocol-specific manuals. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Subject Assignment to Treatment 
All subjects will be centrally randomized in a 1:1:1 ratio to 1 of 3 treatment arms 
(tavapadon 5 mg QD, tavapadon 15 mg QD, or placebo) at the Baseline Visit via an 
Interactive Voice Response System/Interactive Web Response System (IVRS/IWRS), 
according to a computer-generated randomization scheme. Randomization will be 
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during the Treatment Period. Subjects will be sequentially assigned to the next available 
randomization number within the appropriate randomization stratum and will receive the 
IMP that corresponds to that randomization number. Once a randomization number has 
been assigned, it will not be reassigned. 
The telephone number and call-in directions for the IVRS and/or the log-in information 
for and directions for the IWRS will be provided to each trial site before the trial is 
initiated. 
6.3.2 
Blinding 
The tavapadon and placebo tablets will be identical in appearance and will be packaged 
in identically appearing blister cards. All subjects will take 3 tablets once daily of IMP 
throughout the Treatment Period, either all tavapadon tablets, all placebo tablets, or a 
combination of tavapadon and placebo tablets. Tablets will be packaged to allow dosage 
adjustments (as shown in Table 4) to be made without breaking the trial blind. 
Treatment assignments will be blinded to the investigators and other trial site personnel, 
the subjects, and all sponsor personnel who are involved in the conduct of the trial 
(including trial monitoring, data management, and data analysis). Access to the treatment 
codes will be restricted to personnel who are responsible for generating and maintaining 
the randomization code, packaging the IMPs, operating the IVRS/IWRS, analyzing the 
PK blood samples, or reporting serious adverse events (SAEs) or adverse events of 
special interest (AESI) to regulatory agencies. 
At the initiation of the trial, investigators and site personnel will be instructed on the 
method for breaking the blind. The IVRS/IWRS will be programmed with blind-breaking 
instructions. In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of the treatment assignment for an individual subject is 
warranted. Subject 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 before unblinding a subject’s treatment 
assignment unless this could delay emergency treatment of the subject. The sponsor must 
be notified within 24 hours after breaking the blind for a trial subject. 
Documentation of breaking the blind should be recorded in the subject’s medical record 
and electronic case report forms (eCRFs), with the reason for breaking the blind, the date 
and time the blind was broken, and the names of the personnel involved. Once the blind 
is broken for a subject, treatment with the IMP may not be reinitiated for that subject.  
6.4 
Trial Treatment Compliance 
All IMP will be dispensed by responsible trial personnel. Subjects will be counseled on 
the importance of taking the IMP as directed (once daily in the morning, with or without 
food) at each clinic visit and will be instructed to bring all used and unused blister cards 
to each clinic visit. Accountability and compliance (as assessed through self-reporting by 
the subject and by tablet count at each clinic visit) will be documented in the subject’s 
 


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trial records. Deviation(s) from the prescribed dosage regimen should be recorded in the 
eCRF. 
If poor compliance is encountered (eg, multiple missed doses resulting in <80% overall 
compliance at any point in the trial), discontinuation of the subject from the trial should 
be considered. Subjects who habitually miss visits or habitually attend visits outside of 
the protocol-defined visit window are also defined as noncompliant and should be 
considered for discontinuation. The medical monitor should be contacted if the 
investigator is uncertain whether a subject’s lack of compliance merits discontinuation 
from the trial. 
6.5 
Concomitant Therapy 
6.5.1 
Prior and Concomitant Medications 
The investigator will record all medications and therapies (including vaccines, 
over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that are 
used by the subject from 30 days before the informed consent form (ICF) is signed 
through the end of the 4-week Safety Follow-up Period (Week 31 or early termination). 
The investigator will also record all medications and therapies taken or received by a 
subject for treatment of an AE or that cause an AE through Week 31 or early termination.  
The medication, indication, dose, frequency, route, and start and end dates will be 
recorded in the eCRFs for each concomitant medication, and the therapy, indication, and 
start and end dates will be recorded in the eCRFs for any concomitant therapy. The 
medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
All subjects should be counselled on the importance of taking background medications as 
prescribed.  
6.5.2 
Prohibited Medications Before the Trial 
Subjects must agree to discontinue use of all prohibited medications in accordance with 
predefined washout periods, as shown in Table 6. 
 


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Table 6 
List of Medications Prohibited Before the Trial 
 
Medication 
Washout Period 
1. 
Moderate or strong CYP3A4 inducers or CYP3A4 inhibitors 
(refer to Section 10.6 [Appendix 6] for examples), except for 
topical administration 
-- 
2. 
Amantadine 
>14 days before Baseline Visit 
3. 
L-Dopa or a dopamine agonist if exposure was ≥3 months in 
total or within 2 months of the Baseline Visit 
-- 
4. 
Anticholinergic drugs if exposure was >1 month 
-- 
5. 
Anticholinergic drugs if exposure was <1 month 
>14 days before Baseline Visit 
6. 
COMT inhibitors, droxidopa, zonisamide, or istradefylline 
-- 
7. 
Varenicline  
>14 days before Baseline Visit 
8. 
Nonselective MAO inhibitors, methyldopa, reserpine, or 
tricyclic antidepressants  
>2 months before Screening Visit 
9. 
Dopamine antagonists, such as neuroleptics/antipsychotics (eg, 
phenothiazines, butyrophenones, thioxanthenes), including 
haloperidol, trimethobenzamide, or domperidone for 
nausea/vomiting, metoclopramide, and quetiapine for insomnia  
>14 days before Baseline Visit 
10. Atypical antipsychotics, mood stabilizers (lithium or 
anticonvulsants), or prescription stimulants (amphetamine 
derivatives, methylphenidate, bupropion, phentermine, 
phenylpropanolamine modafinil, mazindol)  
Note: use of certain anticonvulsants (eg, pregabalin) for 
medical reasons unrelated to seizures or psychiatric mood 
stabilization may be allowed after discussion with and approval 
by the medical monitor. 
>14 days before Baseline Visit 
(1 full cycle for long-acting depot 
antipsychotics) 
11. Sedatives, hypnotics, antidepressants, or anxiolytics  
No washout is required if dose has 
been stable for >90 days before the 
Baseline Visit; washout of 
>14 days if dosing was started or 
dose was changed ≤90 days before 
the Baseline Visit 
12. MAO-B inhibitors if use was initiated ≤90 days before 
Baseline Visit 
>14 days before Baseline Visit 
13. Other investigational medications  
>60 days before Screening Visit 
Abbreviations: COMT = catechol-O-methyltransferase, CYP = cytochrome P450, ICF = informed consent, 
L-Dopa = levodopa, MAO = monoamine oxidase. 
-- Not applicable. Any prior use is prohibited. 
6.5.3 
Prohibited Medications During the Trial 
The concomitant medications that are prohibited during the trial are listed in Table 7. 
The medical monitor should be contacted regarding the appropriateness of a subject’s 
continued participation in the trial in the event that initiation of therapy with a prohibited 
 


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concomitant medication is deemed necessary, in the investigator’s opinion, for the 
treatment of a treatment-emergent adverse event (TEAE). 
Table 7 
List of Medications Prohibited During the Trial 
Medication 
1. 
Sedatives, hypnotics, antidepressants, and anxiolytics (unless dose has been stable for >90 days 
before the Baseline Visit and will remain stable for the duration of the treatment phase) 
Note: Short-term use of lorazepam (up to 4 mg/day), or its equivalent, for TEAEs of anxiety or 
insomnia may be permitted following consultation with and approval by the medical monitor, but 
may not be taken within 12 hours prior to efficacy assessments during clinic visits. Use should be 
discontinued upon TEAE resolution. 
2. 
Atypical antipsychotics 
3. 
COMT inhibitors 
4. 
Dopamine antagonists, such as neuroleptics/antipsychotics (eg, phenothiazines, butyrophenones, 
thioxanthenes), including:  
a.
Haloperidol
b.
Trimethobenzamide or domperidone (for nausea/vomiting)
c.
Metoclopramide
d.
Quetiapine (for insomnia)
5. 
Droxidopa 
6. 
Istradefylline 
7. 
L-Dopa or dopamine agonists (including levodopa inhalation powder or apomorphine)
8. 
Anticholinergic drugs 
Note: Short-term use of scopolamine for TEAEs of nausea may be permitted following 
consultation with and approval by the medical monitor, but may not be taken within 12 hours prior 
to efficacy assessments during clinic visits. Use should be discontinued upon TEAE resolution. 
9. 
Methyldopa 
10. Amantadine 
11. Moderate or strong CYP3A4 inducersa (refer to Section 10.6 [Appendix 6] for examples) 
12. Moderate or strong CYP3A4 inhibitorsa (refer to Section 10.6 [Appendix 6] for examples) 
13. Mood stabilizers 
a.
Anticonvulsants
b.
Lithium
Note: Use of certain anticonvulsants (eg, pregabalin) for medical reasons unrelated to seizures or 
psychiatric mood stabilization may be allowed after discussion with and approval by the medical 
monitor. 
14. Nonselective MAO inhibitors 
 


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Table 7 
List of Medications Prohibited During the Trial 
 
Medication 
15. Prescription stimulants 
 
a. 
Amphetamine derivatives 
 
b. Bupropion 
 
c. 
Mazindol 
 
d. Methylphenidate 
 
e. 
Modafinil 
 
f. 
Phentermine 
 
g. Phenylpropanolamine 
16. Reserpine 
17. Tricyclic antidepressants 
18. Varenicline  
19. Zonisamide 
20. Other investigational medications 
Abbreviations: COMT = catechol-O-methyltransferase CYP = cytochrome P450, L-Dopa = levodopa, 
MAO = monoamine oxidase; TEAE = treatment-emergent adverse event. 
a. 
Except for topical administration. 
6.5.4 
Dose Modification 
This is a fixed-dose trial of tavapadon 5 mg QD and tavapadon 15 mg QD. The dose of 
tavapadon will be titrated to the randomized dose, as shown in Table 4, and then 
maintained for the remainder of the trial. Procedures for dose modification are provided 
in Section 4.1.2.  
Dose modifications will be achieved by issuing new IMP blister cards with the adjusted 
dose to the subject such that the subject continues to take 3 tablets once daily. The IMP 
will be packaged in a manner that will allow dose modifications to be made without 
unblinding the trial. 
6.6 
Intervention after the End of the Trial 
Subjects who complete through Week 27 of the trial may have the opportunity to receive 
open-label treatment with tavapadon in an open-label extension trial 
(Protocol CVL-751-PD-004). Subjects who are ineligible or elect not to enter the 
open-label extension trial will resume treatment with available antiparkinsonian 
medications at the discretion of and as determined by their physician. 
 


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7 DISCONTINUATION OF TRIAL INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Entire Trial 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, Institutional Review Boards/Independent Ethics Committees 
(IRBs/IECs), and regulatory authorities in accordance with regulatory requirements. 
7.2 
Discontinuation of Individual Site 
Participation of an individual trial site may be discontinued by the sponsor, the 
investigator, or the IRB/IEC if judged to be necessary for medical, safety, regulatory, 
ethical, or other reasons consistent with applicable laws, regulations, and Good Clinical 
Practice (GCP). The investigator will notify the sponsor promptly if the trial is terminated 
by the investigator or the IRB/IEC at the site. 
7.3 
Individual Subject Discontinuation 
After treatment assignment, a subject may stop treatment permanently for a variety of 
reasons. Treatment discontinuation may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator.  
A subject may discontinue the IMP for any of the following reasons: 
• 
Adverse event  
• 
Death 
• 
Worsening of PD symptoms to such an extent that, in the judgment of the 
investigator, the subject requires additional anti-PD medications 
• 
Treatment with prohibited concomitant medications 
• 
Noncompliance with the study schedule 
• 
Noncompliance with the study drug 
• 
Withdrawal by subject 
• 
Pregnancy 
• 
Physician decision 
If a subject discontinues the IMP due to an AE, the investigator or other trial personnel 
will make every effort to follow the event until it has resolved or stabilized.  
All subjects have the right to withdraw consent for further participation in the trial at any 
time without prejudice. Subjects cannot withdraw consent for use of data that have 
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participation. The investigator can also discontinue a subject from the trial at any time if 
medically necessary. Unless the subject provides written withdrawal of consent or there 
is other written documentation by the investigator confirming the subject’s verbal intent 
to completely withdraw from the trial, subjects should be followed for all 
protocol-specified evaluations and assessments, if possible. 
Complete withdrawal of consent requires a subject to refuse of ALL of the following 
methods of follow-up: 
• 
Participation in all follow-up procedures specified in the protocol (whether in-clinic 
or by telephone) 
• 
Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff) 
• 
Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives 
• 
Contact of an alternative person(s) who has been designated in source records as 
being available to discuss the subject’s medical condition, even if only by telephone, 
mail, or e-mail (eg, family, spouse, partner, legal representative [as defined per local 
regulations], friend, neighbor, or physician) 
• 
Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express the desire to interrupt, modify, or discontinue 
administration of the IMP, which is not equivalent to a complete withdrawal of consent 
for further participation. A subject may, however, indicate that further trial participation 
is creating a burden on his or her work, school, or social schedule. Therefore, the 
investigator should determine if the subject can continue participation in the trial if 
modifications to his/her treatment and/or schedule of assessments can be accommodated. 
Only subjects who withdraw their permission for all of the above methods of follow-up 
are considered to have completely withdrawn their consent to participate in the trial. 
Details on the withdrawal of consent for the optional banked biospecimen sample are 
provided in the separate ICF for that sample. 
7.4 
Lost to Follow up 
A subject 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 trial site personnel. 
 


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The following actions must be taken if a subject fails to return to the clinic for a required 
trial visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the trial. 
• 
Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• 
Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the trial.  
8 TRIAL ASSESSMENTS AND PROCEDURES 
Trial procedures and their timing are summarized in the Schedule of Assessments 
(Table 2). Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue trial 
intervention.  
Adherence to the trial design requirements, including those specified in the Schedule of 
Assessments, is essential and required for trial conduct. 
8.1 
Screening and Baseline Assessments 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. Data collected as part of the screening process may 
be submitted to sponsor/clinical research organization (CRO) in order to facilitate 
eligibility assessment. Protocol waivers or exemptions are not allowed. The investigator 
will maintain a screening log to record details of all subjects who are screened and to 
confirm eligibility or record reasons for screening failure, as applicable.  
Procedures that are conducted as part of the subject’s routine clinical management (eg, 
blood count) and obtained before the ICF is signed may be used for screening or baseline 
purposes provided the procedures meet the protocol-specified criteria and were 
performed within the time frame that is defined in the Schedule of Assessments 
(Table 2). 
As part of the screening procedures, the investigator will assess the severity of each 
subject’s PD symptoms using the modified Hoehn and Yahr scale (Hoehn and Yahr, 
1967; Goetz et al, 2004) on which: 
 


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Stage Definition 
1 = Unilateral involvement only 
1.5 = Unilateral and axial involvement 
2 = Bilateral involvement without impairment of balance 
2.5 = Mild bilateral disease with recovery on pull test 
3 = Mild to moderate bilateral disease; some postural instability; physically 
independent 
4 = Severe disability; still able to walk or stand unassisted 
5 = Wheelchair bound or bedridden unless added 
Subjects must have a modified Hoehn and Yahr stage of 1, 1.5, or 2 for inclusion in the 
trial. 
The investigator will also administer the Montreal Cognitive Assessment (MoCA) to 
detect the subject’s level of cognitive impairment (Nasreddine et al, 2005). The MoCA is 
administered over approximately 10 minutes to gauge areas of language, visuospatial 
ability, memory, recall, and abstract thinking. The total possible score is 30, with any 
score greater than 25 considered normal. Scores of 25 or less are considered to be an 
indication of some form of cognitive impairment. Subjects with a MoCA score <26 will 
not be eligible for the trial. 
8.2 
Efficacy Assessments 
The planned time points for efficacy assessments are shown in the Schedule of 
Assessments (Table 2). At each clinic visit, efficacy assessments should be completed 
first, followed by the safety assessments. 
8.2.1 
Movement Disorder Society-Unified Parkinson’s Disease Rating 
Scale 
The MDS-UPDRS (Goetz et al, 2008) is a multidimensional scale that assesses the motor 
and nonmotor impacts of PD across 4 parts. The scale is completed using a combination 
of physician and patient assessments and a collection of information from the patient or 
caregiver: 
• 
Part I, nonmotor aspects of experiences of daily living, comprises 13 items, 6 of 
which are rated by the physician (Part IA) and 7 of which are rated by the patient 
(Part IB).  
• 
Part II, motor aspects of experiences of daily living, comprises 13 items that are 
rated by the patient. The 13 items in Part II and the 7 items in Part IB constitute the 
patient questionnaire portion of the MDS-UPDRS. 
• 
Part III, motor examination, comprises 18 items that are assessed by the investigator 
(resulting in 33 scores by location and lateralization). 
 


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• 
Part IV, motor complications, comprises 6 item (3 items for dyskinesia and 3 items 
for fluctuation) and requires the physician to use historical and objective information 
to assess dyskinesia and motor fluctuations. 
Each item is rated on a scale from 0 to 4 on which 0 = normal, 1 = slight, 2 = mild, 
3 = moderate, and 4 = severe. 
The same individual should perform the ratings for an individual subject throughout the 
course of the trial. The postbaseline MDS-UPDRS assessments will be conducted in the 
clinic, ~2 to ~6 hours after the subjects have taken their daily dose of IMP (at home), at 
the end of Weeks 5, 8, 11, 14, 18, 22, 26, and 27.  
8.2.2 
Clinical Global Impression – Severity of Illness 
The Clinical Global Impression – Severity of Illness (CGI-S) scale is a 7-point scale that 
requires the clinician to rate the severity of the patient’s illness at the time of the 
assessment relative to the clinician’s past experience with patients who have the same 
diagnosis (Guy, 1976). Raters select one response based on the following question: 
“Considering your total clinical experience with this particular population, how ill is the 
patient at this time?” Scores are: 1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 
4=moderately ill; 5=markedly ill; 6=severely ill; and 7=among the most extremely ill 
patients. 
8.2.3 
Clinical Global Impression – Improvement 
The Clinical Global Impression – Improvement (CGI-I) a 7-point scale that requires the 
clinician to assess how much the patient's illness has improved or worsened relative to 
the baseline state at the beginning of the intervention (Guy, 1976). Raters select one 
response based on the following question, “Compared to your patient’s condition at the 
beginning of treatment, how much has your patient changed?” Scores are: 1=very much 
improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 
6=much worse; and 7=very much worse. 
8.2.4 
Patient Global Impression of Change 
The PGIC is the patient-reported outcome counterpoint to the CGI-I. The qualitative 
assessment of meaningful change is determined by the patient in response to the question, 
“Compared to your condition at the beginning of treatment, how much has your condition 
changed?” Scores are: 1=very much improved; 2=much improved; 3=minimally 
improved; 4=no change; 5=minimally worse; 6=much worse; and 7=very much worse. 
8.2.5 
39-Item Parkinson’s Disease Questionnaire 
The 39-item Parkinson’s Disease Questionnaire (PDQ-39) is the most thoroughly 
validated and extensively used self-report measure for the assessment of health-related 
quality of life in people with PD. The questionnaire measures 39 items, which assess 
8 domains of health: mobility (10 items), activities of daily living (6 items), emotional 
 


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well-being (6 items), stigma (4 items), social support (3 items), cognitions (4 items), 
communication (3 items), and bodily discomfort (3 items) (Peto et al, 1998). Each item is 
scored on the following scale: 0=never, 1=occasionally, 2=sometimes, 3=often, and 
4=always. Items in each subscale and the total scale can be summarized into an index and 
transformed linearly to a scale from 0 (perfect health as assessed by the measure) to 100 
(worst health as assessed by the measure).  
8.2.6 
Schwab and England Activities of Daily Living Scale 
The Schwab and England Activities of Daily Living (ADL) scale is a method of assessing 
a person’s ability to perform daily activities in terms of speed and independence through 
a percentage figure (Schwab and England, 1969). The clinician determines the rating 
according to the following criteria, with 100% indicating total independence and 0% 
indicating a state of complete dependence: 
100% Completely independent. Able to do all chores without slowness, 
difficulty or impairment. Essentially normal. Unaware of any difficulty. 
90% 
Completely independent. Able to do all chores with some degree of 
slowness, difficulty and impairment. May take twice as long. Beginning 
to be aware of difficulty 
80% 
Completely independent in most chores. Takes twice as long. Conscious 
of difficulty and slowness. 
70% 
Not completely independent. More difficulty with some chores. Three to 
four times as long in some. May spend a large part of the day with chores. 
60% 
Some dependency. Can do most chores, but exceedingly slowly and with 
much effort. Errors; some impossible. 
50% 
More dependent. Help with half, slower, etc. Difficulty with everything. 
40% 
Very dependent. Can assist with all chores, but few alone 
30% 
With effort, now and then does a few chores alone or begins alone. Much 
help needed 
20% 
Nothing alone. Can be a slight help with some chores. Severe invalid 
10% 
Totally dependent, helpless. Complete invalid. 
0% 
Vegetative functions such as swallowing, bladder and bowel functions are 
not functioning. Bedridden. 
8.2.7 
EuroQol 5 Dimension 5 Level 
The EuroQol 5 Dimension 5 Level (EQ-5D-5L) is a patient-reported outcome that 
measures health in 5 dimensions. It is a widely used survey instrument for measuring 
economic preferences for health states, is applicable to a wide variety of health conditions 
and treatments, and provides a simple descriptive profile and a single index value for 
 


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health status (Herdman et al, 2011). The EQ-5D-5L consists of a descriptive system and a 
visual analog scale (VAS). 
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, 
slight problems, moderate problems, severe problems, and extreme problems. The patient 
is asked to indicate his or her health state by ticking the box next to the most appropriate 
statement in each of the 5 dimensions. This decision results in a 1-digit number that 
expresses the level that was selected for that dimension. The digits for the 5 dimensions 
are combined into a 5-digit number that describes the patient’s health state. 
The EQ-5D-5L VAS records the patient’s self-rated health on a vertical VAS on which 
the endpoints are labeled “the best health quality that you can imagine” and “ the worst 
health quality that you can imagine.” The VAS can be used as a quantitative measure of 
health outcome that reflects the patient’s own judgment. 
8.3 
Safety Assessments 
Planned time points for all safety assessments are provided in the Schedule of 
Assessments (Table 2).  
Safety assessments should be performed after all efficacy assessments have been 
completed. Assessments should be performed in the following order: 
• Epworth Sleepiness Scale (ESS) 
• Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating 
Scale (QUIP-RS) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Physical and neurological examinations 
• Vital signs  
• Electrocardiograms 
• Blood specimen collection 
• Other procedures (eg, concomitant medications, AEs): all other procedures may be 
obtained before or after blood specimen collection 
8.3.1 
Epworth Sleepiness Scale 
The ESS is a scale that is intended to measure daytime sleepiness (Johns, 1991). It 
assesses the likelihood of dozing off or falling asleep in the following common situations: 
sitting and reading, sitting inactive in a public place (eg, in a meeting, theater, dinner 
 


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event), as a passenger in a car for an hour or more without stopping for a break, lying 
down to rest when circumstances permit, sitting and talking to someone, sitting quietly 
after a meal without alcohol, and in a car while stopped for a few minutes in traffic or at a 
light. Each situation is rated as 0=would never nod off, 1=slight chance of nodding off, 
2=moderate chance of nodding off, or 3=high chance of nodding off. A score ≥10 
indicates that the patient may need to get more sleep, improve sleep practices, or seek 
medical attention to determine why he or she is sleepy. 
8.3.2 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease-Rating Scale 
The QUIP-RS is a global screening instrument that assesses ICDs and related disorders 
(punding, hobbyism, and dopamine dysregulation syndrome) in patients with PD 
(Weintraub et al, 2012). The QUIP-RS has 4 primary questions that pertain to commonly 
reported thoughts, urges/desires, and behaviors associated with ICDs, each of which is 
applied to 4 ICDs (compulsive gambling, buying, eating, sexual behavior) and 3 related 
disorders (medication use, punding, and hobbyism).  
The QUIP-RS uses a 5-point Likert scale (score 0–4 for each question) to gauge the 
frequency of behaviors. Patients are instructed to answer questions based on behaviors 
that occurred in the preceding 4 weeks or during any 4-week period in a designated time 
frame and are provided with a brief description of the behaviors that are being assessed 
and with a brief description of the Likert scale categories for frequency (eg, 0=never [not 
at all], 1=rarely [infrequently or 1 day/week]). Scores for each ICD and related disorder 
range from 0 to 16, with a higher score indicating greater severity (frequency) of 
symptoms. The total QUIP-RS score for all ICDs and related disorders combined ranges 
from 0 to 112. 
8.3.3 
Columbia-Suicide Severity Rating Scale 
Suicidality will be monitored during the trial using the C-SSRS. This semi-structured 
interview was originally developed to evaluate the link between antidepressants and 
suicidal behavior and ideation in youth and AEs from pediatric clinical trials (Posner et 
al, 2011). It was designed to quantify the severity of suicidal ideation and behavior. Trial 
personnel who administer the C-SSRS must complete the appropriate training and have 
valid certification. Training on the scale will be provided via the sponsor. 
This trial will use the “Baseline/Screening” and “Since Last Visit” versions of the scale. 
The “Baseline/Screening” version, which assesses the lifetime experience of the subject 
with suicide events and suicidal ideation and the occurrence of suicide events or ideation 
within a specified time period prior to entry into the trial, will be completed for all 
subjects at screening to determine eligibility and confirmed at baseline. Any subject with 
active suicidal ideation or suicidal behaviors within the last 6 months, suicidal behaviors 
within the last 2 years, or who in the clinical judgment of the investigator presents a 
serious risk of suicide should be excluded from the trial (Section 5.2). 
 


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The “Since Last Visit” C-SSRS form will be completed at all visits after screening and 
baseline. The investigator will review the results of the “Since Last Visit” C-SSRS during 
the trial to determine whether it is safe for the subject to continue in the trial. If a subject 
demonstrates potential suicidal ideation associated with actual intent or method or plan as 
indicated by “YES” answers on item 4 or 5 of the C-SSRS, the investigator will evaluate 
whether a risk assessment by a qualified mental health professional (or the investigator 
alone if the investigator is a qualified mental health professional) is needed and whether 
the subject should continue in or be discontinued from the trial. 
8.3.4 
Physical and Neurological Examinations 
A complete physical examination will consist of measurement of height (screening only) 
and weight and a review of the following body systems: head, ears, eyes, nose, mouth, 
skin, heart and lungs, lymph nodes, and gastrointestinal and musculoskeletal systems. 
A full neurological examination will include an assessment of the subject’s mental status 
(level of consciousness, orientation, speech, memory, etc), cranial nerves, motor (muscle 
appearance, tone, strength and reflexes), sensation (including Romberg sign), 
coordination, and gait. 
Height will be measured with a stadiometer, measuring stick, or tape.  
The following guidelines will aid in the standardization of body weight measurements: 
• 
The same scale should be used to weigh a given subject each time, if possible. 
• 
Scales should be calibrated and reliable; scales should be at zero just prior to each 
subject’s weigh-in session. 
• 
A subject should void prior to being weighed and be minimally clothed (ie, no shoes 
or heavy overgarments). 
• 
Weight should be recorded before a subject’s meal and at approximately the same 
time at each visit. 
The investigator (or designee) is responsible for performing the physical and neurological 
examinations. If the appointed designee is to perform these examinations, he or she must 
be permitted by local regulations and his or her name must be included on the delegation 
of authority log. Whenever possible, the same individual should perform all physical and 
neurological examinations.  
Any condition present at the posttreatment physical or neurological examination that was 
not present at the baseline examination should be documented as an AE and followed to a 
satisfactory conclusion. 
8.3.5 
Vital Signs 
Vital signs include systolic and diastolic blood pressures, heart rate, and body 
temperature. Duplicate measurements of blood pressure and heart rate will be obtained in 
 


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supine (after 5 minutes of rest) and 1 measurement of blood pressure and heart rate will 
be obtained on standing (2 minutes after rising from supine to standing). The duplicate 
values will be individually recorded, and the values will be averaged by the sponsor for 
the time point assessment. Body temperature will be obtained once, at the time of the first 
blood pressure measurement. 
Additional information related to measurement of blood pressure and heart rate is 
provided in the appropriate protocol-specific manuals. 
8.3.6 
Electrocardiograms 
Single or triplicate 12-lead ECGs will be obtained during the trial. All ECG recordings 
will be obtained after the subject has been supine and at rest for at least 5 minutes. A 
triplicate set of ECGs is 3 consecutive ECGs collected 1 to 2 minutes apart over a 
5-minute period. 
For US sites, a single ECG will be obtained at the Screening Visit unless additional ECGs 
are required as described below. Three sets of triplicate ECGs will be obtained during the 
45 minutes before administration of the first dose of IMP on Day 1 (at -45, -30, 
and -15 minutes), and a single set of triplicate ECGs will be obtained ~1 hour after 
administration of the first dose of IMP on Day 1, just prior to the time of collection of the 
PK blood sample. One set of triplicate ECGs will be obtained at the Weeks 5, 11, 14, 22, 
and 27 clinic visits, just prior to the time of collection of the PK blood sample. The 
triplicate ECG information from US sites will be used in a C-QT analysis, as described in 
Section 10.7 (Appendix 7). 
For non-US sites, a single ECG will be obtained at the Screening Visit unless additional 
ECGs are required as described below. One set of triplicate ECGs will be obtained before 
administration of the first dose of IMP on Day 1, and a single ECG will be obtained 
~1 hour after administration of the first dose of IMP on Day 1, just prior to the time of 
collection of the PK blood sample. Single ECGs will be obtained at the Weeks 5, 11, 14, 
22, and 27 clinic visits, just prior to the time of collection of the PK blood sample. 
Additional 12-lead ECGs may be obtained at the investigator’s discretion and should 
always be obtained in the event of an early termination.  
The ECG results will be evaluated at the investigational site to determine the subject’s 
eligibility and to monitor safety during the trial. The principal investigator (or qualified 
designee) will review, sign, and date each ECG reading, noting whether or not any 
abnormal results are of clinical significance. The ECG will be repeated if any results are 
considered to be clinically significant. A central ECG service will be used for reading all 
ECGs to standardize interpretations for the safety analysis. 
If, during screening, any abnormal ECG finding is deemed medically significant 
(impacting the safety of the subject or the interpretation of the trial results) or meets an 
exclusion criterion (see Section 5.2), the subject should be excluded from the trial. 
Medically significant or exclusory abnormal results on an ECG at screening should be 
 


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repeated with 2 additional ECG recordings to ensure reproducibility of the abnormality, 
and the 3 ECG recordings read by the central service to confirm the abnormality before 
excluding a subject. For subjects with a QTcF >450 msec at screening, a subject will be 
excluded if the QTcF intervals reported by the central service are >450 msec for 2 or 
more of the 3 ECG recordings, unless due to ventricular pacing. If, at the Baseline Visit, 
the QTcF interval is >450 msec on the machine readings, consult the medical monitor to 
determine whether the subject remains eligible to be randomized while awaiting the 
readings from the central service. 
Exclusion criteria for screening do not apply as mandatory discontinuation criteria for 
subjects who are already randomized. A repeat ECG should be performed to confirm any 
clinically significant abnormality that is identified in a randomized subject during the 
treatment period (which will be confirmed by central service read) and, in these cases, the 
medical monitor should be consulted on the appropriateness of the subject continuing in 
the trial. 
8.3.7 
Clinical Safety Laboratory Assessments 
The list of clinical laboratory tests that are to be performed is provided in Section 10.2 
(Appendix 2). All protocol-required laboratory assessments must be conducted in 
accordance with the laboratory manual and the Schedule of Assessments (Table 2). 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the trial in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
subject's condition. 
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the trial should be repeated until the values return to normal, to 
baseline, or are no longer considered clinically significant by the investigator or medical 
monitor. If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor notified. 
All protocol-required laboratory assessments, as defined in Section 10.2 (Appendix 2), 
must be conducted in accordance with the laboratory manual and the Schedule of 
Assessments (Table 2). 
 


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8.4 
Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest 
The definitions of an AE and SAE are provided in Section 10.3 (Appendix 3). The AESI 
for this trial are defined in Section 8.4.6. 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, 
surrogate, or the subject's legally authorized representative, as defined per local 
regulations).The investigator and any qualified designees are responsible for detecting, 
documenting, and recording events that meet the definition of an AE, SAE, or AESI and 
remain responsible for following up SAEs/AESI that are considered related to the trial 
intervention or trial procedures or that cause the subject to discontinue IMP (see 
Section 7.3). 
8.4.1 
Time Period and Frequency for Collecting AE and SAE/AESI 
Information 
All AEs and SAEs/AESIs will be recorded from the first dose of IMP until follow-up 
contact at the time points specified in the Schedule of Assessments (Table 2). 
 


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Medical occurrences that begin before the start of IMP dosing but after obtaining 
informed consent will be recorded as medical and/or psychiatric history. 
All SAEs/AESI will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Section 10.3 
(Appendix 3). The investigator will submit any updated SAE/AESI data to the sponsor 
within 24 hours of it being available. 
Investigators are not obligated to actively seek AEs, SAEs, or AESI after conclusion of 
the trial participation. However, if the investigator learns of any SAE, including a death, 
at any time after a subject has been discharged from the trial, or AESI and he/she 
considers the event to be reasonably related to the trial intervention or trial participation, 
the investigator must promptly notify the sponsor. 
8.4.2 
Method of Detecting AEs and SAEs/AESI 
The method of recording, evaluating, and assessing causality of AEs and SAEs/AESI and 
the procedures for completing and transmitting SAE/AESI reports are provided in 
Section 10.3 (Appendix 3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs/AESI. 
Open-ended and nonleading verbal questioning of the subject is the preferred method to 
inquire about AE occurrences. 
8.4.3 
Follow-up of AEs and SAEs/AESI 
After the initial AE/SAE/AESI report, the investigator is required to proactively follow 
each subject at subsequent visits/contacts. All SAEs/AESI will be followed until 
resolution, stabilization, the event is otherwise explained, or the subject is lost to 
follow-up (as defined in Section 7.4). Further information on follow-up procedures is 
given in Section 10.3 (Appendix 3). 
8.4.4 
Regulatory Reporting Requirements for SAEs/AESI 
Prompt notification by the investigator to the sponsor of an SAE/AESI is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a trial 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 trial intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
 


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An investigator who receives an investigator safety report describing an SAE/AESI or 
other specific safety information (eg, summary or listing of SAEs/AESI) from the 
sponsor will review and then file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate, according to local requirements. 
8.4.5 
Pregnancy 
Details of all pregnancies in female subjects or in female partners of male subjects will be 
collected after the start of trial intervention and until 4 weeks after the last dose.  
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4 
(Appendix 4). 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.4.6 
Adverse Events of Special Interest 
8.4.6.1 
Adverse Events Potentially Related to Abuse 
A key objective of the Abuse Potential Monitoring Plan (APMP) is to monitor for 
instances of abuse or diversion of the trial medication and other psychoactive substances. 
In addition to monitoring for irregularities in medication handling, AEs that may be 
suggestive of a developing abuse issue will also receive special attention. As part of the 
APMP, medication handling irregularities (MHIs) must be reported, and AEs related to 
abuse potential and AEs involving MHIs must be reported as events subject to additional 
monitoring (ESAM), with detailed narratives. 
Investigators and site staff at each trial site will be trained on reporting potentially 
abuse-related AEs (eg, recording a description of the event in the subject’s own words in 
the source documents as well as the eCRF, in addition to the clinical term, and to be 
aware that a subject’s report may encompass more than one event and that these should 
be recorded separately). The investigators will be provided with examples of potentially 
abuse-related AEs and trained on how to handle such events (eg, additional monitoring). 
While the investigators will be provided with examples of AE terms as a guide during 
trial conduct, the analysis of potentially abuse-related AEs will be based on a search by 
the sponsor of all relevant Medical Dictionary for Regulatory Activities (MedDRA) 
terms, all verbatim terms, and any open text fields within the AE data to identify text 
strings suggestive of abuse potential, consistent with US Food and Drug Administration 
(FDA) guidance (Guidance for Industry: Assessment of Abuse Potential of Drugs, 
January 2017). 
 


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Complete details, including documenting and reporting procedures, examples of 
potentially abuse-related terms and guidance for the training of investigators and trial site 
staff are provided in the APMP. 
8.4.6.2 
Abnormal Liver Function Tests 
The finding of an elevated value for alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) of >3 × the upper limit of normal (ULN) in combination with 
either an elevated value for total bilirubin >2 × ULN or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia is considered to be an indicator of 
severe liver injury. Investigators must report the occurrence of either of the following as 
AESI to the sponsor with 24 hours: 
• 
Treatment-emergent value of >3 × ULN for ALT or AST and >2 × ULN for total 
bilirubin 
• 
Treatment-emergent value of >3 × ULN for ALT or AST and clinical jaundice 
Brief narratives will be written for any subjects who experience abnormalities in liver 
function tests that meet the criteria specified above. 
8.4.6.3 
Adverse Events Leading to Discontinuation 
Any AE that leads to discontinuation of IMP or from the trial will be classified as an 
AESI. Brief narratives will be written for subjects who discontinue IMP or from the trial 
because of AEs. 
8.5 
Treatment of Overdose 
Titrated doses of up to 25 mg QD of tavapadon have been evaluated subjects with PD 
(Trial B7601005). Across all doses (5, 15, and 25 mg QD), nausea, vomiting, headache, 
dizziness, and abnormal dreams were the most commonly reported TEAEs. A 
dose-related increase was observed between the 15 mg QD (n=11) and 25 mg QD (n=19) 
doses in the percentage of subjects who experienced gastrointestinal-related TEAEs (27% 
vs 58%), in particular, nausea (27% vs 42%) and vomiting (9.1% vs 21.1%), and in the 
percentage of subjects who discontinued from the trial due to gastrointestinal TEAEs (0% 
vs 16%). Other TEAEs were reported in comparable percentages of subjects. Based on 
these findings, as well as on PK findings, which showed a less-than-dose-proportional 
increase in exposure between the 15 and 25 mg doses (consistent with the 
moderate-to-low solubility of tavapadon at the pH of the gastrointestinal tract of 6.5), 
15 mg QD was identified as the maximum dose in this trial (see also Section 4.3). 
Any dose >15 mg of tavapadon (maximum dose in this trial) within the same calendar 
day will be considered an overdose. There is no specific antidote for overdose with 
tavapadon. In the event of an overdose, the investigator should: 
 


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1. 
Contact the medical monitor immediately 
2. 
Closely monitor the subject for any AE/SAE/AESI and laboratory abnormalities 
3. 
Document the quantity of the excess dose, as well as the duration of the 
overdose, in the eCRF 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the subject. 
8.6 
Pharmacokinetics 
Blood samples for measurement of plasma concentrations of tavapadon and its major 
metabolite (if required) will be collected ~1 hour after administration of the first dose of 
IMP on Day 1 and at the clinic visits at the end of Weeks 5, 11, 14, 22, and 27 just after 
ECG acquisition at each time point, as shown in the Schedule of Activities (Table 2). The 
date and time of the most recent dose, the dose amount, and the time of the blood draw 
will be recorded. Instructions for the collection and handling of biological samples will 
be provided by the sponsor.  
Plasma samples will be processed, stored, and shipped to the bioanalytical facility 
according to the instructions that will be provided to the investigator in advance of the 
trial. A fully validated bioanalytical method will be used to quantitate plasma 
concentrations of tavapadon and its major metabolite (if required).  
Drug concentration information will not be reported to investigative sites or blinded 
personnel until the trial has been unblinded. 
8.7 
Pharmacodynamics 
Triplicate ECGs will be obtained at US sites according to the Schedule of Assessments 
(Table 2) and as described in Section 8.3.6. The data will be used in a C-QT analysis to 
evaluate the effect of tavapadon the QT interval. Additional information related to this 
analysis is provided in Section 10.7 (Appendix 7). 
8.8 
Future Biospecimen Research 
Studying the variation in genetic markers and other biomarkers may help to explain some 
of the variability in response seen with some drugs among different individuals. This is 
referred to as pharmacogenomic/biomarker research. Comparing the DNA, RNA, protein, 
and metabolite variation patterns of subjects who respond well and those who respond 
poorly to treatment may help to better define the most appropriate group of subjects in 
which to target a given treatment. Collecting biospecimens for exploratory 
pharmacogenomic/biomarker analyses and retaining them at Cerevel makes it possible to 
better understand the drug’s mechanism of action and to seek explanations for differences 
in, for example, exposure, efficacy, tolerability, or safety not anticipated prior to the 
beginning of this trial. 
 


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Banked biospecimen samples will be collected from subjects who consent to this sample 
collection on a separate ICF. Research performed on these samples may include genetic 
analyses (DNA), gene expression profiling (RNA), proteomics, metabolomics and/or the 
measurement of other analytes. Such research is for biomarker testing to address 
emergent questions not described elsewhere in the protocol (as part of the main trial) and 
will only be conducted on specimens from appropriately consented subjects.  
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The primary efficacy endpoint is the change from baseline to endpoint in the MDS-
UPDRS Parts II and III combined score. The hypotheses of interest are 2-sided tests of 
superiority comparing each active tavapadon dose to placebo. 
H01: µplacebo = µ15 mg QD vs H11: µplacebo ≠ µ15 mg QD 
H02: µplacebo = µ5 mg QD vs H12: µplacebo ≠ µ5 mg QD 
The hypotheses H01 and H02 will be tested in a sequential order in that if H01 cannot be 
rejected versus H11 at a 2-sided α level of 0.05, the testing sequence will not continue to 
H02 versus H12. 
9.2 
Sample Size Determination 
A total of 522 subjects are planned to be randomized in a 1:1:1 ratio to the 
tavapadon 5mg QD, tavapadon 15 mg QD, or placebo QD treatment group. A sample 
size of 174 subjects per group will provide at least 90% power to detect a change in the 
primary outcome measure (change from baseline to endpoint in the MDS-UPDRS Parts II 
and III combined score) of 4 points, with a standard deviation of 9, 2-sided alpha 
level = 0.05, and assuming a 27% dropout rate.  
In the event of higher than anticipated early terminations due to COVID-19 or other 
reasons, Cerevel may extend enrollment in order to maintain the planned statistical 
power. 
9.3 
Populations for Analyses 
The analysis populations are defined in Table 8. 
 


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Table 8 
Populations for Analysis 
Population 
Description 
Analysis 
ITT 
All randomized subjects 
Demographic and Baseline 
Characteristics 
FAS 
All randomized subjects who receive at least 
1 dose of IMP. This will be the safety analysis set. 
Safety analysis 
mITT 
All randomized subjects who receive at least 
1 dose of IMP and have both a baseline and at 
least 1 postbaseline MDS-UPDRS assessment 
Primary analysis set for 
efficacy 
Endpoint 
Completers 
All subjects in the mITT population who have an 
MDS-UPDRS assessment at baseline and endpoint 
Sensitivity analysis for 
efficacy 
PK Analysis Set 
All randomized subjects who receive at least 
1 dose of IMP and have at least 1 measurable 
tavapadon (CVL-751) concentration 
PK analysis 
Abbreviations: FAS = full analysis set, IMP = investigational medicinal product, ITT = intent-to-treat, 
MDS-UPDRS = Movement Disorder Society – Unified Parkinson’s Disease Rating Scale, mITT = 
modified intent-to-treat, PK = pharmacokinetic. 
9.4 
Statistical Analyses 
Descriptive statistical methods will be used to summarize the data from this trial, with 
statistical testing performed for the efficacy endpoints. Unless stated otherwise, the term 
“descriptive statistics” refers to number of subjects (n), mean, median, standard 
deviation, minimum, and maximum for continuous data, and frequencies and percentages 
for categorical data. Statistical testing will be 2-sided and will be performed using a 
significance (alpha) level of 0.05. All available data for enrolled subjects will be listed by 
subject. Unless otherwise noted, the data will be sorted first by treatment group and 
subject number and then by date within each subject number.  
All statistical analyses will be conducted with the SAS® System, version 9.4 or higher.  
The remainder of this section is a summary of the planned statistical analyses of the 
primary and secondary endpoints as well as a description of planned safety analyses. Full 
details of these analyses will be included in the statistical analysis plan. The statistical 
analysis plan will be developed and finalized before database lock and will provide 
descriptions of the subject populations that will be used in the analysis and procedures for 
addressing missing, unused, and spurious data. 
9.4.1 
Efficacy Analyses 
The efficacy endpoints will be assessed for each of the 2 dose levels of tavapadon versus 
placebo. A hierarchical testing procedure is planned for the primary and key secondary 
endpoints, in the following order, to control the Type I error rate at the 0.05 level 
(2-sided). 
1. Tavapadon 15 mg QD versus placebo on the primary endpoint 
 


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2. Tavapadon 5 mg QD versus placebo on the primary endpoint 
3. Tavapadon 15 mg QD versus placebo on the key secondary endpoint of 
MDS-UPDRS Part II score change from baseline 
4. Tavapadon 15 mg QD versus placebo on the key secondary endpoint of percentage of 
responders on the PGIC score 
5. Tavapadon 5 mg QD versus placebo on the key secondary endpoint of MDS-UPDRS 
Part II score change from baseline 
6. Tavapadon 5 mg QD versus placebo on the key secondary endpoint of percentage of 
responders on the PGIC score 
The analysis methods for the primary and secondary endpoints are summarized in 
Table 9. Additional details will be provided in the statistical analysis plan. 
Table 9 
Efficacy Analysis 
Endpoint 
Statistical Analysis Methods 
Primary 
 
The primary efficacy endpoint (the change from baseline to endpoint in the 
MDS-UPDRS Parts II and III combined score) will be analyzed using an MMRM. The 
change from baseline at each postbaseline timepoint will be included in the MMRM as 
repeated measures. The baseline score will be included as a covariate, and treatment 
group, visit, the interaction between treatment group and visit, and the stratification 
factor (concurrent use of MAO-B inhibitor; yes/no) will be included as fixed factors. 
An unstructured covariance structure will be utilized. The difference between each 
tavapadon dose level and placebo at endpoint will be estimated based on the LSMeans 
from the MMRM. A hypothetical strategy will be used to address ICEs of potential 
death, treatment discontinuations, missed visits/assessments, and start of prohibited 
concomitant medications. The data after treatment discontinuations or after the start of 
prohibited concomitant medications will be censored under the hypothetical strategy. 
The missing values are assumed to be MAR in the primary analysis, including missing 
due to COVID-19 control measures. Sensitivity analyses will be performed to assess 
the impact of deviation from MAR assumptions on the analysis results. 
Key Secondary 
The key secondary endpoint of the change from baseline to endpoint in the 
MDS-UPDRS Part II score will be analyzed using an MMRM analysis similar to the 
analysis of the primary endpoint. Similar sensitivity analyses will also be performed. 
The key secondary endpoint of percentage of responders at endpoint, defined as a 
score of “much improved” or “very much improved” on the PGIC, will be analyzed 
using the SAS® GLIMMIX procedure for binomial data with logit link. This 
generalized linear mixed model analysis will include response data from each 
postbaseline visit as repeated measures with treatment group, visit, and interaction 
between treatment group and visit as fixed effects. An unstructured covariance 
structure will be used for the repeated measures. If the model fails to converge with 
the unstructured covariance structure, the heterogeneous Toeplitz structure or further 
reduced covariance structure may be used. 
 


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Table 9 
Efficacy Analysis 
Endpoint 
Statistical Analysis Methods 
Secondary  
Continuous secondary endpoints (CGI-S, CGI-I, PDQ-39, Schwab and England ADL 
Scale, and EQ-5D-5L index and VAS scores) will be analyzed in a manner similar to 
that used for the primary efficacy endpoints. Categorical endpoints (proportion of 
subjects who improved based on the CGI-S or CGI-I) will be analyzed in a manner 
similar to that used for the key secondary endpoint of the percentage of responders on 
the PGIC at endpoint. 
Abbreviations: ADL = activities of daily living, CGI-I = Clinical Global Impression – Improvement, CGI-S = Clinical 
Global Impression – Severity of Illness, EQ-5D-5L = EuroQol 5 Dimension 5 Level, ICE = intercurrent event, 
LSMean = least square mean, MAO-B = monoamine oxidase B, MAR = missing at random, 
MDS-UPDRS = Movement Disorder Society – Unified Parkinson’s Disease Rating Scale, MMRM = Mixed Model for 
Repeated Measures, PDQ-39 = 39-Item Parkinson’s Disease Questionnaire, PGIC = Patient Global Impression of 
Change, VAS = visual analog scale. 
9.4.2 
Safety Analyses 
All safety analyses (Table 10) will be performed on the full analysis set (FAS). Should 
any subjects receive a treatment other than their randomized treatment, the treatment as 
received will be used in the safety presentation. 
Table 10 
Safety Analysis 
Endpoint 
Statistical Analysis Methods 
TEAEs, 
including 
abuse-related 
AEs and AEs 
related to MHIs 
TEAEs will be coded according to MedDRA and summarized by treatment group, 
system organ class, and preferred term. Additional summaries by seriousness, 
severity, relationship to IMP, and dose at the time of onset will also be prepared.  
Other safety 
The C-SSRS, ESS, QUIP-RS, laboratory data, vital sign data, and ECG data will be 
summarized with descriptive statistics. 
Abbreviations: AE = adverse events, C-SSRS = Columbia-Suicide Severity Rating Scale, 
ECG = electrocardiogram, ESS = Epworth Sleepiness Scale, IMP = investigational medicinal product, 
MedDRA = Medical Dictionary for Regulatory Activities, MHIs = medication handling irregularities, 
QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders – Rating Scale, 
TEAE = treatment-emergent adverse event. 
9.4.3 
Other Analyses  
Plasma concentrations of tavapadon and its major metabolite (if required) will be 
summarized by dose, visit, and nominal time (if applicable). All PK exposure-response 
analyses will be described in a separate PK analysis plan that will be finalized before 
database lock.  
Plasma concentrations will also be pooled with data from other trials in a population PK 
analysis to describe the time course of plasma concentrations of tavapadon and the 
influence of covariates (eg, body weight, age, sex, race, concomitant medications) on PK 
 


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parameters. The results of population PK analysis and response-exposure analyses will be 
presented separately from the main clinical study report (CSR). 
9.4.4 
Concentration-QT Analysis 
The effect of tavapadon on the QT interval will be evaluated in a US-specific substudy, 
as described in Section 10.7 (Appendix 7). The results of the C-QT analysis will be 
presented separately from the main CSR. 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• 
Applicable International Conference on Harmonisation (ICH) GCP Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the trial is initiated. Any amendments to 
the protocol will require IRB/IEC approval before implementation of changes made to 
the trial design, except for changes necessary to eliminate an immediate hazard to trial 
subjects. 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the trial to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• 
Notifying the IRB/IEC of SAEs/AESI or other significant safety findings as required 
by IRB/IEC procedures 
• 
Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical trials (if applicable), and all 
other applicable local regulations 
 


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10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the trial and for 1 year after completion of the trial. 
10.1.3 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the trial to the subject 
or his/her legally authorized representative (as defined per local regulations) and answer 
all questions regarding the trial. 
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative as, applicable by local law, will be required to sign a statement 
of informed consent (either electronic or written) that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or trial 
center. 
The medical record must include a statement that informed consent was obtained before 
the subject was enrolled in the trial and the date consent was obtained. The authorized 
person obtaining the informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the trial. A copy of the ICF(s) must be provided to the subject or the 
subject’s legally authorized representative (as defined per local regulations). 
A separate and similar consent process will be followed for the optional banked 
biospecimen research samples. The investigator or authorized designee will explain the 
objectives of the exploratory research to each subject. Subjects will be told that they are 
free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate signature will be required to document 
subject agreement to allow specimens to be used for exploratory research. Subjects who 
decline to participate in this optional research will not provide this separate signature. 
10.1.4 
Data Protection 
Subjects will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal trial-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. 
 


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The subject 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 
Dissemination of Clinical Trial Data 
Cerevel fulfills its commitment to publicly disclose clinical trial results through posting 
trial results on ClinicalTrials.gov, the European Clinical Trials Database (EudraCT), and 
other public registries in accordance with applicable local laws/regulations. 
In all cases, trial results are reported by Cerevel in an objective, accurate, balanced, and 
complete manner and are reported regardless of trial outcome or the country in which the 
trial was conducted. 
US Basic Results are posted on Clinicaltrials.gov for all Cerevel-sponsored interventional 
trials that are conducted in subjects and that evaluate the safety and/or efficacy of a 
Cerevel product, regardless of the geographical location in which the trial is conducted. 
US Basic Results are submitted for posting within 1 year of the primary completion date, 
as defined in Section 4.4, for trials in adult populations or within 6 months of the primary 
completion date for trials in pediatric populations. 
Cerevel posts European Union (EU) Basic Results on EudraCT for all Cerevel-sponsored 
interventional trials that are in scope of EU requirements. EU Basic Results are submitted 
for posting within 1 year of the primary completion date as defined in Section 4.4, for 
trials in adult populations or within 6 months of the primary completion date for trials in 
pediatric populations. 
10.1.6 
Data Quality Assurance 
All subject data relating to the trial will be recorded on printed or eCRFs unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Clinical Monitoring Plan. 
 


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The sponsor or designee is responsible for the data management of this trial including 
quality checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations). 
Trial monitors will perform ongoing source data verification to confirm that data entered 
onto the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are being protected; and that the 
trial is being conducted in accordance with the currently approved protocol and any other 
trial agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this trial 
must be retained by the investigator for the longest of the following periods: 
• At least 2 years after the date on which approval to market the drug is obtained (or if 
development of the IMP is discontinued, the date regulatory authorities were notified 
of discontinuation) 
• At least 3 years after the sponsor has notified the investigator that the final report has 
been filed with regulatory authorities  
• A longer period if required by local regulations or institutional policies 
No records may be destroyed during the retention period without the written approval of 
the sponsor. No records may be transferred to another location or party without written 
notification to the sponsor. 
10.1.7 
Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data 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 trial. Also, 
current medical records must be available. 
Definitions of what constitutes source data are included in the Clinical Monitoring Plan. 
10.1.8 
Trial and Site Closure 
The sponsor designee reserves the right to close the trial site or terminate the trial at any 
time for any reason at the sole discretion of the sponsor. Trial sites will be closed upon 
trial completion. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial-site closure visit has been performed. 
 


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The investigator may initiate trial-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by the sponsor or investigator may include but 
are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of subjects by the investigator 
• 
Discontinuation of further trial intervention development 
10.1.9 
Publication Policy 
The results of this trial may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
The sponsor will comply with the requirements for publication of trial results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter trials only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 


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10.2 Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 11 will be performed at the time points designated in the 
Schedule of Assessments (Table 2). Additional tests may be performed at any time during 
the trial as determined necessary by the investigator or required by local regulations. 
Table 11 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
RBC count 
Hemoglobin 
Hematocrit 
MCV 
WBC count with 
differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
 
Chemistry 
BUN 
Creatinine 
Albumin 
Cholesterol 
Total 
HDL-C 
LDL-C 
Triglycerides 
Potassium 
Sodium 
Calcium 
Bicarbonate 
Chloride 
Magnesium 
Glucose 
ALT 
AST 
Alkaline phosphatase 
GGT 
CPK 
Total bilirubin 
Direct bilirubin 
Total protein 
TSH (with reflex-free 
T3/T4 if abnormal) 
Urinalysis 
Specific gravity 
Color 
Dipsticka 
pH 
Glucose 
Protein 
Blood 
Ketones 
Bilirubin 
Urobilinogen 
Nitrite 
Leukocyte esterase 
 
Additional 
Tests 
Prolactin (results will not be reported to investigative sites or other blinded personnel 
until the trial is unblinded). 
Serum pregnancy test (at screening and as needed for WOCBP). 
Urine dipstick pregnancy test (at all other time points as needed for WOCBP), followed 
by serum pregnancy test if urine dipstick test is positive. 
If serum CPK value is >3 × ULN, CPK reflex for isoenzymes. 
If serum CPK value is >5 × ULN, serum and urine myoglobin. 
 


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Table 11 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Screening Tests 
Urine drug screen for illicit drugs 
Serology (HIV, HbsAg, and HCV) 
Abbreviations: AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, 
BUN = blood urea nitrogen, CPK = creatine phosphokinase, eCRF = electronic case report from, 
GGT = gamma-glutamyl transferase, HbsAg = hepatitis B surface antigen, HCV = hepatitis C virus, 
HDL-C = high-density lipoprotein cholesterol, HIV = human immunodeficiency virus, 
LDL-C = low-density lipoprotein cholesterol, MCV = mean corpuscular volume, RBC = red blood cell, 
T3 = triiodothyronine, T4 = thyroxine, TSH = thyroid-stimulating hormone, ULN = upper limit of normal, 
WBC = white blood cell, WOCBP = women of childbearing potential. 
a. 
Results of the dipstick urine analysis will not be recorded on the eCRFs. Any clinically significant 
finding will be captured as an AE. 
Investigators must document their review of each laboratory safety report and file the 
laboratory report as appropriate. Any clinically significant laboratory abnormality must 
be reported as an AE. 
 
 
 














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10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1 
Definitions: 
10.4.1.1 
Highly Effective Birth Control Methods (Failure Rate <1%) 
A highly effective form of contraception (failure rate of <1%) is defined as follows: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
• 
Oral 
• 
Injectable 
• 
Implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the trial treatments. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
subject. 
10.4.1.2 
Acceptable Birth Control Methods (Failure Rate >1% per Year) 
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include: 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 
• 
Male or female condom with or without spermicide*  
• 
Cap, diaphragm or sponge with spermicide.* 
*A combination of male condom with a cap, diaphragm, or sponge with spermicide 
(double-barrier methods) is also considered acceptable but is not a highly effective birth control 
method. 
 


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10.4.1.3 
Contraception and Pregnancy Avoidance Procedures 
The following definitions apply for contraception and pregnancy avoidance procedures: 
A woman is considered to be a woman of childbearing potential (WOCBP) following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy and bilateral oophorectomy.  
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
Sterilized male subjects should be at least 1 year postbilateral vasectomy and must 
confirm that they have obtained documentation of the absence of sperm in the ejaculate 
or have had bilateral orchidectomy. 
10.4.2 
Collection of Pregnancy Information 
10.4.2.1 
Male Subjects With Partners Who Become Pregnant 
• 
The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this trial. This 
applies only to male subjects who receive trial intervention. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
partner’s pregnancy. The female partner will also be followed to determine the 
outcome of the pregnancy. Information on the status of the mother and child will be 
forwarded to the sponsor. Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the pregnancy 
will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure.  
10.4.2.2 
Female Subjects Who Become Pregnant 
• 
The investigator will collect pregnancy information on any female subject who 
becomes pregnant while participating in this trial. Information will be recorded on 
the appropriate form and submitted to the sponsor within 24 hours of learning of a 
subject's pregnancy.  
• 
The subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
 


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SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-trial pregnancy related SAE considered reasonably 
related to the trial 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 trial subjects, he or she may learn of an SAE through 
spontaneous reporting. 
• 
Any female subject who becomes pregnant while participating in the trial will 
discontinue trial intervention and be withdrawn from the trial. 
 


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10.5 Appendix 5: Future Biospecimen Research 
Use/Analysis of DNA 
• 
Genetic variation may impact a subject’s response to trial intervention, susceptibility 
to, and severity and progression of disease. Variable response to trial intervention 
may be due to genetic determinants that impact drug absorption, distribution, 
metabolism, and excretion; mechanism of action of the drug; disease etiology; and/or 
molecular subtype of the disease being treated. Therefore, where local regulations 
and IRB/IEC allow, a blood sample will be collected for DNA analysis from 
consenting subjects. 
• 
DNA samples will be used for research related to tavapadon or PD and related 
diseases. They may also be used to develop tests/assays, including diagnostic tests 
related to tavapadon and PD. Genetic research may consist of the analysis of one or 
more candidate genes or the analysis of genetic markers throughout the genome or 
analysis of the entire genome (as appropriate). 
• 
DNA samples will be analyzed as part of a multi-trial assessment of the genetic 
factors that are involved in response to tavapadon or IMPs of this class to understand 
the trial disease or related conditions 
• 
The results of genetic analyses may be reported in the CSR or in a separate trial 
summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• 
The samples will be retained while research on tavapadon continues but for no 
longer than 15 years or other period as per local requirements. 
 


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10.6 Appendix 6: Examples of Moderate and Strong Inducers and 
Inhibitors of Cytochrome P450 3a (CYP3A) 
Table 19 
Examples of Moderate and Strong Inducers and Inhibitors of 
CYP3A 
CYP3A Inhibitors 
CYP3A Inducers 
HIV antivirals 
HIV antivirals 
Indinavir 
Efavirenz 
Nelfinavir 
Nevirapine 
Ritonavir 
Etravirine 
Saquinavir 
Miscellaneous 
Boceprevir 
Barbiturates 
Lopinavir/ritonavir 
Carbamazepine 
Amprenavir 
Glucocorticoids (systemic) 
Atazanavir 
Modafinil 
Telaprevir 
Oxcarbazepine 
Darunavir/ritonavir 
Phenobarbital 
Fosamprenavir 
Phenytoin 
Antibiotics 
Pioglitazone 
Clarithromycin 
Rifabutin 
Erythromycin 
Rifampin 
Telithromycin 
St. John’s wort 
Ciprofloxacin 
Troglitazone 
Anti-infectives 
Bosentan 
Itraconazole 
Nafcillin 
Ketoconazole 
Avasimibe 
Fluconazole 
Posaconazole 
Voriconazole 
Anti-anginal therapy 
Diltiazem 
Verapamil 
Anti-cancer therapy 
Crizotinib 
Imatinib 
 


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Table 19 
Examples of Moderate and Strong Inducers and Inhibitors of 
CYP3A 
CYP3A Inhibitors 
CYP3A Inducers 
Miscellaneous
Nefazodone
Aprepitant
Grapefruit juicea,b
Conivaptan
Mibefradilc
Abbreviations: CYP = cytochrome P450, HIV = human immunodeficiency virus. 
a.
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and
preparation-dependent. Trials have shown that it can be classified as a “strong CYP3A inhibitor”
when a certain preparation was used (eg, high dose, double strength) or as a “moderate CYP3A
inhibitor” when another preparation was used (eg, low dose, single strength).
b.
A 2-week washout before dosing is required if the subject was consuming grapefruit juice
continually.
c.
Withdrawn from US market.
 


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10.7 Appendix 7: US-Specific Substudy to Evaluate the Effect of 
Tavapadon on the QT Interval 
10.7.1 
Introduction 
For all subjects who participate in the substudy of the evaluation the effect of tavapadon 
on the QT interval, please refer to the protocol for the main trial for all other relevant 
requirements. Detailed information on tavapadon may be found in the Single Reference 
Safety Document, which, for tavapadon, is the current version of the Investigator’s 
Brochure. 
10.7.2 
Background and Rationale 
Delay in cardiac repolarization for non-antiarrhythmic drugs, measured as prolongation 
of QT interval duration, can result in an environment that favors development of cardiac 
arrhythmias, especially, torsades de pointes (TdP). Historically, a thorough QT (TQT) 
study has been conducted routinely in drug development programs to understand the risk 
of QT prolongation for new drug molecules. Recently, concentration-QT (C-QT) 
modelling is being recommended as the primary analyses for assessing the QTc interval 
prolongation risk of new drug (Garnett et al, 2018).  
Data from all Phase 1 and Phase 2 trials suggest minimal impact of steady-state 
concentrations for tavapadon on QT interval. However, a formal evaluation of the QT 
prolongation risk in accordance to ICH E14 has not be conducted. The substudy will 
conduct a formal evaluation of the QT prolongation potential for tavapadon in accordance 
with ICH E14 guidance with C-QT modelling as the primary analyses. The current design 
of the main trial, with titration to fixed doses (5 mg QD and 15 mg QD), a placebo 
control, and multiple site visits, will provide necessary concentration and QT data to 
accomplish a formal evaluation of QT-prolongation risk without significant burden on the 
trial subjects. To this extent, all subjects who are enrolled in the trial at US sites will be 
enrolled into the C-QT substudy. Data from the C-QT study will ensure appropriate 
evaluation of QT prolongation risk at therapeutic concentrations. 
10.7.3 
Objective of C-QT Substudy 
The objective of this substudy is: 
• 
To investigate the effect of therapeutic concentration of tavapadon on QT interval 
duration using C-QT modelling  
10.7.4 
Substudy Design 
The substudy has the same overall design as the main trial. The key addition is the 
collection of triplicate ECGs at each visit where PK samples are being collected in order 
to facilitate valid C-QT modelling. The methodology for collection of triplicate ECGs 
intended for C-QT modelling, will be in accordance with the principles laid out in the 
 


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ICH E14 Q&A document. Exact details for ECG collection and processing methodology 
are provided in the appropriate protocol-specific manual. 
10.7.5 
Subject Selection 
All subjects who are enrolled in the trial at US sites will participate in the QT substudy if 
they meet all eligibility criteria for the main trial (refer to the main trial sections for any 
additional trial requirements). 
10.7.6 
Study Procedures 
For this substudy, the investigational product is tavapadon. All subjects who are enrolled 
in the trial at US sites will have 3 sets of triplicate ECGs collected at baseline (triplicate 
assessments at 3 predose time points over 45 minutes, ie, at -45, -30, and -15 minutes); 
one set of triplicate ECGs will be collected at all visits when a PK sample will be 
collected (at ~1 hour after dosing on Day 1 and at the Weeks 5, 11, 14, 22, and 27 clinic 
visits). Subjects who are enrolled in the trial at non-US sites will have a similar frequency 
of ECG collection. However, except for the predose time point at the Baseline Visit when 
one set of triplicate ECGs will be obtained, single ECGs will be collected at all time 
points. Data from the non-US sites will not be used for C-QT modelling.  
All other trial procedures will remain unchanged between the main trial and the substudy. 
10.7.7 
Data Analysis 
Detailed methodology for summary and statistical analyses of the data that are collected 
in this substudy will be documented in a separate C-QT Statistical Analysis Plan. The 
C-QT analyses plan will provide details on analytical methodology, predictions based on 
C-QT modelling, and final reporting of analyses. 
10.7.8 
Sample Size Determination 
Sample size determination based on estimates of variability in QT interval for patients 
with PD will be documented separately. Based on the currently available estimates of 
recruitment, approximately 240 subjects are expected to provide data for conduct of 
C-QT modelling across three doses (placebo, 5 mg QD, and 15 mg QD) and wide range 
of concentrations. 
 


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10.8 Appendix 8: Abbreviations 
 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
Aetau 
Amount of unchanged drug excreted into the urine over a dosing interval (tau) at 
steady state 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
APMP 
Abuse Potential Monitoring Plan  
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
Cmax 
Maximum observed plasma concentration 
cAMP 
Cyclic adenosine monophosphate 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impressions - Improvement 
CGI-S 
Clinical Global Impressions – Severity of Illness 
CIOMS 
Council for International Organizations of Medical Sciences 
COMT 
Catechol-O-methyltransferase  
CONSORT 
Consolidated Standards of Reporting Trials  
CPK 
Creatine phosphokinase 
C-QT 
Concentration-QT 
CRF 
Case report form 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CVL-751 
Tavapadon 
D1Rs 
Dopamine D1-like receptors 
D2/D3R 
Dopamine D2 and D3 receptor subtypes  
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOT 
End of treatment 
EQ-5D-5L 
EuroQol 5 Dimension 5 Level 
ESAM 
Event subject to additional monitoring 
 


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Abbreviation 
Definition 
ESS 
Epworth Sleepiness Scale 
ET 
Early termination 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human immunodeficiency virus 
ICD 
Impulsive control disorder 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVRS/IWRS 
Interactive Voice Response System/Interactive Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
L-Dopa 
Levodopa 
LSMean 
Least square mean 
MAR 
Missing at random 
MAO 
Monoamine oxidase 
MAO-B 
Monoamine oxidase B 
MCV 
Mean corpuscular volume 
MDS-UPDRS 
Movement Disorder Society – Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHIs 
Medication handling irregularities 
mITT 
Modified intent-to-treat 
MMRM 
Mixed Model for Repeated Measures  
 


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Abbreviation 
Definition 
MoCA 
Montreal Cognitive Assessment  
PD 
Parkinson’s disease 
PDQ-39 
39-Item Parkinson’s Disease Questionnaire 
PF-0664975 
Previous laboratory code for tavapadon 
PGIC 
Patient Global Impression of Change 
PK 
Pharmacokinetic 
Q&A 
Question & Answer 
QD 
Once daily 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula  
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – 
Rating Scale 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SUSAR 
Suspected unexpected serious adverse reaction 
T3 
Triiodothyronine 
T4 
Thyroxine 
TdP 
Torsades de pointes  
TEAE 
Treatment-emergent adverse event 
THC 
Tetrahydrocannabinol 
TQT 
Thorough QT 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 


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10.9 Appendix 9: Protocol Amendment History 
Document History 
Document:  
Date (Day-Month-Year) 
Version 4.0 
06 Jul 2023 
Version 3.0 
03 Sep 2021 
Version 2.0 
29 Jun 2020 
Original Protocol Version 1.0 
07 Oct 2019 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents.  
Amendment: Protocol Version 3.0 (03 Sep 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: The overall rationale for this amendment is to 
correct errors and to harmonize similar content across the Phase 3 tavapadon protocols 
via modification and clarification of eligibility criteria, procedural aspects, and statistical 
considerations. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
CLINICAL PROTOCOL 
PRINCIPAL 
INVESTIGATOR 
SIGNATURE PAGE 
Revised sponsor legal address 
Reflect change in location of 
company headquarters 
1.1 Synopsis 
1.2 Schema 
4.1 Overall Design 
Deleted the following: 
...with bradykinesia and motor 
asymmetry... 
Internal consistency to align 
with same deletion of text from 
Inclusion Criterion #5 
1.1 Synopsis 
3 Objectives and Endpoints 
Objectives and Endpoints, Statistical 
Methods: 
Changed order of key secondary 
endpoints 
Alignment with hierarchical 
testing strategy in current 
statistical analysis plan 
 


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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Statistical Methods: 
Corrected alpha level for sample size 
determination  
Added details regarding analysis of 
primary and key secondary 
endpoints 
Added information on handling of 
intercurrent events 
Alignment with corresponding 
content in current statistical 
analysis plan 
9 STATISTICAL 
CONSIDERATIONS 
Clarified statistical hypotheses, 
corrected alpha level for sample size 
determination, and analyses 
associated with each analysis set 
Specified order for hierarchical 
testing of primary and key secondary 
endpoints 
Added information on handling of 
intercurrent events 
 
1.3 Schedule of Assessments 
Revised vital signs footnote 
language to specify that standing 
blood pressure and heart rate will 
consist of single measurement 
Correction of error in protocol  
 
 
Revised table to indicate that 
medical occurrences before the start 
of IMP dosing but after obtaining 
informed consent will be recorded as 
medical and/or psychiatric history 
and that AEs will be recorded from 
the first dose of IMP 
Clarification of recording 
timeframes relative to informed 
consent and first dose of IMP 
 
For single ECG at non-US sites, 
changed footnote to refer to the 
postdose ECG footnote rather than to 
the preceding footnote that defines 
triplicate ECGs 
Correction of error in protocol  
 
Clarified ECG footnote language 
about timing of postbaseline PK 
samples relative to ECG assessments 
Consistency with Section 8.6 
Pharmacokinetics 
 


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Section # and Name 
Description of Change 
Brief Rationale 
4.1.2 Treatment Period 
Added the following and deleted 
redundant text: 
Titration of tavapadon should be 
guided by absence of tolerability 
issues that are reported as AEs and 
that are of sufficient severity 
resulting in significant dysfunction 
or distress to the subject. Any 
questions regarding tolerability 
issues and titration of tavapadon 
should be directed to the medical 
monitor before adjustments are 
initiated. 
To emphasize that titration of 
tavapadon should be related to 
tolerability issues and to further 
define tolerability issues 
4.4 Definition of Completed 
Subject 
Changed definition of completed 
subject from the contact at the end of 
the Safety Follow-up Period to the 
end of the Treatment Period 
(Week 27) 
Consistency with other sponsor 
protocols that define completed 
subject according to last site 
visit rather than the final contact 
5.1 Inclusion Criteria 
Inclusion Criterion #5: 
Deleted the following: 
...with bradykinesia and motor 
asymmetry 
Added the following: 
Note: Motor asymmetry may or may 
not be present at the time of 
Screening, and is not an explicit 
requirement for inclusion, as long as 
the subject meets the UK 
Parkinson’s Disease Society Brain 
Bank diagnostic criteria based on 
medical history or physical 
examination. 
Clarification regarding presence 
of motor asymmetry with 
respect to inclusion criteria 
 
Added the following: 
Note: Subjects having more than one 
affected relative (Step 2 UK 
Parkinson’s Disease Society Brain 
Bank exclusion criterion) but 
meeting all other criteria consistent 
with the UK criteria will be 
considered to have met eligibility 
criteria for a diagnosis of PD (Litvan 
et al, 2003; Massano and Bhatia, 
2012). 
Consistency with utilization of 
the historical UK criteria in 
current clinical practice, which 
no longer considers having more 
than one affected relative 
exclusory of a diagnosis of 
idiopathic PD based on the more 
recent understanding of the 
complex contributory genetic 
factors 
 
Inclusion Criterion #8: 
Added requirement for minimum 
MDS-UPDRS Part II and Part III 
scores at the Baseline Visit  
To ensure that criteria met at 
Screening continue to be met at 
Baseline  
 


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Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria 
(continued) 
Inclusion Criterion #10: 
Changed timing of treatment with 
dopaminergic agents and MAO-B 
inhibitors to be relative to Baseline 
Visit rather than signing of informed 
consent 
Correction to be consistent with 
other sponsor protocols that 
define timing of washout 
periods for prohibited 
medications relative to the 
Baseline Visit 
5.2 Exclusion Criteria 
Exclusion Criterion #12: 
Added the following: 
Note: Subjects who were previously 
infected with hepatitis C but have 
been successfully treated (defined as 
a sustained virologic response or 
undetectable hepatitis C viral RNA 
levels at 12 or more weeks after the 
end of treatment) may be enrolled 
after discussion with the medical 
monitor. 
Consistency with other sponsor 
protocols that allow enrollment 
of subjects with history of 
hepatitis C that has been 
successfully treated 
5.4 Screen Failures 
Deleted language about SAEs 
Alignment with changes to 
language about AE recording 
starting from first dose of IMP 
6.5.2 Prohibited Medications 
Before the Trial 
Changed timing of treatment with 
dopaminergic agents to be relative to 
Baseline Visit 
Added line for MAO-B inhibitors 
Consistency with Inclusion 
Criterion #10 
6.5.3 Prohibited Medications 
During the Trial 
Combined separate items for 
sedatives, hypnotics, antidepressants, 
anxiolytics into single item 
Consistency with table for 
medications prohibited before 
the trial 
 
Added text to allow short-term use 
of lorazepam (or equivalent) if 
approved by the medical monitor 
To provide options for treatment 
of anxiety or insomnia  
 
Added levodopa inhalation powder 
and apomorphine as prohibited 
medications to existing row for 
L-Dopa and dopamine agonists 
Clarification regarding rescue 
therapies 
 
Added text to allow short-term use 
of scopolamine if approved by the 
medical monitor 
To provide options for treatment 
of nausea during the trial 
 
Added text to allow use of certain 
anticonvulsants (eg, pregabalin) if 
approved by the medical monitor 
To provide options for use in 
treatment of events unrelated to 
seizures or psychiatric mood 
stabilization 
7.3 Individual Subject 
Discontinuation 
Revised list of potential reasons for 
subject discontinuation of IMP 
To align more closely with 
eCRF 
 


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Section # and Name 
Description of Change 
Brief Rationale 
8.1 Screening and Baseline 
Assessments 
Added the following: 
Data collected as part of the 
screening process may be submitted 
to sponsor/clinical research 
organization (CRO) in order to 
facilitate eligibility assessment. 
To address recent regulatory 
updates observed during trial 
conduct 
8.2.1 Movement Disorder 
Society-Unified Parkinson’s 
Disease Rating Scale 
Removed Week 2 
Correction of error in protocol  
8.3.4 Physical and 
Neurological Examinations 
Removal of genitourinary 
examination  
Update in standard sponsor 
processes 
8.3.5 Vital Signs 
Added clarification that standing 
blood pressure and heart rate will 
consist of single measurement 
Alignment across Phase 3 
protocols and consistency with 
changes to Section 1.3 
8.4.1 Time Period and 
Frequency for Collecting AE 
and SAE/AESI Information 
Clarified that AEs will be recorded 
from the first dose of IMP and 
medical occurrences that begin 
before the start of IMP dosing but 
after obtaining informed consent will 
be recorded as medical and/or 
psychiatric history 
Confirm timeframes for medical 
history and AE recording 
relative to informed consent and 
first dose of IMP 
10.3.3 Recording and 
Follow-Up of AEs and/or 
SAEs/AESI 
Deleted the following language: 
...that are identified at any time 
during the trial... 
.. having been identified throughout 
the trial... 
Alignment with changes to 
language about AE recording 
starting from first dose of IMP 
11 REFERENCES 
Added new references: 
Litvan et al, 2003 
Massano and Bhatia, 2012 
To reflect revision to Inclusion 
Criterion #5 
Overall 
Corrections/clarifications of 
grammar or typographical errors 
To address minor errors in the 
previous version of the protocol 
Abbreviations: AE = adverse event, AESI = adverse event of special interest, ECG = electrocardiogram, 
eCRF = electronic case report form, IMP = investigational medicinal product, L-Dopa = levodopa, 
MAO-B = monoamine oxidase B, MDS-UPDRS = Movement Disorder Society-Unified Parkinson’s 
Disease Rating Scale, PD = Parkinson’s disease, PK = pharmacokinetic, RNA = ribonucleic acid, 
SAE = serious adverse event. 
Amendment: Protocol Version 2.0 (29 Jun 2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: 
The overall rationale for this amendment is to incorporate measures into the protocol to 
ensure the safety of the trial subjects and the validity of the trial data in the environment 
 


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of the COVID-19 pandemic and to clarify other aspects of trial conduct unrelated to the 
COVID-19 pandemic. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Sponsor Signatories 
Changed name of biostatistician 
Change in study personnel 
1.1, Synopsis (Statistical 
Methods) 
9.2, Sample Size Determination 
Added provision to extend 
enrollment to maintain the 
planned statistical power in the 
event of higher than expected 
early terminations due to 
COVID-19 or other reasons 
Unknown effect of COVID-19 
pandemic on trial enrollment 
1.3, Schedule of Assessments  
Added a footnote to the 
Weeks 2, 5, 8, 11, 14, 18, and 22 
visits in Table 2 to allow the 
visit to be completed remotely if 
the subject cannot attend the 
clinic visit in person due to 
restrictions related to COVID-19 
Unknown effect of COVID-19 
pandemic on trial conduct 
 
Added a footnote to the 
laboratory header in Table 2 to 
allow individual sites to conduct 
COVID-19 testing before 
randomization and after 
randomization at the discretion 
of the investigator 
Provide flexibility for 
COVID-19 testing based on 
varying prevalence across 
regions 
 
Specified the urine pregnancy 
test as a urine dipstick test in 
Table 2 
Clarify type of test 
2.3, Benefit/Risk Assessment 
Added a statement that, in 
response to the COVID-19 
pandemic, Cerevel has 
performed a risk assessment of 
this trial and the investigator of 
each individual trial site and has 
implemented measures 
throughout the protocol, which 
prioritizes trial participant safety 
and data validity 
Clarify that steps have been 
taken to mitigate potential 
effects of COVID-19 pandemic 
on subject safety and trial 
conduct 
5.1, Inclusion Criteria 
Modified the wording related to 
use of contraceptives in 
inclusion criterion #2 
Clarify contraceptive 
requirement 
 
Added “PD” (missing word) into 
inclusion criterion #5 
Correct grammar 
 
Modified wording related to 
prior use of dopaminergic agents 
in inclusion criterion #10 
Clarify requirement 
 


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Section # and Name 
Description of Change 
Brief Rationale 
5.2, Exclusion Criteria 
Modified the wording related to 
current and prior use of 
prohibited medications in 
exclusion criterion #19 
Simplify language by referring 
to the tables that detail 
prohibited medications before 
(Table 6) and during (Table 7) 
the trial 
 
Modified the wording of 
exclusion criterion #21 to 
specify that the average of 
2 supine blood pressure readings 
will be used to assess trial 
eligibility 
Correct lack of clarity 
surrounding duplicate readings 
and the value that should be used 
to assess trial eligibility 
 
Expanded exclusion criteria 
related to prolonged QTcF 
interval in exclusion criterion 
#23  
Align exclusion criterion with 
methods for obtaining ECGs in 
Section 8.3.6 
 
Clarified the process to be 
followed for subjects with 
medically significant or 
exclusionary abnormal ECG 
results in exclusion criterion #26 
Align exclusion criterion with 
methods for obtaining ECGs in 
Section 8.3.6 
6.5.2, Prohibited Medications 
Before the Trial 
Added additional exposure 
information to the entry related 
to prior use of dopaminergic 
drugs in Table 6 
Align information in table with 
inclusion criterion #10 
 
Added anticholinergic drugs to 
Table 6 
Allow prior treatment with 
anticholinergic drugs for 
<1 month, with a >14-day 
washout period before the 
Baseline Visit 
6.5.3, Prohibited Medications 
During the Trial 
Added anticholinergic drugs to 
Table 7 
Exclude use of anticholinergic 
drugs during the trial 
 
Changed “stable for the duration 
of the trial” to “stable for the 
duration of the treatment phase” 
in entries 1, 2, 8, and 19 of 
Table 7 
Clarify that subjects who do not 
proceed into the open-label 
extension trial may resume 
antiparkinsonian treatment 
during the Safety Follow-up 
Period 
7.3, Individual Subject 
Discontinuation 
8.4, Adverse Events, Serious 
Adverse Events, and Adverse 
Events of Special Interest 
10.1.3, Informed Consent 
Process 
Added language to specify that 
individuals who are considered 
to be a “legal representative” for 
the subject will be defined per 
local regulations 
Clarify term, which may differ 
among regions in which the trial 
is conducted 
 


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Section # and Name 
Description of Change 
Brief Rationale 
8.2.6, Schwab and England 
Activities of Daily Living Scale 
Modified definitions for 90% 
and 70% ratings to replace 
“might” and “must,” 
respectively, with “may” 
Align wording in protocol with 
actual wording on the scale 
8.3.5, Vital Signs 
Modified the section to specify 
that individual values from 
duplicate blood pressure and 
heart rate readings will be 
averaged by the sponsor 
Clarify process for data 
collection 
8.3.6, Electrocardiograms 
Modified the section to provide 
additional information related to 
ECG collection 
Clarify the processes for 
acquiring ECGs at the Screening 
and Baseline Visits 
10.2, Appendix 2: Clinical 
Laboratory Tests 
Specified the urine pregnancy 
test as a urine dipstick test in 
Table 11 
Clarify type of test 
10.3, Appendix 3: Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting 
Revised section to remove 
redundant language and to 
clarify AE/SAE/AESI reporting 
procedures 
Align wording with actual 
processes that will be followed 
in trial and for consistency 
across Cerevel clinical 
development programs 
10.4, Contraceptive Guidance 
and Collection of Pregnancy 
Information 
Revised title of Section 10.4.1.1 
Consistency across Cerevel 
clinical development programs 
10.8, Appendix 8: Protocol 
Amendment History 
Added section 
Consistency with corporate 
template 
Overall 
Minor grammatical corrections 
Correct minor errors in the 
previous version of the protocol 
Abbreviations: AE = adverse event, AESI = adverse event of special interest, ECG = electrocardiogram, 
PD = Parkinson’s disease, QTcF = QT interval corrected for heart rate by Fridericia’s formula, 
SAE = serious adverse event. 
 


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11 REFERENCES 
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 
5th ed. Arlington, VA: American Psychiatric Publishing; 2013. 
Binde CD, Tvete IF, Gåsemyr J, Natvig B, Klemp M. A multiple treatment comparison 
meta-analysis of monoamine oxidase type B inhibitors for Parkinson's disease. Br J Clin 
Pharmacol. 2018;84(9):1917-27. 
Connolly BS, Lang AE. Pharmacologic treatment of Parkinson’s disease: a review. 
JAMA. 2014;11(16):1670-83. 
de Rijk MC, Breteler MM, Graveland GA, et al. Prevalence of Parkinson's disease in the 
elderly: the Rotterdam Study. Neurology. 1995;45(12):2143-6. 
Dietrichs E, Odin P. Algorithms for the treatment of motor problems in Parkinson's 
disease. Acta Neurol Scand. 2017;136(5):378-85. 
Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with 
Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 
2007;68(5):384-6. 
Drutyte G, Forjaz MJ, Rodriguez-Blazquez C, Martinez-Martin P, Breen KC. What 
impacts on the stress symptoms of Parkinson's carers? Results from the Parkinson's UK 
Members' Survey. Disabil Rehabil. 2014;36(3):199-204. 
Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 2018;45(3):383-97. 
Correction in: J Pharmacokinet Pharmacodyn. 2018;45(3):399. 
Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, et al. Movement 
Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and 
recommendations. Mov Disord. 2004;19(9):1020-8. 
Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. 
Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease 
Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov 
Disord. 2008;15;23(15):2129-70. 
Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: 
US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug 
Abuse, and Mental Health Administration; 1976. 
Hauser RA, Auinger P; Parkinson Study Group. Determination of minimal clinically 
important change in early and advanced Parkinson's disease. Mov Disord. 
2011;26(5):813-8. 
 


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Hauser RA, Gordon MF, Mizuno Y, Poewe W, Barone P, Schapira AH, et al. Minimal 
clinically important difference in Parkinson's disease as assessed in pivotal trials of 
pramipexole extended release. Parkinsons Dis. 2014;2014:467131. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011; 20(10):1727–36. 
Hoehn M, Yahr M. Parkinsonism onset, progression and mortality. Neurology. 
1967;17(5):427-42. 
Horváth K, Aschermann Z, Ács P, Deli G, Janszky J, Komoly S, et al. Minimal clinically 
important difference on the Motor Examination part of MDS-UPDRS. Parkinsonism 
Relat Disord. 2015;21(12):1421-6. 
Jasinska-Myga B, Heckman MG, Wider C, Putzke JD, Wszolek ZK, Uitti RJ. Loss of 
ability to work and ability to live independently in Parkinson's disease. Parkinsonism 
Relat Disord. 2012;18(2):130-5. 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness 
scale. Sleep. 1991;14(6):540-5. 
Litvan I, Bhatia KP, Burn DJ, et al. Movement Disorders Society Scientific Issues 
Committee report: SIC Task Force appraisal of clinical diagnostic criteria for 
Parkinsonian disorders. Mov Disord. 2003;18(5):467-86. 
Makkos A, Kovács M, Aschermann Z, Harmat M, Janszky J, Karádi K, et al. Are the 
MDS-UPDRS-Based Composite Scores Clinically Applicable? Mov Disord. 
2018;33(5):835-9. 
Marconi R, Lefebvre-Caparros D, Bonnet AM, Vidailhet M, Dubois B, Agid Y. 
Levodopa-induced dyskinesias in Parkinson's disease phenomenology and 
pathophysiology. Mov Disord. 1994;9(1):2-12. 
Massano J, Bhatia KP. Clinical approach to Parkinson's disease: features, diagnosis, and 
principles of management. Cold Spring Harb Perspect Med. 2012;2(6):a008870. 
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. 
The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive 
impairment. J Am Geriatr Soc. 2005;53(4):695-9. 
Peto V, Jenkinson C, Fitzpatrick R. PDQ-39: a review of the development, validation and 
application of a Parkinson's disease quality of life questionnaire and its associated 
measures. J Neurol. 1998;245(Suppl 1):S10-4. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia–Suicide Severity Rating Scale: Initial validity and internal consistency 
 


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findings from three multisite studies with adolescents and adults. Am J Psych. 
2011;168(12):1266-1277. 
Rizek P, Kumar N, Jog MS. An update on the diagnosis and treatment of Parkinson 
disease. CMAJ. 2016;188(16):1157-65. 
Schwab RS, England AC. Projection technique for evaluating surgery in Parkinson’s 
disease. In: Gillingham FJ, Donaldson MC, eds. Third symposium on Parkinson’s 
disease. Edinburgh: Livingston, 1969:152-7. 
Stocchi F, Torti M, Fossati C. Advances in dopamine receptor agonists for the treatment 
of Parkinson's disease. Expert Opin Pharmacother. 2016;17(14):1889-902. 
Stowe R, Ives N, Clarke CE, et al. Dopamine agonist therapy in early Parkinson’s 
disease. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006564. 
Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of 
Parkinson's disease. Mov Disord. 2003;18(1):19-31. 
US Food and Drug Administration (FDA). Guidance for Industry: E10 choice of control 
group and related issues in clinical trials; May 2001. 
Vijayakumar D, Jankovic J. Drug-induced dyskinesia, part 1: treatment of 
levodopa-induced dyskinesia. Drugs. 2016;76(7):759-77. 
Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire for 
Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale. MovDisord. 
2012;27(2):242-7. 
Zhuo C, Zhu X, Jiang R, et al. Comparison for efficacy and tolerability among ten drugs 
for treatment of Parkinson's disease: A network meta-analysis. Sci Rep. 2017;8:45865. 
 


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CLINICAL PROTOCOL PRINCIPAL INVESTIGATOR 
SIGNATURE PAGE 
A PHASE 3, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, PARALLEL-GROUP, 27-WEEK TRIAL 
TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY 
OF TWO FIXED DOSES OF TAVAPADON IN EARLY 
PARKINSON’S DISEASE (TEMPO-1 TRIAL) 
 
Protocol Number: CVL-751-PD-001 
Compound: Tavapadon (CVL-751) 
Trial Phase: 3 
Sponsor Name: Cerevel Therapeutics, LLC 
Legal Registered Address: 222 Jacobs Street, Suite 200, Cambridge, MA 02141 USA 
Version 4.0: 06 Jul 2023  
 
I, the undersigned principal investigator, have read and understand the protocol 
and agree that it contains the ethical, legal, and scientific information necessary to 
conduct this trial in accordance with the principles of Good Clinical Practices and 
as described herein and in the sponsor’s (or designee’s) Clinical Research 
Agreement. 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
 
Date (DD MMM YYYY) 
 
 

SAP_001.pdf: 
 
Protocol CVL-751-PD-001 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 1 of 154 
Version 1.0: 31 July 2024
 
STATISTICAL ANALYSIS PLAN 
 
A PHASE 3, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 27-WEEK TRIAL TO EVALUATE THE EFFICACY, SAFETY, 
AND TOLERABILITY OF TWO FIXED DOSES OF TAVAPADON IN EARLY 
PARKINSON’S DISEASE (TEMPO-1 TRIAL) 
Protocol Number: CVL-751-PD-001 
Compound: Tavapadon (CVL-751) 
Trial Phase: 3 
Short Title: Fixed-Dose Trial in Early Parkinson’s Disease 
Sponsor Name: Cerevel Therapeutics, LLC 
Protocol Version: 
Version 4.0 
Date: 06 Jul 2023 
 
 
Version 3.0  
03 Sep 2021 
 
Version 2.0  
29 Jun 2020 
 
Original Version 1.0  Date: 07 Oct 2019 
Analysis Plan Version: 
Final 1.0: 31 July 2024 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 
NCT04201093




 
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Approved by:  
 
Cerevel Therapeutics, LLC 
 
Date 
 
Global Clinical Development 
Cerevel Therapeutics, LLC 
 
Date 
 
 
 Head of Clinical Pharmacology  
Cerevel Therapeutics, LLC 
 
Date 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
01-Aug-2024 | 17:57 EDT
01-Aug-2024 | 17:54 EDT
01-Aug-2024 | 18:19 EDT
 
 


 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ................................................2 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................10 
1. 
INTRODUCTION ......................................................................................................11 
1.1. 
Study Overview ..........................................................................................................11 
1.2. 
Sample Size Considerations .......................................................................................12 
1.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................12 
1.3.1. 
Subject Assignment to Treatment ...............................................................................12 
1.3.2. 
Blinding ......................................................................................................................12 
1.4. 
Treatment Period ........................................................................................................12 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................14 
3. 
KEY ASSESSMENTS AND DERIVATIONS ..........................................................15 
3.1. 
Efficacy Assessments .................................................................................................15 
3.1.1. 
Movement Disorder Society-Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) ...........................................................................................................15 
3.1.1.1. 
Part I Score .................................................................................................................15 
3.1.1.2. 
Part II Score ................................................................................................................15 
3.1.1.3. 
Part III Score ...............................................................................................................15 
3.1.1.4. 
Handling of Missing Items from MDS-UPDRS .........................................................15 
3.1.1.5. 
Part II + III Combined Score ......................................................................................16 
3.1.1.6. 
Part I, Part II, and Part III Combined Score ...............................................................16 
3.1.2. 
Patient Global Impression of Change (PGIC) ............................................................16 
3.1.3. 
Clinical Global Impression – Severity of Illness (CGI-S) ..........................................16 
3.1.4. 
Clinical Global Impression – Improvement (CGI-I) ..................................................16 
3.1.5. 
39-Item Parkinson’s Disease Questionnaire (PDQ-39) Score ....................................17 
3.1.6. 
EuroQol 5 Dimension 5 Level ....................................................................................17 
3.1.7. 
Schwab and England Activities of Daily Living (ADL) Scale ...................................18 
3.2. 
Safety Assessments .....................................................................................................18 
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3.2.1. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease 
Rating Scale (QUIP-RS) Scores .................................................................................18 
3.2.2. 
Epworth Sleepiness Scale (ESS) Total Score .............................................................19 
3.2.3. 
Adverse Event (AE) ....................................................................................................19 
3.2.3.1. 
Adverse Event of Special Interest (AESI) ..................................................................19 
3.2.3.2. 
Treatment-emergent Adverse Event (TEAE) .............................................................19 
3.2.4. 
Clinical Safety Laboratory Assessments ....................................................................20 
3.2.4.1. 
Treatment-emergent Laboratory Abnormality and Toxicity ......................................20 
3.2.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................20 
3.2.6. 
Vital Signs ..................................................................................................................21 
3.2.7. 
Electrocardiograms .....................................................................................................21 
3.2.8. 
Prior Medications, Concomitant Medications and Medications Taken Post 
Last Dose of IMP ........................................................................................................21 
3.2.9. 
Physical and Neurological Examinations ...................................................................22 
3.2.10. 
Eye Examinations .......................................................................................................22 
3.3. 
Pharmacokinetics ........................................................................................................22 
4. 
DATA CONVENTIONS AND VISIT WINDOWS ..................................................23 
4.1. 
Data Conventions ........................................................................................................23 
4.1.1. 
Age ..............................................................................................................................23 
4.1.2. 
Day 1 ...........................................................................................................................23 
4.1.3. 
Endpoint ......................................................................................................................23 
4.1.4. 
Study Day of an Event ................................................................................................23 
4.1.5. 
Days on Study .............................................................................................................23 
4.1.6. 
Days on IMP ...............................................................................................................23 
4.1.7. 
Baseline Value ............................................................................................................23 
4.1.8. 
Change from Baseline .................................................................................................24 
4.1.9. 
Orthostatic Change .....................................................................................................24 
4.1.10. 
Duration of Titration Phase ........................................................................................24 
4.1.11. 
Duration of Maintenance Phase ..................................................................................24 
4.1.12. 
Average Dose of Titration Phase ................................................................................24 
4.1.13. 
Average Dose of Maintenance Phase .........................................................................24 
4.1.14. 
Compliance with Study Drug .....................................................................................24 
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4.1.15. 
Handling of Incomplete or Missing Dates Associated with an Event ........................25 
4.1.16. 
Handling of Alphanumeric Data .................................................................................26 
4.2. 
Visit Windows ............................................................................................................27 
5. 
STATISTICAL ANALYSIS METHODS ..................................................................28 
5.1. 
General Considerations ...............................................................................................28 
5.2. 
Populations for Analyses ............................................................................................28 
5.3. 
Statistical Hypotheses .................................................................................................29 
5.4. 
Multiplicity Adjustment..............................................................................................29 
5.5. 
Strata and Covariates ..................................................................................................30 
5.6. 
Subject Disposition, Demographic and Baseline Characteristics ...............................30 
5.7. 
Medical and Psychiatric History .................................................................................30 
5.8. 
Exposure to Treatment ................................................................................................31 
5.9. 
Primary Efficacy Analysis ..........................................................................................31 
5.9.1. 
Primary Estimand .......................................................................................................31 
5.9.2. 
Main Analytical Approach .........................................................................................32 
5.9.3. 
Sensitivity Analyses ....................................................................................................32 
5.9.3.1. 
Treatment Effect at Final Dose Levels .......................................................................32 
5.9.3.2. 
Treatment Effect based on Actual Treatment Received .............................................32 
5.9.3.3. 
Remote Assessments Excluded (treated as missing) ..................................................32 
5.9.3.4. 
Impact of Missing Values Handling ...........................................................................33 
5.9.4. 
Subgroup Analyses .....................................................................................................34 
5.10. 
Key Secondary Efficacy Analyses ..............................................................................35 
5.10.1. 
Secondary Estimand 1 ................................................................................................35 
5.10.1.1. 
Main Analytical Approach .........................................................................................35 
5.10.1.2. 
Sensitivity Analyses ....................................................................................................36 
5.10.1.3. 
Subgroup Analyses .....................................................................................................36 
5.10.2. 
Secondary Estimand 2 ................................................................................................36 
5.10.2.1. 
Main Analytical Approach .........................................................................................36 
5.10.2.2. 
Sensitivity Analyses ....................................................................................................37 
5.10.2.3. 
Subgroup Analyses .....................................................................................................37 
5.11. 
Summary of Primary and Key Secondary Efficacy Analyses ....................................38 
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5.12. 
Other Efficacy Analyses .............................................................................................39 
5.13. 
Interim and Final Analysis..........................................................................................41 
5.14. 
Safety Analyses ..........................................................................................................41 
5.14.1. 
Adverse Events ...........................................................................................................41 
5.14.2. 
Epworth Sleepiness Scale (ESS) ................................................................................42 
5.14.3. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson Disease 
Rating Scale (QUIP-RS) .............................................................................................42 
5.14.4. 
Non-IMP Medications and Non-Drug Therapy/Procedures .......................................43 
5.14.5. 
Clinical Laboratory Assessments ...............................................................................43 
5.14.6. 
Vital Signs ..................................................................................................................44 
5.14.6.1. 
Blood Pressure and Heart Rate ...................................................................................44 
5.14.6.2. 
Body Weight ...............................................................................................................46 
5.14.6.3. 
Temperature ................................................................................................................46 
5.14.7. 
Electrocardiograms (ECGs) ........................................................................................46 
5.14.8. 
Physical and Neurological Examinations ...................................................................46 
5.14.9. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................47 
5.14.10. 
Eye Examinations .......................................................................................................47 
5.15. 
Pharmacokinetics ........................................................................................................47 
5.15.1. 
Pharmacokinetic Data Analysis ..................................................................................47 
5.16. 
Protocol Deviations ....................................................................................................47 
6. 
CHANGES IN THE PLANNED ANALYSES ..........................................................48 
7. 
REVISION HISTORY ...............................................................................................49 
8. 
REFERENCES ...........................................................................................................50 
9. 
APPENDICES ............................................................................................................51 
9.1. 
Schedule of Assessments ............................................................................................52 
9.2. 
EQ-5D-5L Dimensions ...............................................................................................57 
9.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation and 
Suicidal Behavior Scores ............................................................................................58 
9.4. 
Programming Conventions .........................................................................................60 
9.5. 
MNAR Cases Identified Prior to Database Lock .......................................................62 
9.6. 
Core Codes for imputation of MAR and MNAR .......................................................64 
9.6.1. 
Imputation of Missing at Random (MAR) Cases .......................................................64 
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9.6.2. 
Imputation of Missing Not at Random (MNAR) Cases .............................................64 
9.7. 
Randomization Stratum Errors ...................................................................................65 
9.8. 
CTCAE Based Laboratory Test Results Grading Specifications ...............................66 
9.9. 
EQ-5D-5L Index Cross-walk Mapping ......................................................................90 
9.10. 
Abbreviations ............................................................................................................152 
 
 
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LIST OF TABLES 
Table 1: 
Tavapadon and Placebo Dosing Schedule ..................................................................13 
Table 2: 
Trial Objectives and Endpoints ..................................................................................14 
Table 3: 
Visit Windows ............................................................................................................27 
Table 4: 
Populations for Analysis .............................................................................................28 
Table 5: 
Schedule of Assessments ............................................................................................52 
 
 
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LIST OF FIGURES 
Figure 1: 
Trial Design Schematic ...............................................................................................11 
 
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1.2. 
Sample Size Considerations 
A sample size of 174 subjects per group will provide 90% power to detect a change in the 
primary outcome measure (change from baseline to endpoint in the MDS-UPDRS Parts II and III 
combined score) of 4 points, with a standard deviation of 9, 2-sided alpha level = 0.025, and 
assuming a 27% dropout rate. 
In the event of higher than anticipated early terminations due to COVID-19 or other reasons, 
Cerevel may extend enrollment in order to maintain the planned statistical power. 
1.3. 
Measures to Minimize Bias: Randomization and Blinding 
1.3.1. 
Subject Assignment to Treatment 
All subjects will be centrally randomized in a 1:1:1 ratio to 1 of 3 treatment arms (tavapadon 
5 mg QD, tavapadon 15 mg QD, or placebo) at the Baseline Visit via an Interactive Voice 
Response System/Interactive Web Response System (IVRS/IWRS), according to a 
computer-generated randomization scheme. Randomization will be stratified by concurrent use 
of allowed antiparkinsonian medication (MAO-B inhibitor). 
1.3.2. 
Blinding 
The tavapadon and placebo tablets will be identical in appearance and will be packaged in 
identically appearing blister cards. All subjects will take 3 tablets once daily of IMP throughout 
the Treatment Period, either all tavapadon tablets, all placebo tablets, or a combination of 
tavapadon and placebo tablets. Tablets will be packaged to allow dosage adjustments to be made 
without breaking the trial blind. 
Treatment assignments will be blinded to the investigators and other trial site personnel, the 
subjects, and all sponsor personnel who are involved in the conduct of the trial (including trial 
monitoring, data management, and data analysis). Access to the treatment codes will be restricted 
to personnel who are responsible for generating and maintaining the randomization code, 
packaging the IMPs, operating the IVRS/IWRS, analyzing the PK blood samples, or reporting 
serious adverse events (SAEs) or adverse events of special interest (AESI) to regulatory 
agencies. 
Documentation of breaking the blind should be recorded in the subject’s medical record and 
eCRFs, with the reason for breaking the blind, the date and time the blind was broken, and the 
names of the personnel involved. Once the blind is broken for a subject, treatment with the IMP 
may not be reinitiated for that subject. 
1.4. 
Treatment Period 
The dose of tavapadon will be titrated to either 5 mg QD or 15 mg QD and then maintained for 
the duration of the 27-week Treatment Period. The titration schedule, as shown in Table 1, will 
be used for all subjects who are randomized to receive tavapadon. Subjects will take 3 tablets of 
investigational medicinal product (IMP), either all tavapadon tablets, all placebo tablets, or a 
combination of tavapadon and placebo tablets, throughout the trial to maintain the trial blind. 
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No deviations in the titration schedule up through 
 will be allowed. Titration of tavapadon 
should be guided by absence of tolerability issues that are reported as AEs and that are of 
sufficient severity resulting in significant dysfunction or distress to the subject. Any questions 
regarding tolerability issues and titration should be directed to the medical monitor before 
adjustments are initiated. Subjects who cannot achieve or tolerate the dose at 
 (5 mg QD) 
or 
 (10 mg QD) must be discontinued from the trial. 
Starting on Day 74, subjects who achieve but do not tolerate the dose at 
 may go back to 
the dose at 
 Subjects may remain at the 
 dose or will be permitted a one-time 
rechallenge back to the
 dose if needed for symptomatic control. Subjects must receive 
the 
 dose for at least 7 days before a rechallenge to the 
 dose is attempted. Subjects 
who are unable to tolerate the 
 dose upon rechallenge will be discontinued from the trial. 
Table 1: 
Tavapadon and Placebo Dosing Schedule 
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2. 
OBJECTIVES AND ENDPOINTS 
Table 2: 
Trial Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To assess the efficacy of 2 fixed doses of 
tavapadon in subjects with early PD 
Primary Efficacy Endpoint 
• 
Change from baseline to endpoint in the MDS-UPDRS 
Parts II and III combined score 
 
Key Secondary Efficacy Endpoints 
• 
Change from baseline to endpoint in the MDS-UPDRS 
Part II score  
• 
Percentage of responders at endpoint, defined as a score 
of “much improved” or “very much improved” on the 
PGIC 
 
Secondary Efficacy Endpoints (All Time Points) 
• 
Change from baseline in the MDS-UPDRS Parts II and 
III combined score 
• 
Change from baseline in the MDS-UPDRS Parts I, II, 
and III combined score 
• 
Change from baseline in the MDS-UPDRS Part I, 
Part II, and Part III individual scores 
• 
Change from baseline in the CGI-S score 
• 
CGI-I score 
• 
PGIC score 
 
Other Endpoints 
• 
Change from baseline in PDQ-39 score 
• 
Change from baseline in Schwab and England ADL 
score 
• 
Change from baseline in the EQ-5D-5L index and VAS 
scores 
Secondary 
 
• 
To assess the safety and tolerability of 2 
fixed doses of tavapadon in subjects with 
early PD 
• 
ESS 
• 
QUIP-RS 
• 
C-SSRS 
• 
Nature, frequency, and temporality of TEAEs, including 
abuse-related AEs and AEs related to MHIs 
• 
Clinical laboratory evaluations 
• 
Vital signs 
• 
Physical and neurological examinations 
• 
ECGs 
Pharmacokinetic 
 
• 
To evaluate the PK of tavapadon in this 
population 
• 
Plasma concentrations of tavapadon and its major 
metabolite (if required) at baseline (Day 1) and 
Weeks 5, 11, 14, 22, and 27 
Abbreviations: ADL = activities of daily living, AE = adverse event, CGI-I = Clinical Global Impression – Improvement, 
CGI-S = Clinical Global Impression – Severity of Illness, C-SSRS = Columbia-Suicide Severity Rating Scale, 
ECG = electrocardiogram, EQ-5D-5L = EuroQol 5 Dimension 5 Level, ESS = Epworth Sleepiness Scale, 
MDS-UPDRS = Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, MHIs = medication handling 
irregularities, PD = Parkinson’s disease, PDQ-39 = 39-Item Parkinson’s Disease Rating Scale, PGIC = Patient Global Impression 
of Change, PK = pharmacokinetic, QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease-Rating Scale, TEAE = treatment-emergent adverse event, VAS = visual analog scale. 
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3. 
KEY ASSESSMENTS AND DERIVATIONS 
3.1. 
Efficacy Assessments 
3.1.1. 
Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS)  
The MDS-UPDRS (Goetz et al, 2008) is a multidimensional scale that assesses the motor and 
nonmotor impacts of PD across 4 parts. The scale is completed using a combination of physician 
and patient assessments and a collection of information from the patient or caregiver. Each 
evaluation item is rated on a scale from 0 to 4 on which 0 = normal, 1 = slight, 2 = mild, 
3 = moderate, and 4 = severe. This trial incorporates Part I, II, and III assessments for the 
specific trial population. 
3.1.1.1. 
Part I Score 
Part I of the MDS-UPDRS focuses on the non-motor aspects of experiences of daily living. The 
MDS-UPDRS Part I score value for a given visit is obtained as the sum of all 13 evaluation items 
in the MDS-UPDRS Part I subscale, including the 6 items which are rated by the Physician. 
Valid values for the sum are integers from 0-52, with 0 being the least severe and 52 being the 
most severe. 
3.1.1.2. 
Part II Score 
Part II of the MDS-UPDRS focuses on the motor aspects of experiences of daily living. The 
MDS-UPDRS Part II score value for a given visit is obtained as the sum of all 13 evaluation 
items in the MDS-UPDRS Part II subscale. Valid values for the sum are integers from 0-52, with 
0 being the least severe and 52 being the most severe. 
3.1.1.3. 
Part III Score 
Part III of the MDS-UPDRS is the motor evaluation comprises 18 items that are assessed by the 
investigator (resulting in 33 scores by location and lateralization). Valid values for the sum are 
integers from 0-132, with 0 being the least severe and 132 being the most severe.   
3.1.1.4. 
Handling of Missing Items from MDS-UPDRS 
If individual items are missing from a given part of the MDS-UPDRS, the corresponding total 
score may be generated by prorating the response if the number of missing items is not 
excessive. For Part I and Part II assessments, only a single missing item score is allowable. For 
Part III, up to 7 missing item scores are allowable. To prorate the value, the following formula is 
utilized 
U
n
j
P
n
i
i












= 
=1
 
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Where n is the number of non-missing items, j1-jn represents the n non-missing values reported 
by the subject for the given subscale, and U is the number of total items in the subscale. If more 
than the allowable items are missing, the total score will be treated as missing. 
3.1.1.5. 
Part II + III Combined Score 
The MDS-UPDRS Part II + III Combined Score is defined as the sum of the total scores for Part 
II and Part III within a given assessment (i.e., to have a Part II + III Total score, the subject must 
have a non-missing Part II total score and a non-missing Part III total score on the same date). 
The Part II + III Combined Score will be derived after any imputation of missing values within 
each individual total score.  
3.1.1.6. 
Part I, Part II, and Part III Combined Score 
The MDS-UPDRS Part I, Part II, and Part III Combined Score is defined as the sum of the total 
scores for Parts I, II, and  III within a given assessment (i.e., to have a Part I, Part II, and Part III 
Combined score, the subject must have a non-missing Part I total score, a non-missing Part II 
total score, and a non-missing Part III total score on the same date). The Part I, Part II, and Part 
III Combined Score will be derived after any imputation of missing values within each individual 
total score. 
3.1.2. 
Patient Global Impression of Change (PGIC) 
The PGIC is the patient-reported outcome in a 7 point scale to rate how much the patient's illness 
has improved or worsened relative to the baseline state at the beginning of the intervention. The 
qualitative assessment of meaningful change is determined by the patient in response to the 
question, “Compared to your condition at the beginning of treatment, how much has your 
condition changed?” Scores are: 1=very much improved; 2=much improved; 3=minimally 
improved; 4=no change; 5=minimally worse; 6=much worse; and 7=very much worse. 
3.1.3. 
Clinical Global Impression – Severity of Illness (CGI-S) 
The CGI-S scale is a 7 point scale that requires the clinician to rate the severity of the patient’s 
illness at the time of the assessment relative to the clinician’s experience with patients who have 
the same diagnosis. Raters select one response based on the following question: “Considering 
your total clinical experience with this particular population, how ill is the patient at this time?” 
Scores are: 1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly 
ill; 6=severely ill; and 7=among the most extremely ill patients. 
3.1.4. 
Clinical Global Impression – Improvement (CGI-I) 
The CGI-I is a 7 point scale that requires the clinician to assess how much the patient's illness 
has improved or worsened relative to the baseline state at the beginning of the intervention. 
Raters select one response based on the following question, “Compared to your patient’s 
condition at the beginning of treatment, how much has your patient changed?” Scores are: 
1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally 
worse; 6=much worse; and 7=very much worse. 
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3.1.5. 
39-Item Parkinson’s Disease Questionnaire (PDQ-39) Score 
The 39-item Parkinson’s Disease Questionnaire (PDQ-39) measures 39 items, which assess 
8 domains of health: mobility (10 items), activities of daily living (6 items), emotional well being 
(6 items), stigma (4 items), social support (3 items), cognitions (4 items), communication 
(3 items), and bodily discomfort (3 items) (Peto et al, 1998). Each item is scored on the 
following scale: 0=never, 1=occasionally, 2=sometimes, 3=often, and 4=always. Items in each 
subscale and the total scale can be summarized into an index and transformed linearly to a scale 
from 0 (perfect health as assessed by the measure) to 100 (worst health as assessed by the 
measure).  
A dimension score is calculated using the following formula: 

=
=
n
j
jt
n
d
1
4
*
1
*100 
where n is the number of items in the dimension, and tj is the jth item in the dimension. This 
transforms the scale linearly from 0 (perfect health as assessed by the measure) to 100 (worst 
health as assessed by the measure). If items are missing within a domain, the n in the above 
formula will be changed to the number of items in the dimension that the subject answered if at 
least half of the questions in the domain were answered. Otherwise, a domain and summary 
index will not be calculated.  
A summary index called PDQ-39 SI, is calculated as the average of the 8-dimension scores. 
3.1.6. 
EuroQol 5 Dimension 5 Level  
The EuroQol 5 Dimension 5 Level (EQ 5D 5L) is a patient-reported outcome that measures 
health in 5 dimensions. It is a widely used survey instrument for measuring economic 
preferences for health states, is applicable to a wide variety of health conditions and treatments, 
and provides a simple descriptive profile and a single index value for health status 
(Herdman et al, 2011). The EQ 5D 5L consists of a descriptive system and a visual analog scale 
(VAS). 
The descriptive system comprises 5 dimensions: mobility, self care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The patient is asked to 
indicate his or her health state by ticking the box next to the most appropriate statement in each 
of the 5 dimensions (Section 9.2). This decision results if a 1 digit number that expresses the 
level that was selected for that dimension. The digits for the 5 dimensions are combined into a 
5 digit number that describes the patient’s health state. For example, 11122 would represent the 
health state for someone who has no problems with mobility, self-care, or usual activities, but 
who has slight pain or discomfort and slight anxiety or depression. For each subject and visit, the 
5-digit health state will be converted into a single summary index, the EQ-5D Index, using the 
EQ-5D-5L Index calculator with US value set (van Hout, Janssen et al. 2012; Section 9.9). 
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The EQ VAS records the patient’s self-rated health on a 20-cm vertical visual analogue scale 
(VAS). The VAS is numbered from 0 to 100 with 0 meaning ‘the worst health you can imagine’ 
and 100 meaning ‘the best health you can imagine’. This information can be used as a 
quantitative measure of health outcome that reflects the patient’s own judgement. 
The EQ-5D-5L asks respondents to simply ‘mark an X on the scale to indicate how your health 
is TODAY’ and then to ‘write the number you marked on the scale in the box below’. 
3.1.7. 
Schwab and England Activities of Daily Living (ADL) Scale  
The Schwab and England ADL scale is a method of assessing a person’s ability to perform daily 
activities in terms of speed and independence through a percentage figure. The clinician 
determines the rating according to the following criteria, with 100% indicating total 
independence and 0% indicating a state of complete dependence: 
100% Completely independent. Able to do all chores without slowness, 
difficulty, or impairment. Essentially normal. Unaware of any difficulty. 
90% 
Completely independent. Able to do all chores with some degree of 
slowness, difficulty, and impairment. May take twice as long. Beginning 
to be aware of difficulty 
80% 
Completely independent in most chores. Takes twice as long. Conscious 
of difficulty and slowness. 
70% 
Not completely independent. More difficulty with some chores. Three to 
four times as long in some. May spend a large part of the day with chores. 
60% 
Some dependency. Can do most chores, but exceedingly slowly and with 
much effort. Errors; some impossible. 
50% 
More dependent. Help with half, slower, etc. Difficulty with everything. 
40% 
Very dependent. Can assist with all chores, but few alone 
30% 
With effort, now and then does a few chores alone or begins alone. Much 
help needed 
20% 
Nothing alone. Can be a slight help with some chores. Severe invalid 
10% 
Totally dependent, helpless. Complete invalid. 
0% 
Vegetative functions such as swallowing, bladder and bowel functions are 
not functioning. Bedridden. 
3.2. 
Safety Assessments 
3.2.1. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease 
Rating Scale (QUIP-RS) Scores 
The QUIP RS has 4 primary questions that pertain to commonly reported thoughts, urges/desires, 
and behaviors associated with impulse control disorders (ICDs), each of which is applied to 
4 ICDs (compulsive gambling, buying, eating, sexual behavior) and 3 related disorders 
(medication use, punding, and hobbyism).  
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Each question is scored using a 5 point Likert scale (score, 0=never [not at all], 1=rarely 
[infrequently or 1 day/week], 2=sometimes, 3=often, 4=very often). Scores for each ICD and 
related disorder range from 0 to 16, with a higher score indicating greater severity (frequency) of 
symptoms.  
The total QUIP-RS score for all ICDs and related disorders combined ranges from 0 to 112. In 
case of missing item scores, the missing value will be replaced by the average of non-missing 
scores at the same visit from the same subject. In case all item scores in any subcategory are 
missing, the total score will be set as missing. 
3.2.2. 
Epworth Sleepiness Scale (ESS) Total Score 
The ESS scale is used to determine the level of daytime sleepiness. There are 8 situations listed 
for which patients rate their likelihood of dozing or sleeping (0=no chance of dozing, 1=slight 
chance of dosing, 2=moderate chance of dosing, or 3=high chance of dozing). The total score is 
the sum of 8 item scores and can range between 0 and 24. The higher total score indicates the 
higher level of daytime sleepiness. A score of 10 or more is considered sleepy, and a score of 18 
or more is very sleepy.   
In case of missing item scores from the ESS, the missing value will be replaced by the average of 
non-missing scores at the same visit from the same subject. In case all item scores are missing, 
the total score will be set as missing. 
3.2.3. 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject, 
temporally associated with the use of trial intervention, whether considered related to the trial 
intervention. NOTE: Signs and symptoms and/or abnormal laboratory test result indicating a 
common underlying pathology/diagnosis should be reported as a single AE.  
All adverse events will be recorded on the ADVERSE EVENTS eCRF. Adverse events with 
missing severity will have the severity imputed as ‘Severe’ for the AE tabulations. Adverse 
events with missing relationship to IMP will have the relationship imputed as ‘Related’ for the 
AE tabulations if the AE started on or after the first dose of IMP. However, in the data listings 
these missing severity and/or relationship will be presented as missing. 
3.2.3.1. 
Adverse Event of Special Interest (AESI)  
For this study, any AEs related to abuse potential, AEs involving MHIs, abnormal liver function 
tests with a value >3 × ULN for ALT or AST and >2 × ULN for total bilirubin within the same 
visit, a value of >3 × ULN for ALT or AST and clinical jaundice, an AE leading to the 
discontinuation of IMP or from the study will be considered AESIs. These events will be noted 
by the investigator in the ADVERSE EVENTS eCRF. 
3.2.3.2. 
Treatment-emergent Adverse Event (TEAE) 
Any event reported on the eCRF that occurs on or after the initiation of IMP until the end of AE 
reporting period per protocol is considered treatment emergent. 
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Additionally, it is assumed that an Adverse Event which was reported to have started on Day 1 
without an associated onset time is assumed to be treatment emergent. 
3.2.4. 
Clinical Safety Laboratory Assessments 
The clinical laboratory tests as listed in the protocol will be performed in accordance with the 
laboratory manual and the Schedule of Assessments. All results, including repeats, will be 
included in the laboratory reports. The investigator must review the laboratory report, document 
this review, and record any clinically relevant changes occurring during the trial in the AE 
section of the eCRF. 
3.2.4.1. 
Treatment-emergent Laboratory Abnormality and Toxicity 
A treatment-emergent laboratory abnormality is defined as value outside the normal range which 
occurs on or after the start of IMP and up to the last contact following discontinuation of IMP. 
A treatment-emergent laboratory toxicity is defined as an increase of at least one abnormality 
severity grade (specifications in Section 9.8) from the baseline assessment at any post baseline 
visit which occurs after the first administration of IMP and through last test results of the study. 
If a laboratory assessment obtained on Day 1 with unknown collection times will be assumed to 
be an assessment prior to the initiation of IMP. If the relevant baseline assessments are missing 
for a given subject, any post-baseline severity grade at 1 or more is considered a 
treatment-emergent laboratory toxicity. 
3.2.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the trial using the C-SSRS. It was designed to quantify the 
severity of suicidal ideation and behavior.  
This trial will use the “Baseline/Screening” and “Since Last Visit” versions of the scale. The 
“Baseline/Screening” version, which assesses the lifetime experience of the subject with suicide 
events and suicidal ideation and the occurrence of suicide events or ideation within a specified 
time period prior to entry into the trial, will be completed for all subjects at screening to 
determine eligibility and confirmed at baseline. Any subject with active suicidal ideation or 
suicidal behaviors within the last 6 months, suicidal behaviors within the last 2 years, or who in 
the clinical judgment of the investigator presents a serious risk of suicide should be excluded 
from the trial. 
The “Since Last Visit” C-SSRS form will be completed at all visits after screening and baseline. 
The investigator will review the results of the “Since Last Visit” C-SSRS during the trial to 
determine whether it is safe for the subject to continue in the trial. If a subject demonstrates 
potential suicidal ideation associated with actual intent or method or plan as indicated by “YES” 
answers on item 4 or 5 of the C-SSRS, the investigator will evaluate whether a risk assessment 
by a qualified mental health professional (or the investigator alone if the investigator is a 
qualified mental health professional) is needed and whether the subject should continue in or be 
discontinued from the trial. 
Details of C-SSR categories as well as definition of treatment emerging events are provided in 
Section 9.3. 
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3.2.6. 
Vital Signs 
Vital signs include systolic and diastolic blood pressures, heart rate, and body temperature. 
Duplicate measurements of blood pressure and heart rate will be obtained supine (after 5 minutes 
of rest) and 1 measurement of blood pressure and heart rate will be obtained on standing 
(2 minutes after rising from supine to standing). The duplicate values will be individually 
recorded, and the values will be averaged by the sponsor for the time point assessment. Body 
temperature will be obtained once, at the time of the first blood pressure measurement. 
3.2.7. 
Electrocardiograms 
Single or triplicate 12 lead ECGs will be obtained during the trial. All ECG recordings be 
obtained after the subject has been supine and at rest for at least 5 minutes. A triplicate set of 
ECGs is 3 consecutive ECGs collected 1 to 2 minutes apart over a 5 minute period. 
A single ECG will be obtained at the Screening Visit. For US sites, three sets of triplicate ECGs 
will be obtained during the 45 minutes before administration of the first dose of IMP on Day 1 
(at -45, -30, and -15 minutes), and a single set of triplicate ECGs will be obtained ~1 hour after 
administration of the first dose of IMP on Day 1, just prior to the time of collection of the PK 
blood sample. One set of triplicate ECGs will be obtained at the Weeks 5, 11, 14, 22, and 27 
clinic visits, just prior to the time of collection of the PK blood sample. The triplicate ECG 
information from US sites will be used in a C-QT analysis with results reported separately. For 
non-US sites, one set of triplicate ECGs will be obtained before administration of the first dose 
of IMP on Day 1, and a single ECG will be obtained ~1 hour after administration of the first dose 
of IMP on Day 1, just prior to the time of collection of the PK blood sample. Single ECGs will 
be obtained at the Weeks 5, 11, 14, 22, and 27 clinic visits, just prior to the time of collection of 
the PK blood sample. A central ECG service will be used for reading all ECGs to standardize 
interpretations for the safety analysis. 
3.2.8. 
Prior Medications, Concomitant Medications and Medications Taken Post Last 
Dose of IMP 
Prior medications are those medications taken prior and ended prior to the initiation of IMP. 
These medications will be captured in the CONCOMITANT MEDICATIONS eCRF.  
Concomitant medications are those medications taken on or after the initiation of IMP. These 
medications include those medications started before the initiation of IMP and continuing post 
Day 1. Medications that start after the last dose of IMP until the end of protocol-specified 
reporting period will be classified as taken post last dose and will not be considered concomitant. 
These medications will be recorded in the eCRF. The investigator will record all medications and 
therapies (including vaccines, over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) that are used by the subject from 30 days before the informed consent form (ICF) 
is signed through the end of the Safety Follow-up Period (Week 31 or early termination). The 
investigator will also record all medications and therapies taken or received by a subject for 
treatment of an AE or that cause an AE through Week 31 or early termination. 
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3.2.9. 
Physical and Neurological Examinations 
A complete physical and neurological examinations will be conducted at screening and at the end 
of treatment visit (Visit 11 or early termination visit). Any condition present post-baseline 
physical or neurological examination that was not present at the baseline examination should be 
documented as an AE and followed to a satisfactory conclusion. 
3.3. 
Pharmacokinetics 
Blood samples for measurement of plasma concentrations of tavapadon and CVL-0000053, its 
major metabolite, will be collected ~1 hour after administration of the first dose of IMP on Day 1 
and at the clinic visits at the end of Weeks 5, 11, 14, 22, and 27. 
Drug concentration information will not be reported to investigative sites, clinical database or 
any blinded study personnel until the trial has been completed and unblinded. 
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4. 
DATA CONVENTIONS AND VISIT WINDOWS 
4.1. 
Data Conventions 
4.1.1. 
Age 
Age is the age at the time of informed consent and is as captured on the eCRF (note: date of birth 
is not captured on the eCRF). 
4.1.2. 
Day 1  
Day 1 is the day IMP is first initiated. 
4.1.3. 
Endpoint 
Endpoint as defined as the primary time point for the efficacy assessments is Week 26. 
4.1.4. 
Study Day of an Event 
Study day of an event is defined relative to Day 1 as: 
 
Study Day = event date – date of Day 1 (+ 1, if event date ≥ date of Day 1). 
This calculation will result in negative study days for an event occurring prior to the start of IMP 
and positive study days for an event on or after the start of IMP.  There will be no Day 0 value to 
match the schedule of events. 
4.1.5. 
Days on Study 
Days on Study is the number of days from Day 1 to the date of study completion or early 
termination as recorded on the END OF STUDY eCRF. 
4.1.6. 
Days on IMP 
Days on IMP is the number of days from Day 1 to the date of last dose of IMP as recorded on the 
EXPOSURE eCRF. 
4.1.7. 
Baseline Value 
For purposes of analysis, the baseline value of a given assessment is defined as the last value 
obtained prior to initiation of IMP. Should the Day 1 visit value be obtained after the first dose of 
IMP or if this value is not available at Day 1, the most recent value obtained prior to the first 
dose of IMP will be used for the baseline value.  
For US subjects with triplicate ECGs taken at 3 pre-dose timepoints, the baseline value will be 
defined as the average of the available pre-dose ECG values (i.e. triplicate ECGs at -45 minutes 
pre-dose, -30 minutes pre-dose, and -15 minutes pre-dose). For non-US subjects, the baseline 
value will be defined as the average of the available pre-dose ECG values. Scheduled records 
will be selected over unscheduled records if a tie breaker is needed.  
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For blood pressure and heart rate measurements, baseline is defined as the average of the 
duplicates at the last visit prior to the IMP administration. If no duplicate is available, the last 
non-missing value prior to the initiation of IMP will be used. 
4.1.8. 
Change from Baseline 
Change from baseline for a given variable is defined as the value on a given Study Day (Time 
Point) minus the Baseline Value. 
4.1.9. 
Orthostatic Change 
Orthostatic change is calculated as the difference in the standing value from the supine value 
(i.e., supine value – standing value). If an average value is available at a given visit and date, it 
will be used for the calculation of orthostatic change. If an average value is not available, the 
individual record obtained on a given visit and date will be used. 
4.1.10. 
Duration of Titration Phase 
The duration of the titration phase will be calculated as the days in 
 of the dosing 
schedule. 
4.1.11. 
Duration of Maintenance Phase 
The duration of the maintenance phase will be calculated as the days in 
 of the dosing 
schedule. 
4.1.12. 
Average Dose of Titration Phase 
The average dose of the titration phase will be calculated as the sum of the milligrams of study 
drug taken in 
 of the dosing schedule divided by the duration of days in the titration 
phase. 
4.1.13. 
Average Dose of Maintenance Phase 
The average dose of the maintenance phase will be calculated as the sum of the milligrams of 
study drug taken in 
 of the dosing schedule divided by the duration of days in the 
maintenance phase. 
4.1.14. 
Compliance with Study Drug 
Accountability and compliance will be assessed through self-reporting by the subject and by 
tablet count at each clinic visit. For analysis purposes, evaluation of compliance will be based on 
the site assessment of compliance as recorded on the DRUG ACCOUNTABILITY eCRF. 
Compliance will be calculated as a percentage based on the total number of tablets taken relative 
to the total expected number of tablets based on days on study. If a kit was lost and return 
information was available, the return information will be used for the compliance calculation. If 
a kit was lost and no return information was available, it is assumed that the tablets were not 
taken for the compliance calculation. If return information is not available and the kit was not 
lost, it is assumed that the tablets were taken for the compliance calculation. 
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If a kit was redispensed and the number of tablets redispensed is not available, it is assumed that 
the number of tablets that were partially returned were redispensed for the compliance 
calculation. 
4.1.15. 
Handling of Incomplete or Missing Dates Associated with an Event 
An incomplete date occurs when the exact date an event (e.g. an adverse event) occurred or 
ended cannot be obtained from a subject. The database contains data fields for month, day, and 
year. A date is incomplete if at least one of these three fields is not known.  
For many of the planned analyses, a complete date is necessary to determine if the event should 
be included in the analysis (e.g. if the event is treatment-emergent) or to establish the duration of 
an event. In such cases, incomplete dates will be imputed as described below. 
For the purposes of handling partially reported start and stop dates for an event the following 
algorithm will be applied: 
• Missing start day, but month and year present: 
If the event occurs same month and year as the occurrence of IMP, then the start day 
of the event will be assigned to the day of first dose of IMP (i.e., Day 1). 
Otherwise the start day will be set to the first day of the month. 
• Missing start day and month, but year present: 
If event occurs in the same year as IMP, then the start date of the event will be 
assigned to Day 1. 
Otherwise the start day and month will be set to 01 January. 
• In the unlikely event of a completely missing start date (year not present), the start 
date will be imputed as Day 1. 
• Missing end day, but month and year present: 
The day will be set to the last day of the month. 
• Missing end day and month, but year present: 
The end day and month will be set to the date of study completion. However, if study 
completion year is greater than the year of the event, then the day and month will be 
set to 31 December. 
• Missing all components of an end date and the event is not marked as ongoing: 
The event will be considered as ‘ongoing’ and will be considered treatment-emergent 
if the start date is on or after Day 1. 
If any imputed start date causes the start date to occur after the end date, the end date will be 
used for the imputation of the start date. If any imputed end date causes the end date to occur 
prior to the start date of the event, the start date of the event will be used for the imputation of the 
end date. If the imputed date is later than the date of study withdrawal, then the date of study 
withdrawal will be used to impute the date in question. In subject data listings, start and stop date 
of events will be displayed as reported on the eCRF without imputed dates. 
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For the purposes of handling partially reported diagnosis date of Parkinson’s disease, the 
following algorithm will be applied to randomized subjects: 
• Missing day, but month and year present: 
If the diagnosis date occurs same month and year as the occurrence of the subject’s 
screening date, then the day of the diagnosis date will be assigned to the day of the 
subject’s screening date.  
Otherwise the diagnosis day will be set to the first day of the month. 
• Missing day and month, but year present: 
If the diagnosis date occurs in the same year as the occurrence of the subject’s 
screening date, then the diagnosis date will be assigned to the subject’s screening 
date. 
Otherwise the diagnosis day and month will be set to 01 January. 
• In the event of missing year or a completely missing diagnosis date, the diagnosis 
date will be assigned to the subject’s screening date. 
In subject data listings, diagnosis dates will be displayed as reported on the eCRF without 
imputed dates. For screen failures, no imputation will be made to the date of diagnosis of 
Parkinson’s disease. 
4.1.16. 
Handling of Alphanumeric Data  
Should there be instances where a clinical laboratory parameter is reported with imbedded 
non-numeric characters, as for example, “<0.1” or “>10”, the data will be imputed as described 
below for quantitative summaries. The actual alphanumeric values as reported in the database 
will be presented in data listings. 
• The values < LLN will be replaced with ½ the value of the lower limit. For example, 
“< 0.1” will be replaced with 0.05 if the LLN is 0.1.   
• The values > ULN will be replaced by values of increased precision by one level. For 
example, “>0.1” will be imputed to “0.11” if the ULN is 0.1, and “>10” will be 
imputed to “10.1” if the ULN is 10. 
Additionally, in the event of the upper limit of normal (ULN)/lower limit of normal (LLN) 
reported as alphanumeric (e.g., ‘<5’, ‘≤5’, ‘>5’, ‘≥5’), the determination of the laboratory 
abnormality severity grade will be based on the convention on the ULN and LLN below: 
• If the ULN is in the form of ≤5, only the numeric part will be used for determining 
the abnormality severity grade of the test results (i.e., the ULN is set to 5). If the ULN 
is in the form of <5, the numeric value of the ULN will be decreased by two levels of 
precision in the direction of the symbol (i.e., the ULN is set to 4.99).  
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• If the LLN is in the form of ≥5, only the numeric part will be used for determining the 
abnormality severity grade of the test results (i.e., the LLN is set to 5). If the LLN is 
in the form of >5, the numeric value of LLN will be increased by two levels of 
precision in the direction of the symbol (i.e., the LLN is set to 5.01). 
4.2. 
Visit Windows 
Data collected longitudinally across visits will be summarized and analyzed by visit.  
Laboratory data will be presented according to the nominal visit as collected from the eCRF or 
laboratory data unless the visit is an early termination or unscheduled visit. Early termination and 
unscheduled visits will be assigned visit windows based on the study day completed according to 
Table 3. Baseline will be determined per the baseline definition in Section 4.1.7. Other 
assessment data, including efficacy assessments data, will be mapped to the appropriate time 
point based on the window as defined in Table 3 from Baseline to Week 22 to appropriately 
captured time of assessment in cases of visit schedule variations. Due to the short interval 
between Visit 10 (Week 26) and Visit 11 (Week 27), data obtained at the nominal visit at this 
two time points will be used with the exception of early termination/unscheduled visits.  
Table 3: 
Visit Windows 
Analysis Visit 
Analysis Visit Target Day 
Analysis Visit Window 
Baseline 
1 
≤ 1 
Day 1* 
1 
1 
Week 2 
14 
2 - 24 
Week 5 
35 
25 - 45 
Week 8 
56 
46 – 66 
Week 11 
77 
67 – 86 
Week 14 
98 
87 – 111 
Week 18 
126 
112 – 140 
Week 22 
154 
141 – 168 
Week 26 
182 
169 – 185 
Week 27 
189 
186 and higher 
* Day 1 assessments are pre-IMP except ECG with a 60 minute post-dose assessment 
If assessments are collected multiple times within a given visit window the result closest to the 
analysis visit target day will be used for summary presentations. If two measurements have the 
same distance to the target day, the later value will be used. If a subject has multiple non-missing 
values on the same date, the average record will be used (if applicable). If there are multiple 
average records on the same date, the average based on the scheduled measurements will be 
used. If no averages exist, the last record as determined by the time collected will be used.  
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5. 
STATISTICAL ANALYSIS METHODS 
5.1. 
General Considerations 
Descriptive statistical methods will be used to summarize the data from this trial, with statistical 
testing performed for the efficacy endpoints. Unless stated otherwise, the term “descriptive 
statistics” refers to number of subjects (N), number of observations (n), arithmetic mean, median, 
standard deviation (SD), geometric mean and coefficient of variation (CV%) (for concentration 
data only), first quartile (Q1), third quartile (Q3), minimum, and maximum for continuous data, 
and frequencies and percentages for categorical data. Certain figure presentations will include 
the standard error of the mean (SE). The term “treatment group” refers to treatment assignment: 
placebo, tavapadon 5 mg, and tavapadon 15 mg. All data collected from subjects who sign the 
informed consent form, including screen failures, will be included in data listings. Unless 
otherwise noted, the data listings will be sorted first by treatment group and subject number and 
then by date within each subject number. 
The number and proportion of missing visits and key assessments due to COVID-19 control 
measures and the frequency of remote assessments performed due to COVID-19 restrictions will 
be tabulated by treatment, visit, and assessment as well as the overall number and proportion of 
subjects with any such missing visits, assessments, or remote visits in each treatment group. 
The statistical analyses will be conducted with the SAS® software package version 9.4 or higher. 
5.2. 
Populations for Analyses 
The analysis populations are defined Table 4. 
Table 4: 
Populations for Analysis 
Population 
Description 
Analysis 
ITT 
All randomized subjects 
Demographic and Baseline 
Characteristics 
FAS 
All randomized subjects who receive at least 1 
dose of IMP. This will be the safety analysis set. 
Safety analysis 
mITT 
All randomized subjects who receive at least 1 
dose of IMP and have a baseline and at least one 
postbaseline MDS-UPDRS assessment.  
Primary analysis set for efficacy 
Endpoint completers 
All subjects in the mITT population who have an 
MDS-UPDRS assessment at baseline and endpoint 
Sensitivity analysis set for 
efficacy 
PK 
All randomized subjects who receive at least 1 
dose of tavapadon and have at least one 
measurable scheduled tavapadon (CVL751) 
concentration  
PK analysis set 
Abbreviations: FAS = full analysis set, IMP = investigational medicinal product, ITT = intent-to-treat, mITT = 
modified intent-to-treat, PK = pharmacokinetic, MDS-UPDRS = Movement Disorder Society – Unified Parkinson’s 
Disease Rating Scale. 
 
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5.3.
Statistical Hypotheses
The primary and key secondary hypotheses are summarized below. All will be tested based on 
2-sided .
Primary Endpoint
Tavapadon 15 mg QD vs Placebo
Tavapadon 5 mg QD vs Placebo
Change from baseline to endpoint 
in MDS-UPDRS Part II and III 
combined score
H1 : µactive = µplacebo
vs  µactive ≠ µplacebo
H2 : µactive = µplacebo
vs  µactive ≠ µplacebo
Key Secondary Endpoints
Change from baseline to endpoint 
in the MDS-UPDRS Part II score
H3 : µactive = µplacebo
vs  µactive ≠ µplacebo
H5 : µactive = µplacebo
vs  µactive ≠ µplacebo
Proportion of responders on the 
PGIC at endpoint
H4 : active = placebo
vs  active ≠ placebo
H6 : active = placebo
vs  active ≠ placebo
5.4.
Multiplicity Adjustment
A graphical approach depicted below is utilized to illustrate the hierarchal multiple testing 
strategy planned for the hypotheses described above to control the overall Type I error rate.  The 
primary endpoint of the tavapadon 15 mg QD will be compared with that of placebo (H1) with 
full of 0.05 and, if successful, the available will be passed along fully (r=1) to the 
comparison of the primary endpoint of tavapadon 5 mg QD with placebo (H2). If H2 is 
successful, the full will be available to the secondary hypothesis H3. The sequence will 
continue until H6 or until the sequence breaks with no remaining available.
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5.5. 
Strata and Covariates 
The randomization is stratified by concurrent use of MAO-B inhibitor. This factor is planned to 
be included as a covariate in the efficacy analyses. However, due to isolated administrative errors 
at a few sites during randomization through IRT system, 15 subjects were randomized to the 
incorrect strata (3 non-MAO-B inhibitor users were randomized to the MAO-B inhibitor use 
stratum and 12 MAO-B inhibitor users were randomized to the non-user stratum; details in 
Section 9.7). The actual MAO-B inhibitor use status, as recorded in eCRF, will be used as a 
covariate instead of the randomization strata in these cases.  
The baseline value of each efficacy variable (if applicable) will also be included as a covariate in 
the efficacy analyses. 
5.6. 
Subject Disposition, Demographic and Baseline Characteristics 
Subject disposition will be based on the ITT population with tabulation of the number of subjects 
who complete the study and the number of discontinued and from the study and the reasons by 
treatment group. Additionally, the number of days on study will be summarized.  
Tabulation of subject randomization by country and site will be presented for the ITT population 
and for completed subjects. A listing of randomization number, subject, treatment randomized, 
country, and site will be provided. Further tabulation by region (United States, Non-US) and 
country will also be presented. Subject disposition data will also be tabulated for all subjects 
screened to include the number of subjects screened, the number of screen failures, and the 
reason for screen failure. 
Kaplan-Meier plots will be used to assess time to discontinuation of study treatment, time to 
discontinuation of treatment due to adverse events, and time to discontinuation of treatment due 
to subject withdrawal. The complete subjects or subjects discontinued treatment for reasons other 
than adverse events and withdrawal of consent will be censored at the time of end of treatment 
for the respective KM analyses. If a subject died without treatment discontinuation date 
information, date of death will be used as the time of discontinuation. 
Number of subjects in each analysis population set will be summarized. 
Demographic data and baseline characteristics including age, age categorical distribution, sex, 
childbearing potential, race, ethnicity, height at screening, weight at screening and at baseline, 
BMI at screening and at baseline, MAO-B inhibitor use at baseline, history of Parkinson's 
disease (including years from initial diagnosis), Montreal Cognitive Assessment (MoCA) total 
score, Modified Hoehn & Yahr assessment at screening, MDS-UPDRS (all parts, Part I + Part II 
+ Part III combined, and Part II + III combined) score at baseline, and CGI-S at baseline will be 
summarized using descriptive statistics for the ITT population. Further tabulation by region and 
country will also be presented. 
5.7. 
Medical and Psychiatric History 
Medical and psychiatric history events will be mapped to a Medical Dictionary for Regulatory 
Activities (MedDRA) version 27.0 or higher preferred term and system organ class. 
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Medical and psychiatric history will be summarized by treatment group using preferred terms 
and system organ classes. All events will be listed. 
5.8. 
Exposure to Treatment 
The number of days on study drug, reasons for premature discontinuation of IMP, treatment 
compliance, days in each phase (Titration and Maintenance), and average dose in each phase, 
will be summarized by treatment group for the FAS Population. Exposure data, including dose 
level as received, will be listed. 
5.9. 
Primary Efficacy Analysis 
5.9.1. 
Primary Estimand 
The key research question for the primary endpoint will be addressed with an estimand based on 
the following attributes:  
1) 
Treatments: treatments as randomized regardless of the actual treatment received or the 
final dose level achieved following the titration steps. 
2) 
Target study population of interest: subjects in the modified intent-to-treat (mITT) 
population regardless the completion status of dose titration steps. 
3) 
Endpoint (variable) of interest: change from baseline to Week 26 in the MDS-UPDRS 
Part II + III Combined Score. 
4) 
Population level summary of interest: estimated mean difference between each tavapadon 
dose group and placebo group in the endpoint of interest. 
5) 
Strategy for Intercurrent events (ICEs): a hypothetical strategy will be used to address 
intercurrent events (ICEs) of potential death, treatment discontinuations, missed 
visits/assessments, and start of prohibited concomitant Parkinson’s disease medications. 
The data after treatment discontinuations or after the start of prohibited Parkinson’s 
disease concomitant medications will be censored under the hypothetical strategy. 
Prohibited Parkinson’s disease concomitant medications are defined as medications in 
ATC classifications of ADAMANTANE DERIVATIVES, DOPAMINE AGONISTS, 
MONOAMINE OXIDASE B INHIBITORS, OTHER ANTIPARKINSON DRUGS, 
OTHER DOPAMINERGIC AGENTS, or DOPA AND DOPA DERIVATIVES that are 
started after the first dose of IMP and prior to the last dose of IMP with duration of use 
7 days or more. The hypothetical strategy allows the study to assess the effect of 
tavapadon treatment without the confounding effect of prohibited concomitant 
Parkinson’s disease treatments.  
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5.9.2. 
Main Analytical Approach 
The change from baseline to each study visit in MDS-UPDRS Part II and III combined score will 
be summarized by visit and treatment group. A mixed model repeated measures (MMRM) 
analysis will be used to analyze the data from all post-randomization timepoints up to Week 27 
with fixed effect of treatment group, visits, interaction between treatment group and visit, and 
baseline MAO-B inhibitor use. The baseline value of MDS-UPDRS Part II and III combined 
score will also be included as a covariate. Subject will be included as a random effect. An 
unstructured covariance structure will be used for the repeated measures. If the unstructured 
covariance matrix results in convergence issue, the heterogeneous Toeplitz covariance structure 
followed by the heterogeneous first-order autoregressive (AR(1)) structure will be used. The 
Kenward-Roger approximation will be used to estimate the denominator degrees of freedom. 
The difference between each active dose and placebo at the endpoint visit (Week 26) will be 
estimated based on the Least Squares Mean (LSMean) difference derived from the MMRM with 
the associated 95% confidence intervals (CI) and P-values. A Cohen’s D value will also be 
derived as the ratio of the estimated difference to the population standard deviation at each visit 
estimated from the model (the square root of the diagonal elements of the estimated covariance 
matrix). The missing values, including missing due to missed visits or early termination due to 
COVID-19 control measures, are assumed to be missing at random (MAR) in the main MMRM 
analysis. Sensitivity analyses will be performed to assess the impact of deviation from MAR 
assumptions on the analysis results. Time curve plots will be presented for both raw Mean 
(SEM) and LSMean (SE). 
5.9.3. 
Sensitivity Analyses 
5.9.3.1. 
Treatment Effect at Final Dose Levels 
To assess the treatment effect at the final dose level, a sensitivity analysis will be conducted on 
the mITT set using the MMRM analysis method described in Section 5.9.2 with treatment 
defined as the actual final dose level achieved. The final dose level is defined as the dose 
received at the Week 26 timepoint or at the time of early termination if the subject achieved a 
minimum of 5 mg prior to discontinuation. 
5.9.3.2. 
Treatment Effect based on Actual Treatment Received 
Should a discrepancy between the study treatment received and the randomized treatment 
assignment occurred in 6 or more subjects, a sensitivity analysis may be conducted based on the 
study treatments that subjects actually received using the MMRM analysis method described in 
Section 5.9.2. 
5.9.3.3. 
Remote Assessments Excluded (treated as missing) 
In addition, a sensitivity analysis excluding the MDS-UPDRS Part II + Part III combined score 
obtained remotely may be performed if such remote assessments are conducted due to 
COVID-19 restrictions. It should be noted that the study only has provision of remote 
assessments for Parts I & II of the MDS-UPDRS assessments, as the clinician administered 
motor examination required for Part III cannot be reliably completed remotely. 
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5.9.3.4. 
Impact of Missing Values Handling 
Whilst every effort will be made to prevent avoidable missing values during the study conduct 
(National Research Council, 2010), it is unrealistic to expect no missing values in clinical trials. 
The impact of missing values on the analysis results will be assessed by the sensitivity analyses 
described below. 
Under Missing at Random (MAR) Assumption 
Multiple imputation (MI) will be performed to replace each missing value with a set of plausible 
values that represent the uncertainty about the correct value to impute. The Markov chain 
(MCMC) method will be utilized for the mITT set. SAS PROC MI will be used to generate 27 
possible imputed datasets: Each of these datasets will be analyzed using PROC MIXED in SAS 
using the MMRM model as described in Section 5.9.2. The results of the analyses of the datasets 
will be combined using PROC MIANALYZE to produce an inferential result. 
Considerations of Data Potentially Missing Not at Random (MNAR)  
A pattern mixture model (PMM) approach will be used to address potentially MNAR patterns. 
The following three patterns of subjects in the mITT set will be considered: 
1) 
Subjects with no missing values from discontinuation or from initiation of prohibited 
Parkinson’s disease concomitant mediation during treatment period. 
2) 
Subjects with missing values from the types of ICEs below will be considered having 
MNAR 
a. Subjects who discontinue due to reasons, as recorded on the eCRF, of lack of 
efficacy, adverse events associated with motor symptoms of Parkinson’s disease, 
physician decision, and withdrawal by subject. 
b. Subjects who initiated concomitant Parkinson’s disease medications (ATC 
classifications of ADAMANTANE DERIVATIVES, DOPAMINE AGONISTS, 
MONOAMINE OXIDASE B INHIBITORS, OTHER ANTIPARKINSON DRUGS, 
OTHER DOPAMINERGIC AGENTS, or DOPA AND DOPA DERIVATIVES) after 
the first dose of IMP and prior to the last dose of IMP with a use duration of 7 days or 
more will be considered having a potential confounding ICE. The efficacy data post 
ICE will be treated as missing with the missing pattern of MNAR.  
The MNAR cases will be identified and documented prior to database lock and unblinding 
(Section 9.5).  
3) 
Subjects with missing values from the type of ICEs below will be considered as having 
MAR 
a. Missing values after discontinuation due to reasons, as recorded on the eCRF, of 
death, pregnancy, loss to follow-up, adverse event unrelated to motor symptoms of 
Parkinson’s disease, non-compliance, site termination, protocol deviation, failure to 
meet continuation criteria and other will be considered as MAR. 
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The MNAR pattern 2) above in the active treatment group will be imputed using the jump to 
reference (J2R) method (Cro et. al. 2020) by assuming that patients jump to behave like those in 
the placebo group following their last observed time point. However, such MNAR in the placebo 
group will still be imputed as MAR using the standard multiple imputation method. 
The MAR patterns 3) will be imputed using the standard multiple imputation method described 
above.  
Other missing values due to missed visits/assessments before endpoint or discontinuation will 
also be assumed as MAR and imputed using the standard multiple imputation method for all 
three patterns. 
Core codes for MAR and MNAR imputations are provided in Section 9.6. 
Under Missing Completely at Random (MCAR) Assumption 
An additional sensitivity analysis will be conducted on the Endpoint (Week 26) Completer set 
using the MMRM analysis method described in Section 5.9.2. 
5.9.4. 
Subgroup Analyses 
Subgroup analyses of the primary endpoint will be made based on the mITT set to assess 
consistency of the intervention effect across the following subgroups:  
• Age group: < 65 vs ≥ 65 years 
• Sex: female vs male 
• Hoehn and Yahr Status at screening: 1 vs 1.5 vs 2 
• Baseline MDS-UPDRS Part II score: ≤ baseline median vs > baseline median 
(median of the mITT set regardless of treatment group) 
• Baseline MDS-UPDRS Part III score: ≤ baseline median vs > baseline median 
(median of the mITT set regardless of treatment group) 
• Use of concomitant MAO-B inhibitor: yes vs no 
• Years since initial diagnosis:(<1 year vs 1 to < 2 years vs 2 to < 3 years 
• Race: white vs other 
• Region: United States vs Non-US 
If the number of subjects within a subgroup is too small (less than 10% of the mITT set), the 
subgroup categories may be redefined prior to unblinding the study or the specific subgroup 
analysis may not be performed. Provided that the sample sizes in the subgroups allow, the 
MMRM analysis method described in Section 5.9.2 will be applied to the subgroup analysis 
(excluding the covariate of MAO-B inhibitor use in the MAO-B subgroup models). The 
treatment effect across subgroups will be summarized by forest plots. 
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5.10. 
Key Secondary Efficacy Analyses 
5.10.1. 
Secondary Estimand 1 
The key research question for the first secondary efficacy variable will be addressed with an 
estimand based on the following attributes:  
1) 
Treatments: treatments as randomized regardless of the actual treatment received or the 
final dose level achieved following the titration steps. 
2) 
Target study population of interest: subjects in the modified intent-to-treat (mITT) 
population regardless the completion status of dose titration steps. 
3) 
Endpoint (variable) of interest: change from baseline to Week 26 in the MDS-UPDRS 
Part II Score. 
4) 
Population level summary of interest: estimated mean difference between each tavapadon 
(CVL-751) dose group and placebo group in the endpoint of interest. 
5) 
Strategy for Intercurrent events (ICEs): a hypothetical strategy will be used to address 
intercurrent events (ICEs) of potential death, treatment discontinuations, missed 
visits/assessments, and start of prohibited concomitant Parkinson’s disease medications 
(see definitions in Section 5.9.1). The data after treatment discontinuations or after the 
start of prohibited concomitant Parkinson’s disease treatments will be censored under the 
hypothetical strategy. 
5.10.1.1. Main Analytical Approach 
Similar to the analysis of the primary efficacy variable, the change from baseline to each study 
visit in MDS-UPDRS Part II score will be summarized by visit and treatment group. A mixed 
model repeated measures (MMRM) analysis will be used with fixed effect of treatment group, 
visits, and interaction between treatment group and visit, and MAO-B inhibitor use. The baseline 
value of MDS-UPDRS Part II score will be included as a covariate. Subject will be included as a 
random effect. An unstructured covariance structure will be used for the repeated measures. If 
the unstructured covariance matrix results in convergence issue, the heterogeneous Toeplitz 
covariance structure followed by the heterogeneous first-order autoregressive (AR(1)) structure 
will be used. The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom. The difference between each active dose and placebo at the endpoint visit 
(Week 26) will be estimated based on the Least Squares Mean (LSMean) difference derived 
from the MMRM with the associated 95% confidence intervals (CI) and P-values. A Cohen’s D 
value will also be derived as the ratio of the estimated difference to the population standard 
deviation at each visit estimated from the model (the square root of the diagonal elements of the 
estimated covariance matrix). The missing values, including missing due to missed visits or early 
termination due to COVID-19 control measures, are assumed to be missing at random (MAR) in 
the main MMRM analysis. Sensitivity analyses will be performed to assess the impact of 
deviation from MAR assumptions on the analysis results. Time curve plots will be presented for 
both raw Mean (SEM) and LSMean (SE). 
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5.10.1.2. Sensitivity Analyses 
The sensitivity analyses described in Section 5.9.3 for the primary estimand will also be 
performed for the secondary efficacy estimand 1. 
5.10.1.3. Subgroup Analyses 
The subgroup analyses described in Section 5.9.4 for the primary estimand will also be 
performed for the secondary efficacy estimand 1. 
5.10.2. 
Secondary Estimand 2 
The key research question for the second secondary efficacy variable will be addressed with an 
estimand based on the following attributes:  
1) 
Treatments: treatments as randomized regardless of the actual treatment received or the 
final dose level achieved following the titration steps. 
2) 
Target study population of interest: subjects in the modified intent-to-treat (mITT) 
population regardless the completion status of dose titration steps. 
3) 
Endpoint (variable) of interest: proportion of responders, defined as subjects with a score 
of “much improved” or “very much improved” on the PGIC, at Week 26. 
4) 
Population level summary of interest: : estimated difference expressed as odds ratio 
between each tavapadon (CVL-751) dose group and placebo group in achieving response. 
5) 
Strategy for Intercurrent events (ICEs): a hypothetical strategy will be used to address 
intercurrent events (ICEs) of potential death, treatment discontinuations, missed 
visits/assessments, and start of prohibited concomitant Parkinson’s disease medications 
(see definitions in Section 5.9.1). The data after treatment discontinuations or after the 
start of prohibited concomitant Parkinson’s disease treatments will be censored under the 
hypothetical strategy. 
5.10.2.1. Main Analytical Approach 
The number and percentage of responders will be summarized by visit and treatment group. The 
binomial repeated measures up to Week 27 will be analyzed using a generalized linear mixed 
model with logit link (SAS® GLIMMIX procedure). The treatment group, MAO-B inhibitor use, 
visits, and interaction between treatment group and visit will be included as fixed effect. An 
unstructured covariance structure will be used for the repeated measures. If the model does not 
converge with the unstructured covariance structure, the heterogeneous Toeplitz structure will be 
used. The odds ratio of each active dose to placebo at the endpoint visit will be estimated based 
on the Least Squares Mean difference in logit between the treatment groups from the GLIMMIX 
model with the associated 95% confidence intervals (CI) and P-values. The missing values are 
assumed to be missing at random, including missing due to missed visits or early termination due 
to COVID-19 control measures. Sensitivity analyses will be performed to assess the impact of 
deviation from MAR assumptions on the analysis results. 
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5.10.2.2. Sensitivity Analyses 
The sensitivity analyses described in Section 5.9.3 for the primary estimand will also be 
performed for the secondary efficacy estimand 2 except for the sensitivity analyses to assess the 
impact of missing value handling. For the secondary efficacy estimand 2, the case of potential 
MNAR will be imputed as “non-responder” for the sensitivity analysis. No additional sensitivity 
analysis under the MAR assumption using multiple imputations will be performed. In addition, a 
sensitivity analysis excluding the PGIC score obtained remotely may be performed if such 
remote assessments are conducted due to COVID-19 restrictions. 
5.10.2.3. Subgroup Analyses 
The subgroup analyses described in Section 5.9.4 for the primary estimand will also be 
performed for the secondary efficacy estimand 2: proportion of responders at Week 26. 
 
 
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5.11. 
Summary of Primary and Key Secondary Efficacy Analyses 
ICE Strategy 
Primary Analysis 
Sensitivity Analysis 
Subgroup Analysis 
Primary Endpoint: Change from baseline in the MDS UPDRS Part II + III combined score at Week 26 
Hypothetical 
strategy with data 
after treatment 
discontinuations 
or after the start 
of prohibited 
concomitant 
medications 
censored  
• mITT population 
• Treatment as 
randomized 
• MMRM described 
in Section 5.9.2 
 
• Treatment effect at final dose 
levels 
• Treatment effect based on actual 
treatment received, if applicable 
• Missing values imputation using 
multiple imputations (MI) 
• Missing values imputation using 
pattern mixture model (PMM) 
• Endpoint completer analysis 
• Analysis with remote 
assessments excluded (treated as 
missing) 
• Age 
• Sex 
• Hoehn&Yahr Status 
• MAO-B inhibitor use 
• Baseline MDS-UPDRS 
Part II and Part III baseline  
• Years since diagnosis 
• Race 
• Region 
Key Secondary Endpoint 1: Change from baseline in the MDS UPDRS Part II score at Week 26 
Hypothetical 
strategy with data 
after treatment 
discontinuations 
or after the start 
of prohibited 
concomitant 
medications 
censored  
• mITT population 
• Treatment as 
randomized 
• MMRM described 
in Section 5.9.2 
 
• Treatment effect at final dose 
levels 
• Treatment effect based on actual 
treatment received, if applicable 
• Missing values imputation using 
multiple imputations (MI) 
• Missing values imputation using 
pattern mixture model (PMM) 
• Endpoint completer analysis 
• Analysis with remote 
assessments excluded (treated as 
missing) 
• Age 
• Sex 
• Hoehn&Yahr Status 
• MAO-B inhibitor use 
• Baseline MDS-UPDRS 
Part II and Part III baseline  
• Years since diagnosis 
• Race 
• Region 
Key Secondary Endpoint 2: Proportion of PGIC responders at Week 26 
Hypothetical 
strategy with data 
after treatment 
discontinuations 
or after the start 
of prohibited 
concomitant 
medications 
censored  
• mITT population 
• Treatment as 
randomized 
• GLIMMIX model 
described in 
Section 5.10.2.1 
 
• Treatment effect at final dose 
levels 
• Treatment effect based on actual 
treatment received, if applicable 
• Potential MNAR missing values 
treated as non-responders 
• Endpoint completer analysis 
• Analysis with remote 
assessments excluded (treated as 
missing) 
• Age 
• Sex 
• Hoehn&Yahr Status 
• MAO-B inhibitor use 
• Baseline MDS-UPDRS 
Part II and Part III baseline  
• Years since diagnosis 
• Race 
• Region 
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5.12. 
Other Efficacy Analyses 
Endpoint 
Analysis 
Population 
ICE Strategy 
Analysis Method 
Subgroup Analysis 
Secondary Endpoints 
Change from 
baseline in the MDS 
UPDRS Part II + III 
combined score (all 
time points) 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
• Age 
• Sex 
• Hoehn&Yahr Status 
• MAO-B inhibitor use 
• Baseline MDS-UPDRS Part II 
and Part III baseline  
• Years since diagnosis 
• Race 
• Region 
Change from 
baseline in the MDS 
UPDRS Part I, 
Part II, and Part III 
combined score (all 
time points) 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
• Age 
• Sex 
• Hoehn&Yahr Status 
• MAO-B inhibitor use 
• Baseline MDS-UPDRS Part II 
and Part III baseline  
• Years since diagnosis 
• Race 
• Region 
Change from 
baseline in the MDS 
UPDRS Part I score 
(all time points) 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
• Age 
• Sex 
• Hoehn&Yahr Status 
• MAO-B inhibitor use 
• Baseline MDS-UPDRS Part II 
and Part III baseline  
• Years since diagnosis 
• Race 
• Region 
Change from 
baseline in the MDS 
UPDRS Part II 
score (all time 
points) 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
• Age 
• Sex 
• Hoehn&Yahr Status 
• MAO-B inhibitor use 
• Baseline MDS-UPDRS Part II 
and Part III baseline  
• Years since diagnosis 
• Race 
• Region 
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Endpoint 
Analysis 
Population 
ICE Strategy 
Analysis Method 
Subgroup Analysis 
Change from 
baseline in the MDS 
UPDRS Part III 
score (all time 
points) 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
• Age 
• Sex 
• Hoehn&Yahr Status 
• MAO-B inhibitor use 
• Baseline MDS-UPDRS Part II 
and Part III baseline  
• Years since diagnosis 
• Race 
• Region 
Change from 
baseline in the 
CGI-S score (all 
time points) 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
• Age 
• Sex 
• Hoehn&Yahr Status 
• MAO-B inhibitor use 
• Baseline MDS-UPDRS Part II 
and Part III baseline  
• Years since diagnosis 
• Race 
• Region 
CGI-I score (all 
time points) 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
• Age 
• Sex 
• Hoehn&Yahr Status 
• MAO-B inhibitor use 
• Baseline MDS-UPDRS Part II 
and Part III baseline  
• Years since diagnosis 
• Race 
• Region 
PGIC score (all time 
points) 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
• Age 
• Sex 
• Hoehn&Yahr Status 
• MAO-B inhibitor use 
• Baseline MDS-UPDRS Part II 
and Part III baseline  
• Years since diagnosis 
• Race 
• Region 
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Endpoint 
Analysis 
Population 
ICE Strategy 
Analysis Method 
Subgroup Analysis 
Other Endpoints 
Change from 
baseline in the PDQ 
39 score 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
None 
Change from 
baseline in the 
Schwab and 
England ADL score 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
None 
Change from 
baseline in the 
EQ-5D-5L index 
score 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
None 
Change from 
baseline in 
EQ-5D-5L VAS 
score 
mITT 
Hypothetical 
MMRM described 
in Section 5.9.2 
None 
Cohen’s D effect size by time point will be derived for MDS-UPDRS Part II+III and MDS-UPDRS Part II only. 
Time curve plots will be presented for LSMean (SE) of change from baseline for MDS-UPDRS Part II+III, Part 
I+II+III, individual Part I, II and III, CGI-S, and Schwab and England ADL scores as well as for LSMean (SE) of 
CGI-I and PGIC over time. 
5.13. 
Interim and Final Analysis 
A final analysis will be conducted once the last subject completes or discontinues the study, and 
the resulting clinical database has been cleaned, quality checked, and the database has been 
locked. 
No interim analysis is planned. 
5.14. 
Safety Analyses 
All safety analyses will be performed on the full analysis set (FAS). Should any subjects receive 
a treatment other than their randomized treatment, the treatment as received will be used in the 
safety presentation.  
5.14.1. 
Adverse Events 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
version 27.0 or higher preferred term and system organ class. If a subject experiences multiple 
events that map to a single preferred term, the greatest severity and strongest investigator 
assessment of relation to IMP will be assigned to the preferred term for the appropriate 
summaries. Events with missing severity or relationship will be classified as outlined in 
Section 3.2. Missing onset dates will be imputed as previously outlined in Section 4.1 as required 
to determine treatment-emergent events. 
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Summaries of treatment-emergent AEs will include any AEs reported beginning with the 
initiation of study drug on Day 1 through end of reporting period specified in the protocol post 
the last dose of IMP. The occurrence of TEAEs will be summarized by treatment group using 
preferred terms, system organ classes, and severity. The TEAEs by subgroup of MAO-B 
inhibitor use will be summarized by treatment, organ class, and preferred term. Separate 
summaries of treatment-emergent serious adverse events (TESAEs), TEAEs related to IMP, 
AESIs (including AEs related to abuse potential and AEs involving medication handling 
irregularities), events leading to the discontinuation of IMP, and AESIs that did not result in 
discontinuation of IMP or study will be generated respectively. A summary of AEs by treatment 
phase and by dose at event onset will also be presented. Adverse events leading to the 
discontinuation of IMP by preferred term and phase at onset will be prepared. All adverse events 
reported will be listed for individual subjects showing both verbatim and preferred terms. All 
adverse events that occurred prior to the initiation of study treatment or after the protocol-
specified reporting period post the last dose of IMP will be excluded from the summary tables 
but will be included in the listings.  
In addition, TEAEs rate per 100 person-years of exposure (PYE) will be summarized by 
treatment group using system organ class and preferred term. TEAEs with ≥2% incidence in 
either tavapadon dose group and a greater incidence than the placebo group will be summarized 
by treatment group using preferred term in descending order of the incidence in the tavapadon15 
mg group followed by that in the tavapadon 5 mg group. The most common TEAEs, defined as 
an incidence ≥5% in either tavapadon dose group and greater than 2 times of the incidence in the 
placebo group, will also be summarized by treatment group using preferred term in descending 
order of the incidence in the tavapadon15 mg group followed by that in the tavapadon 5 mg 
group. 
5.14.2. 
Epworth Sleepiness Scale (ESS) 
The ESS individual questions and total score and corresponding changes from baseline will be 
summarized by treatment group and study visit. The percentage of subjects with sleepy (10 or 
more) and very sleepy (18 or more) scores will also be summarized. ESS individual question 
score as well as the total score will be presented in a listing. The ESS total score will also be 
analyzed using the same method (MMRM analysis) describer in Section 5.9.2 to explore any 
treatment difference in sleepiness. Time curve plot will be presented for LSMean (SE) of change 
from baseline. 
5.14.3. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson Disease Rating 
Scale (QUIP-RS) 
The QUIP-RS component scores (Gambling, Sex, Buying, Eating, Hobbyism-Punding, PD 
Medication Use), total ICD score, and total score and corresponding changes from baseline will 
be summarized by treatment group and study visit. QUIP-RS individual data will be presented in 
a listing. The total ICD score will also be analyzed using the same method (MMRM analysis) 
describer in Section 5.9.2 to explore any treatment difference in impulsive-compulsive 
behaviors. Time curve plots will be presented for LSMean (SE) of change from baseline. 
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5.14.4. 
Non-IMP Medications and Non-Drug Therapy/Procedures 
The use of non-IMP medications will be coded using the World Health Organization (WHO) 
drug dictionary (WHODrug) (Version: Global B3 September 2019 or later). Concomitant 
medications, with start date on or after the date of the first IMP through the last IMP dose date, 
will be summarized by treatment group, frequency of drug classification, and generic drug name. 
Medications with start date after the last dose of IMP through the end of protocol-defined 
reporting period, will also be summarized. Prior medications use will be similarly summarized. 
All prior, concomitant, and post IMP medications will be presented in a data listing.  
The use of non-drug therapy/procedures will be coded using MedDRA Version 27.0 or higher. 
Concomitant and post-IMP non-drug therapy/procedures will be summarized by treatment group, 
frequency of system organ class and preferred term. All non-drug therapy/procedures will be 
presented in a data listing. 
5.14.5. 
Clinical Laboratory Assessments 
Descriptive summaries of selected (quantitative) clinical laboratory results will be presented by 
treatment group and study visit. Laboratory values outside the normal range for each 
systematically collected hematology, blood chemistry, and urinalysis parameter will be 
identified. Each subject’s hematology, blood chemistry, and quantitative urinalysis values will be 
flagged as “low” (below the lower limit of normal/LLN), “normal” (within the normal range), or 
“high” (above the upper limit of normal/ULN) relative to the normal ranges of the central 
laboratory. Each subject’s qualitative urinalysis results will be flagged as “normal” or 
“abnormal”. In addition, the severity of laboratory abnormality will be graded based on toxicity 
criteria specified in Section 9.8 in reference to Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0. The result of each laboratory test for individual subjects will be 
presented in a listing with the normal range defined by the central laboratory, the status relative 
to the normal range, and the toxicity grade. 
Shift table will be used to summarize shifts from baseline toxicity grades to greatest (worst) 
treatment-emergent laboratory toxicity grade. For hematology and, blood chemistry, and 
quantitative urinalysis parameters that toxicity grade was not defined, a shift table for each 
laboratory test will be based on the shift from baseline high/normal/low status to the status of the 
maximum post-baseline value and the minimum post-baseline value (including test results from 
unscheduled visits, if any). Similarly, for qualitative urinalysis parameters, shifts from baseline 
normal/abnormal status to the worst post-baseline status will be summarized. 
The number and percentage of subjects who have post-baseline elevations in liver transaminase 
(alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) or bilirubin abnormalities 
in relation to fold above the upper limit of normal will be summarized according to the Food and 
Drug Administration's Premarketing Clinical Evaluation on Drug-Induced Liver Injury Guidance 
for Industry (FDA 2009). Abnormal hepatic laboratory values will be categorized and evaluated 
for any occurrence among all post-baseline assessments (where “and” in the bulleted list below 
indicates elevations occurring at the same visit). Within each laboratory parameter grouping, a 
subject may be counted once per elevation criteria using the worst-case result.  
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That is, a subject with a worst case ALT elevation > 5 × the ULN would be counted once in the 
ALT > 3 × ULN category and once in the ALT > 5 × ULN category, regardless of how many 
ALT elevations the subject had that met the > 3 × ULN and > 5 × ULN elevation criteria. 
• ALT and/or AST > 3 × ULN and total bilirubin > 1.5 or 2 × ULN 
• AST > 3, 5, 10, 20 × ULN 
• ALT > 3, 5, 10, 20 × ULN  
• Total bilirubin > 1.5, 2 × ULN  
• Alkaline phosphatase (ALP) > 1.5 × ULN 
In addition, an eDISH plot, a shift plot showing liver safety panel tests over time (baseline vs. 
post-baseline), and distribution plots of ALT, AST, ALP, and bilirubin over time will be 
produced to aid identification of any potential cases (Merz M. et. al. 2014). The plots to be 
included are the scatter plot of maximum transaminase versus maximum bilirubin, the liver test 
safety panel over time, and the distribution of ALT by time. The distribution plots for AST, ALP, 
and bilirubin will use the same format as used for ALT. 
5.14.6. 
Vital Signs 
Vital signs include systolic and diastolic blood pressures, heart rate, and body temperature. 
Supine (after 5 minutes of rest) and standing (2 minutes after rising from supine to standing) 
measurements will be obtained for blood pressure and heart rate. Duplicate readings of supine 
blood pressure and heart rate will be taken. The duplicate values will be individually recorded, 
and the values will be averaged by the sponsor for the time point assessment. Orthostatic changes 
will be derived using standing and supine values. Body temperature will be obtained once, at the 
time of the first blood pressure measurement.  
5.14.6.1. Blood Pressure and Heart Rate 
Blood pressure and heart rate measurements and corresponding changes from baseline will be 
summarized by treatment group, position (if applicable), and visit using descriptive statistics. 
The distribution of diastolic and systolic blood pressure over time will be evaluated using box 
plots. Average records will be used for the analysis where available. 
Number and percent of subjects with at least one of the out-of-range value in blood pressure and 
heart rate will be summarized by treatment group based on the following criteria: 
Supine Systolic Blood Pressure (mmHg) 
• < 80 mmHg 
• < 90 mmHg 
• > 140 mmHg 
• > 160 mmHg 
• > 200 mmHg 
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Change from Baseline in Supine Systolic Blood Pressure (mmHg) 
• < -20 mmHg 
• < -10 mmHg 
• > 10 mmHg 
• > 20 mmHg 
Orthostatic Systolic Blood Pressure (mmHg) 
• ≥ 20 mmHg decrease upon standing compared with supine position 
• ≥ 20 mmHg increase upon standing compared with supine position 
Supine Diastolic Blood Pressure (mmHg) 
• < 50 mmHg 
• > 90 mmHg 
• > 100 mmHg 
• > 120 mmHg 
Change from Baseline in Supine Diastolic Blood Pressure (mmHg) 
• < -15 mmHg 
• < -10 mmHg 
• > 10 mmHg 
• > 25 mmHg 
Orthostatic Diastolic Blood Pressure (mmHg) 
• ≥ 10 mmHg decrease upon standing compared with supine position 
• ≥ 10 mmHg increase upon standing compared with supine position 
Supine Heart Rate (beats/min) 
• < 50 bpm 
• < 60 bpm 
• > 100 bpm and ≤ 120 bpm 
• > 120 bpm 
The number and percentage of the out-of-range values will also be summarized by treatment 
phase (titration and maintenance phase). For supine measurements, the average of the duplicate 
will be used to determined out-of-range status, unless in isolated cases where only a single 
measurement was taken. 
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5.14.6.2. Body Weight 
Body weight measurements at baseline and at the end of treatment with corresponding changes 
from baseline will be summarized by treatment group using descriptive statistics. 
Number and percent of subjects with out-of-range body weight changes will be summarized 
based on the following criteria: 
• Decrease from Baseline 7% or more (i.e. change from baseline ≤ -7%) 
• Increase from baseline 7% or more (i.e. change from baseline ≥7%) 
5.14.6.3. Temperature 
Temperature and corresponding changes from baseline will be summarized by treatment group, 
and visit using descriptive statistics. Number and percent of subjects with out-of-range 
temperature will be summarized based on the following criteria: 
• >38.0 °C 
• <36.0 °C 
5.14.7. 
Electrocardiograms (ECGs) 
Single or triplicate 12 lead ECGs will be obtained during the trial. All ECG recordings will be 
obtained after the subject has been supine and at rest for at least 5 minutes. A triplicate set of 
ECGs is 3 consecutive ECGs collected 1 to 2 minutes apart over a 5 minute period. Any values 
taken in triplicate will be averaged for analysis. ECGs and corresponding changes from baseline 
will be summarized by treatment group and visit using descriptive statistics. Average records 
will be used for the analysis where available. 
The number and percentage of subjects who experience any post-baseline occurrence of 
potentially clinically significant corrected QT values using Fridericia's method (QTcF) will be 
summarized by treatment group. These presentations will include QTcF values > 450 to ≤ 480, 
> 480 to ≤ 500, and > 500 msec; or changes of > 30 to ≤ 60 or > 60 msec (FDA, 2005). For this 
categorization, the average of triplicate values will be utilized rather than the individual values 
comprising the triplicate measurement. An out-of-range categorical tabulation will also be 
presented for the subgroup of U.S subjects.  
Additionally, a distribution plot of QTcF over time will be presented as an aid in identification of 
any possible time trend and outliers. 
A substudy to evaluate the effect of tavapadon on the QT interval using C-QT modelling is also 
included in this trial. Matched triplicate ECGs and plasma tavapadon concentrations that are 
collected at preselected sites will be used to characterize the effects of tavapadon on the QT 
interval. The analysis plan is summarized separately. 
5.14.8. 
Physical and Neurological Examinations 
Physical and Neurological examination data will be listed. 
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5.14.9. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The maximum post-baseline results from the C-SSRS will be summarized. The maximum of 
each subscale (suicidal ideation [Categories 1-5], suicidal behavior [Categories 6-10], suicidal 
ideation or behavior [Categories 1-10], and self-injurious behavior without suicidal intent) will 
be presented. The number of patients with suicide-related treatment-emergent events, 
treatment-emergent suicidal ideation, and suicidal behavior, based on a comparison of the 
C-SSRS at baseline and/or previous lifetime experience to maximum C-SSRS scores across all 
post-baseline assessments will be provided. All C-SSRS elements will be reflected in a listing. 
5.15. 
Pharmacokinetics 
Plasma concentrations of tavapadon and CV-0000053 (metabolite) will be determined using a 
validated LC-MS/MS method. PK data listings will be presented for the PK population. PK 
summary tables and mean figures will be presented using the PK analysis set. 
5.15.1. 
Pharmacokinetic Data Analysis 
Plasma concentrations of tavapadon and CV-0000053 (metabolite) will be summarized 
separately using descriptive statistics by visit. Plasma concentrations of tavapadon and 
CV-0000053 that are <LLOQ will be reported as ‘BLQ’ in the data listings. Plasma 
concentrations that are BLQ will be treated as 0 for calculation of descriptive statistics. The 
geometric mean, however, will be calculated by imputing BLQ values as ½ LLOQ. If the 
calculated mean concentration is below the limit of quantitation, the mean will be reported as 
BLQ and the SD and CV% shall be reported as not determined (ND). Mean plasma 
concentrations (SD) of tavapadon and CV-0000053 will also be plotted versus time (in both 
linear and semi-logarithmic scale) based on nominal visit.  
5.16. 
Protocol Deviations 
All protocol deviations will be reviewed by the project team prior to database lock and 
unblinding to identify subjects with important protocol deviations. The number and percentage 
of subjects with important deviations will be tabulated by treatment and further tabulated by 
category and treatment. All deviations from the protocol will be listed by category along with a 
description and any additional comments. 
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6. 
CHANGES IN THE PLANNED ANALYSES 
Should any deviations from the analyses specified in the final approved (prior to database lock 
and unblinding) statistical analysis plan arise, such deviations will be documented in the final 
clinical study report. 
 
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7. 
REVISION HISTORY 
 
Date 
Revision 
Rationale 
 
 
 
 
 
 
 
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8. 
REFERENCES 
Cro S, Morris TP, Kenward MG, Carpenter JR. Sensitivity analysis for clinical trials with 
missing continuous outcome data using controlled multiple imputation: A practical guide. 
Statistics in Medicine. 2020;39:2815–2842. 
Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement 
Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale 
(MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 
2008;15;23(15):2129-70. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011; 
20(10):1727–36. 
Merz M, Lee KR, Kullak-Ublick GA, Brueckner A, Watkins PB. Methodology to Assess 
Clinical Liver Safety Data. Drug Saf (2014) 37 (Suppl 1):S33–S45 
National Research Council. The Prevention and Treatment of Missing Data in Clinical Trials; 
2010. 
Peto V, Jenkinson C, Fitzpatrick R. PDQ-39: a review of the development, validation and 
application of a Parkinson's disease quality of life questionnaire and its associated measures. J 
Neurol. 1998 May;245 Suppl 1:S10-4.  
US Food and Drug Administration (FDA). Guidance for Industry: Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation; 2009. 
US Food and Drug Administration (FDA). Guidance for Industry: E14 Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, 
2005. 
van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone L, 
Kind P, Pickard AS. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L 
value sets. Value Health. 2012 Jul-Aug;15(5):708-15. 
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9. 
APPENDICES 
 
 
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9.1. 
Schedule of Assessments 
Table 5: 
Schedule of Assessments 
Trial Period: 
Screen 
Baseline 
Treatment 
Safety 
Follow-upa 
Trial Week: 
-4 to -1 
1 
2 
5 
8 
11 
14 
18 
22 
26 
27b 
31 
Trial Day: 
-31 to -1 
1 
14±3 
35±3 
56±3 
77±3 
98±3 
126±3 
154±3 
182±3 
189±3 
217±3 
Visit/Contact: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
(EOT/ET) 
Telephonec 
Entrance and History 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric historye  
----------------- 
 
 
 
 
 
 
 
 
 
 
Medical historye 
----------------- 
 
 
 
 
 
 
 
 
 
 
Alcohol/illicit drug use inquiry 
X 
 
 
 
 
 
 
 
 
 
 
 
Modified Hoehn and Yahr stage 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
MoCA 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Efficacy and Other Endpoint Assessments 
MDS-UPDRSf 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-S 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-Ig 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
PGICg 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
PDQ-39 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Schwab and England ADL 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
EQ-5D-5L 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
Safety Assessments 
ESS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Trial Period: 
Screen 
Baseline 
Treatment 
Safety 
Follow-upa 
Trial Week: 
-4 to -1 
1 
2 
5 
8 
11 
14 
18 
22 
26 
27b 
31 
Trial Day: 
-31 to -1 
1 
14±3 
35±3 
56±3 
77±3 
98±3 
126±3 
154±3 
182±3 
189±3 
217±3 
Visit/Contact: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
(EOT/ET) 
Telephonec 
QUIP-RS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical/neurological examinationi  
X 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Vital signsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECGs 
 
 
 
 
 
 
 
 
 
 
 
 
US sites 
 
 
 
 
 
 
 
 
 
 
 
 
Single ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
Three sets of triplicate ECGsk 
(-45, -30, and -15 min prior to 
first dose of IMP) 
 
X 
 
 
 
 
 
 
 
 
 
 
One set of triplicate ECGsk,l 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Non-US sites 
 
 
 
 
 
 
 
 
 
 
 
 
Single ECGl 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
One set of triplicate ECGsk,l 
prior to first dose of IMP 
 
X 
 
 
 
 
 
 
 
 
 
 
Eye examination 
 
 
 
 
 
Xv 
 
 
 
 
Xw 
 
Prior/concomitant medications 
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
Adverse eventsm 
 
------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
Laboratoryn 
Safety laboratory blood sample 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
Prolactin level 
 
Xu 
 
 
 
 
 
 
 
 
Xu 
 
Serology (HIV, HbsAg, and HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
Dipstick urinalysiso 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
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Trial Period: 
Screen 
Baseline 
Treatment 
Safety 
Follow-upa 
Trial Week: 
-4 to -1 
1 
2 
5 
8 
11 
14 
18 
22 
26 
27b 
31 
Trial Day: 
-31 to -1 
1 
14±3 
35±3 
56±3 
77±3 
98±3 
126±3 
154±3 
182±3 
189±3 
217±3 
Visit/Contact: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
(EOT/ET) 
Telephonec 
Serum pregnancy testp 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick pregnancy testp 
 
------------------------------------------------------------------------------------------------------------------------------------- 
 
Urine drug screenq 
X 
------------------------------------------------------------------------------------------------------------------- 
X 
 
Plasma PK sampler 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Future biospecimen research blood 
samples 
 
X 
 
 
 
 
 
 
 
 
 
 
IMP Administration and Compliancet 
Dispense IMP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assess IMP compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: ADL = activities of daily living, CGI-I = Clinical Global Impression – Improvement, CGI-S = Clinical Global Impression – Severity of Illness, 
C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, eCRF = electronic case report form, EQ-5D-5L = EuroQol 5 Dimension 5 Level, ESS = Epworth 
Sleepiness Scale, EOT = end of treatment, ET = early termination, HbsAg = hepatitis B surface antigen, HCV = hepatitis C virus, HIV = human immunodeficiency virus, 
IMP = investigational medicinal product
, MDS-UPDRS = Movement Disorder Society – Unified Parkinson’s Disease Rating Scale, MoCA = Montreal 
Cognitive Assessment, PDQ-39 = 39-Item Parkinson’s Disease Questionnaire, PGIC = Patient Global Impression of Change, PK = pharmacokinetic, QUIP-RS = Questionnaire for 
Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale. 
a. 
Subjects who prematurely discontinue from the trial or who are not eligible for or choose not to participate in the open-label extension trial (Protocol CVL-751-PD-004) are to 
participate in the 4-week Safety Follow-Up Period. Subjects who proceed into the open-label extension trial will go directly into that trial and will not complete the Safety 
Follow-Up Period. 
b. 
The assessments scheduled for the Week 27 visit are to be performed for any subject who prematurely discontinues from the trial. 
c. 
Contact with subjects via telephone call or other means of communication to check on their status. 
d. 
Informed consent must be obtained before any trial-related procedures are performed. 
e. 
Medical occurrences that begin before the start of IMP dosing but after obtaining informed consent will be recorded as medical and/or psychiatric history. 
f. 
MDS-UPDRS Parts I, II, and III will be conducted before the first dose of IMP at the Baseline Visit and at ~2 to ~6 hours after dosing (at home) at clinic visits during the 
Treatment Period. 
g. 
All responses will be relative to the subject’s condition at the Baseline Visit (Day 1) before the first dose of IMP. 
h. 
The “Baseline/Screening” C-SSRS form will be completed at the Screening Visit to determine eligibility. The “Since Last Visit” C-SSRS form will be completed at the 
Baseline Visit to ensure that the subject continues to qualify for the trial and at all visits after the Baseline Visit. 
i. 
Full physical and neurological examinations should be completed at the Screening Visit and at Week 27. The physical examination should include height at the Screening 
Visit only. Physical and/or neurological examinations can be done at any time point during the trial at the investigator's discretion.  
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Trial Period: 
Screen 
Baseline 
Treatment 
Safety 
Follow-upa 
Trial Week: 
-4 to -1 
1 
2 
5 
8 
11 
14 
18 
22 
26 
27b 
31 
Trial Day: 
-31 to -1 
1 
14±3 
35±3 
56±3 
77±3 
98±3 
126±3 
154±3 
182±3 
189±3 
217±3 
Visit/Contact: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
(EOT/ET) 
Telephonec 
j. 
Duplicate measurements of blood pressure and heart rate will be obtained in supine (after 5 minutes of rest) and 1 measurement of blood pressure and heart rate will be 
obtained on standing (2 minutes after rising from supine to standing). 
k. 
A triplicate set of ECGs is 3 consecutive ECGs collected 1 to 2 minutes apart over a 5-minute period. 
l. 
The postdose ECGs (triplicate set for US sites at all visits and single for non-US sites at all visits) will be obtained at ~1 hour after administration of the first dose of IMP at 
the Baseline Visit just prior to the time of collection of the PK blood sample. ECGs at all postbaseline visits will be obtained just prior to the time of collection of the PK 
blood sample. 
m. All adverse events that are observed by trial personnel or volunteered by the subject in response to open-ended questioning will be recorded from the first dose of IMP through 
the end of the Safety Follow-up Period. Serious adverse events will be followed until resolution. 
n. 
Individual sites may require subjects to have COVID-19 testing done prior to randomization. COVID-19 testing may be performed after randomization per the principal 
investigator’s discretion. 
o. 
Dipstick urinalysis results are not to be recorded on the eCRFs; any clinically significant abnormality should be captured as an adverse event. 
p. 
For women of childbearing potential only. All positive urine dipstick pregnancy tests must be confirmed by a serum test. Pregnancy tests can be performed at any time during 
the trial at the discretion of the investigator. Female subjects with exclusively the same sex partners may not be required to have pregnancy tests per investigator discretion; 
confirmation with the medical monitor is required. 
q. 
A urine drug screen is required at screening (see exclusion criteria for exclusions based on the urine drug screen) and may be obtained at other times, at investigator discretion, 
if use of prohibited drugs is suspected. 
r. 
PK samples will be collected ~1 hour after administration of the first dose (Day 1) and at the clinic visits at the end of Weeks 5, 11, 14, 22, and 27 just after ECG acquisition 
at each time point. The date and time of the most recent dose, the dose amount, and the time of the blood draw will be recorded.  
s. 
Future biospecimen research sample is optional and is to only be collected if signed consent is obtained from the subject. 
t. 
The first dose of IMP (at the Baseline Visit) will be taken in the clinic; all other doses will be taken on an outpatient basis. Subjects will be instructed to bring their IMP to 
each clinic visit. Compliance will be assessed through self-reporting by the subject and by tablet count. 
u. 
Prolactin results will be blinded. 
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Trial Period: 
Screen 
Baseline 
Treatment 
Safety 
Follow-upa 
Trial Week: 
-4 to -1 
1 
2 
5 
8 
11 
14 
18 
22 
26 
27b 
31 
Trial Day: 
-31 to -1 
1 
14±3 
35±3 
56±3 
77±3 
98±3 
126±3 
154±3 
182±3 
189±3 
217±3 
Visit/Contact: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
(EOT/ET) 
Telephonec 
 
 
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9.2. 
EQ-5D-5L Dimensions 
EQ-5D-5L Dimensions (UK English Sample Version) 
Dimensions  
Item 
Coded Value 
Mobility 
I have no problems in walking about 
1 
I have slight problems in walking about 
2 
I have moderate problems in walking about 
3 
I have severe problems in walking about 
4 
I am unable to walk about 
5 
Self-care 
I have no problems washing or dressing myself 
1 
I have slight problems washing or dressing myself 
2 
I have moderate problems washing or dressing myself 
3 
I have severe problems washing or dressing myself 
4 
I am unable to wash or dress myself 
5 
Usual activities 
(e.g., work, study, housework, family 
or leisure activities) 
I have no problems doing my usual activities  
1 
I have slight problems doing my usual activities 
2 
I have moderate problems doing my usual activities 
3 
I have severe problems doing my usual activities 
4 
I am unable to do my usual activities 
5 
Pain/discomfort 
I have no pain or discomfort  
1 
I have slight pain or discomfort 
2 
I have moderate pain or discomfort 
3 
I have severe pain or discomfort 
4 
I have extreme pain or discomfort 
5 
Anxiety/depression 
I am not anxious or depressed 
1 
I am slightly anxious or depressed 
2 
I am moderately anxious or depressed 
3 
I am severely anxious or depressed 
4 
I am extremely anxious or depressed 
5 
 
 
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9.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation 
and Suicidal Behavior Scores 
The C-SSRS is comprised of 10 categories with binary responses. The 10 categories include: 
Category 1 – Wish to be Dead  
Category 2 – Non-specific Active Suicidal Thoughts  
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act  
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
Category 5 – Active Suicidal Ideation with Specific Plan and Intent  
Category 6 – Preparatory Acts or Behavior  
Category 7 – Aborted Attempt  
Category 8 – Interrupted Attempt  
Category 9 – Actual Attempt (non-fatal)  
Category 10 – Completed Suicide 
Categories 1-5 represent Suicidal Ideation and categories 6-10 represent Suicidal Behavior. Each 
category is scored as 1 if there is a positive response in the category and a 0 if there are no 
positive responses in the category.   
• Self-Injurious Behavior Without Suicidal Intent During Treatment 
A subject will be categorized as having self-injurious behavior without suicidal intent if there is 
an occurrence of non-suicidal self-injurious behavior on the C-SSRS – Since Last Visit eCRF at 
any post-baseline visit. 
• Baseline C-SSRS Score  
Baseline represents the pre-treatment assessment of recent history, with elements of suicidal 
ideation assessed over the prior 6 months and elements of suicidal behavior assessed over the 
prior 2 years. It is scaled from 0 (no suicidal ideation or behavior) to 10 (completed suicide) 
• Treatment-Emergent Suicide-Related Event  
A subject will be categorized as having a treatment-emergent suicide-related event if at least one 
post-baseline suicidal ideation or suicidal behavior score is greater than 0.  
• Treatment-Emergent Suicidal Ideation Compared to Recent History 
A subject will be categorized as having treatment-emergent suicidal ideation compared to recent 
history when there is at least one post-baseline suicidal ideation score > 0 and is an increase from 
baseline. Lifetime scores are not considered for baseline suicidal ideation responses. 
• Treatment-Emergent Serious Suicidal Ideation Compared to Recent History 
A subject will be categorized as having treatment-emergent serious suicidal ideation compared to 
recent history if the baseline score was < 4 and the post-baseline suicidal ideation score increases 
to 4 or 5. Lifetime scores are not considered for baseline suicidal ideation responses. 
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• Emergence of Serious Suicidal Ideation Compared to Recent History 
A subject will be categorized as having emergence of serious suicidal ideation compared to 
recent history if baseline score was 0 (no suicidal ideation) and post-baseline C-SSRS suicidal 
ideation score is either 4 or 5. Lifetime scores are not considered for baseline suicidal ideation 
responses.  
• Emergence of Suicidal Behavior Compared to all Prior History 
A subject will be categorized as having emergence of suicidal behavior compared to all prior 
history if there had been no suicidal behavior in Categories 6-10 reported at any pre-treatment 
assessment, including responses to lifetime history questions, and there is at least one positive 
post-baseline C-SSRS assessment in Categories 6-10. ‘All Prior History’ represents lifetime 
history. 
 
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9.4. 
Programming Conventions 
• Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in 
landscape orientation. There should be a 1.0” boundary on the left and right edges. The 
top and bottom margins are 1.0” for tables and listings, but may vary for figures. Output 
should be printed in Courier New with a point size of 8.  
• Identification of analysis population: Every summary table, listing, and figure will clearly 
specify the analysis population being summarized/listed. Listings will be prepared for all 
subjects randomized. 
• Group headers: In the summary tables, the group headers will identify the within-group 
sample size for the indicated analysis population. Of note, the header’s sample size does 
not necessarily equal the number of subjects actually summarized within any given 
summary module; some subjects in the analysis population may have missing values and 
thus may not be summarized. 
• Suppression of percentages corresponding to null categories: When count data are 
presented as category frequencies and corresponding percentages, the percent should be 
suppressed when the count is zero in order to draw attention to the non-zero counts. 
• Presentation of sample sizes: Summary modules should indicate, in one way or another, 
the number of subjects actually contributing to the summary statistics presented in any 
given summary module. As mentioned above, this may be less than the number of 
subjects in the analysis population. 
 In the quantitative modules describing continuous variables (and thus presenting 
sample size, means, and standard deviations), the sample size should be the 
number of non-missing observations 
 For categorical variables that are presented in frequency tables, the module should 
present the total count in addition to the count in each category. Percentages 
should be calculated using this total as the denominator, and the percentage 
corresponding to the sum itself (that is, 100%) should be presented so as to 
indicate clearly to a reviewer the method of calculation. 
• Sorting: Listings will be sorted by treatment, subject number and date, if applicable. If a 
listing is sorted in a different manner, it will be indicated on the listing shells.  
• General formatting rules: Rounding for all variables will occur only as the last step, 
immediately prior to presentation in listings, tables, and figures. No intermediate 
rounding will be performed on derived variables. The standard rounding practice of 
rounding numbers ending in 0-4 down and numbers ending in 5-9 up will be employed.  
• The presentation of numerical values will adhere to the following guidelines (exceptions 
may be necessary in some circumstances for derived analysis variables to allow readability):  
 Raw measurements will be reported to the number of significant digits as captured 
electronically or on the eCRFs.  
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 Standard deviations will be reported to two decimal places beyond the number of 
decimal places the original parameter is presented. EQ-5D-5L Index Score 
summaries will use 4 decimal places for standard deviation. 
 Means medians, and quartiles will be reported to one decimal place beyond the 
number of decimal places the original parameter is presented.  
 will be reported to the one decimal place beyond the number of decimal places the 
original parameter is presented. 
 Calculated percentages will be reported with one decimal place.  
 Coefficient of variation will be reported to the same number of decimal places as 
the standard deviation.  
 P-values will be reported to 4 decimal places 
• Dates will be formatted as DDMMMYYYY. Partial dates will be presented on data 
listings as recorded on eCRFs. 
• Time will be presented according to the 24-hour clock (HH:MM). 
• Verification of Results: All analyses will be subject to formal verification procedures. 
Specifically, results will be verified utilizing independent programming prior to issuance 
of the draft statistical report. All documents will be verified by the lead statistician to 
ensure accuracy and consistency of analyses. 
 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 






 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 64 of 154 
Version 1.0: 31 July 2024
 
9.6. 
Core Codes for imputation of MAR and MNAR 
9.6.1. 
Imputation of Missing at Random (MAR) Cases 
SAS PROC MI will be used to generate 27 possible imputed datasets using the following SAS 
code: 
proc mi data=mcmc1 seed=SEED1 nimpute=27 out=Out1X; 
mcmc chain=multiple displayinit initial=em(itprint); 
var TRT y0 y1 y2 … yn; 
run; 
Here, TRT is an indicator variable representing treatment with values of ‘CVL-751 5 mg’, CVL-
751 15 mg’, or ‘Placebo’, Y1 - YN represent the response variable (e.g., MDS-UPDRS Part II+III 
score) for each visit, Y0 is the baseline score, and SEED1 is a random number. 
Each of these datasets will be analyzed using PROC MIXED in SAS using the MMRM model. 
The results of the analyses of the datasets will be combined using PROC MIANALYZE to 
produce an inferential result. 
9.6.2. 
Imputation of Missing Not at Random (MNAR) Cases 
The MNAR cases are imputed using reference based imputation (J2R) method. The five macros; 
SAS code for reference based multiple imputation [https://www.lshtm.ac.uk/research/centres-
projects-groups/missing-data#dia-working-group] will be used to generate 27 possible imputed 
datasets using the following sample SAS code: 
%include "&Path\part1A_33.sas"; 
%include "&Path\part1B_47.sas"; 
%include "&Path\part2A 40.sas"; 
%include "&Path\part2B_31.sas"; 
%include "&Path\part3_55.sas"; 
%include "&Path\plotter_7.sas"; 
 
%part1A(Jobname=X,Data=XX,Subject=usubjid,Response=aval,Time=avisitn,Treat=Tr
t01pn, cov=BASE, Catcov=MAOBINHI, covgroup=trt01pn,Debug=1); 
%part1b(Jobname=X, Ndraws=27, thin=350, seed=s, Debug=1); 
 
%part2a(Jobname=X J2R, inname=XX, method=J2R,ref=0, Debug=1); 
%part2b(Jobname=X_J2R, seed=s, Debug=1); 
 
Each of these datasets will be analyzed using PROC MIXED in SAS using the MMRM model. 
The results of the analyses of the datasets will be combined using PROC MIANALYZE to 
produce an inferential result. 
 
 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 




















































 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 90 of 154 
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9.9. 
EQ-5D-5L Index Cross-walk Mapping 
US Value Set 
Health State (5L profile) 
US 
11111 
1.000 
11112 
0.876 
11113 
0.844 
11114 
0.700 
11115 
0.550 
11121 
0.861 
11122 
0.820 
11123 
0.809 
11124 
0.669 
11125 
0.524 
11131 
0.827 
11132 
0.806 
11133 
0.800 
11134 
0.661 
11135 
0.517 
11141 
0.682 
11142 
0.663 
11143 
0.659 
11144 
0.544 
11145 
0.426 
11151 
0.463 
11152 
0.450 
11153 
0.446 
11154 
0.369 
11155 
0.289 
11211 
0.888 
11212 
0.846 
11213 
0.835 
11214 
0.695 
11215 
0.550 
11221 
0.832 
11222 
0.796 
11223 
0.786 
11224 
0.654 
11225 
0.517 
11231 
0.818 
11232 
0.783 
11233 
0.774 
11234 
0.644 
11235 
0.508 
11241 
0.676 
11242 
0.647 
11243 
0.640 
11244 
0.532 
11245 
0.421 
11251 
0.463 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 91 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
11252 
0.443 
11253 
0.437 
11254 
0.365 
11255 
0.289 
11311 
0.860 
11312 
0.839 
11313 
0.833 
11314 
0.694 
11315 
0.550 
11321 
0.825 
11322 
0.790 
11323 
0.781 
11324 
0.650 
11325 
0.515 
11331 
0.816 
11332 
0.778 
11333 
0.768 
11334 
0.639 
11335 
0.506 
11341 
0.675 
11342 
0.643 
11343 
0.635 
11344 
0.529 
11345 
0.419 
11351 
0.463 
11352 
0.441 
11353 
0.435 
11354 
0.363 
11355 
0.289 
11411 
0.783 
11412 
0.764 
11413 
0.759 
11414 
0.641 
11415 
0.518 
11421 
0.751 
11422 
0.721 
11423 
0.713 
11424 
0.601 
11425 
0.485 
11431 
0.742 
11432 
0.710 
11433 
0.701 
11434 
0.591 
11435 
0.477 
11441 
0.618 
11442 
0.591 
11443 
0.584 
11444 
0.490 
11445 
0.393 
11451 
0.431 
11452 
0.412 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 92 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
11453 
0.406 
11454 
0.338 
11455 
0.266 
11511 
0.626 
11512 
0.613 
11513 
0.609 
11514 
0.532 
11515 
0.452 
11521 
0.599 
11522 
0.579 
11523 
0.574 
11524 
0.501 
11525 
0.425 
11531 
0.592 
11532 
0.571 
11533 
0.565 
11534 
0.493 
11535 
0.418 
11541 
0.501 
11542 
0.483 
11543 
0.478 
11544 
0.410 
11545 
0.339 
11551 
0.365 
11552 
0.352 
11553 
0.348 
11554 
0.285 
11555 
0.220 
12111 
0.854 
12112 
0.815 
12113 
0.805 
12114 
0.665 
12115 
0.520 
12121 
0.802 
12122 
0.765 
12123 
0.756 
12124 
0.623 
12125 
0.486 
12131 
0.789 
12132 
0.753 
12133 
0.743 
12134 
0.613 
12135 
0.478 
12141 
0.647 
12142 
0.617 
12143 
0.609 
12144 
0.502 
12145 
0.390 
12151 
0.433 
12152 
0.413 
12153 
0.408 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 93 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
12154 
0.335 
12155 
0.259 
12211 
0.828 
12212 
0.792 
12213 
0.782 
12214 
0.650 
12215 
0.513 
12221 
0.778 
12222 
0.731 
12223 
0.719 
12224 
0.595 
12225 
0.467 
12231 
0.765 
12232 
0.716 
12233 
0.703 
12234 
0.581 
12235 
0.455 
12241 
0.630 
12242 
0.587 
12243 
0.576 
12244 
0.477 
12245 
0.374 
12251 
0.426 
12252 
0.393 
12253 
0.385 
12254 
0.320 
12255 
0.252 
12311 
0.822 
12312 
0.786 
12313 
0.776 
12314 
0.646 
12315 
0.511 
12321 
0.772 
12322 
0.723 
12323 
0.710 
12324 
0.588 
12325 
0.462 
12331 
0.759 
12332 
0.707 
12333 
0.693 
12334 
0.574 
12335 
0.449 
12341 
0.625 
12342 
0.580 
12343 
0.568 
12344 
0.471 
12345 
0.370 
12351 
0.424 
12352 
0.388 
12353 
0.379 
12354 
0.316 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 94 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
12355 
0.250 
12411 
0.748 
12412 
0.717 
12413 
0.709 
12414 
0.597 
12415 
0.482 
12421 
0.703 
12422 
0.659 
12423 
0.648 
12424 
0.545 
12425 
0.438 
12431 
0.692 
12432 
0.645 
12433 
0.632 
12434 
0.531 
12435 
0.427 
12441 
0.573 
12442 
0.533 
12443 
0.522 
12444 
0.437 
12445 
0.348 
12451 
0.395 
12452 
0.364 
12453 
0.356 
12454 
0.295 
12455 
0.230 
12511 
0.596 
12512 
0.576 
12513 
0.571 
12514 
0.498 
12515 
0.422 
12521 
0.562 
12522 
0.529 
12523 
0.521 
12524 
0.456 
12525 
0.388 
12531 
0.554 
12532 
0.518 
12533 
0.508 
12534 
0.445 
12535 
0.380 
12541 
0.466 
12542 
0.437 
12543 
0.429 
12544 
0.368 
12545 
0.304 
12551 
0.335 
12552 
0.315 
12553 
0.310 
12554 
0.251 
12555 
0.190 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 95 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
13111 
0.825 
13112 
0.803 
13113 
0.797 
13114 
0.658 
13115 
0.514 
13121 
0.790 
13122 
0.754 
13123 
0.745 
13124 
0.614 
13125 
0.479 
13131 
0.781 
13132 
0.742 
13133 
0.732 
13134 
0.603 
13135 
0.470 
13141 
0.640 
13142 
0.608 
13143 
0.599 
13144 
0.493 
13145 
0.383 
13151 
0.427 
13152 
0.406 
13153 
0.400 
13154 
0.328 
13155 
0.253 
13211 
0.816 
13212 
0.781 
13213 
0.771 
13214 
0.641 
13215 
0.505 
13221 
0.767 
13222 
0.718 
13223 
0.705 
13224 
0.583 
13225 
0.456 
13231 
0.755 
13232 
0.702 
13233 
0.689 
13234 
0.569 
13235 
0.444 
13241 
0.620 
13242 
0.575 
13243 
0.563 
13244 
0.466 
13245 
0.364 
13251 
0.418 
13252 
0.383 
13253 
0.374 
13254 
0.311 
13255 
0.244 
13311 
0.814 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 96 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
13312 
0.775 
13313 
0.765 
13314 
0.636 
13315 
0.503 
13321 
0.761 
13322 
0.709 
13323 
0.695 
13324 
0.575 
13325 
0.451 
13331 
0.748 
13332 
0.693 
13333 
0.678 
13334 
0.560 
13335 
0.438 
13341 
0.615 
13342 
0.567 
13343 
0.554 
13344 
0.459 
13345 
0.360 
13351 
0.416 
13352 
0.378 
13353 
0.368 
13354 
0.306 
13355 
0.242 
13411 
0.740 
13412 
0.707 
13413 
0.699 
13414 
0.589 
13415 
0.474 
13421 
0.693 
13422 
0.647 
13423 
0.635 
13424 
0.533 
13425 
0.428 
13431 
0.682 
13432 
0.632 
13433 
0.619 
13434 
0.519 
13435 
0.416 
13441 
0.564 
13442 
0.521 
13443 
0.510 
13444 
0.426 
13445 
0.339 
13451 
0.387 
13452 
0.355 
13453 
0.346 
13454 
0.286 
13455 
0.223 
13511 
0.590 
13512 
0.569 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 97 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
13513 
0.563 
13514 
0.491 
13515 
0.416 
13521 
0.555 
13522 
0.519 
13523 
0.510 
13524 
0.447 
13525 
0.381 
13531 
0.546 
13532 
0.507 
13533 
0.497 
13534 
0.436 
13535 
0.372 
13541 
0.459 
13542 
0.427 
13543 
0.419 
13544 
0.359 
13545 
0.297 
13551 
0.329 
13552 
0.308 
13553 
0.302 
13554 
0.244 
13555 
0.184 
14111 
0.753 
14112 
0.733 
14113 
0.728 
14114 
0.604 
14115 
0.475 
14121 
0.720 
14122 
0.688 
14123 
0.680 
14124 
0.563 
14125 
0.442 
14131 
0.712 
14132 
0.677 
14133 
0.668 
14134 
0.553 
14135 
0.434 
14141 
0.583 
14142 
0.554 
14143 
0.546 
14144 
0.450 
14145 
0.349 
14151 
0.388 
14152 
0.369 
14153 
0.364 
14154 
0.294 
14155 
0.221 
14211 
0.746 
14212 
0.715 
14213 
0.706 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 98 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
14214 
0.590 
14215 
0.469 
14221 
0.701 
14222 
0.656 
14223 
0.644 
14224 
0.536 
14225 
0.423 
14231 
0.690 
14232 
0.641 
14233 
0.629 
14234 
0.523 
14235 
0.412 
14241 
0.567 
14242 
0.525 
14243 
0.514 
14244 
0.426 
14245 
0.333 
14251 
0.382 
14252 
0.350 
14253 
0.342 
14254 
0.280 
14255 
0.215 
14311 
0.745 
14312 
0.710 
14313 
0.701 
14314 
0.586 
14315 
0.467 
14321 
0.696 
14322 
0.648 
14323 
0.635 
14324 
0.529 
14325 
0.419 
14331 
0.684 
14332 
0.633 
14333 
0.619 
14334 
0.515 
14335 
0.407 
14341 
0.563 
14342 
0.518 
14343 
0.506 
14344 
0.420 
14345 
0.330 
14351 
0.380 
14352 
0.346 
14353 
0.337 
14354 
0.276 
14355 
0.213 
14411 
0.681 
14412 
0.651 
14413 
0.644 
14414 
0.544 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 99 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
14415 
0.440 
14421 
0.638 
14422 
0.595 
14423 
0.584 
14424 
0.492 
14425 
0.397 
14431 
0.627 
14432 
0.581 
14433 
0.569 
14434 
0.479 
14435 
0.386 
14441 
0.517 
14442 
0.478 
14443 
0.468 
14444 
0.390 
14445 
0.310 
14451 
0.353 
14452 
0.324 
14453 
0.316 
14454 
0.257 
14455 
0.196 
14511 
0.551 
14512 
0.532 
14513 
0.527 
14514 
0.457 
14515 
0.384 
14521 
0.518 
14522 
0.486 
14523 
0.478 
14524 
0.416 
14525 
0.351 
14531 
0.510 
14532 
0.475 
14533 
0.466 
14534 
0.406 
14535 
0.343 
14541 
0.425 
14542 
0.396 
14543 
0.389 
14544 
0.331 
14545 
0.270 
14551 
0.297 
14552 
0.278 
14553 
0.273 
14554 
0.217 
14555 
0.160 
15111 
0.529 
15112 
0.516 
15113 
0.512 
15114 
0.435 
15115 
0.355 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 100 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
15121 
0.503 
15122 
0.482 
15123 
0.477 
15124 
0.404 
15125 
0.328 
15131 
0.496 
15132 
0.474 
15133 
0.468 
15134 
0.396 
15135 
0.321 
15141 
0.405 
15142 
0.386 
15143 
0.381 
15144 
0.313 
15145 
0.242 
15151 
0.268 
15152 
0.255 
15153 
0.251 
15154 
0.188 
15155 
0.123 
15211 
0.529 
15212 
0.509 
15213 
0.503 
15214 
0.430 
15215 
0.354 
15221 
0.496 
15222 
0.463 
15223 
0.454 
15224 
0.389 
15225 
0.321 
15231 
0.487 
15232 
0.452 
15233 
0.442 
15234 
0.379 
15235 
0.312 
15241 
0.400 
15242 
0.370 
15243 
0.362 
15244 
0.301 
15245 
0.237 
15251 
0.268 
15252 
0.248 
15253 
0.242 
15254 
0.184 
15255 
0.123 
15311 
0.529 
15312 
0.507 
15313 
0.501 
15314 
0.429 
15315 
0.354 
15321 
0.494 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 101 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
15322 
0.458 
15323 
0.449 
15324 
0.385 
15325 
0.319 
15331 
0.485 
15332 
0.446 
15333 
0.436 
15334 
0.374 
15335 
0.310 
15341 
0.398 
15342 
0.366 
15343 
0.358 
15344 
0.298 
15345 
0.235 
15351 
0.268 
15352 
0.246 
15353 
0.240 
15354 
0.183 
15355 
0.123 
15411 
0.497 
15412 
0.478 
15413 
0.472 
15414 
0.403 
15415 
0.332 
15421 
0.464 
15422 
0.434 
15423 
0.426 
15424 
0.364 
15425 
0.299 
15431 
0.456 
15432 
0.423 
15433 
0.414 
15434 
0.354 
15435 
0.291 
15441 
0.372 
15442 
0.344 
15443 
0.337 
15444 
0.279 
15445 
0.219 
15451 
0.245 
15452 
0.226 
15453 
0.221 
15454 
0.167 
15455 
0.110 
15511 
0.431 
15512 
0.418 
15513 
0.414 
15514 
0.351 
15515 
0.286 
15521 
0.404 
15522 
0.384 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 102 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
15523 
0.379 
15524 
0.320 
15525 
0.260 
15531 
0.397 
15532 
0.376 
15533 
0.370 
15534 
0.313 
15535 
0.253 
15541 
0.318 
15542 
0.300 
15543 
0.295 
15544 
0.241 
15545 
0.186 
15551 
0.199 
15552 
0.186 
15553 
0.182 
15554 
0.134 
15555 
0.084 
21111 
0.880 
21112 
0.840 
21113 
0.830 
21114 
0.690 
21115 
0.544 
21121 
0.826 
21122 
0.790 
21123 
0.780 
21124 
0.648 
21125 
0.511 
21131 
0.813 
21132 
0.777 
21133 
0.768 
21134 
0.638 
21135 
0.502 
21141 
0.671 
21142 
0.641 
21143 
0.634 
21144 
0.526 
21145 
0.415 
21151 
0.457 
21152 
0.437 
21153 
0.432 
21154 
0.359 
21155 
0.283 
21211 
0.853 
21212 
0.816 
21213 
0.807 
21214 
0.675 
21215 
0.538 
21221 
0.803 
21222 
0.756 
21223 
0.744 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 103 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
21224 
0.620 
21225 
0.491 
21231 
0.790 
21232 
0.741 
21233 
0.728 
21234 
0.606 
21235 
0.480 
21241 
0.655 
21242 
0.612 
21243 
0.601 
21244 
0.502 
21245 
0.398 
21251 
0.451 
21252 
0.418 
21253 
0.409 
21254 
0.344 
21255 
0.276 
21311 
0.846 
21312 
0.810 
21313 
0.801 
21314 
0.671 
21315 
0.536 
21321 
0.797 
21322 
0.748 
21323 
0.735 
21324 
0.613 
21325 
0.486 
21331 
0.785 
21332 
0.732 
21333 
0.719 
21334 
0.599 
21335 
0.474 
21341 
0.651 
21342 
0.605 
21343 
0.593 
21344 
0.495 
21345 
0.394 
21351 
0.449 
21352 
0.413 
21353 
0.404 
21354 
0.340 
21355 
0.274 
21411 
0.772 
21412 
0.741 
21413 
0.733 
21414 
0.622 
21415 
0.507 
21421 
0.728 
21422 
0.684 
21423 
0.673 
21424 
0.569 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 104 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
21425 
0.462 
21431 
0.717 
21432 
0.670 
21433 
0.658 
21434 
0.556 
21435 
0.451 
21441 
0.598 
21442 
0.558 
21443 
0.547 
21444 
0.462 
21445 
0.373 
21451 
0.420 
21452 
0.389 
21453 
0.381 
21454 
0.319 
21455 
0.255 
21511 
0.620 
21512 
0.600 
21513 
0.595 
21514 
0.522 
21515 
0.446 
21521 
0.586 
21522 
0.554 
21523 
0.546 
21524 
0.480 
21525 
0.412 
21531 
0.578 
21532 
0.543 
21533 
0.534 
21534 
0.470 
21535 
0.404 
21541 
0.491 
21542 
0.462 
21543 
0.454 
21544 
0.392 
21545 
0.329 
21551 
0.359 
21552 
0.339 
21553 
0.334 
21554 
0.276 
21555 
0.215 
22111 
0.823 
22112 
0.786 
22113 
0.777 
22114 
0.645 
22115 
0.507 
22121 
0.772 
22122 
0.725 
22123 
0.713 
22124 
0.589 
22125 
0.461 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 105 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
22131 
0.760 
22132 
0.710 
22133 
0.697 
22134 
0.575 
22135 
0.449 
22141 
0.624 
22142 
0.581 
22143 
0.570 
22144 
0.471 
22145 
0.368 
22151 
0.420 
22152 
0.387 
22153 
0.379 
22154 
0.314 
22155 
0.246 
22211 
0.799 
22212 
0.751 
22213 
0.739 
22214 
0.616 
22215 
0.487 
22221 
0.738 
22222 
0.678 
22223 
0.662 
22224 
0.547 
22225 
0.427 
22231 
0.723 
22232 
0.659 
22233 
0.643 
22234 
0.530 
22235 
0.412 
22241 
0.594 
22242 
0.537 
22243 
0.523 
22244 
0.432 
22245 
0.338 
22251 
0.400 
22252 
0.354 
22253 
0.342 
22254 
0.285 
22255 
0.226 
22311 
0.793 
22312 
0.743 
22313 
0.730 
22314 
0.609 
22315 
0.483 
22321 
0.729 
22322 
0.666 
22323 
0.649 
22324 
0.536 
22325 
0.419 
22331 
0.714 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 106 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
22332 
0.647 
22333 
0.629 
22334 
0.518 
22335 
0.403 
22341 
0.587 
22342 
0.527 
22343 
0.511 
22344 
0.422 
22345 
0.330 
22351 
0.396 
22352 
0.346 
22353 
0.333 
22354 
0.278 
22355 
0.221 
22411 
0.724 
22412 
0.680 
22413 
0.668 
22414 
0.565 
22415 
0.459 
22421 
0.666 
22422 
0.608 
22423 
0.593 
22424 
0.498 
22425 
0.400 
22431 
0.652 
22432 
0.590 
22433 
0.574 
22434 
0.482 
22435 
0.386 
22441 
0.540 
22442 
0.485 
22443 
0.471 
22444 
0.394 
22445 
0.314 
22451 
0.372 
22452 
0.327 
22453 
0.316 
22454 
0.262 
22455 
0.207 
22511 
0.583 
22512 
0.550 
22513 
0.542 
22514 
0.477 
22515 
0.409 
22521 
0.537 
22522 
0.490 
22523 
0.478 
22524 
0.421 
22525 
0.362 
22531 
0.525 
22532 
0.475 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 107 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
22533 
0.462 
22534 
0.407 
22535 
0.351 
22541 
0.444 
22542 
0.401 
22543 
0.390 
22544 
0.337 
22545 
0.282 
22551 
0.322 
22552 
0.289 
22553 
0.281 
22554 
0.230 
22555 
0.178 
23111 
0.811 
23112 
0.775 
23113 
0.766 
23114 
0.635 
23115 
0.500 
23121 
0.761 
23122 
0.712 
23123 
0.699 
23124 
0.577 
23125 
0.451 
23131 
0.749 
23132 
0.696 
23133 
0.683 
23134 
0.563 
23135 
0.439 
23141 
0.615 
23142 
0.569 
23143 
0.557 
23144 
0.460 
23145 
0.359 
23151 
0.413 
23152 
0.377 
23153 
0.368 
23154 
0.305 
23155 
0.239 
23211 
0.788 
23212 
0.738 
23213 
0.726 
23214 
0.604 
23215 
0.477 
23221 
0.725 
23222 
0.662 
23223 
0.645 
23224 
0.532 
23225 
0.414 
23231 
0.709 
23232 
0.643 
23233 
0.626 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 108 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
23234 
0.514 
23235 
0.399 
23241 
0.582 
23242 
0.522 
23243 
0.507 
23244 
0.418 
23245 
0.326 
23251 
0.390 
23252 
0.341 
23253 
0.328 
23254 
0.273 
23255 
0.216 
23311 
0.782 
23312 
0.729 
23313 
0.716 
23314 
0.596 
23315 
0.472 
23321 
0.716 
23322 
0.649 
23323 
0.632 
23324 
0.521 
23325 
0.405 
23331 
0.700 
23332 
0.630 
23333 
0.611 
23334 
0.502 
23335 
0.389 
23341 
0.574 
23342 
0.511 
23343 
0.494 
23344 
0.408 
23345 
0.318 
23351 
0.385 
23352 
0.332 
23353 
0.319 
23354 
0.266 
23355 
0.211 
23411 
0.714 
23412 
0.667 
23413 
0.655 
23414 
0.554 
23415 
0.449 
23421 
0.654 
23422 
0.593 
23423 
0.577 
23424 
0.484 
23425 
0.388 
23431 
0.639 
23432 
0.574 
23433 
0.558 
23434 
0.467 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 109 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
23435 
0.373 
23441 
0.528 
23442 
0.471 
23443 
0.456 
23444 
0.381 
23445 
0.303 
23451 
0.362 
23452 
0.315 
23453 
0.303 
23454 
0.251 
23455 
0.197 
23511 
0.576 
23512 
0.540 
23513 
0.531 
23514 
0.468 
23515 
0.402 
23521 
0.527 
23522 
0.477 
23523 
0.464 
23524 
0.409 
23525 
0.352 
23531 
0.515 
23532 
0.462 
23533 
0.448 
23534 
0.395 
23535 
0.340 
23541 
0.435 
23542 
0.389 
23543 
0.377 
23544 
0.325 
23545 
0.272 
23551 
0.315 
23552 
0.279 
23553 
0.270 
23554 
0.221 
23555 
0.170 
24111 
0.741 
24112 
0.709 
24113 
0.701 
24114 
0.584 
24115 
0.463 
24121 
0.695 
24122 
0.650 
24123 
0.638 
24124 
0.530 
24125 
0.418 
24131 
0.684 
24132 
0.636 
24133 
0.623 
24134 
0.517 
24135 
0.407 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 110 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
24141 
0.561 
24142 
0.519 
24143 
0.508 
24144 
0.420 
24145 
0.328 
24151 
0.376 
24152 
0.344 
24153 
0.336 
24154 
0.274 
24155 
0.210 
24211 
0.722 
24212 
0.677 
24213 
0.665 
24214 
0.557 
24215 
0.444 
24221 
0.663 
24222 
0.604 
24223 
0.589 
24224 
0.489 
24225 
0.385 
24231 
0.648 
24232 
0.586 
24233 
0.570 
24234 
0.472 
24235 
0.371 
24241 
0.532 
24242 
0.477 
24243 
0.462 
24244 
0.382 
24245 
0.299 
24251 
0.357 
24252 
0.312 
24253 
0.301 
24254 
0.247 
24255 
0.191 
24311 
0.717 
24312 
0.669 
24313 
0.656 
24314 
0.550 
24315 
0.440 
24321 
0.655 
24322 
0.593 
24323 
0.577 
24324 
0.479 
24325 
0.377 
24331 
0.640 
24332 
0.574 
24333 
0.557 
24334 
0.461 
24335 
0.362 
24341 
0.525 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 111 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
24342 
0.466 
24343 
0.451 
24344 
0.373 
24345 
0.292 
24351 
0.353 
24352 
0.305 
24353 
0.292 
24354 
0.240 
24355 
0.186 
24411 
0.659 
24412 
0.616 
24413 
0.604 
24414 
0.513 
24415 
0.418 
24421 
0.602 
24422 
0.545 
24423 
0.531 
24424 
0.447 
24425 
0.361 
24431 
0.588 
24432 
0.528 
24433 
0.512 
24434 
0.431 
24435 
0.347 
24441 
0.485 
24442 
0.432 
24443 
0.418 
24444 
0.349 
24445 
0.277 
24451 
0.331 
24452 
0.288 
24453 
0.277 
24454 
0.226 
24455 
0.173 
24511 
0.539 
24512 
0.507 
24513 
0.499 
24514 
0.437 
24515 
0.372 
24521 
0.494 
24522 
0.448 
24523 
0.437 
24524 
0.383 
24525 
0.327 
24531 
0.483 
24532 
0.434 
24533 
0.421 
24534 
0.369 
24535 
0.315 
24541 
0.404 
24542 
0.362 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 112 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
24543 
0.351 
24544 
0.301 
24545 
0.248 
24551 
0.286 
24552 
0.254 
24553 
0.245 
24554 
0.197 
24555 
0.148 
25111 
0.523 
25112 
0.503 
25113 
0.498 
25114 
0.425 
25115 
0.349 
25121 
0.490 
25122 
0.457 
25123 
0.449 
25124 
0.383 
25125 
0.315 
25131 
0.481 
25132 
0.446 
25133 
0.437 
25134 
0.373 
25135 
0.307 
25141 
0.394 
25142 
0.365 
25143 
0.357 
25144 
0.295 
25145 
0.232 
25151 
0.262 
25152 
0.242 
25153 
0.237 
25154 
0.179 
25155 
0.118 
25211 
0.517 
25212 
0.484 
25213 
0.475 
25214 
0.410 
25215 
0.342 
25221 
0.470 
25222 
0.424 
25223 
0.412 
25224 
0.355 
25225 
0.296 
25231 
0.459 
25232 
0.409 
25233 
0.397 
25234 
0.342 
25235 
0.284 
25241 
0.377 
25242 
0.335 
25243 
0.324 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 113 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
25244 
0.270 
25245 
0.215 
25251 
0.255 
25252 
0.223 
25253 
0.214 
25254 
0.164 
25255 
0.111 
25311 
0.515 
25312 
0.479 
25313 
0.470 
25314 
0.406 
25315 
0.340 
25321 
0.465 
25322 
0.416 
25323 
0.403 
25324 
0.348 
25325 
0.291 
25331 
0.453 
25332 
0.400 
25333 
0.387 
25334 
0.334 
25335 
0.279 
25341 
0.373 
25342 
0.328 
25343 
0.316 
25344 
0.264 
25345 
0.211 
25351 
0.253 
25352 
0.218 
25353 
0.209 
25354 
0.160 
25355 
0.109 
25411 
0.486 
25412 
0.455 
25413 
0.447 
25414 
0.385 
25415 
0.320 
25421 
0.441 
25422 
0.397 
25423 
0.386 
25424 
0.332 
25425 
0.276 
25431 
0.430 
25432 
0.383 
25433 
0.371 
25434 
0.319 
25435 
0.265 
25441 
0.352 
25442 
0.311 
25443 
0.301 
25444 
0.251 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 114 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
25445 
0.199 
25451 
0.234 
25452 
0.203 
25453 
0.195 
25454 
0.148 
25455 
0.099 
25511 
0.425 
25512 
0.405 
25513 
0.400 
25514 
0.341 
25515 
0.280 
25521 
0.391 
25522 
0.359 
25523 
0.350 
25524 
0.299 
25525 
0.247 
25531 
0.383 
25532 
0.347 
25533 
0.338 
25534 
0.289 
25535 
0.238 
25541 
0.308 
25542 
0.278 
25543 
0.270 
25544 
0.223 
25545 
0.174 
25551 
0.194 
25552 
0.173 
25553 
0.168 
25554 
0.124 
25555 
0.078 
31111 
0.854 
31112 
0.833 
31113 
0.827 
31114 
0.688 
31115 
0.543 
31121 
0.819 
31122 
0.783 
31123 
0.774 
31124 
0.643 
31125 
0.508 
31131 
0.810 
31132 
0.771 
31133 
0.761 
31134 
0.632 
31135 
0.499 
31141 
0.669 
31142 
0.637 
31143 
0.628 
31144 
0.522 
31145 
0.412 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 115 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
31151 
0.456 
31152 
0.435 
31153 
0.429 
31154 
0.357 
31155 
0.282 
31211 
0.845 
31212 
0.810 
31213 
0.801 
31214 
0.670 
31215 
0.535 
31221 
0.796 
31222 
0.748 
31223 
0.735 
31224 
0.613 
31225 
0.486 
31231 
0.784 
31232 
0.732 
31233 
0.719 
31234 
0.598 
31235 
0.473 
31241 
0.650 
31242 
0.604 
31243 
0.593 
31244 
0.495 
31245 
0.393 
31251 
0.448 
31252 
0.413 
31253 
0.403 
31254 
0.340 
31255 
0.273 
31311 
0.843 
31312 
0.804 
31313 
0.794 
31314 
0.666 
31315 
0.533 
31321 
0.791 
31322 
0.739 
31323 
0.725 
31324 
0.605 
31325 
0.480 
31331 
0.778 
31332 
0.723 
31333 
0.708 
31334 
0.590 
31335 
0.467 
31341 
0.645 
31342 
0.597 
31343 
0.584 
31344 
0.488 
31345 
0.389 
31351 
0.446 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 116 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
31352 
0.407 
31353 
0.397 
31354 
0.335 
31355 
0.271 
31411 
0.769 
31412 
0.736 
31413 
0.728 
31414 
0.618 
31415 
0.504 
31421 
0.723 
31422 
0.676 
31423 
0.664 
31424 
0.563 
31425 
0.457 
31431 
0.711 
31432 
0.662 
31433 
0.649 
31434 
0.549 
31435 
0.445 
31441 
0.594 
31442 
0.551 
31443 
0.539 
31444 
0.455 
31445 
0.368 
31451 
0.417 
31452 
0.384 
31453 
0.375 
31454 
0.315 
31455 
0.252 
31511 
0.619 
31512 
0.598 
31513 
0.592 
31514 
0.520 
31515 
0.445 
31521 
0.584 
31522 
0.549 
31523 
0.540 
31524 
0.476 
31525 
0.410 
31531 
0.575 
31532 
0.537 
31533 
0.527 
31534 
0.465 
31535 
0.401 
31541 
0.488 
31542 
0.457 
31543 
0.449 
31544 
0.389 
31545 
0.326 
31551 
0.358 
31552 
0.337 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 117 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
31553 
0.331 
31554 
0.274 
31555 
0.214 
32111 
0.816 
32112 
0.780 
32113 
0.770 
32114 
0.640 
32115 
0.505 
32121 
0.766 
32122 
0.716 
32123 
0.704 
32124 
0.582 
32125 
0.455 
32131 
0.753 
32132 
0.701 
32133 
0.687 
32134 
0.567 
32135 
0.443 
32141 
0.619 
32142 
0.573 
32143 
0.561 
32144 
0.464 
32145 
0.364 
32151 
0.418 
32152 
0.382 
32153 
0.372 
32154 
0.309 
32155 
0.244 
32211 
0.792 
32212 
0.743 
32213 
0.730 
32214 
0.608 
32215 
0.482 
32221 
0.729 
32222 
0.666 
32223 
0.650 
32224 
0.536 
32225 
0.419 
32231 
0.714 
32232 
0.647 
32233 
0.630 
32234 
0.518 
32235 
0.403 
32241 
0.586 
32242 
0.527 
32243 
0.511 
32244 
0.422 
32245 
0.330 
32251 
0.395 
32252 
0.346 
32253 
0.333 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 118 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
32254 
0.278 
32255 
0.221 
32311 
0.786 
32312 
0.734 
32313 
0.720 
32314 
0.600 
32315 
0.476 
32321 
0.720 
32322 
0.654 
32323 
0.636 
32324 
0.525 
32325 
0.410 
32331 
0.704 
32332 
0.634 
32333 
0.616 
32334 
0.506 
32335 
0.393 
32341 
0.578 
32342 
0.515 
32343 
0.499 
32344 
0.412 
32345 
0.322 
32351 
0.389 
32352 
0.337 
32353 
0.323 
32354 
0.270 
32355 
0.215 
32411 
0.719 
32412 
0.672 
32413 
0.659 
32414 
0.558 
32415 
0.454 
32421 
0.658 
32422 
0.597 
32423 
0.581 
32424 
0.489 
32425 
0.392 
32431 
0.643 
32432 
0.579 
32433 
0.562 
32434 
0.471 
32435 
0.377 
32441 
0.533 
32442 
0.475 
32443 
0.460 
32444 
0.385 
32445 
0.307 
32451 
0.367 
32452 
0.319 
32453 
0.307 
32454 
0.255 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 119 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
32455 
0.202 
32511 
0.581 
32512 
0.545 
32513 
0.535 
32514 
0.472 
32515 
0.407 
32521 
0.531 
32522 
0.482 
32523 
0.469 
32524 
0.414 
32525 
0.357 
32531 
0.519 
32532 
0.466 
32533 
0.452 
32534 
0.399 
32535 
0.344 
32541 
0.440 
32542 
0.393 
32543 
0.381 
32544 
0.330 
32545 
0.277 
32551 
0.320 
32552 
0.284 
32553 
0.274 
32554 
0.226 
32555 
0.175 
33111 
0.808 
33112 
0.769 
33113 
0.759 
33114 
0.630 
33115 
0.497 
33121 
0.755 
33122 
0.703 
33123 
0.689 
33124 
0.569 
33125 
0.445 
33131 
0.742 
33132 
0.687 
33133 
0.672 
33134 
0.554 
33135 
0.432 
33141 
0.609 
33142 
0.561 
33143 
0.548 
33144 
0.453 
33145 
0.354 
33151 
0.410 
33152 
0.371 
33153 
0.361 
33154 
0.300 
33155 
0.236 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 120 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
33211 
0.782 
33212 
0.729 
33213 
0.716 
33214 
0.596 
33215 
0.471 
33221 
0.716 
33222 
0.650 
33223 
0.633 
33224 
0.521 
33225 
0.405 
33231 
0.700 
33232 
0.630 
33233 
0.612 
33234 
0.502 
33235 
0.389 
33241 
0.574 
33242 
0.511 
33243 
0.495 
33244 
0.408 
33245 
0.317 
33251 
0.384 
33252 
0.332 
33253 
0.319 
33254 
0.265 
33255 
0.210 
33311 
0.775 
33312 
0.720 
33313 
0.705 
33314 
0.587 
33315 
0.465 
33321 
0.706 
33322 
0.637 
33323 
0.619 
33324 
0.509 
33325 
0.395 
33331 
0.689 
33332 
0.616 
33333 
0.597 
33334 
0.490 
33335 
0.378 
33341 
0.565 
33342 
0.499 
33343 
0.482 
33344 
0.397 
33345 
0.309 
33351 
0.378 
33352 
0.323 
33353 
0.308 
33354 
0.257 
33355 
0.204 
33411 
0.709 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 121 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
33412 
0.659 
33413 
0.646 
33414 
0.546 
33415 
0.443 
33421 
0.645 
33422 
0.581 
33423 
0.565 
33424 
0.474 
33425 
0.379 
33431 
0.630 
33432 
0.562 
33433 
0.545 
33434 
0.456 
33435 
0.363 
33441 
0.520 
33442 
0.460 
33443 
0.444 
33444 
0.371 
33445 
0.295 
33451 
0.356 
33452 
0.306 
33453 
0.293 
33454 
0.244 
33455 
0.192 
33511 
0.573 
33512 
0.534 
33513 
0.524 
33514 
0.463 
33515 
0.399 
33521 
0.521 
33522 
0.468 
33523 
0.454 
33524 
0.401 
33525 
0.346 
33531 
0.508 
33532 
0.452 
33533 
0.437 
33534 
0.386 
33535 
0.333 
33541 
0.430 
33542 
0.380 
33543 
0.368 
33544 
0.318 
33545 
0.267 
33551 
0.312 
33552 
0.273 
33553 
0.263 
33554 
0.216 
33555 
0.167 
34111 
0.739 
34112 
0.704 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 122 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
34113 
0.695 
34114 
0.580 
34115 
0.461 
34121 
0.690 
34122 
0.642 
34123 
0.629 
34124 
0.523 
34125 
0.413 
34131 
0.678 
34132 
0.627 
34133 
0.613 
34134 
0.509 
34135 
0.401 
34141 
0.556 
34142 
0.512 
34143 
0.500 
34144 
0.413 
34145 
0.324 
34151 
0.374 
34152 
0.339 
34153 
0.330 
34154 
0.270 
34155 
0.207 
34211 
0.717 
34212 
0.668 
34213 
0.656 
34214 
0.550 
34215 
0.439 
34221 
0.655 
34222 
0.593 
34223 
0.577 
34224 
0.479 
34225 
0.377 
34231 
0.639 
34232 
0.574 
34233 
0.557 
34234 
0.461 
34235 
0.362 
34241 
0.525 
34242 
0.466 
34243 
0.451 
34244 
0.373 
34245 
0.291 
34251 
0.352 
34252 
0.304 
34253 
0.292 
34254 
0.240 
34255 
0.186 
34311 
0.711 
34312 
0.660 
34313 
0.646 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 123 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
34314 
0.542 
34315 
0.434 
34321 
0.646 
34322 
0.581 
34323 
0.564 
34324 
0.468 
34325 
0.369 
34331 
0.630 
34332 
0.561 
34333 
0.543 
34334 
0.450 
34335 
0.352 
34341 
0.517 
34342 
0.455 
34343 
0.439 
34344 
0.363 
34345 
0.284 
34351 
0.347 
34352 
0.296 
34353 
0.282 
34354 
0.232 
34355 
0.180 
34411 
0.654 
34412 
0.608 
34413 
0.596 
34414 
0.506 
34415 
0.413 
34421 
0.594 
34422 
0.535 
34423 
0.519 
34424 
0.438 
34425 
0.353 
34431 
0.580 
34432 
0.516 
34433 
0.500 
34434 
0.421 
34435 
0.338 
34441 
0.478 
34442 
0.422 
34443 
0.407 
34444 
0.340 
34445 
0.270 
34451 
0.326 
34452 
0.280 
34453 
0.268 
34454 
0.219 
34455 
0.169 
34511 
0.537 
34512 
0.502 
34513 
0.493 
34514 
0.433 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 124 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
34515 
0.370 
34521 
0.489 
34522 
0.440 
34523 
0.428 
34524 
0.375 
34525 
0.321 
34531 
0.477 
34532 
0.425 
34533 
0.411 
34534 
0.361 
34535 
0.309 
34541 
0.400 
34542 
0.354 
34543 
0.343 
34544 
0.294 
34545 
0.244 
34551 
0.283 
34552 
0.248 
34553 
0.239 
34554 
0.193 
34555 
0.145 
35111 
0.522 
35112 
0.501 
35113 
0.495 
35114 
0.423 
35115 
0.348 
35121 
0.487 
35122 
0.452 
35123 
0.443 
35124 
0.379 
35125 
0.313 
35131 
0.478 
35132 
0.440 
35133 
0.430 
35134 
0.368 
35135 
0.304 
35141 
0.391 
35142 
0.360 
35143 
0.352 
35144 
0.292 
35145 
0.229 
35151 
0.261 
35152 
0.240 
35153 
0.234 
35154 
0.177 
35155 
0.117 
35211 
0.514 
35212 
0.479 
35213 
0.469 
35214 
0.406 
35215 
0.339 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 125 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
35221 
0.465 
35222 
0.416 
35223 
0.403 
35224 
0.348 
35225 
0.290 
35231 
0.452 
35232 
0.400 
35233 
0.387 
35234 
0.334 
35235 
0.278 
35241 
0.372 
35242 
0.327 
35243 
0.315 
35244 
0.264 
35245 
0.210 
35251 
0.252 
35252 
0.217 
35253 
0.208 
35254 
0.159 
35255 
0.108 
35311 
0.512 
35312 
0.473 
35313 
0.463 
35314 
0.401 
35315 
0.337 
35321 
0.459 
35322 
0.407 
35323 
0.393 
35324 
0.340 
35325 
0.285 
35331 
0.446 
35332 
0.391 
35333 
0.376 
35334 
0.325 
35335 
0.272 
35341 
0.368 
35342 
0.319 
35343 
0.307 
35344 
0.257 
35345 
0.206 
35351 
0.250 
35352 
0.212 
35353 
0.202 
35354 
0.155 
35355 
0.106 
35411 
0.483 
35412 
0.450 
35413 
0.441 
35414 
0.381 
35415 
0.318 
35421 
0.436 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 126 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
35422 
0.389 
35423 
0.377 
35424 
0.325 
35425 
0.271 
35431 
0.424 
35432 
0.374 
35433 
0.361 
35434 
0.312 
35435 
0.260 
35441 
0.347 
35442 
0.304 
35443 
0.293 
35444 
0.245 
35445 
0.195 
35451 
0.231 
35452 
0.198 
35453 
0.190 
35454 
0.144 
35455 
0.097 
35511 
0.424 
35512 
0.403 
35513 
0.397 
35514 
0.339 
35515 
0.279 
35521 
0.389 
35522 
0.353 
35523 
0.344 
35524 
0.295 
35525 
0.244 
35531 
0.380 
35532 
0.341 
35533 
0.331 
35534 
0.284 
35535 
0.235 
35541 
0.305 
35542 
0.273 
35543 
0.265 
35544 
0.219 
35545 
0.172 
35551 
0.193 
35552 
0.171 
35553 
0.165 
35554 
0.122 
35555 
0.077 
41111 
0.824 
41112 
0.804 
41113 
0.798 
41114 
0.663 
41115 
0.523 
41121 
0.790 
41122 
0.755 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 127 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
41123 
0.747 
41124 
0.620 
41125 
0.489 
41131 
0.781 
41132 
0.744 
41133 
0.734 
41134 
0.609 
41135 
0.480 
41141 
0.643 
41142 
0.612 
41143 
0.604 
41144 
0.501 
41145 
0.394 
41151 
0.436 
41152 
0.415 
41153 
0.410 
41154 
0.339 
41155 
0.264 
41211 
0.816 
41212 
0.782 
41213 
0.773 
41214 
0.647 
41215 
0.516 
41221 
0.769 
41222 
0.721 
41223 
0.708 
41224 
0.590 
41225 
0.468 
41231 
0.757 
41232 
0.706 
41233 
0.692 
41234 
0.576 
41235 
0.456 
41241 
0.626 
41242 
0.581 
41243 
0.570 
41244 
0.475 
41245 
0.376 
41251 
0.429 
41252 
0.394 
41253 
0.386 
41254 
0.322 
41255 
0.256 
41311 
0.814 
41312 
0.777 
41313 
0.767 
41314 
0.643 
41315 
0.514 
41321 
0.763 
41322 
0.712 
41323 
0.699 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 128 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
41324 
0.583 
41325 
0.462 
41331 
0.751 
41332 
0.696 
41333 
0.682 
41334 
0.568 
41335 
0.450 
41341 
0.621 
41342 
0.574 
41343 
0.561 
41344 
0.468 
41345 
0.371 
41351 
0.427 
41352 
0.389 
41353 
0.380 
41354 
0.318 
41355 
0.254 
41411 
0.744 
41412 
0.711 
41413 
0.703 
41414 
0.596 
41415 
0.485 
41421 
0.698 
41422 
0.653 
41423 
0.641 
41424 
0.542 
41425 
0.439 
41431 
0.687 
41432 
0.638 
41433 
0.625 
41434 
0.529 
41435 
0.428 
41441 
0.572 
41442 
0.530 
41443 
0.519 
41444 
0.437 
41445 
0.351 
41451 
0.398 
41452 
0.366 
41453 
0.358 
41454 
0.298 
41455 
0.236 
41511 
0.599 
41512 
0.578 
41513 
0.573 
41514 
0.501 
41515 
0.427 
41521 
0.565 
41522 
0.531 
41523 
0.522 
41524 
0.459 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 129 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
41525 
0.393 
41531 
0.556 
41532 
0.519 
41533 
0.509 
41534 
0.448 
41535 
0.384 
41541 
0.470 
41542 
0.439 
41543 
0.431 
41544 
0.372 
41545 
0.310 
41551 
0.340 
41552 
0.320 
41553 
0.314 
41554 
0.257 
41555 
0.198 
42111 
0.787 
42112 
0.752 
42113 
0.743 
42114 
0.617 
42115 
0.486 
42121 
0.738 
42122 
0.690 
42123 
0.677 
42124 
0.560 
42125 
0.437 
42131 
0.726 
42132 
0.674 
42133 
0.661 
42134 
0.545 
42135 
0.425 
42141 
0.595 
42142 
0.550 
42143 
0.539 
42144 
0.444 
42145 
0.346 
42151 
0.399 
42152 
0.364 
42153 
0.355 
42154 
0.292 
42155 
0.227 
42211 
0.764 
42212 
0.716 
42213 
0.704 
42214 
0.586 
42215 
0.464 
42221 
0.703 
42222 
0.641 
42223 
0.624 
42224 
0.515 
42225 
0.402 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 130 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
42231 
0.687 
42232 
0.622 
42233 
0.605 
42234 
0.498 
42235 
0.386 
42241 
0.563 
42242 
0.505 
42243 
0.490 
42244 
0.403 
42245 
0.314 
42251 
0.377 
42252 
0.329 
42253 
0.316 
42254 
0.262 
42255 
0.205 
42311 
0.759 
42312 
0.707 
42313 
0.694 
42314 
0.578 
42315 
0.459 
42321 
0.694 
42322 
0.629 
42323 
0.612 
42324 
0.504 
42325 
0.393 
42331 
0.678 
42332 
0.609 
42333 
0.591 
42334 
0.486 
42335 
0.377 
42341 
0.555 
42342 
0.494 
42343 
0.477 
42344 
0.393 
42345 
0.306 
42351 
0.372 
42352 
0.320 
42353 
0.307 
42354 
0.254 
42355 
0.200 
42411 
0.694 
42412 
0.648 
42413 
0.636 
42414 
0.538 
42415 
0.436 
42421 
0.635 
42422 
0.575 
42423 
0.559 
42424 
0.469 
42425 
0.376 
42431 
0.620 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 131 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
42432 
0.557 
42433 
0.540 
42434 
0.452 
42435 
0.361 
42441 
0.512 
42442 
0.455 
42443 
0.441 
42444 
0.367 
42445 
0.291 
42451 
0.349 
42452 
0.303 
42453 
0.291 
42454 
0.240 
42455 
0.187 
42511 
0.562 
42512 
0.527 
42513 
0.518 
42514 
0.455 
42515 
0.390 
42521 
0.513 
42522 
0.465 
42523 
0.452 
42524 
0.398 
42525 
0.341 
42531 
0.501 
42532 
0.449 
42533 
0.436 
42534 
0.383 
42535 
0.329 
42541 
0.422 
42542 
0.377 
42543 
0.365 
42544 
0.314 
42545 
0.261 
42551 
0.303 
42552 
0.268 
42553 
0.259 
42554 
0.210 
42555 
0.160 
43111 
0.779 
43112 
0.741 
43113 
0.732 
43114 
0.607 
43115 
0.478 
43121 
0.728 
43122 
0.677 
43123 
0.663 
43124 
0.547 
43125 
0.427 
43131 
0.715 
43132 
0.660 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 132 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
43133 
0.646 
43134 
0.533 
43135 
0.414 
43141 
0.585 
43142 
0.538 
43143 
0.525 
43144 
0.433 
43145 
0.336 
43151 
0.391 
43152 
0.353 
43153 
0.344 
43154 
0.282 
43155 
0.219 
43211 
0.754 
43212 
0.703 
43213 
0.690 
43214 
0.574 
43215 
0.454 
43221 
0.689 
43222 
0.625 
43223 
0.608 
43224 
0.500 
43225 
0.389 
43231 
0.673 
43232 
0.605 
43233 
0.587 
43234 
0.482 
43235 
0.372 
43241 
0.551 
43242 
0.489 
43243 
0.473 
43244 
0.389 
43245 
0.301 
43251 
0.367 
43252 
0.316 
43253 
0.302 
43254 
0.249 
43255 
0.195 
43311 
0.748 
43312 
0.693 
43313 
0.679 
43314 
0.566 
43315 
0.448 
43321 
0.680 
43322 
0.612 
43323 
0.594 
43324 
0.488 
43325 
0.379 
43331 
0.663 
43332 
0.591 
43333 
0.573 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 133 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
43334 
0.469 
43335 
0.362 
43341 
0.542 
43342 
0.477 
43343 
0.461 
43344 
0.378 
43345 
0.293 
43351 
0.361 
43352 
0.306 
43353 
0.292 
43354 
0.241 
43355 
0.189 
43411 
0.684 
43412 
0.635 
43413 
0.623 
43414 
0.526 
43415 
0.426 
43421 
0.622 
43422 
0.559 
43423 
0.543 
43424 
0.455 
43425 
0.363 
43431 
0.606 
43432 
0.540 
43433 
0.523 
43434 
0.437 
43435 
0.347 
43441 
0.500 
43442 
0.440 
43443 
0.425 
43444 
0.353 
43445 
0.279 
43451 
0.339 
43452 
0.290 
43453 
0.277 
43454 
0.228 
43455 
0.177 
43511 
0.554 
43512 
0.516 
43513 
0.507 
43514 
0.445 
43515 
0.382 
43521 
0.503 
43522 
0.452 
43523 
0.438 
43524 
0.385 
43525 
0.330 
43531 
0.490 
43532 
0.435 
43533 
0.421 
43534 
0.370 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 134 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
43535 
0.318 
43541 
0.412 
43542 
0.364 
43543 
0.352 
43544 
0.303 
43545 
0.252 
43551 
0.295 
43552 
0.257 
43553 
0.248 
43554 
0.201 
43555 
0.152 
44111 
0.712 
44112 
0.678 
44113 
0.669 
44114 
0.558 
44115 
0.442 
44121 
0.664 
44122 
0.618 
44123 
0.605 
44124 
0.502 
44125 
0.395 
44131 
0.653 
44132 
0.602 
44133 
0.589 
44134 
0.488 
44135 
0.384 
44141 
0.534 
44142 
0.490 
44143 
0.479 
44144 
0.394 
44145 
0.306 
44151 
0.355 
44152 
0.322 
44153 
0.313 
44154 
0.253 
44155 
0.190 
44211 
0.691 
44212 
0.644 
44213 
0.632 
44214 
0.529 
44215 
0.422 
44221 
0.630 
44222 
0.570 
44223 
0.554 
44224 
0.459 
44225 
0.361 
44231 
0.615 
44232 
0.551 
44233 
0.535 
44234 
0.442 
44235 
0.346 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 135 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
44241 
0.503 
44242 
0.446 
44243 
0.431 
44244 
0.355 
44245 
0.276 
44251 
0.335 
44252 
0.288 
44253 
0.276 
44254 
0.224 
44255 
0.170 
44311 
0.686 
44312 
0.636 
44313 
0.622 
44314 
0.521 
44315 
0.417 
44321 
0.622 
44322 
0.558 
44323 
0.541 
44324 
0.449 
44325 
0.352 
44331 
0.606 
44332 
0.539 
44333 
0.521 
44334 
0.430 
44335 
0.336 
44341 
0.496 
44342 
0.435 
44343 
0.419 
44344 
0.345 
44345 
0.268 
44351 
0.330 
44352 
0.279 
44353 
0.266 
44354 
0.217 
44355 
0.165 
44411 
0.631 
44412 
0.586 
44413 
0.574 
44414 
0.487 
44415 
0.396 
44421 
0.572 
44422 
0.514 
44423 
0.499 
44424 
0.419 
44425 
0.337 
44431 
0.558 
44432 
0.496 
44433 
0.480 
44434 
0.403 
44435 
0.322 
44441 
0.458 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 136 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
44442 
0.403 
44443 
0.389 
44444 
0.323 
44445 
0.255 
44451 
0.309 
44452 
0.264 
44453 
0.252 
44454 
0.204 
44455 
0.154 
44511 
0.518 
44512 
0.485 
44513 
0.476 
44514 
0.416 
44515 
0.353 
44521 
0.471 
44522 
0.424 
44523 
0.411 
44524 
0.360 
44525 
0.306 
44531 
0.460 
44532 
0.409 
44533 
0.395 
44534 
0.346 
44535 
0.294 
44541 
0.382 
44542 
0.338 
44543 
0.327 
44544 
0.279 
44545 
0.229 
44551 
0.266 
44552 
0.233 
44553 
0.224 
44554 
0.178 
44555 
0.131 
45111 
0.502 
45112 
0.481 
45113 
0.476 
45114 
0.404 
45115 
0.330 
45121 
0.468 
45122 
0.434 
45123 
0.425 
45124 
0.362 
45125 
0.296 
45131 
0.459 
45132 
0.422 
45133 
0.412 
45134 
0.351 
45135 
0.287 
45141 
0.373 
45142 
0.342 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 137 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
45143 
0.334 
45144 
0.275 
45145 
0.213 
45151 
0.243 
45152 
0.223 
45153 
0.217 
45154 
0.160 
45155 
0.101 
45211 
0.495 
45212 
0.460 
45213 
0.452 
45214 
0.388 
45215 
0.322 
45221 
0.447 
45222 
0.399 
45223 
0.387 
45224 
0.332 
45225 
0.274 
45231 
0.435 
45232 
0.384 
45233 
0.370 
45234 
0.318 
45235 
0.263 
45241 
0.355 
45242 
0.311 
45243 
0.299 
45244 
0.248 
45245 
0.195 
45251 
0.235 
45252 
0.201 
45253 
0.193 
45254 
0.144 
45255 
0.093 
45311 
0.493 
45312 
0.455 
45313 
0.446 
45314 
0.384 
45315 
0.320 
45321 
0.441 
45322 
0.390 
45323 
0.377 
45324 
0.324 
45325 
0.269 
45331 
0.429 
45332 
0.374 
45333 
0.360 
45334 
0.309 
45335 
0.257 
45341 
0.350 
45342 
0.303 
45343 
0.291 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 138 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
45344 
0.242 
45345 
0.191 
45351 
0.233 
45352 
0.196 
45353 
0.187 
45354 
0.140 
45355 
0.091 
45411 
0.464 
45412 
0.432 
45413 
0.424 
45414 
0.364 
45415 
0.302 
45421 
0.418 
45422 
0.373 
45423 
0.361 
45424 
0.310 
45425 
0.256 
45431 
0.407 
45432 
0.358 
45433 
0.345 
45434 
0.296 
45435 
0.245 
45441 
0.330 
45442 
0.288 
45443 
0.277 
45444 
0.229 
45445 
0.180 
45451 
0.215 
45452 
0.183 
45453 
0.175 
45454 
0.129 
45455 
0.082 
45511 
0.406 
45512 
0.386 
45513 
0.380 
45514 
0.323 
45515 
0.263 
45521 
0.372 
45522 
0.337 
45523 
0.328 
45524 
0.280 
45525 
0.229 
45531 
0.363 
45532 
0.325 
45533 
0.316 
45534 
0.269 
45535 
0.220 
45541 
0.289 
45542 
0.258 
45543 
0.250 
45544 
0.205 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 139 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
45545 
0.158 
45551 
0.177 
45552 
0.156 
45553 
0.150 
45554 
0.108 
45555 
0.064 
51111 
0.442 
51112 
0.429 
51113 
0.426 
51114 
0.349 
51115 
0.268 
51121 
0.416 
51122 
0.396 
51123 
0.391 
51124 
0.318 
51125 
0.242 
51131 
0.409 
51132 
0.388 
51133 
0.382 
51134 
0.310 
51135 
0.235 
51141 
0.318 
51142 
0.300 
51143 
0.295 
51144 
0.227 
51145 
0.156 
51151 
0.181 
51152 
0.168 
51153 
0.165 
51154 
0.102 
51155 
0.037 
51211 
0.442 
51212 
0.422 
51213 
0.417 
51214 
0.344 
51215 
0.268 
51221 
0.409 
51222 
0.377 
51223 
0.368 
51224 
0.303 
51225 
0.235 
51231 
0.400 
51232 
0.365 
51233 
0.356 
51234 
0.293 
51235 
0.226 
51241 
0.313 
51242 
0.284 
51243 
0.276 
51244 
0.215 
51245 
0.150 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 140 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
51251 
0.181 
51252 
0.161 
51253 
0.156 
51254 
0.097 
51255 
0.036 
51311 
0.442 
51312 
0.421 
51313 
0.415 
51314 
0.343 
51315 
0.268 
51321 
0.407 
51322 
0.372 
51323 
0.363 
51324 
0.299 
51325 
0.233 
51331 
0.398 
51332 
0.360 
51333 
0.350 
51334 
0.288 
51335 
0.224 
51341 
0.311 
51342 
0.280 
51343 
0.272 
51344 
0.211 
51345 
0.149 
51351 
0.181 
51352 
0.160 
51353 
0.154 
51354 
0.096 
51355 
0.036 
51411 
0.410 
51412 
0.391 
51413 
0.386 
51414 
0.317 
51415 
0.245 
51421 
0.378 
51422 
0.347 
51423 
0.340 
51424 
0.277 
51425 
0.213 
51431 
0.369 
51432 
0.337 
51433 
0.328 
51434 
0.268 
51435 
0.205 
51441 
0.285 
51442 
0.258 
51443 
0.251 
51444 
0.193 
51445 
0.132 
51451 
0.158 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 141 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
51452 
0.140 
51453 
0.135 
51454 
0.080 
51455 
0.023 
51511 
0.344 
51512 
0.331 
51513 
0.327 
51514 
0.264 
51515 
0.199 
51521 
0.318 
51522 
0.297 
51523 
0.292 
51524 
0.233 
51525 
0.173 
51531 
0.311 
51532 
0.289 
51533 
0.283 
51534 
0.226 
51535 
0.166 
51541 
0.232 
51542 
0.213 
51543 
0.208 
51544 
0.154 
51545 
0.099 
51551 
0.112 
51552 
0.099 
51553 
0.096 
51554 
0.047 
51555 
-0.003 
52111 
0.413 
52112 
0.392 
52113 
0.387 
52114 
0.314 
52115 
0.238 
52121 
0.379 
52122 
0.346 
52123 
0.338 
52124 
0.272 
52125 
0.204 
52131 
0.371 
52132 
0.335 
52133 
0.325 
52134 
0.262 
52135 
0.196 
52141 
0.283 
52142 
0.253 
52143 
0.246 
52144 
0.184 
52145 
0.120 
52151 
0.151 
52152 
0.131 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 142 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
52153 
0.126 
52154 
0.068 
52155 
0.007 
52211 
0.406 
52212 
0.373 
52213 
0.364 
52214 
0.299 
52215 
0.231 
52221 
0.359 
52222 
0.313 
52223 
0.301 
52224 
0.244 
52225 
0.185 
52231 
0.347 
52232 
0.298 
52233 
0.285 
52234 
0.230 
52235 
0.173 
52241 
0.266 
52242 
0.223 
52243 
0.212 
52244 
0.159 
52245 
0.104 
52251 
0.144 
52252 
0.112 
52253 
0.103 
52254 
0.052 
52255 
-0.001 
52311 
0.404 
52312 
0.368 
52313 
0.358 
52314 
0.295 
52315 
0.230 
52321 
0.354 
52322 
0.305 
52323 
0.292 
52324 
0.237 
52325 
0.180 
52331 
0.341 
52332 
0.289 
52333 
0.275 
52334 
0.222 
52335 
0.167 
52341 
0.262 
52342 
0.216 
52343 
0.204 
52344 
0.153 
52345 
0.100 
52351 
0.143 
52352 
0.107 
52353 
0.097 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 143 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
52354 
0.049 
52355 
-0.002 
52411 
0.374 
52412 
0.344 
52413 
0.336 
52414 
0.274 
52415 
0.210 
52421 
0.330 
52422 
0.286 
52423 
0.275 
52424 
0.221 
52425 
0.165 
52431 
0.319 
52432 
0.272 
52433 
0.259 
52434 
0.208 
52435 
0.154 
52441 
0.240 
52442 
0.200 
52443 
0.189 
52444 
0.140 
52445 
0.088 
52451 
0.123 
52452 
0.092 
52453 
0.084 
52454 
0.037 
52455 
-0.012 
52511 
0.314 
52512 
0.294 
52513 
0.289 
52514 
0.230 
52515 
0.170 
52521 
0.280 
52522 
0.248 
52523 
0.239 
52524 
0.189 
52525 
0.136 
52531 
0.272 
52532 
0.236 
52533 
0.227 
52534 
0.178 
52535 
0.128 
52541 
0.196 
52542 
0.167 
52543 
0.159 
52544 
0.112 
52545 
0.064 
52551 
0.083 
52552 
0.062 
52553 
0.057 
52554 
0.013 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 144 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
52555 
-0.032 
53111 
0.407 
53112 
0.385 
53113 
0.379 
53114 
0.307 
53115 
0.232 
53121 
0.372 
53122 
0.336 
53123 
0.327 
53124 
0.263 
53125 
0.197 
53131 
0.363 
53132 
0.324 
53133 
0.314 
53134 
0.252 
53135 
0.188 
53141 
0.276 
53142 
0.244 
53143 
0.236 
53144 
0.176 
53145 
0.113 
53151 
0.145 
53152 
0.124 
53153 
0.118 
53154 
0.061 
53155 
0.001 
53211 
0.398 
53212 
0.363 
53213 
0.353 
53214 
0.290 
53215 
0.224 
53221 
0.349 
53222 
0.300 
53223 
0.287 
53224 
0.232 
53225 
0.175 
53231 
0.337 
53232 
0.284 
53233 
0.271 
53234 
0.218 
53235 
0.162 
53241 
0.257 
53242 
0.211 
53243 
0.199 
53244 
0.148 
53245 
0.094 
53251 
0.137 
53252 
0.102 
53253 
0.092 
53254 
0.043 
53255 
-0.008 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 145 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
53311 
0.396 
53312 
0.357 
53313 
0.347 
53314 
0.286 
53315 
0.222 
53321 
0.343 
53322 
0.291 
53323 
0.277 
53324 
0.224 
53325 
0.169 
53331 
0.330 
53332 
0.275 
53333 
0.260 
53334 
0.209 
53335 
0.156 
53341 
0.252 
53342 
0.203 
53343 
0.191 
53344 
0.141 
53345 
0.090 
53351 
0.135 
53352 
0.096 
53353 
0.086 
53354 
0.039 
53355 
-0.010 
53411 
0.367 
53412 
0.334 
53413 
0.325 
53414 
0.265 
53415 
0.203 
53421 
0.320 
53422 
0.274 
53423 
0.261 
53424 
0.210 
53425 
0.156 
53431 
0.308 
53432 
0.259 
53433 
0.246 
53434 
0.196 
53435 
0.144 
53441 
0.232 
53442 
0.188 
53443 
0.177 
53444 
0.129 
53445 
0.079 
53451 
0.116 
53452 
0.083 
53453 
0.074 
53454 
0.028 
53455 
-0.019 
53511 
0.308 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 146 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
53512 
0.287 
53513 
0.281 
53514 
0.224 
53515 
0.164 
53521 
0.273 
53522 
0.238 
53523 
0.229 
53524 
0.180 
53525 
0.129 
53531 
0.264 
53532 
0.226 
53533 
0.216 
53534 
0.169 
53535 
0.120 
53541 
0.189 
53542 
0.158 
53543 
0.149 
53544 
0.104 
53545 
0.057 
53551 
0.077 
53552 
0.055 
53553 
0.049 
53554 
0.006 
53555 
-0.038 
54111 
0.368 
54112 
0.348 
54113 
0.343 
54114 
0.273 
54115 
0.200 
54121 
0.335 
54122 
0.303 
54123 
0.295 
54124 
0.232 
54125 
0.167 
54131 
0.327 
54132 
0.292 
54133 
0.283 
54134 
0.222 
54135 
0.159 
54141 
0.242 
54142 
0.213 
54143 
0.206 
54144 
0.147 
54145 
0.086 
54151 
0.114 
54152 
0.094 
54153 
0.089 
54154 
0.034 
54155 
-0.024 
54211 
0.361 
54212 
0.330 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 147 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
54213 
0.321 
54214 
0.259 
54215 
0.194 
54221 
0.316 
54222 
0.271 
54223 
0.259 
54224 
0.205 
54225 
0.149 
54231 
0.305 
54232 
0.256 
54233 
0.244 
54234 
0.192 
54235 
0.138 
54241 
0.226 
54242 
0.184 
54243 
0.173 
54244 
0.123 
54245 
0.071 
54251 
0.107 
54252 
0.076 
54253 
0.068 
54254 
0.020 
54255 
-0.030 
54311 
0.360 
54312 
0.325 
54313 
0.316 
54314 
0.256 
54315 
0.193 
54321 
0.311 
54322 
0.263 
54323 
0.251 
54324 
0.198 
54325 
0.144 
54331 
0.299 
54332 
0.248 
54333 
0.234 
54334 
0.184 
54335 
0.132 
54341 
0.222 
54342 
0.177 
54343 
0.166 
54344 
0.117 
54345 
0.067 
54351 
0.106 
54352 
0.071 
54353 
0.062 
54354 
0.016 
54355 
-0.032 
54411 
0.332 
54412 
0.303 
54413 
0.295 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 148 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
54414 
0.236 
54415 
0.175 
54421 
0.289 
54422 
0.246 
54423 
0.235 
54424 
0.185 
54425 
0.132 
54431 
0.278 
54432 
0.232 
54433 
0.220 
54434 
0.172 
54435 
0.121 
54441 
0.202 
54442 
0.163 
54443 
0.153 
54444 
0.106 
54445 
0.057 
54451 
0.088 
54452 
0.059 
54453 
0.051 
54454 
0.006 
54455 
-0.040 
54511 
0.276 
54512 
0.257 
54513 
0.252 
54514 
0.197 
54515 
0.140 
54521 
0.243 
54522 
0.212 
54523 
0.204 
54524 
0.156 
54525 
0.106 
54531 
0.235 
54532 
0.201 
54533 
0.192 
54534 
0.146 
54535 
0.098 
54541 
0.162 
54542 
0.134 
54543 
0.126 
54544 
0.082 
54545 
0.037 
54551 
0.053 
54552 
0.033 
54553 
0.027 
54554 
-0.013 
54555 
-0.055 
55111 
0.247 
55112 
0.234 
55113 
0.230 
55114 
0.167 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 149 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
55115 
0.102 
55121 
0.221 
55122 
0.200 
55123 
0.195 
55124 
0.136 
55125 
0.076 
55131 
0.214 
55132 
0.192 
55133 
0.186 
55134 
0.129 
55135 
0.069 
55141 
0.135 
55142 
0.116 
55143 
0.111 
55144 
0.057 
55145 
0.002 
55151 
0.016 
55152 
0.003 
55153 
-0.001 
55154 
-0.050 
55155 
-0.100 
55211 
0.247 
55212 
0.227 
55213 
0.222 
55214 
0.163 
55215 
0.102 
55221 
0.214 
55222 
0.181 
55223 
0.173 
55224 
0.122 
55225 
0.069 
55231 
0.205 
55232 
0.170 
55233 
0.160 
55234 
0.111 
55235 
0.060 
55241 
0.129 
55242 
0.100 
55243 
0.092 
55244 
0.045 
55245 
-0.004 
55251 
0.015 
55252 
-0.005 
55253 
-0.010 
55254 
-0.054 
55255 
-0.100 
55311 
0.247 
55312 
0.226 
55313 
0.220 
55314 
0.162 
55315 
0.102 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 150 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
55321 
0.212 
55322 
0.176 
55323 
0.167 
55324 
0.118 
55325 
0.067 
55331 
0.203 
55332 
0.164 
55333 
0.154 
55334 
0.107 
55335 
0.058 
55341 
0.128 
55342 
0.096 
55343 
0.088 
55344 
0.042 
55345 
-0.005 
55351 
0.015 
55352 
-0.006 
55353 
-0.012 
55354 
-0.055 
55355 
-0.100 
55411 
0.224 
55412 
0.206 
55413 
0.201 
55414 
0.146 
55415 
0.089 
55421 
0.192 
55422 
0.162 
55423 
0.154 
55424 
0.106 
55425 
0.057 
55431 
0.184 
55432 
0.151 
55433 
0.142 
55434 
0.096 
55435 
0.049 
55441 
0.111 
55442 
0.084 
55443 
0.077 
55444 
0.033 
55445 
-0.012 
55451 
0.002 
55452 
-0.016 
55453 
-0.021 
55454 
-0.061 
55455 
-0.103 
55511 
0.178 
55512 
0.165 
55513 
0.162 
55514 
0.113 
55515 
0.063 
55521 
0.152 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 151 of 154 
Version 1.0: 31 July 2024
 
Health State (5L profile) 
US 
55522 
0.132 
55523 
0.127 
55524 
0.083 
55525 
0.037 
55531 
0.145 
55532 
0.124 
55533 
0.118 
55534 
0.075 
55535 
0.030 
55541 
0.078 
55542 
0.060 
55543 
0.055 
55544 
0.015 
55545 
-0.026 
55551 
-0.024 
55552 
-0.037 
55553 
-0.040 
55554 
-0.074 
55555 
-0.109 
 
 
 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 152 of 154 
Version 1.0: 31 July 2024
 
9.10. 
Abbreviations 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
APMP 
Abuse Potential Monitoring Plan  
AST 
Aspartate aminotransferase 
BLQ 
Below limit of quantification 
BUN 
Blood urea nitrogen 
Cmax 
Maximum observed plasma concentration 
cAMP 
Cyclic adenosine monophosphate 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CGI-I 
Clinical Global Impressions - Improvement 
CGI-S 
Clinical Global Impressions – Severity of Illness 
CIOMS 
Council for International Organizations of Medical Sciences 
COMT 
Catechol-O-methyltransferase  
CONSORT 
Consolidated Standards of Reporting Trials  
CPK 
Creatine phosphokinase 
C-QT 
Concentration-QT 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CVL-751 
Tavapadon 
D1Rs 
Dopamine D1-like receptors 
D2/D3R 
Dopamine D2 and D3 receptor subtypes  
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOT 
End of treatment 
EQ-5D-5L 
EuroQol 5 Dimension 5 Level 
ESAMs 
Events subject to additional monitoring 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 153 of 154 
Version 1.0: 31 July 2024
 
ESS 
Epworth Sleepiness Scale 
ET 
Early termination 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human immunodeficiency virus 
ICD 
Impulsive control disorder 
ICE 
Intercurrent event 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVRS/IWRS 
Interactive Voice Response System/Interactive Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
L-Dopa 
Levodopa 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
LSMean 
Least square mean 
MAO 
Monoamine oxidase 
MAO-B 
Monoamine oxidase B 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MNAR 
Missing not at random 
MCV 
Mean corpuscular volume 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326
 
 


 
Protocol CVL-751-PD-001 
 
Tavapadon 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 154 of 154 
Version 1.0: 31 July 2024
 
 
 
 
MDS-UPDRS 
Movement Disorder Society – Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHIs 
Medication handling irregularities 
mITT 
Modified intent-to-treat 
MMRM 
Mixed Model for Repeated Measures  
MoCA 
Montreal Cognitive Assessment  
PD 
Parkinson’s disease 
PDQ-39 
39-Item Parkinson’s Disease Questionnaire 
PGIC 
Patient Global Impression of Change 
PK 
Pharmacokinetic 
QD 
Once daily 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula  
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating 
Scale 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
TEAE 
Treatment-emergent adverse event 
THC 
Tetrahydrocannabinol 
TQT 
 
Thorough QT 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WBC 
White blood cell 
Docusign Envelope ID: 0A124D29-7852-4AAE-935B-41AE5A167326