Conditions: Parkinson Disease
Keywords: Parkinsonian Disorders Brain Diseases Central Nervous System Diseases Nervous System Disease Movement Disorders Neurodegenerative Diseases
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 507
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the effect of tavapadon on the change from baseline in total daily hours of "on" time without troublesome dyskinesia in L-Dopa-treated participants with Parkinson's Disease (PD) who are experiencing motor fluctuations.

Detailed description:

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

Interventions: intervention 1: Tavapadon intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will be randomized to receive tavapadon 5 to 15 mg tablet QD orally for 27 weeks. intervention 2: Participants will receive placebo matching to tavapadon QD 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, 
FLEXIBLE-DOSE, 27-WEEK TRIAL TO EVALUATE THE 
EFFICACY, SAFETY, AND TOLERABILITY OF TAVAPADON AS 
ADJUNCTIVE THERAPY FOR PARKINSON’S DISEASE IN 
LEVODOPA-TREATED ADULTS 
WITH MOTOR FLUCTUATIONS (TEMPO-3 TRIAL) 
Protocol Number: CVL-751-PD-003 
Compound: Tavapadon (CVL-751) 
Trial Phase: 3 
Short Title: Flexible-Dose, Adjunctive Therapy Trial in Adults With Parkinson’s 
Disease With Motor Fluctuations 
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 
2019-002951-40 
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. 
NCT04542499




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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 “w” and “x” 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 
4.2 
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 ...........................................................................................31 
6.1 
Trial Intervention(s) Administered ....................................................................31 
6.2 
Preparation/Handling/Storage/Accountability .................................................31 
6.3 
Measures to Minimize Bias: Randomization and Blinding..............................32 
6.3.1 
Subject Assignment to Treatment ................................................................32 
6.3.2 
Blinding ...........................................................................................................32 
6.4 
Trial Treatment Compliance ..............................................................................33 
6.5 
Concomitant Therapy ..........................................................................................33 
6.5.1 
Prior and Concomitant Medications ............................................................33 
6.5.2 
Allowed Medications Before and During the Trial .....................................33 
6.5.3 
Prohibited Medications Before the Trial .....................................................34 
6.5.4 
Prohibited Medications During the Trial ....................................................35 
6.5.5 
Dose Modification ..........................................................................................37 
6.6 
Intervention after the End of the Trial ..............................................................37 
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 ..................................................................................................39 
8 
TRIAL ASSESSMENTS AND PROCEDURES ....................................................39 
8.1 
Screening and Baseline Assessments ..................................................................40 
8.2 
Efficacy Assessments ...........................................................................................41 
8.2.1 
Hauser Diary ..................................................................................................41 
8.2.2 
Movement Disorder Society-Unified Parkinson’s Disease Rating 
Scale .................................................................................................................41 
8.2.3 
39-Item Parkinson’s Disease Questionnaire ................................................42 
8.2.4 
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 ......................................................................................43 
8.3.3 
Columbia-Suicide Severity Rating Scale .....................................................44 
8.3.4 
Physical and Neurological Examinations.....................................................44 
8.3.5 
Vital Signs .......................................................................................................45 
8.3.6 
Electrocardiograms........................................................................................45 
8.3.7 
Clinical Safety Laboratory Assessments ......................................................46 
8.3.8 
.........................................................................................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 ..................................................48 
8.4.3 
Follow-up of AEs and SAEs/AESI................................................................48 
8.4.4 
Regulatory Reporting Requirements for SAEs/AESI ................................49 
8.4.5 
Pregnancy .......................................................................................................49 
8.4.6 
Adverse Events of Special Interest ...............................................................49 
8.5 
Treatment of Overdose ........................................................................................51 
8.6 
Pharmacokinetics .................................................................................................51 
8.7 
Future Biospecimen Research ............................................................................52 
9 
STATISTICAL CONSIDERATIONS ....................................................................52 
9.1 
Statistical Hypotheses ..........................................................................................52 
9.2 
Sample Size Determination .................................................................................52 
9.3 
Populations for Analyses .....................................................................................52 
9.4 
Statistical Analyses...............................................................................................53 
9.4.1 
Efficacy Analyses ...........................................................................................53 
9.4.2 
Safety Analyses ...............................................................................................55 
9.4.3 
Other Analyses ...............................................................................................56 
9.5 
Interim Analysis ...................................................................................................56 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................57 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations .........57 


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10.1.1 
Regulatory and Ethical Considerations .......................................................57 
10.1.2 
Financial Disclosure .......................................................................................57 
10.1.3 
Informed Consent Process ............................................................................58 
10.1.4 
Data Protection...............................................................................................58 
10.1.5 
Dissemination of Clinical Trial Data ............................................................58 
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: Abbreviations .................................................................................76 
10.8 
Appendix 8: Protocol Amendment History .......................................................79 
11 REFERENCES .........................................................................................................87 
CLINICAL PROTOCOL PRINCIPAL INVESTIGATOR 
SIGNATURE PAGE ................................................................................................90 
 


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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 ..................................36 
Table 8 
Populations for Analysis ..........................................................................53 
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, Flexible-Dose, 27-Week Trial to Evaluate the Efficacy, Safety, and 
Tolerability of Tavapadon as Adjunctive Therapy for Parkinson’s Disease in 
Levodopa-Treated Adults With Motor Fluctuations (TEMPO-3 Trial) 
Short Title: Flexible-Dose, Adjunctive Therapy Trial in Adults With Parkinson’s 
Disease With Motor Fluctuations 
IND Number: 118,647 
EudraCT Number: 2019-002951-40 
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 
Efficacy  
 
Primary 
 
• 
To assess the effect of tavapadon on the 
change from baseline in total daily 
hours of “on” time without troublesome 
dyskinesia in L-Dopa-treated subjects 
with PD who are experiencing motor 
fluctuations 
Primary Efficacy Endpoint 
• 
Change from baseline to endpoint the total “on” time 
without troublesome dyskinesia based on the 2-day 
average of the self-completed home diary for motor 
functional status (Hauser diary) 
Secondary  
 
• 
To assess the effect of tavapadon on the 
change from baseline in total daily 
hours of “off” time in L-Dopa treated 
subjects with PD who are experiencing 
motor fluctuations 
Key Secondary Efficacy Endpoint 
• 
Change from baseline to endpoint in total daily “off” 
time based on the 2-day average of the 
self-completed home diary for motor function status 
(Hauser diary) 
Secondary Efficacy Endpoints (at all time points) 
• 
Change from baseline in the total “on” time without 
troublesome dyskinesia based on the 2-day average 
of the self-completed home diary for motor function 
status (Hauser diary) 
• 
Change from baseline in the total “off” time without 
troublesome dyskinesia based on the 2-day average 
of the self-completed home diary for motor function 
status (Hauser diary) 
 
• 
Change from baseline in the MDS-UPDRS Part I 
score 
 
• 
Change from baseline in the MDS-UPDRS Part II 
score 
 
• 
Change from baseline in the MDS-UPDRS Part III 
score 
 
Other Endpoints 
• 
Change from baseline in the PDQ-39 score 
• 
Change from baseline in the EQ-5D-5L index and 
VAS scores 
Safety and Tolerability 
 
• 
To assess the safety and tolerability of 
tavapadon in L-Dopa-treated subjects 
with PD who are experiencing motor 
fluctuations 
• 
QUIP-RS 
• 
ESS 
• 
C-SSRS 
• 
Nature, frequency, and temporality of TEAEs, 
including abuse-related AEs and AEs related to 
MHIs 
 
• 
Clinical laboratory evaluations 
 
• 
Vital signs 
• 
Physical examinations 
• 
ECGs 


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Table 1 
Objectives and Endpoints 
Objectives 
Endpoints 
Pharmacokinetic 
 
• 
To evaluate the PK of tavapadon in 
this population 
Plasma concentrations of tavapadon and its metabolite (if 
required) at baseline (Day 1) and at Weeks 5, 11, 14, 22, 
and 27 
Abbreviations: AE = adverse event, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, 
EQ-5D-5L = EuroQol 5 Dimension 5 Level, ESS = Epworth Sleepiness Scale, L-Dopa = levodopa, 
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, PK = pharmacokinetic, 
QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale, 
TEAE = treatment-emergent adverse event, VAS = visual analog scale. 
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 tavapadon as adjunctive therapy to levodopa (L-Dopa) 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 score of 2, 2.5, or 3 in the “on” state; a minimum of 2½ hours of “off” 
time on 2 consecutive days; and a good response to L-Dopa in the judgment of the 
investigator. 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).  
Disclosure Statement: This is a parallel-group trial to evaluate the efficacy, safety, 
tolerability, and PK of flexible doses of tavapadon and placebo in subjects with advanced 
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 368 subjects are planned to be randomized into 
2 treatment groups (184 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 score of 2, 2.5, or 3 in the “on” state, a minimum of 
2½ hours of “off” time on 2 consecutive days, and a good response to L-Dopa in the 
judgment of the investigator will be enrolled. 
Intervention Groups, Trial Treatments, and Duration: Subjects will be randomized in 
a 1:1 ratio to receive tavapadon 5 to 15 mg QD or placebo QD. The planned duration of 
treatment is 27 weeks, including the Dose Titration, Dose Adjustment, and Maintenance 
Phases. The IMPs will be taken orally. 


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Interim Analysis Review Committee: Given that the assumptions for the sample size 
were based on a preliminary study using a different dosing schedule, it is unknown if 
these assumptions are appropriate for this study as designed. To this end, an interim 
analysis of the primary efficacy endpoint will be included to assess the adequacy of the 
overall sample size relative to achieving the study objectives. This analysis will be 
conducted by an independent Interim Analysis Review Committee (IARC), which may 
make a recommendation to increase the overall sample size up to a maximum of 
528 subjects. Full details and rules for the IARC and planned interim analysis will be 
provided in a separate IARC charter and in the statistical analysis plan. 
Statistical Methods 
Sample Size Estimation: A sample size of 184 subjects per group (total, 368 subjects) 
will provide at least 90% power to detect a change in the primary outcome measure 
(change from baseline in “on” time without troublesome dyskinesia) of 1 hour with a 
standard deviation of 2.5, a 2-sided alpha level = 0.049, 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 analysis of the primary and each secondary endpoint will include 
the comparison of tavapadon versus placebo. The hypothesis testing will be done in 
hierarchical order from the primary endpoint onward. To control for any potential 
inflation of Type I error that may be incurred from the interim analysis, the primary 
hypothesis will be tested at an α level of 0.049 (2-sided) to ensure that the overall Type I 
error rate is below 0.05. Subsequent testing in the secondary endpoints will be conducted 
at an α level of 0.05 (2-sided). 
The primary endpoint (change from baseline to endpoint in “on” time without 
troublesome dyskinesia) will be analyzed using a Mixed Model for Repeated Measures 
(MMRM) on the modified intent-to-treat (mITT) population. This estimand will be based 
on the 2-day average of the self-completed Hauser diary from each postbaseline visit. A 
hypothetical strategy will be used to address the intercurrent events of discontinuation or 
use of prohibited medications with the data post intercurrent events treated as censored. 
The baseline value will be included as a covariate, and the treatment group (tavapadon or 
placebo), visit, and interaction between treatment group and visit will be included as 
fixed factors in the MMRM. The difference between tavapadon versus placebo at 
endpoint will be estimated based on the least square means (LSMeans) from the MMRM. 
The key secondary endpoint (change from baseline to endpoint in “off” time) and other 
continuous secondary endpoints (as listed in Table 1) will be analyzed in a similar 
manner to the primary endpoint. Categorical endpoints will be analyzed on the mITT 
population using the SAS® GLIMMIX procedure for binomial data with logit link. This 
generalized linear mixed model analysis will include response data from each 




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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 
Hauser diary training video and 
on/off time concordance testingf 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense Hauser diaryg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect/review Hauser diaryg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MDS-UPDRSh 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
PDQ-39 
 
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-SSRSi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical/neurological examinationj  
X 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Vital signsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Single 12-lead ECGl 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
One set of triplicate ECGs prior to 
first dose of IMPm 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xw 
 
 
 
 
Xx 
 
Prior/concomitant medications 
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
Adverse eventsn 
 
-------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
Laboratoryo 
Safety laboratory blood sample 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
Prolactin level 
 
Xv 
 
 
 
 
 
 
 
 
Xv 
 
Serology (HIV, HbsAg, and HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
Dipstick urinalysisp 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
Serum pregnancy testq 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick pregnancy testq 
 
-------------------------------------------------------------------------------------------------------------------------------------→ 
 
Urine drug screenr 
X 
------------------------------------------------------------------------------------------------------------------→ 
X 
 
Plasma PK samples 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Future biospecimen research blood 
samplet 
 
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 
IMP Administration and Complianceu 
Dispense IMP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assess IMP compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: 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, 
L-Dopa = levodopa, MDS-UPDRS = Movement Disorder Society – Unified Parkinson’s Disease 
Rating Scale, MoCA = Montreal Cognitive Assessment, PDQ-39 = 39-Item Parkinson’s Disease Questionnaire, 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. 
Subjects and investigators (or qualified designees) will independently complete concordance testing. Full details and requirements for the conduct and successful completion 
of concordance testing are provided in the appropriate protocol-specific manual. 
g. 
Subjects will record entries for 24 hours on 2 consecutive days within the 7 days before randomization at the Baseline Visit, after diary training and concordance testing has 
occurred. Subject will record entries for 24 hours on 2 consecutive days within the 7 days before each postbaseline clinic visit. 
h. 
MDS-UPDRS Parts I, II, and III should be conducted approximately 2 to 3 hours after the last dose of L-Dopa on that day. 
i. 
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. 
j. 
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.  
k. 
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). 
l. 
The postdose ECG 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. A triplicate set of ECGs is 3 consecutive ECGs collected 1 to 2 minutes apart over a 5-minute period. 




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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 flexible doses of tavapadon (5 mg to 15 mg 
once daily [QD]) as adjunctive therapy for PD in levodopa (L-Dopa)-treated adults with 
motor fluctuations to further define and confirm the magnitude of efficacy and 
risk/benefit profile of this target dose range. 
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 
disease-modifying therapeutic approaches can be identified. However, there remains 
significant current and future need for improved symptomatic therapies. 
* China, India, United States, Indonesia, Brazil, Pakistan, Bangladesh, Russia, Nigeria, and Japan.


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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. 
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. 
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 


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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 
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 


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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. 
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. 


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3 OBJECTIVES AND ENDPOINTS 
The trial objectives and endpoints are summarized in Table 3. 
Table 3 
Objectives and Endpoints 
Objectives 
Endpoints 
Efficacy  
 
Primary 
 
• 
To assess the effect of tavapadon on the 
change from baseline in total daily 
hours of “on” time without troublesome 
dyskinesia in L-Dopa-treated subjects 
with PD who are experiencing motor 
fluctuations 
Primary Efficacy Endpoint 
• 
Change from baseline to endpoint the total “on” time 
without troublesome dyskinesia based on the 2-day 
average of the self-completed home diary for motor 
function status (Hauser diary) 
Secondary  
 
• 
To assess the effect of tavapadon on the 
change from baseline in total daily 
hours of “off” time in L-Dopa treated 
subjects with PD who are experiencing 
motor fluctuations 
Key Secondary Efficacy Endpoint 
• 
Change from baseline to endpoint in total daily “off” 
time based on the 2-day average of the 
self-completed home diary for motor function status 
(Hauser diary) 
Secondary Efficacy Endpoints (at all time points) 
• 
Change from baseline in the total “on” time without 
troublesome dyskinesia based on the 2-day average 
of the self-completed home diary for motor function 
status (Hauser diary) 
• 
Change from baseline in the total “off” time without 
troublesome dyskinesia based on the 2-day average 
of the self-completed home diary for motor function 
status (Hauser diary) 
 
• 
Change from baseline in the MDS-UPDRS Part I 
score 
 
• 
Change from baseline in the MDS-UPDRS Part II 
score 
 
• 
Change from baseline in the MDS-UPDRS Part III 
score 
 
Other Endpoints 
• 
Change from baseline in the PDQ-39 score 
• 
Change from baseline in the EQ-5D-5L index and 
VAS scores 
Safety and Tolerability 
 
• 
To assess the safety and tolerability of 
tavapadon in L-Dopa-treated subjects 
with PD who are experiencing motor 
fluctuations 
• 
QUIP-RS 
• 
ESS 
• 
C-SSRS 
• 
Nature, frequency, and temporality of TEAEs, 
including abuse-related AEs and AEs related to 
MHIs 
 
• 
Clinical laboratory evaluations 
 
• 
Vital signs 
• 
Physical 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 metabolite (if 
required) at baseline (Day 1) and at Weeks 5, 11, 14, 22, 
and 27 
Abbreviations: AE = adverse event, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, 
EQ-5D-5L = EuroQol 5 Dimension 5 Level, ESS = Epworth Sleepiness Scale, L-Dopa = levodopa, 
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, PK = pharmacokinetic, 
QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale, 
TEAEs = treatment-emergent adverse events, VAS = visual analog scale. 
4 TRIAL DESIGN 
4.1 
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 tavapadon as adjunctive therapy to levodopa (L-Dopa) 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 
score of 2, 2.5, or 3 in the “on” state; a minimum of 2½ hours of “off” time on 
2 consecutive days; and a good response to L-Dopa in the judgment of the investigator. 
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 
Screening Period. During the Screening Period, subjects will be trained in the use of the 
home diary (Hauser diary), and subjects and investigators (or qualified designee) will 
independently complete concordance testing on the Hauser diary (full details and 
requirements for conduct and successful completion of concordance testing are provided 
in the appropriated protocol-specific manual). Subjects who successfully meet the 
concordance testing criteria will complete the Hauser diary on at least 2 consecutive days 
(24-hour periods) within the 7 days before the Baseline Visit. 
Subjects whose diary shows a minimum of 2½ hours of “off” time on each of the 2 days 
and who continue to satisfy the trial eligibility criteria at the Baseline Visit will be 
randomized in a 1:1 ratio to receive: 


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• Tavapadon ranging from 5 to 15 mg QD 
• Placebo QD 
4.1.2 
Treatment Period 
The dose of tavapadon will be gradually titrated to 15 mg QD in all subjects over the first 
14 weeks of the trial during the Dose Titration and Dose Adjustment Phases unless 
prevented by intolerance. A reduction in dose (from 15 mg QD to 10 mg QD or from 
10 mg QD to 5 mg QD) will be allowed based on individual subject tolerability. Subjects 
who require a dose reduction may be rechallenged with the higher dose, at the discretion 
of the investigator, to address symptomatic needs.  
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 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 
Trial Day 
Titration Step 
Blinded Treatment Assignment 
Maintenance Phasec 
 
 
Maximum tolerated tavapadon dose (5-15 mg) or placebo QD 
Abbreviation: QD = once daily. 
a. 
No deviations in the titration schedule up through 5 mg QD
 will be allowed. 
b. The dose will be adjusted over the range of 5 to 15 mg 
 based on individual 
subject tolerability. 
c. 
Subjects will receive the highest tolerated dose level that is achieved during the Dose Adjustment 
Phase. No adjustment in the tavapadon dose will be allowed during the Maintenance Phase. 


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No deviations in the titration schedule up through 
 (5 mg QD) 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. The dose of tavapadon will be 
gradually titrated to the 
 dose (15 mg QD) in all subjects, as shown Table 4, 
unless prevented by intolerance.  
Subjects who are unable to achieve or tolerate the 
 dose (15 mg QD) may receive 
the 
 dose (10 mg QD). Subjects who cannot achieve or tolerate the 
 dose 
(10 mg QD) may receive the 
 dose (5 mg QD). Subjects who cannot achieve or 
tolerate the 
 dose (5 mg QD) will be discontinued from the trial. Subjects who 
require a dose reduction may be rechallenged with a higher dose to address symptomatic 
needs after at least 7 days at the lower dose during the Dose Adjustment Phase. 
Subjects will receive the highest tolerated dose level that is achieved during the Dose 
Adjustment Phase for the duration of the subsequent 13-week Maintenance Phase. 
Adjustments in the dose of tavapadon will not be allowed during the Maintenance Phase. 
Subjects who cannot tolerate their maintenance dose 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 at the 
end of Weeks 2, 5, 8, 11, 14, 18, 22, 26, and 27. Subjects will complete the Hauser diary 
on 2 consecutive days within the 7 days before each scheduled postbaseline clinic visit. 
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 trial treatment (either after completing the full 27-week treatment 
period or upon premature discontinuation from the 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 Hauser diary (Hauser et al, 2000) assesses patient-defined clinical status over a 
period of time and provides a tool for assessment of the change in “off” time and “on” 


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time with troublesome dyskinesia (which is a more accurate reflection of clinical 
response than “off” time alone. The minimum clinically important difference (smallest 
change that is meaningful to patients) for a reduction in “off” time (key secondary 
efficacy endpoint) has been reported to be 1.0 hour (Hauser et al, 2011; Hauser et al, 
2014). 
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 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 


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(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. 
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. 


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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 2, 2.5, or 3 in the “on” state. 
7.  
Subjects with a good response to L-Dopa in the judgment of the investigator. 
Note: Subjects using levodopa/carbidopa intestinal gel are not eligible to participate in the trial. 
8.  
Subjects who return a completed self-reported home diary for motor function status (Hauser 
diary) during the screening period (after diary training and concordance testing has occurred), 
with recordings for 2 consecutive days (ie, 2 consecutive 24-hour periods) showing at least 
2½ hours of “off” time on each of the 2 days. 
Concomitant Parkinson’s Disease Medications 
9.  
Subjects who are on a stable dose of L-Dopa for at least 4 weeks prior to screening and are taking 
a minimum total daily dose of 400 mg divided in at least 4 doses per day of standard 
carbidopa/levodopa or divided in at least 3 doses per day of extended-release carbidopa/levodopa 
capsules. The carbidopa/levodopa dose and frequency must be maintained for the duration of the 
trial.  
Standard or extended-release levodopa/benserazide is allowed as an alternative to 
levodopa/carbidopa, where available. The minimum dose and frequency requirements for 
levodopa still apply. 
10.  
Prior and concurrent use of COMT inhibitors, MAO-B inhibitors, amantadine, istradefylline, or 
anticholinergic drugs 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 COMT, MAO-B 
inhibitor, amantadine, istradefylline, or anticholinergic dose is permitted during the trial). 
Abbreviations: COMT = catechol-O-methyl transferase, ICF = informed consent form, IMP = investigational 
medicinal product, L-Dopa = levodopa, MAO-B = monoamine oxidase inhibitor B, 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 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. 


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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). 
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. 
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. 


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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. 
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). 


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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, 
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). Subjects who 


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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). 
Table 5 
Investigational Medicinal Products Administered 
ARM Name 
Tavapadon 5-15 mg QD 
Placebo QD 
Type  
Drug 
Matching drug 
Dose Formulation 
Tablet 
Matching tablet 
Unit Dose Strength(s) 
 
0 mg 
Dosage Level(s) 
5 mg 
0 mg 
Route of Administration 
Oral 
Oral 
Sourcing 
Cerevel Therapeutics 
Cerevel Therapeutics 
Packaging and Labeling 
Blister cards labeled according 
to local regulations 
Blister cards labeled according 
to local regulations 
Former Name(s) 
PF-06649751, CVL-751 
-- 
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). 


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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 ratio to 2 treatment arms (tavapadon 
5 to 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. Subjects will be sequentially assigned to the 
next available randomization number 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 
during 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 


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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 
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 
Allowed Medications Before and During the Trial 
Subjects must be on a stable dose of L-Dopa for at least 4 weeks prior to screening and be 
taking a minimum total daily dose of 400 mg divided in at least 4 doses per day of 
standard carbidopa/levodopa or divided in at least 3 doses per day of extended-release 
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the same dose and frequency for the duration of the trial. No adjustment in the dose of 
frequency of carbidopa/levodopa is permitted during the study. 
Standard or extended-release levodopa/benserazide is allowed as an alternative to 
levodopa/carbidopa, where available. 
6.5.3 
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. 
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. 
Levodopa inhalation powder 
>7 days before Baseline Visit 
3. 
Dopamine agonists, including apomorphine 
>14 days before Baseline Visit 
4. 
Varenicline  
>14 days before Baseline Visit 
5. 
Nonselective MAO inhibitors, methyldopa, reserpine, or 
tricyclic antidepressants  
>2 months before Screening Visit 
6. 
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 
7. 
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) 
8. 
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. 
9. 
COMT inhibitors, MAO-B inhibitors, amantadine, 
istradefylline, or anticholinergic drugs if use was initiated 
≤90 days before the Baseline Visit 
>14 days before Baseline Visit 
10. Other investigational medications  
>60 days before Screening Visit 
Abbreviations: COMT = catechol-O-methyl transferase, CYP = cytochrome P450, ICF = informed consent, 
MAO = monoamine oxidase. 
-- Not applicable. Any prior use is prohibited. 


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6.5.4 
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 
concomitant medication is deemed necessary, in the investigator’s opinion, for the 
treatment of a treatment-emergent adverse event (TEAE). 


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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. 
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) 
4. 
COMT inhibitors, MAO-B inhibitors, amantadine, istradefylline, or anticholinergic drugs (unless 
use was initiated >90 days before the Baseline Visit and dose will remain stable for the duration of 
the treatment phase) 
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. 
5. 
Levodopa inhalation powder 
6. 
Dopamine agonists, including apomorphine 
7. 
Methyldopa 
8. 
Moderate or strong CYP3A4 inducersa (refer to Section 10.6 [Appendix 6] for examples) 
9. 
Moderate or strong CYP3A4 inhibitorsa (refer to Section 10.6 [Appendix 6] for examples) 
10. 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. 
11. Nonselective MAO inhibitors 
12. Prescription stimulants 
 
a. 
Amphetamine derivatives 
 
b. Bupropion 
 
c. 
Mazindol 
 
d. Methylphenidate 
 
e. 
Modafinil 
 
f. 
Phentermine 
 
g. Phenylpropanolamine 
13. Reserpine 
14. Tricyclic antidepressants 


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15. Varenicline  
16. Zonisamide 
17. Other investigational medications 
Abbreviations: COMT = catechol-O-methyl transferase, CYP = cytochrome P450, MAO = monoamine oxidase; 
TEAE = treatment-emergent adverse event. 
a. 
Except for topical administration. 
6.5.5 
Dose Modification 
The dose of tavapadon will be gradually titrated to 15 mg QD in all subjects, as shown in 
Table 4, unless prevented by intolerance, and then maintained for the duration of the trial. 
Procedures for dose modifications 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. 
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 


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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 study schedule  
• 
Noncompliance with 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 
already been collected as part of the trial but can withdraw consent for future 
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) 


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• 
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. 
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. 


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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 that are 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 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: 
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 2, 2.5, or 3 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 


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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 
Hauser Diary 
The Hauser diary assesses patient-defined motor function status over a period and 
provides a tool for assessment of change in “off” time and “on” time with troublesome 
dyskinesia (Hauser et al, 2000). The Hauser diary asks patients to rate their mobility for 
each 30-minute period and to record their status for the majority of the period in 1 of 
5 categories as: “on” time without dyskinesia, “on” time with nontroublesome dyskinesia, 
“on” time with troublesome dyskinesia, “off” time, or asleep. 
During the Screening Period, subjects will be trained in the use of the home diary (Hauser 
diary), and subjects and investigators (or qualified designee) will independently complete 
concordance testing on the Hauser diary (full details and requirements for conduct and 
successful completion of concordance testing are provided in the appropriated 
protocol-specific manual). Subjects who successfully meet the concordance testing 
criteria will complete the Hauser diary at home on at least 2 consecutive days (24-hour 
periods) within the 7 days before the Baseline Visit. 
Subjects will record diary entries at home at 30-minute intervals for 24 hours on 2 
consecutive days within the 7 days before randomization at the Baseline Visit and at 
30-minute intervals for 24 hours on 2 consecutive days within the 7 days before each 
postbaseline clinic visit. 
8.2.2 
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. 


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• 
Part III, motor examination, comprises 18 items that are assessed by the investigator 
(resulting in 33 scores by location and lateralization). 
• 
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 Parts I, II, and III should 
be conducted approximately 2 to 3 hours after the last dose of L-Dopa on the day of the 
clinic visit.  
8.2.3 
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 
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).  
8.2.4 
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. 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. 
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 


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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 
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 


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(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, exclusion 8). 
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.  


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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 readings 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). 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 be 
obtained after the subject has been supine and at rest for at least 5 minutes. A triplicate 
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A single ECG will be obtained at the Screening Visit. 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, just prior to the time of 
collection of the PK blood sample on Day 1. 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 
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 


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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, considered related to the trial 
intervention or trial procedures, or 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). 
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 


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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. 
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 


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abuse potential and AEs involving MHIs must be reported as events subject to additional 
monitoring (ESAMs), 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). 
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. Therefore, 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. 


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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: 
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. 


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8.7 
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. 
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 in “on” time without 
troublesome dyskinesias. The hypothesis of interest is a 2-sided test of superiority 
comparing tavapadon (CVL) to placebo: 
H0: µ placebo = µCVL-751 vs H1: µ placebo ≠ µCVL-751 
9.2 
Sample Size Determination 
A sample size of 184 subjects per group (total, 368 subjects) will provide at least 90% 
power to detect a change in the primary outcome measure (change from baseline in “on” 
time without troublesome dyskinesia) of 1 hour with a standard deviation of 2.5, a 
2-sided alpha level = 0.049, 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 (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 
Hauser diary entry 
Primary analysis set for efficacy 
Endpoint 
completers 
All subjects in the mITT population 
who complete the Hauser diary at 
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, 
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. 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 analysis of the primary and each secondary endpoint (Table 9) will include the 
comparison of tavapadon versus placebo. The hypothesis testing will be done in 
hierarchical order from the primary endpoint onward. To control for any potential 
inflation of Type I error that may be incurred from the interim analysis, the primary 


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hypothesis will be tested at an α level of 0.049 (2-sided) to ensure that the overall Type I 
error rate is below 0.05. Subsequent testing in the secondary endpoints will be conducted 
at an α level of 0.05 (2-sided). 


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Table 9 
Efficacy Analysis 
Endpoint 
Statistical Analysis Methods 
Primary and 
Key Secondary 
The primary endpoint (change from baseline to endpoint in “on” time without 
troublesome dyskinesia) and the key secondary endpoint (change from baseline to 
endpoint in “off” time) will be analyzed using an MMRM on the mITT population. 
This estimand will be based on the 2-day average of the self-completed Hauser diary 
from each postbaseline visit. A hypothetical strategy will be used to address the 
intercurrent events of discontinuation or use of prohibited medications with the data 
post intercurrent events treated as censored. The baseline value will be included as a 
covariate, and the treatment group (tavapadon or placebo), visit, and interaction 
between treatment group and visit will be included as fixed factors in the MMRM. 
The difference between tavapadon versus placebo at endpoint will be estimated based 
on the LSMeans from the MMRM. The key secondary endpoint will be analyzed in a 
similar manner. 
 
Sensitivity analyses for the primary and secondary endpoints will be conducted with 
different assumptions on missing mechanism. Sensitivity analysis will also be 
conducted on the endpoint completer set with MMRM. 
Secondary and 
Other 
Continuous secondary and other endpoints (MDS-UPDRS, EQ-5D-5L index and VAS 
scores and PDQ-39 score) will be analyzed in a manner similar to that used for the 
primary and key secondary efficacy endpoints. Categorical endpoints will be analyzed 
on the mITT population 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 that occurs before discontinuation of treatment or addition 
of rescue medication through endpoint. The model will include the treatment group, 
visit, and interaction between treatment group and visit. 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 instead. The odds ratio for the treatment 
difference, 95% CIs for the odds ratio, and p-value will be provided. 
Abbreviations: CI = confidence interval, EQ-5D-5L = EuroQol 5 Dimension 5 Level, mITT = modified 
intent-to-treat, MDS-UPDRS = Movement Disorder Society – Unified Parkinson’s Disease Rating Scale, 
LSMean = least squares mean, mITT = modified intent to treat, MMRM = Mixed Model for Repeated Measures, 
PDQ-39 = 39-Item Parkinson’s Disease Questionnaire, 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. 


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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 
parameters. The results of population PK analysis and response-exposure analyses will be 
presented separately from the main clinical study report (CSR). 
9.5 
Interim Analysis 
Given that the assumptions for the sample size were based on a preliminary study using a 
different dosing schedule, it is unknown if these assumptions are appropriate for this 
study as designed. To this end, an interim analysis of the primary efficacy endpoint will 
be included to assess the adequacy of the overall sample size relative to achieving the 
study objectives. This analysis will be conducted by an independent Interim Analysis 
Review Committee (IARC), which may make a recommendation to increase the overall 
sample size up to a maximum of 528 subjects. Full details and rules for the IARC and 
planned interim analysis will be provided in a separate IARC charter and in the statistical 
analysis plan. 


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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 
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. 


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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 the consent was obtained. The authorized 
person obtaining the informed consent must also sign the ICF. 
Subjects must be reconsented 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. 
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. 


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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. 
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. 


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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. 
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 


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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: Abbreviations 
 
Abbreviation 
Definition 
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 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COMT 
Catechol-O-methyltransferase  
CONSORT 
Consolidated Standards of Reporting Trials  
CPK 
Creatine phosphokinase 
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 
ESAMs 
Events subject to additional monitoring 
ESS 
Epworth Sleepiness Scale 
ET 
Early termination 
EU 
European Union 


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Abbreviation 
Definition 
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 
IRAC 
Interim Analysis Review Committee 
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 
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  
MoCA 
Montreal Cognitive Assessment  
PD 
Parkinson’s disease 
PDQ-39 
39-Item Parkinson’s Disease Questionnaire 


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Abbreviation 
Definition 
PF-0664975 
Previous laboratory code for tavapadon 
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 
SUSAR 
Suspected unexpected serious adverse reaction 
T3 
Triiodothyronine 
T4 
Thyroxine 
TEAE 
Treatment-emergent adverse event 
THC 
Tetrahydrocannabinol 
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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10.8 Appendix 8: 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 
3 OBJECTIVES AND 
ENDPOINTS 
Objectives and Endpoints tables: 
Changed metabolites to singular 
(metabolite) 
Correction of error in protocol 
1.1 Synopsis 
 
Statistical Methods: 
Added details regarding analysis of 
efficacy endpoints 
Alignment with corresponding 
content in current statistical 
analysis plan 
9 STATISTICAL 
CONSIDERATIONS 
Clarified analyses associated with 
each analysis set 
Added details regarding analysis of 
efficacy endpoints 
 
1.2 Schema 
Hauser Diary: 
Added text to specify completion 
“within 7 days” before each clinic 
visit 
Consistency with diary 
completion instructions in 
Schedule of Assessments and 
Hauser Diary sections 


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Section # and Name 
Description of Change 
Brief Rationale 
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  
1.3 Schedule of Assessments 
(continued) 
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 
 
Clarified ECG footnote language 
about timing of postbaseline PK 
samples relative to ECG 
assessments 
Consistency with Section 8.6 
Pharmacokinetics 
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 


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Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria 
Inclusion Criterion #5: 
Deleted the following 
...with bradykinesia and motor 
asymmetry 
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 #7: 
Added note that subjects receiving 
levodopa/carbidopa intestinal gel are 
not eligible 
Clarification of eligibility 
criteria; inclusion criteria 
specify requirement of good 
response to levodopa, whereas 
levodopa/carbidopa intestinal 
gel is indicated for use when 
available combinations of 
Parkinson’s treatments 
medicinal products have not 
yielded satisfactory results 
 
Inclusion Criterion #10: 
Added istradefylline as a permitted 
prior or concomitant medication 
To reflect health authority 
approval and increase in 
common usage as adjunctive 
treatment in Parkinson’s disease 
5.1 Inclusion Criteria 
6.5.2 Allowed Medications 
Before and During the Trial 
Added language to allow use of 
levodopa/benserazide 
Levodopa/benserazide is an 
acceptable alternative to 
levodopa/carbidopa that is 
commonly used in some 
countries where this trial is 
being conducted 


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Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria 
6.5.3 Prohibited Medications 
Before the Trial 
Changed timing of treatment with 
COMT inhibitors, MAO-B 
inhibitors, amantadine, and 
anticholinergic drugs 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 
6.5.3 Prohibited Medications 
Before the Trial 
Added istradefylline to item that 
includes COMT inhibitors, MAO-B 
inhibitors, amantadine, and 
anticholinergic drugs 
Alignment with change to 
Inclusion Criterion #10 and to 
define washout, if required 
6.5.3 Prohibited Medications 
Before the Trial 
6.5.4 Prohibited Medications 
During the Trial 
Added levodopa inhalation powder 
to prohibited medications 
Added apomorphine as a prohibited 
medication (ie, in the dopamine 
agonist rows of the corresponding 
tables) 
Clarification regarding rescue 
therapies  
 
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 
6.5.4 Prohibited Medications 
During the Trial 
Combined separate items for 
sedatives, hypnotics, 
antidepressants, anxiolytics into 
single item 
Consistency with table of 
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 text to allow short-term use 
of scopolamine if approved by the 
medical monitor 
To provide options for treatment 
of nausea during the trial 


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Section # and Name 
Description of Change 
Brief Rationale 
6.5.4 Prohibited Medications 
During the Trial (continued) 
Added the following: 
COMT inhibitors, MAO-B 
inhibitors, amantadine, 
istradefylline, or anticholinergic 
drugs (unless use was initiated >90 
days before the Baseline Visit and 
dose will remain stable for the 
duration of the treatment phase) 
Consistency with Table 6 
(medications prohibited before 
the trial) and convention used 
for sedatives, hypnotics, 
antidepressants, and anxiolytics 
in the table of medications 
prohibited during the trial 
7.3 Individual Subject 
Discontinuation 
Revised list of potential reasons for 
subject discontinuation of IMP 
To align more closely with 
eCRF 
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 
8.3.4 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, COMT = catechol-O-methyl 
transferase, eCRF = electronic case report form, ECG = electrocardiogram, IMP = investigational 
medicinal product, MAO-B = monoamine oxidase inhibitor B, PD = Parkinson’s disease, PK = 
pharmacokinetic, RNA = ribonucleic acid, SAE = serious adverse event. 
Amendment: Protocol Version 2.0 (29 Jun 2020) 


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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 
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 


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Section # and Name 
Description of Change 
Brief Rationale 
5.1, Inclusion Criteria 
Modified the wording related to 
use of contraceptives in 
inclusion criterion #2 
Clarify contraceptive 
requirement 
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 
6.5.3, Prohibited Medications 
Before the Trial 
Added use of COMT inhibitors, 
MAO-B inhibitors, amantadine, 
or anticholinergic drugs 
<90 days before signing ICF and 
washout period to Table 6 
Align information in table with 
inclusion criterion #10 
6.5.4, Prohibited Medications 
During the Trial 
Changed “stable for the duration 
of the trial” to “stable for the 
duration of the treatment phase” 
in entries 1, 2, 5, and 14 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 
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 


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Section # and Name 
Description of Change 
Brief Rationale 
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, COMT = catechol-O-methyl 
transferase, ICF = informed consent form, MAO-B = monoamine oxidase inhibitor B, SAE = serious 
adverse event. 
 


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Connolly BS, Lang AE. Pharmacologic treatment of Parkinson’s disease: a review. 
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Dietrichs E, Odin P. Algorithms for the treatment of motor problems in Parkinson's 
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Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with 
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Drutyte G, Forjaz MJ, Rodriguez-Blazquez C, Martinez-Martin P, Breen KC. What 
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Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, et al. Movement 
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Hauser RA, Auinger P; Parkinson Study Group. Determination of minimal clinically 
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Hauser RA, Friedlander J, Zesiewicz TA, Adler CH, Seeberger LC, O'Brien CF, et al. A 
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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 
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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 
findings from three multisite studies with adolescents and adults. Am J Psych. 
2011;168(12):1266-1277. 


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Rizek P, Kumar N, Jog MS. An update on the diagnosis and treatment of Parkinson 
disease. CMAJ. 2016;188(16):1157-65. 
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, 
FLEXIBLE-DOSE, 27-WEEK TRIAL TO EVALUATE THE 
EFFICACY, SAFETY, AND TOLERABILITY OF TAVAPADON AS 
ADJUNCTIVE THERAPY FOR PARKINSON’S DISEASE IN 
LEVODOPA-TREATED ADULTS 
WITH MOTOR FLUCTUATIONS (TEMPO-3 TRIAL) 
Protocol Number: CVL-751-PD-003 
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: 
 
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STATISTICAL ANALYSIS PLAN 
 
A PHASE 3, DOUBLE-BLIND, RANDOMIZED, PLACEBO CONTROLLED, 
PARALLEL GROUP, FLEXIBLE DOSE, 27 WEEK TRIAL TO EVALUATE THE 
EFFICACY, SAFETY, AND TOLERABILITY OF TAVAPADON AS ADJUNCTIVE 
THERAPY F
IN LEVODOPA TREATED ADULTS WITH 
MOTOR FLUCTUATIONS (TEMPO 3 TRIAL) 
Protocol Number: CVL-751-PD-003 
Compound: Tavapadon (CVL-751) 
Trial Phase: 3 
Short Title: Flexible-
With Motor Fluctuations 
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: 11 March 2024 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
NCT04542499


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STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL
specifications. 
Prepared by:
Biostatistics
PharPoint Research, Inc.
Date
Approved by: 
PharPoint Research, Inc.
Date
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 


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Approved by: 
Cerevel Therapeutics, LLC
Date
Global Clinical Development
Cerevel Therapeutics, LLC
Date
Cerevel Therapeutics, LLC
Date
 
 
 
 
 
  
 
 
  
 
 
  
 
 


 
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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 ........................................13 
1.3.1. 
Subject Assignment to Treatment ...............................................................................13 
1.3.2. 
Blinding ......................................................................................................................13 
1.4. 
Treatment Period ........................................................................................................13 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................15 
3. 
KEY ASSESSMENTS AND DERIVATIONS ..........................................................16 
3.1. 
Efficacy Assessments .................................................................................................16 
3.1.1. 
Hauser Diary ...............................................................................................................16 
3.1.1.1. 
 ..............16 
3.1.1.2. 
 ...................................................................17 
3.1.1.3. 
Handling Missing Hauser Diary Entries .....................................................................17 
3.1.2. 
Movement Disorder Society-
(MDS-UPDRS) ...........................................................................................................17 
3.1.2.1. 
Handling of Missing Items from MDS-UPDRS .........................................................18 
3.1.3. 
39-Item Par
 ...............................................................18 
3.1.4. 
EuroQol 5 Dimension 5 Level ....................................................................................19 
3.2. 
Safety Assessments .....................................................................................................19 
3.2.1. 
Questionnaire for Impulsive-
Rating Scale (QUIP-RS) Scores .................................................................................19 
3.2.2. 
Epworth Sleepiness Scale (ESS) Total Score .............................................................20 
3.2.3. 
Adverse Event (AE) ....................................................................................................20 
3.2.3.1. 
Adverse Event of Special Interest (AESI) ..................................................................20 
3.2.3.2. 
Treatment-emergent Adverse Event (TEAE) .............................................................20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3.2.4. 
Clinical Safety Laboratory Assessments ....................................................................21 
3.2.4.1. 
Treatment-emergent Laboratory Abnormality and Toxicity ......................................21 
3.2.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................21 
3.2.6. 
Vital Signs ..................................................................................................................22 
3.2.7. 
Electrocardiograms .....................................................................................................22 
3.2.8. 
Concomitant Medications and Medications Taken Post Last Dose of IMP ...............22 
3.2.9. 
Physical and Neurological Examinations ...................................................................22 
3.2.10. 
Eye Examinations .......................................................................................................22 
3.3. 
Pharmacokinetics ........................................................................................................23 
4. 
DATA CONVENTIONS AND VISIT WINDOWS ..................................................24 
4.1. 
Data Conventions ........................................................................................................24 
4.1.1. 
Age ..............................................................................................................................24 
4.1.2. 
Day 1 ...........................................................................................................................24 
4.1.3. 
Endpoint ......................................................................................................................24 
4.1.4. 
Study Day of an Event ................................................................................................24 
4.1.5. 
Days on Study .............................................................................................................24 
4.1.6. 
Days on IMP ...............................................................................................................24 
4.1.7. 
Baseline Value ............................................................................................................24 
4.1.8. 
Change from Baseline .................................................................................................25 
4.1.9. 
Orthostatic Change .....................................................................................................25 
4.1.10. 
Duration of Titration Phase ........................................................................................25 
4.1.11. 
Duration of Adjustment Phase ....................................................................................25 
4.1.12. 
Duration of Maintenance Phase ..................................................................................25 
4.1.13. 
Average Dose of Titration Phase ................................................................................25 
4.1.14. 
Average Dose of Adjustment Phase ...........................................................................25 
4.1.15. 
Average Dose of Maintenance Phase .........................................................................25 
4.1.16. 
Average Dose of L-Dopa ............................................................................................26 
4.1.17. 
Maximum Tolerated Dose (Final Dose Level) ...........................................................26 
4.1.18. 
Compliance with Study Drug .....................................................................................26 
4.1.19. 
Handling of Incomplete or Missing Dates Associated with an Event ........................26 
4.1.20. 
Handling of Alphanumeric Data .................................................................................27 
 
 
 
 
 


 
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4.2. 
Visit Windows ............................................................................................................28 
5. 
STATISTICAL ANALYSIS METHODS ..................................................................29 
5.1. 
General Considerations ...............................................................................................29 
5.2. 
Populations for Analyses ............................................................................................29 
5.3. 
Statistical Hypotheses .................................................................................................30 
5.4. 
Multiplicity Adjustment..............................................................................................30 
5.5. 
Strata and Covariates ..................................................................................................30 
5.6. 
Subject Disposition, Demographic and Baseline Characteristics ...............................30 
5.7. 
Medical and Psychiatric History .................................................................................31 
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. 
Impact of Missing Values Handling ...........................................................................33 
5.9.4. 
Subgroup Analyses .....................................................................................................34 
5.10. 
Key Secondary Efficacy Analyses ..............................................................................34 
5.10.1. 
Secondary Estimand ...................................................................................................34 
5.10.2. 
Main Analytical Approach .........................................................................................35 
5.10.3. 
Sensitivity Analyses ....................................................................................................35 
5.10.4. 
Subgroup Analyses .....................................................................................................35 
5.11. 
Summary of Primary and Key Secondary Efficacy Analyses ....................................36 
5.12. 
Other Secondary Efficacy Analyses ...........................................................................37 
5.13. 
Summary of Analyses of Other Efficacy and Exploratory Endpoints ........................37 
5.14. 
Interim and Final Analysis..........................................................................................37 
5.15. 
Safety Analyses ..........................................................................................................38 
5.15.1. 
Adverse Events ...........................................................................................................38 
5.15.2. 
Epworth Sleepiness Scale (ESS) ................................................................................39 
5.15.3. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson Disease 
Rating Scale (QUIP-RS) .............................................................................................39 
 
 
 
 
 


 
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5.15.4. 
Non-IMP Medications and Non-Drug Therapy/Procedures .......................................39 
5.15.5. 
Clinical Laboratory Assessments ...............................................................................39 
5.15.6. 
Vital Signs ..................................................................................................................40 
5.15.6.1. 
Blood Pressure and Heart Rate ...................................................................................41 
5.15.6.2. 
Body Weight ...............................................................................................................42 
5.15.6.3. 
Temperature ................................................................................................................42 
5.15.7. 
Electrocardiograms (ECGs) ........................................................................................42 
5.15.8. 
Physical and Neurological Examinations ...................................................................43 
5.15.9. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................43 
5.15.10. 
Eye Examinations .......................................................................................................43 
5.16. 
Pharmacokinetics ........................................................................................................43 
5.16.1. 
Pharmacokinetic Data Analysis ..................................................................................43 
5.17. 
Protocol Deviations ....................................................................................................43 
6. 
CHANGES IN THE PLANNED ANALYSES ..........................................................44 
7. 
REVISION HISTORY ...............................................................................................45 
8. 
REFERENCES ...........................................................................................................46 
9. 
APPENDICES ............................................................................................................47 
9.1. 
Interim Analysis Procedures .......................................................................................47 
9.1.1. 
Description of Interim Analysis ..................................................................................47 
9.1.2. 
Operational Characteristics of the Interim Sample Size Re-estimation .....................47 
9.1.2.1. 
Power Loss with Original Sample Size Under Circumstance of Increased 
Variability ...................................................................................................................47 
9.1.2.2. 
Sample Size Re-estimation Rule ................................................................................48 
9.1.2.3. 
Operating Characteristics Assessments ......................................................................48 
9.1.3. 
Conduct of the Interim Analysis .................................................................................50 
9.1.4. 
Simulation Codes (in R) .............................................................................................51 
9.2. 
Schedule of Assessments ............................................................................................53 
9.3. 
EQ-5D-5L Dimensions ...............................................................................................57 
9.4. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation and 
Suicidal Behavior Scores ............................................................................................58 
9.5. 
Programming Conventions .........................................................................................60 
9.6. 
MNAR Cases Identified Prior to Database Lock .......................................................62 
 
 
 
 
 


 
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9.7. 
Core Codes for imputation of MAR and MNAR .......................................................64 
9.7.1. 
Imputation of Missing at Random (MAR) Cases .......................................................64 
9.7.2. 
Imputation of  Missing Not at Random (MNAR) Cases ............................................64 
9.8. 
CTCAE Based Laboratory Test Results Grading Specifications ...............................65 
9.9. 
EQ-5D-5L Index Cross-walk Mapping ......................................................................89 
9.10. 
Abbreviations ............................................................................................................151 
 
 
 
 
 
 
 


 
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LIST OF TABLES 
Table 1: 
Tavapadon and Placebo Dosing Schedule ..................................................................14 
Table 2: 
Objectives and Endpoints ...........................................................................................15 
Table 3: 
Visit Windows ............................................................................................................28 
Table 4: 
Populations for Analysis .............................................................................................29 
Table 5: 
Impact of Standard Deviation Assumption on Statistical Power ................................47 
Table 6: 
Operating Characteristics of Sample Size Re-estimation Procedure ..........................49 
Table 7: 
Schedule of Assessments ............................................................................................53 
 
 
 
 
 
 
 


 
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LIST OF FIGURES 
Figure 1: 
Trial Schematic ...........................................................................................................12 
 
 
 
 
 
 


 
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1. 
INTRODUCTION 
This document describes the statistical methods and data presentations planned for the analysis 
of the efficacy and safety data from Protocol CVL-751-PD-003. Background information is 
provided for the study designs and objectives. Further details of study conduct, and data 
collection are provided in the study protocol and electronic case report forms (eCRFs) 
1.1. 
Study Overview 
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 
pharmacokinetics (PK) of flexible doses of tavapadon (5 mg to 15 mg once daily [QD]) as 
adjunctive therapy to levodopa (L Dopa) in male and female subjects aged 40 to 80 years who 
diagnostic criteria); a modified Hoehn and Yahr score of 2, 2.5, or 3 i
judgment of the investigator. The trial will include a Screening Period (maximum of 4 weeks), a 
27 week Treatment Period, and a 4 week Safety Follow up Period. Details of schedule of 
assessments are provided in Section 9.2. 
A total of 368 subjects are planned to be randomized in a 1:1 ratio to receive tavapadon or 
placebo once daily (184 subjects per treatment group). The dose of tavapadon will be titrated and 
adjusted over the first 13 weeks of the trial and then maintained for 14 weeks. The planned 
duration of treatment is 27 weeks, including the Titration and Maintenance Phases. The 
investigational medicinal products (IMPs) will be taken orally.  
The trial design is depicted in Figure 1. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
   
  
 




 
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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 ratio to 2 treatment arms (tavapadon 5 to 
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 
generated by a non-study statistician and be kept strictly confidential. Subjects will be 
sequentially assigned to the next available randomization number and will receive the IMP that 
corresponds to that randomization number. Once a randomization number has been assigned, it 
will not be reassigned. 
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 during 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 1) 
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. 
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 gradually titrated to 15 mg QD in all subjects over the first 
14 weeks of the trial during the Dose Titration and Dose Adjustment Phases unless prevented by 
intolerance. A reduction in dose (from 15 mg QD to 10 mg QD or from 10 mg QD to 5 mg QD) 
will be allowed based on individual subject tolerability. Subjects who require a dose reduction 
may be rechallenged with the higher dose, at the discretion of the investigator, to address 
symptomatic needs. 
The titration schedule, as shown in Table 1, will be used for all subjects who are randomized. 
Subjects will take 3 tablets of 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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Objectives 
Endpoints 
Pharmacokinetic 
 
 
To evaluate the PK of tavapadon in this 
population 
Plasma concentrations of tavapadon and its metabolite (if 
required) at baseline (Day 1) and at Weeks 5, 11, 14, 22, and 
27 
Abbreviations: AE = adverse event, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, 
EQ-5D-5L = EuroQol 5 Dimension 5 Level, ESS = Epworth Sleepiness Scale, L-Dopa = levodopa, MDS-UPDRS = Movement 
Disorder Society-
 = medication handling irregularities, PD = 
disease, PDQ-39 = 39-
ale, PK = pharmacokinetic, QUIP-RS = Questionnaire for Impulsive-
-Rating Scale, TEAEs = treatment-emergent adverse events, VAS = visual analog 
scale. 
3. 
KEY ASSESSMENTS AND DERIVATIONS 
3.1. 
Efficacy Assessments 
3.1.1. 
Hauser Diary 
The Hauser diary assesses patient-defined motor function status over a period and provides a tool 
Hauser et al, 
2000). The Hauser diary asks patients to rate their mobility for each 30 minute period and to 
-
 
Subjects will record diary entries at home at 30 minute intervals for 24 hours on 2 consecutive 
days within the 7 days before randomization at the Baseline Visit and at 30 minute intervals for 
24 hours on 2 consecutive days within the 7 days before each postbaseline clinic visit.  
Valid Hauser diaries should contain no more than 2 hours (four 30-minute periods) of missing 
entries total per 24 hours diary. If a diary contains more than 2 hours of missing data, it will not 
be considered valid. Valid diaries of the 2 days prior to a given visit should be averaged for the 
parameters needed for analysis. 
3.1.1.1. 
it 
-troublesome dyskinesia of the day.  
troublesome dyskinesia as recorded in the subject diary prior to a given office visit. To be 
included in the average, the subject diary must be deemed valid as defined above. The analysis 
following formula: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 




 
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 Part III, motor examination, comprises 18 items that are assessed by the investigator 
(resulting in 33 scores by location and lateralization). 
 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. 
Whenever possible, the same individual should perform the ratings for an individual subject 
throughout the course of the trial. The postbaseline MDS UPDRS assessments Parts I, II, and III 
should be conducted approximately 2 to 3 hours after the last dose of L-Dopa on the day of the 
clinic visit. Part IV is not to be assessed in this study as more detailed data will be collected 
through Hauser diary. 
3.1.2.1. 
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. A single missing value in Parts I, II, and IV is allowable.  For Part III, up to 7 values 
may be missing.  To prorate the value, the following formula is utilized: 
 
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 given Part of the 
scale. 
3.1.3. 
39-
 
The 39-
-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: 
*100 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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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. 
3.1.4. 
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 9.3). 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 
e, 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). 
-rated health on a 20-cm vertical visual analogue scale 
(VAS). The VAS is numb
-5D-5L 
asks re
 
3.2. 
Safety Assessments 
3.2.1. 
Questionnaire for Impulsive-
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).  
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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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 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=would never nod off, 1=slight 
chance of nodding off, 2=moderate chance of nodding off, or 3=high chance of nodding off). 
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 
bulations. Adverse 
AE tabulations if the AE started on or after the first dose of IMP. However, in the data listings 
these missing intensity 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, 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. 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. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
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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 28 days following discontinuation of IMP. 
A treatment-emergent laboratory toxicity is defined as an increase of at least one CTCAE 
toxicity grade (Version 5) 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, then any post-baseline graded toxicity (i.e., at least Grade 1) 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.  
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. 
-SSRS form will be completed at all visits after screening and baseline. 
-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 
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 9.4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 


 
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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. 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, just prior to the time of collection of the PK 
blood sample on Day 1. 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. 
Concomitant Medications and Medications Taken Post Last Dose of IMP 
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 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. 
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. 
 
 
 
 
 


 
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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  
 
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 ECGs, baseline is defined as the average of the triplicates at predose timepoint prior to the 
IMP administration. If the predose triplicate is not available, the average of the triplicates at the 
last visit prior to the IMP administration will be used (scheduled records will be selected over 
unscheduled records if both are present). If no triplicate is available, the last non-missing value 
prior to the initiation of IMP will be used.   
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 


 
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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 Adjustment Phase 
The duration of the adjustment phase will be calculated as the days in 
 of the dosing 
schedule. 
4.1.12. 
Duration of Maintenance Phase 
The duration of the maintenance phase will be calculated as the days in 
 of the dosing 
schedule. 
4.1.13. 
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. 
4.1.14. 
Average Dose of Adjustment Phase 
The average dose of the adjustment 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 
adjustment phase. 
4.1.15. 
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. 
 
 
 
 
 


 
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4.1.16. 
Average Dose of L-Dopa 
The average dose of L-Dopa is calculated as the sum of the milligrams of L-Dopa taken from the 
time of informed consent to the date of study completion or early termination divided by the 
number of days on study. Records with a dosing frequency that is unknown or as needed will be 
excluded from the calculation. 
4.1.17. 
Maximum Tolerated Dose (Final Dose Level) 
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. 
4.1.18. 
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. 
4.1.19. 
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. 
 
 
 
 
 
 
 


 
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 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: 
-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 (i.e., imputed values will not be listed). 
4.1.20. 
Handling of Alphanumeric Data  
Should there be instances where a clinical laboratory parameter is reported with imbedded non-
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 
 if the ULN is 0.1
 if the ULN is 10. 
Additionally, in the event of the upper limit of normal (ULN)/lower limit of normal (LLN) 
r
, the determination of the laboratory 
toxicity grade or out-of-range status will be based on the convention on the ULN and LLN 
below: 
 If the ULN 
only the numeric part will be used for determining 
the toxicity 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).  
 If the LLN 
only the numeric part will be used for determining the 
toxicity grade of the test results (i.e., the LLN is set to 5). If the LLN is in the form of 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 




 
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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 
r 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 
placebo and tavapadon 5-15 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 both a valid 
baseline and at least 1 postbaseline valid 
Hauser diary entry 
Primary analysis set for efficacy 
Endpoint completers 
All subjects in the mITT population who 
complete a valid Hauser diary at 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, mITT = 
modified intent-to-treat, PK = pharmacokinetic. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
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Number of subjects in each analysis population set will be summarized. 
Demographic data and baseline characteristics including age, age categorical distribution, 
gender, childbearing potential, race, ethnicity, height at screening, weight at screening and 
baseline, BMI at screening and baseline, history of Parkinson's disease (including years from 
initial diagnosis), baseline on time without troublesome dyskinesia, baseline off time, Montreal 
Cognitive Assessment (MoCA) total score, Modified Hoehn & Yahr assessment at screening, 
MDS-UPDRS score at baseline, and L-dopa dose at baseline will be summarized using 
descriptive statistics for the ITT population. Use of PD medications (ATC classifications of 
ADAMANTANE DERIVATIVES, OTHER DOPAMINERGIC AGENTS, OTHER 
ANTIPARKINSON DRUGS, MONOAMINE OXIDASE B INHIBITORS, or 
ANTICHOLINESTERASES) at baseline will also be summarized . 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 23.1 or higher preferred term and system organ class. 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, Adjustment, and Maintenance), average dose in each 
phase, average L-Dopa dose during treatment period, and maximum tolerated dose will be 
summarized by treatment group for the FAS Population. 
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.  
2) 
Target study population of interest: subjects in the modified intent-to-treat (mITT) 
population.  
3) 
without troublesome dyskinesia based on the 2 day average of the self-completed home 
diary for motor function status (Hauser diary). 
4) 
Population level summary of interest: estimated mean difference between tavapadon 
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 Parkinso
medications. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
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The data after treatment discontinuations or after the start of prohibited Parkinson
disease concomitant medications (ATC classifications of ADAMANTANE 
DERIVATIVES, OTHER DOPAMINERGIC AGENTS, OTHER ANTIPARKINSON 
DRUGS, MONOAMINE OXIDASE B INHIBITORS, or ANTICHOLINESTERASES 
after the first dose of IMP and prior to the last dose of IMP with duration of 7 days or 
more) will be censored under the hypothetical strategy. The hypothetical strategy allows 
the study to assess the effect of tavapadon treatment without the confounding effect of 
prohibited concomitant Parkinson
 treatments.  
5.9.2. 
Main Analytical Approach 
dyskinesia based on the 2 day average of the self-completed home diary prior to each visit 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, and interaction between treatment group and visit. 
average prior to the baseline visit) 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 tavapadon and placebo at the endpoint visit will be 
estimated based on the Least Squares Mean (LSMean) difference between the treatment groups 
at the endpoint visit from the MMRM with the associated 95% confidence interval (CI) and P-
value. The missing values are assumed to be missing at random for the main analysis, including 
missing due to missed visits or early termination due to COVID-19 control measures. 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 4 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. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


 
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5.9.3.3. 
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 
. 
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 
physician decision, and withdrawal by subject. 
b. Subjects who initiated concomitant 
medications (ATC 
classifications of ADAMANTANE DERIVATIVES, OTHER DOPAMINERGIC 
AGENTS, OTHER ANTIPARKINSON DRUGS, MONOAMINE OXIDASE B 
INHIBITORS, or ANTICHOLINESTERASES) 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 9.6).  
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 
-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 9.7. 
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:  
 
 
 Sex: female vs male 
 
 
 
troublesome 
baseline median (median of the mITT set regardless treatment group) 
 
mITT set regardless treatment group) 
 Race: white vs others  
 Region: United State 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 or excluded prior to unblinding the study. 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. The treatment effect across subgroups will be 
summarized by forest plots. 
5.10. 
Key Secondary Efficacy Analyses 
5.10.1. 
Secondary Estimand 
The key research question for the first secondary efficacy variable will be addressed with an 
estimand based on the following attributes:  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
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1) 
Treatments: treatments as randomized regardless of the actual treatment received.  
2) 
Target study population of interest: subjects in the modified intent-to-treat (mITT) 
population.  
3) 
based on the 2 day average of the self completed home diary. 
4) 
Population level summary of interest: estimated mean difference between tavapadon 
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 
medications. 
The data after treatment discontinuations or after the start of prohibited concomitant 
e treatments will be censored under the hypothetical strategy. 
5.10.2. 
Main Analytical Approach 
Similar to the analysis of the primary efficacy variable, the change from baseline to each study 
-completed home diary prior 
to each visit 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. The base
2 day average prior to the baseline visit) 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 tavapadon and placebo at the endpoint visit will be 
estimated based on the Least Squares Mean (LSMean) difference between the treatment groups 
at the endpoint visit from the MMRM with the associated 95% confidence intervals (CI) and 
P-values. The missing values are assumed to be missing at random for the main analysis, 
including missing due to missed visits or early termination due to COVID-19 control measures. 
Time curve plots will be presented for both raw Mean (SEM) and LSMean (SE). 
5.10.3. 
Sensitivity Analyses 
The sensitivity analyses described in Section 5.9.3 for the primary estimand will also be 
performed for the key secondary efficacy estimand. 
5.10.4. 
Subgroup Analyses 
The subgroup analyses described in Section 5.9.4 for the primary estimand will also be 
performed for the key secondary efficacy estimand. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






 
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Designs for Clinical Trials of Drugs and Biologics Guidance for Industry (FDA, 2019). The 
approach generally has limited impact on the overall type I error rate and minimize the risk of 
operational bias, provided the integrity of blind is rigorously maintained. Details of the sample 
size re-estimation algorithm and the rules for the IARC are provided in Section 9.1. 
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, the pre-analysis meeting has 
occurred, and the database has been locked. 
5.15. 
Safety Analyses 
All safety analyses will be performed on the Safety analysis set. Should any subjects receive a 
treatment other than their randomized treatment, the treatment as received will be used in the 
safety presentation.  
5.15.1. 
Adverse Events 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
version 26.1 or higher preferred term and system organ class. If a subject experiences multiple 
events that map to a single preferred term, the greatest intensity and strongest investigator 
assessment of relation to IMP will be assigned to the preferred term for the appropriate 
summaries. Events with missing intensity or relationship will be classified as outlined in 
Section 3.2. Missing onset dates will be imputed as previously outlined in Section 3.2 as required 
to determine treatment-emergent events. 
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 intensity. 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), and events leading to the 
discontinuation of IMP will be generated respectively. A summary of AEs by treatment phase 
and by dose at event onset will also be presented. 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 leading to dose reduction 
will be summarized by treatment group using preferred terms and system organ classes. 
Furthermore, TEAEs 
treatment 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 tavapadon group. The most common TEAEs in the tavapadon group, 
5% 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 tavapadon group. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


 
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5.15.2. 
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. 
5.15.3. 
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. 
5.15.4. 
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. 
Incidence of dosage adjustment of levodopa (L-Dopa) or equivalent during treatment period, 
prohibited by the protocol, for duration longer than one week will be summarized. Medications 
with start date after the last dose of IMP through the end of protocol-defined reporting period, 
will also be 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 26.1 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 prior, concomitant, and post-IMP  non-
drug therapy/procedures will be presented in a data listing. 
5.15.5. 
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 
, blood chemistry, and quantitative urinalysis values will be 
qualitative urinalysis results 
In addition, toxicity grade will be determined for laboratory tests with toxicity grade 
based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 with 
implementation specifications in Section 9.8. The result of each laboratory test for individual 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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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 CTCAE toxicity grade. 
Shift table will be used to summarize shifts from baseline toxicity grades to greatest (worst) 
treatment-emergent laboratory toxicity grades based on CTCAE criteria. For hematology and, 
blood chemistry, and quantitative urinalysis parameters that no CTCAE toxicity grade was 
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-
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. 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 
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. 
5.15.6. 
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 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
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will be derived using standing and supine values. Body temperature will be obtained once, at the 
time of the first blood pressure measurement.  
5.15.6.1. 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. 
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 
Change from Baseline in Supine Systolic Blood Pressure (mmHg) 
 < -20 mmHg 
 < -10 mmHg 
 > 10 mmHg 
 > 20 mmHg 
Orthostatic Systolic Blood Pressure (mmHg) 
 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Orthostatic Diastolic Blood Pressure (mmHg) 
 
 
 
 
Supine Heart Rate (beats/min) 
 < 50 bpm 
 < 60 bpm 
 
 
 > 120 bpm 
The number of percentage of the out-of-range values will also be summarized by treatment phase 
(titration, dose adjustment 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. 
5.15.6.2. 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 m
-7%) 
 
 
5.15.6.3. Temperature 
Number and percent of subjects with out-of-range temperature will be summarized based on the 
following criteria: 
 >38.0 °C 
 <36.0 °C 
5.15.7. 
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.  
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 
480 
 (FDA, 2005). For this 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
  
 
 
 
 
 
 
 
   
 
 
 
 


 
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categorization, the average of triplicate values will be utilized rather than the individual values 
comprising the triplicate measurement. 
Additionally, a distribution plot of QTcF over time will be produced aid identification of any 
possible time trend and outliers. 
5.15.8. 
Physical and Neurological Examinations 
Physical and Neurological examination data will be listed. 
5.15.9. 
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. 
5.15.10. 
Eye Examinations 
All individual level data from eye examinations following protocol amendment 4.0 will be 
presented in a listing.  
5.16. 
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 FAS population. PK 
summary tables and mean figures will be presented using the PK analysis set. 
5.16.1. 
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 be also be plotted versus time based on nominal visit.  
5.17. 
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. Summaries of important 
deviations will be presented by category of deviation. All protocol deviations will be presented 
in a listing 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 authorized 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. 
Hauser RA, Friedlander J, Zesiewicz TA, Adler CH, Seeberger LC, O'Brien CF, et al. A home 
diary to assess functional status in patients with Parkinson's disease with motor fluctuations and 
dyskinesia. Clin Neuropharmacol. 2000;23(2):75-81. 
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: Adaptive Designs for Clinical 
Trials of Drugs and Biologics; 2019. 
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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9.1.2.2.
Sample Size Re-estimation Rule
The sample size re-estimation will follow the rule below.
where 368 is the originally planned sample size, 528 is the maximum allowable sample size, and 
is the total sample size (two treatment group combined) for 90% power to detect a 
dplan), at a two-
sided alpha level of 0.049 calculated using pooled standard deviation at the IA.
where
is the targeted difference in group means as originally planned
is the nominal type 1 error rate for final analysis
=0.1, i.e. P(z>
)=1-0.9 for 90% power
is the pooled variance derived as
np and nT  are the number of observations of placebo and tavapadon excluding missing 
values at the IA and
and 
are the sample variance of placebo and tavapadon at the 
IA.
The factor of 0.73 is applied based on the expected dropout rate of 0.27.
9.1.2.3.
Operating Characteristics Assessments
The impact of the sample re-estimation approach on the overall type I error rate and the 
statistical power were investigated using simulations. Data of 1,000,000 simulated trials for each 
of the two treatment groups were generated using random number generator following normal 
distribution under the null and the targeted alternative hypotheses with different standard 
deviations (Section 9.1.4). Table 6 below summarize the results from the simulation study.  It 
confirms that the overall type I error rate is controlled below 0.05 level while  the statistical 
power under the originally targeted alternative hypothesis is increased in cases where the 
assumption of SD is not realistic. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
   
 
 
   
 
  
 
  
 
 
 
 
  
   




 
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9.1.3. 
Conduct of the Interim Analysis 
The interim analysis will be conducted by an independent IARC.  The roles and responsibilities 
of the IARC members will be defined in the IARC charter. 
Once the interim analysis time point is reached, the blinded statistical team will prepare a dataset 
containing the two key variables, a subject identifier and the change from baseline to endpoint 
(Week 26) in total daily 
population who have completed the study or discontinued will be included in this analysis. 
Missing data will not be imputed (i.e., only observed data will be included in the analysis). This 
dataset will be transferred via secured method to an independent unblinded statistical team 
outside the study personnel to apply treatment assignment information to the data and to 
calculate the pooled variance. This value then will be used to recalculate the final sample size 
(see Section 9.1.2.2) and be presented to the IARC. Based the outcome of the re-estimation, the 
IARC will make one of the following recommendations to Cerevel: 
 Recommendation 1: If the re-calculated sample size 
 is >528 , the IARC will 
recommend increasing the sample size to 528, provided no known or identified safety 
issues at the time of interim analysis, to ensure adequate power at the final analysis. 
 Recommendation 2: If the re-calculated sample size 
 is between 368 and 528 
inclusively, the IARC will recommend increasing the sample size to 
, provided no 
known or identified safety issues at the time of interim analysis, to ensure adequate 
power at the final analysis. 
 Recommendation 3: If the re-calculated sample size 
 is less than 368, the IARC 
will recommend that the trial enrollment will continue to 368 as planned. 
Strict firewall will be set in place for the interim analysis to guard the integrity of blinding.  The 
blinded team will in no time have any access to treatment assignments and the unblinded 
independent statistical team, as well as the IARC, will in no time have access to the ongoing live 
clinical database and will keep the treatment assignment information in strict confidence. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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9.1.4. 
Simulation Codes (in R) 
 
#type-I error simulation program: 
nsim=1000000 
mu=1 
sd=3 
nIA=ceiling(368*2/3*0.73) 
alpha=0.049 
t=2/3 #information fraction of the IA; 
Nmax=528 
r=Nmax/368 
Cb=qnorm(1-alpha/2)+qnorm(0.9) 
 
 
res=sapply(1:nsim, function(x){ 
  set.seed(x) 
  #simulate 368*2/3*0.73 IA subjects from the null hypothesis  
  y=rnorm(nIA, mean=mu, sd=sd) 
  y_p=y[1:(nIA/2)] 
  y_t=y[-(1:(nIA/2))] 
   
  #d is planned difference; 
  d=1 
  var_pool=mean(c(var(y_t), var(y_p))) 
 
  delta_fac=Cb 
  N.new=ceiling(4*var_pool*delta_fac^2/d^2/0.73) 
  N.new=ceiling(N.new/2)*2 
 
  N.new=ifelse(N.new>Nmax, Nmax, ifelse(N.new<368, 368, N.new)) 
  #then simulate more samples based on the new sample size 
  N.new_nonmiss=ceiling(N.new*0.73/2)*2 
  Ndelta=N.new_nonmiss-nIA 
  y_p_final=c(y_p, rnorm(Ndelta/2, mean=mu, sd=sd)) 
  y_t_final=c(y_t, rnorm(Ndelta/2, mean=mu, sd=sd)) 
  
  test.sim=t.test(y_p_final, y_t_final) 
  
  return(c(N.new, test.sim$p.value)) 
}) 
res=t(res) 
alpha_sim=mean(res[,2]<alpha) 
mean(res[,1]==368) 
mean(res[,1]==528) 
 
 
 
 
 


 
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mean(res[,1]) 
range(res[,1]) 
 
#power simulation program: 
nsim=1000000 
mu_p=0 
mu_t=1 
d_p=1  #planned difference for sample size estimation 
 
sd=2.5 
nIA=ceiling(368*2/3*0.73) 
alpha=0.049 
t=2/3 #information fraction of the IA; 
Nmax=528 
r=Nmax/368 
Cb=qnorm(1-alpha/2)+qnorm(0.9) 
 
#power simulations: 
res=sapply(1:nsim, function(x){ 
  set.seed(x) 
  #simulate 368*2/3*0.73 IA subjects from the null hypothesis  
  y_p=rnorm(nIA/2, mean=mu_p, sd=sd) 
  y_t=rnorm(nIA/2, mean=mu_t, sd=sd) 
 
  var_pool=(var(y_t)+var(y_p))/2 
  delta_fac=Cb 
  N.new=ceiling(4*var_pool*delta_fac^2/d_p^2/0.73) 
  N.new=ceiling(N.new/2)*2 
  N.new=ifelse(N.new>Nmax, Nmax, ifelse(N.new<368, 368, N.new)) 
  #then simulate more samples based on the new sample size 
  N.new_actual=ceiling(N.new*0.73/2)*2 
  Ndelta=N.new_actual-nIA 
  y_p_final=c(y_p, rnorm(Ndelta/2, mean=mu_p, sd=sd)) 
  y_t_final=c(y_t, rnorm(Ndelta/2, mean=mu_t, sd=sd)) 
  d_final=mean(y_t_final)-mean(y_p_final) 
 
  test.sim=t.test(y_p_final, y_t_final) 
  return(c(N.new,  d_final,  test.sim$p.value)) 
}) 
res=t(res) 
alpha_sim=mean(res[,3]<alpha) 
bias=mean(res[,2])-1 
 
mean(res[,1]==368) 
mean(res[,1]==528) 
mean(res[,1]) 
range(res[,1]) 
 
 
 
 
 
 
 
 






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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 
IMP Administration and Complianceu 
Dispense IMP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assess IMP compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: 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, L-Dopa = levodopa, MDS-UPDRS = Movement Disorder Society  
 = Montreal 
Cognitive Assessment, PDQ-39 = 39-
 = pharmacokinetic, QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders in 
-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. 
Subjects and investigators (or qualified designees) will independently complete concordance testing. Full details and requirements for the conduct and successful completion 
of concordance testing are provided in the appropriate protocol-specific manual. 
g. 
Subjects will record entries for 24 hours on 2 consecutive days within the 7 days before randomization at the Baseline Visit, after diary training and concordance testing has 
occurred. Subject will record entries for 24 hours on 2 consecutive days within the 7 days before each postbaseline clinic visit. 
h. 
MDS-UPDRS Parts I, II, and III should be conducted approximately 2 to 3 hours after the last dose of L-Dopa on that day. 
i. 
-
-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. 
j. 
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.  
k. 
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). 
l. 
The postdose ECG 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. A triplicate set of ECGs is 3 consecutive ECGs collected 1 to 2 minutes apart over a 5-minute period. 
n. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
  


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o. 
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 
 
p. 
Dipstick urinalysis results are not to be recorded on the eCRFs; any clinically significant abnormality should be captured as an adverse event. 
q. 
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. 
r. 
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. 
s. 
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. 
t. 
Future biospecimen research sample is optional and is to only be collected if signed consent is obtained from the subject. 
u. 
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. 
v. 
Prolactin results will be blinded.  
w. 
At Week 11 or later (for participants who have passed this visit), participants will be instructed to schedule at their first opportunity a complete eye examination, including 
evaluation of IOP, to evaluate for glaucoma or glaucoma risk factors at their first opportunity. For additional information on eye examination please refer to Protocol Version 
4.0. If the eye examination results are normal, no further examinations are required. If the eye examination results show ocular findings consistent with glaucoma or an 
increased risk of glaucoma, ophthalmologic follow-up is recommended in 6 months or within 4 weeks of EOT, whichever is sooner. Any more frequent ophthalmologic 
follow-up may be recommended at the discretion of the ophthalmologist, optometrist, or PI. If the eye examination results are abnormal but not consistent with glaucoma or 
its risk factors, ophthalmologic follow-up may be done at the discretion of the ophthalmologist, optometrist, or PI and additional eye examinations are no longer required per 
protocol for safety monitoring. 
x. 
Ophthalmologic follow-up (6 months after prior examination or within 4 weeks of EOT, whichever is sooner) is only for participants whose first examination showed ocular 
findings consistent with glaucoma or an increased risk of glaucoma. If additional ophthalmologic follow-up due to ocular findings consistent with glaucoma or an increased 
risk of glaucoma is suggested by the ophthalmologist or optometrist, contact the medical monitor with results of the eye examination for further discussion. 
 
 
 
 
 
 
 
 
 
 


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9.3. 
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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9.4. 
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-
history. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.5. 
Programming Conventions 
 Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in 
gs, 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 
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:  
 Raw measurements will be reported to the number of significant digits as captured 
electronically or on the eCRFs.  
 Standard deviations will be reported to two decimal places beyond the number of 
decimal places the original parameter is presented. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Means 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.  
 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. 
 
 
 
 
 
 
 
 
 






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9.7. 
Core Codes for imputation of MAR and MNAR 
9.7.1. 
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); 
 
run; 
-
1 - YN 
dyskinesias) 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. 
9.7.2. 
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, 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 


















































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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
 
 
 
 
 


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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
 
 
 
 
 


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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
 
 
 
 
 


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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
 
 
 
 
 


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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
 
 
 
 
 


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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
 
 
 
 
 


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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
 
 
 
 
 


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Confidential
Page 96 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 97 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 98 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 99 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 100 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 101 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 102 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 103 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 104 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 105 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 106 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 107 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 108 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 109 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 110 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 111 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 112 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 113 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 114 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 115 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 116 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 117 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 118 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 119 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 120 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 121 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 122 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 123 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 124 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 125 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 126 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 127 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 128 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 129 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 130 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 131 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 132 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 133 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 134 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 135 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 136 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 137 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 138 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 139 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 140 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 141 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 142 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 143 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 144 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 145 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 146 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 147 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 148 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 149 of 153
Version 1.0: 11 March 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
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 150 of 153
Version 1.0: 11 March 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 
 
 
 
 
 
 
 
 


Protocol CVL-751-PD-003
Tavapadon
 
 
Final Statistical Analysis Plan 
 
 
Confidential
Page 151 of 153
Version 1.0: 11 March 2024
 
9.10. 
Abbreviations 
Abbreviation 
Definition 
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 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COMT 
Catechol-O-methyltransferase  
CONSORT 
Consolidated Standards of Reporting Trials  
CPK 
Creatine phosphokinase 
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 
ESAMs 
Events subject to additional monitoring 
ESS 
Epworth Sleepiness Scale 
ET 
Early termination 
EU 
European Union