A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, 27-Week Trial to Evaluate the Efficacy, Safety, and Tolerability of Two Fixed Doses of Tavapadon in Early Parkinson's Disease (TEMPO-1 TRIAL)
Phase: PHASE3
Conditions: Parkinson Disease
Sponsor: AbbVie

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Table 5 
Investigational Medicinal Products Administered 
ARM Name 
Tavapadon 5 mg QD 
Tavapadon 15 mg QD 
Placebo QD 
Type  
Drug 
Drug 
Matching drug 
Dose Formulation 
Tablet 
Tablet 
Matching tablet 
Unit Dose Strength(s) 
 
 
0 mg 
Dosage Level(s) 
5 mg 
15 mga 
0 mg 
Route of Administration 
Oral 
Oral 
Oral 
Sourcing 
Cerevel Therapeutics 
Cerevel Therapeutics 
Cerevel Therapeutics 
Packaging and Labeling 
Blister cards labeled 
according to local 
regulations 
Blister cards labeled 
according to local 
regulations 
Blister cards labeled 
according to local 
regulations 
Former Name(s) 
PF-06649751, 
CVL-751 
PF-06649751, 
CVL-751 
-- 
a. 
Subjects who achieve but do not tolerate a dose of 15 mg once daily (QD) may titrate down to a dose of 10 mg 
QD. Subjects may remain at 10 mg QD or will be permitted a one-time rechallenge back to 15 mg QD as needed 
for symptomatic control. Subjects must receive 10 mg QD for at least 7 days before a rechallenge to 15 mg QD is 
attempted.  
6.2 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit (original shipment and/or moving of IMP supply from one 
office or facility to another within the sites network) for all IMP received and any 
discrepancies are reported and resolved before use of the IMP. 
Only subjects who are enrolled in the trial may receive IMP and only authorized site staff 
may supply or administer IMP. All IMP must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions, with access limited to the investigator and authorized site staff. 
The investigator is responsible for IMP accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused IMPs are provided in 
the appropriate protocol-specific manuals. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Subject Assignment to Treatment 
All subjects will be centrally randomized in a 1:1:1 ratio to 1 of 3 treatment arms 
(tavapadon 5 mg QD, tavapadon 15 mg QD, or placebo) at the Baseline Visit via an 
Interactive Voice Response System/Interactive Web Response System (IVRS/IWRS), 
according to a computer-generated randomization scheme. Randomization will be 
stratified by concurrent use of allowed antiparkinsonian medication (MAO-B inhibitor) 
 

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during the Treatment Period. Subjects will be sequentially assigned to the next available 
randomization number within the appropriate randomization stratum and will receive the 
IMP that corresponds to that randomization number. Once a randomization number has 
been assigned, it will not be reassigned. 
The telephone number and call-in directions for the IVRS and/or the log-in information 
for and directions for the IWRS will be provided to each trial site before the trial is 
initiated. 
6.3.2 
Blinding 
The tavapadon and placebo tablets will be identical in appearance and will be packaged 
in identically appearing blister cards. All subjects will take 3 tablets once daily of IMP 
throughout the Treatment Period, either all tavapadon tablets, all placebo tablets, or a 
combination of tavapadon and placebo tablets. Tablets will be packaged to allow dosage 
adjustments (as shown in Table 4) to be made without breaking the trial blind. 
Treatment assignments will be blinded to the investigators and other trial site personnel, 
the subjects, and all sponsor personnel who are involved in the conduct of the trial 
(including trial monitoring, data management, and data analysis). Access to the treatment 
codes will be restricted to personnel who are responsible for generating and maintaining 
the randomization code, packaging the IMPs, operating the IVRS/IWRS, analyzing the 
PK blood samples, or reporting serious adverse events (SAEs) or adverse events of 
special interest (AESI) to regulatory agencies. 
At the initiation of the trial, investigators and site personnel will be instructed on the 
method for breaking the blind. The IVRS/IWRS will be programmed with blind-breaking 
instructions. In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of the treatment assignment for an individual subject is 
warranted. Subject safety must always be the first consideration in making such a 
determination. If the investigator decides that unblinding is warranted, the investigator 
should make every effort to contact the sponsor before unblinding a subject’s treatment 
assignment unless this could delay emergency treatment of the subject. The sponsor must 
be notified within 24 hours after breaking the blind for a trial subject. 
Documentation of breaking the blind should be recorded in the subject’s medical record 
and electronic case report forms (eCRFs), with the reason for breaking the blind, the date 
and time the blind was broken, and the names of the personnel involved. Once the blind 
is broken for a subject, treatment with the IMP may not be reinitiated for that subject.  
6.4 
Trial Treatment Compliance 
All IMP will be dispensed by responsible trial personnel. Subjects will be counseled on 
the importance of taking the IMP as directed (once daily in the morning, with or without 
food) at each clinic visit and will be instructed to bring all used and unused blister cards 
to each clinic visit. Accountability and compliance (as assessed through self-reporting by 
the subject and by tablet count at each clinic visit) will be documented in the subject’s 
 

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

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

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

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

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7 DISCONTINUATION OF TRIAL INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Entire Trial 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, Institutional Review Boards/Independent Ethics Committees 
(IRBs/IECs), and regulatory authorities in accordance with regulatory requirements. 
7.2 
Discontinuation of Individual Site 
Participation of an individual trial site may be discontinued by the sponsor, the 
investigator, or the IRB/IEC if judged to be necessary for medical, safety, regulatory, 
ethical, or other reasons consistent with applicable laws, regulations, and Good Clinical 
Practice (GCP). The investigator will notify the sponsor promptly if the trial is terminated 
by the investigator or the IRB/IEC at the site. 
7.3 
Individual Subject Discontinuation 
After treatment assignment, a subject may stop treatment permanently for a variety of 
reasons. Treatment discontinuation may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator.  
A subject may discontinue the IMP for any of the following reasons: 
• 
Adverse event  
• 
Death 
• 
Worsening of PD symptoms to such an extent that, in the judgment of the 
investigator, the subject requires additional anti-PD medications 
• 
Treatment with prohibited concomitant medications 
• 
Noncompliance with the study schedule 
• 
Noncompliance with the study drug 
• 
Withdrawal by subject 
• 
Pregnancy 
• 
Physician decision 
If a subject discontinues the IMP due to an AE, the investigator or other trial personnel 
will make every effort to follow the event until it has resolved or stabilized.  
All subjects have the right to withdraw consent for further participation in the trial at any 
time without prejudice. Subjects cannot withdraw consent for use of data that have 
already been collected as part of the trial but can withdraw consent for future 
 

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participation. The investigator can also discontinue a subject from the trial at any time if 
medically necessary. Unless the subject provides written withdrawal of consent or there 
is other written documentation by the investigator confirming the subject’s verbal intent 
to completely withdraw from the trial, subjects should be followed for all 
protocol-specified evaluations and assessments, if possible. 
Complete withdrawal of consent requires a subject to refuse of ALL of the following 
methods of follow-up: 
• 
Participation in all follow-up procedures specified in the protocol (whether in-clinic 
or by telephone) 
• 
Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff) 
• 
Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives 
• 
Contact of an alternative person(s) who has been designated in source records as 
being available to discuss the subject’s medical condition, even if only by telephone, 
mail, or e-mail (eg, family, spouse, partner, legal representative [as defined per local 
regulations], friend, neighbor, or physician) 
• 
Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express the desire to interrupt, modify, or discontinue 
administration of the IMP, which is not equivalent to a complete withdrawal of consent 
for further participation. A subject may, however, indicate that further trial participation 
is creating a burden on his or her work, school, or social schedule. Therefore, the 
investigator should determine if the subject can continue participation in the trial if 
modifications to his/her treatment and/or schedule of assessments can be accommodated. 
Only subjects who withdraw their permission for all of the above methods of follow-up 
are considered to have completely withdrawn their consent to participate in the trial. 
Details on the withdrawal of consent for the optional banked biospecimen sample are 
provided in the separate ICF for that sample. 
7.4 
Lost to Follow up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by trial site personnel. 
 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5 
Dissemination of Clinical Trial Data 
Cerevel fulfills its commitment to publicly disclose clinical trial results through posting 
trial results on ClinicalTrials.gov, the European Clinical Trials Database (EudraCT), and 
other public registries in accordance with applicable local laws/regulations. 
In all cases, trial results are reported by Cerevel in an objective, accurate, balanced, and 
complete manner and are reported regardless of trial outcome or the country in which the 
trial was conducted. 
US Basic Results are posted on Clinicaltrials.gov for all Cerevel-sponsored interventional 
trials that are conducted in subjects and that evaluate the safety and/or efficacy of a 
Cerevel product, regardless of the geographical location in which the trial is conducted. 
US Basic Results are submitted for posting within 1 year of the primary completion date, 
as defined in Section 4.4, for trials in adult populations or within 6 months of the primary 
completion date for trials in pediatric populations. 
Cerevel posts European Union (EU) Basic Results on EudraCT for all Cerevel-sponsored 
interventional trials that are in scope of EU requirements. EU Basic Results are submitted 
for posting within 1 year of the primary completion date as defined in Section 4.4, for 
trials in adult populations or within 6 months of the primary completion date for trials in 
pediatric populations. 
10.1.6 
Data Quality Assurance 
All subject data relating to the trial will be recorded on printed or eCRFs unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Clinical Monitoring Plan. 
 

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

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

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

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

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

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

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SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-trial pregnancy related SAE considered reasonably 
related to the trial intervention by the investigator will be reported to the sponsor as 
described in Section 8.4.4. While the investigator is not obligated to actively seek 
this information in former trial subjects, he or she may learn of an SAE through 
spontaneous reporting. 
• 
Any female subject who becomes pregnant while participating in the trial will 
discontinue trial intervention and be withdrawn from the trial. 
 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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