Conditions: Parkinson Disease
Keywords: Early Parkinson Disease Phase 2
Allocation: RANDOMIZED | Intervention model: 
Enrollment: 57
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy, safety and tolerability of PF-06649751 in Parkinson's disease patients at early stage of the disease.

Detailed description:
The B7601011 study has a randomized, double-blind, placebo-controlled parallel group design. Approximately 88 subjects will be randomized to 2 treatment groups. Each subject will participate in the study for approximately 23 weeks including a 30 day screening period, 15 week double blind treatment period, and an approximately 28 day follow-up period.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Placebo intervention 2: PF-06649751
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
PF-06649751
B7601011
Final Protocol Amendment 1, 20 July 2016
Page 1
A 15-WEEK, PHASE 2, DOUBLE BLIND, RANDOMIZED,
PLACEBO-CONTROLLED, FLEXIBLE DOSE STUDY TO INVESTIGATE THE 
EFFICACY, SAFETY AND TOLERABILITY OF PF-06649751 IN SUBJECTS WITH 
EARLY STAGE PARKINSON’S DISEASE
Compound:
PF-06649751
Compound Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
118647
European Clinical Trials Database 
(EudraCT) Number:
2016-001575-71
Protocol Number:
B7601011
Phase:
2
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Document History
Document
Version Date
Summary of Changes
Amendment 1
20 July 2016
1. Protocol Summary and Section 1.4.1: 
Clarification that 104 healthy volunteer subjects 
have participated in the completed Phase 1 
studies, with 88 having received PF-06649751.
2. Schedule of Activities Footnote #6: Clarification 
that FSH test at Screening is mandatory for 
female subjects in order to confirm 
non-childbearing potential, unless documented 
hysterectomy, bilateral oophorectomy or 
medically confirmed ovarian failure.
3. Schedule of Activities Footnote #13, and 
Section 7.5.8:
 
4. Section 1.3.3: Results of Study 8001294 included.
5. Section 4.2, Exclusion Criteria #3: Fever added.
6. Section 4.2, Exclusion Criteria #4: “Epilepsy” 
definition clarified with reference added.
7. Section 4.2, Exclusion Criteria #10: History of 
vasculitis added. 
8. Section 4.2, Exclusion Criteria #12: History of 
malignancy criteria clarified.
9. Section 5.5.1, Table 2: Clarifying footnote that 
the increase in dose level from Stage 1 to Stage 2 
is a mandatory step at Visit 2 (from Day 8).
10. Section 6, Section 7.2.1 and Section 7.2.9: 
Additional safety laboratory tests added at 
Screening and Visit 15 (and during the study if 
deemed necessary by the investigator) for 
monitoring of vascular inflammation.
11. Section 7.6:
 
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12. Section 7.7: Blood volume table updated.
13. Section 13.2: End of Trial template language 
included.
14. Appendix 2: Stable low doses of benzodiazepines 
are permitted. The planned prescription of 
benzodiazepines for P.r.n. (“as needed”) use
throughout the study should be discussed with the 
medical monitor.
15. Minor administrative updates throughout.
16. References updated.
Original 
protocol
24 May 2016
Not applicable (N/A)
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
LIST OF FIGURES ...................................................................................................................9
APPENDICES .........................................................................................................................10
PROTOCOL SUMMARY.......................................................................................................11
SCHEDULE OF ACTIVITIES................................................................................................15
1. INTRODUCTION ...............................................................................................................20
1.1. Indication.................................................................................................................20
1.2. Purpose of Study .....................................................................................................20
1.3. Background and Rationale ......................................................................................20
1.3.1. Parkinson’s Disease....................................................................................20
1.3.2. PF-06649751 Mechanism of Action...........................................................21
1.3.3. Summary of Preclinical Toxicology...........................................................22
1.4. Previous Human Clinical Experience .....................................................................23
1.4.1. Clinical Studies...........................................................................................23
1.4.2. Safety..........................................................................................................25
1.4.3. Pharmacokinetics........................................................................................29
1.5. Rationale..................................................................................................................30
1.5.1. Study Rationale...........................................................................................30
1.5.2. Dose Rationale............................................................................................30
1.5.3. Summary of Benefit-Risk Assessment.......................................................31
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................31
2.1. Study Objectives .....................................................................................................31
2.1.1. Primary Objective.......................................................................................31
2.1.2. Secondary Objectives .................................................................................32
2.2. Endpoints.................................................................................................................32
2.2.1. Primary Endpoint (Efficacy).......................................................................32
2.2.2. Safety and Tolerability ...............................................................................32
3. STUDY DESIGN.................................................................................................................33
3.1. Study Overview.......................................................................................................33
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3.1.1. Screening ....................................................................................................34
3.1.2. Double Blind Period ...................................................................................34
3.1.3. Follow-up Period ........................................................................................35
4. SUBJECT SELECTION......................................................................................................35
4.1. Inclusion Criteria.....................................................................................................35
4.2. Exclusion Criteria....................................................................................................36
4.3. Randomization Criteria ...........................................................................................40
4.4. Lifestyle Guidelines ................................................................................................40
4.4.1. Meals and Dietary Restrictions...................................................................40
4.4.2. Alcohol, Caffeine, and Tobacco .................................................................40
4.4.3. Activity .......................................................................................................40
4.4.4. Contraception – Females ............................................................................40
4.4.5. Contraception – Males................................................................................40
4.5. Sponsor’s Qualified Medical Personnel..................................................................42
4.6. Rater Qualifications.................................................................................................42
5. STUDY TREATMENTS.....................................................................................................43
5.1. Allocation to Treatment ..........................................................................................43
5.2. Breaking the Blind ..................................................................................................43
5.3. Subject Compliance.................................................................................................44
5.4. Investigational Product Supplies.............................................................................44
5.4.1. Dosage Form(s) and Packaging..................................................................44
5.4.2. Preparation and Dispensing........................................................................44
5.5. Administration.........................................................................................................44
5.5.1. Dose Optimization of Investigational Product ...........................................45
5.5.1.1. Dose Optimization Period .........................................................46
5.5.2. Dose Maintenance Period...........................................................................49
5.6. Investigational Product Storage ..............................................................................49
5.7. Investigational Product Accountability...................................................................50
5.7.1. Destruction of Investigational Product Supplies ........................................50
5.8. Concomitant Treatment(s).......................................................................................50
5.8.1. Medications for Parkinson’s Disease..........................................................50
5.9. Other Prohibited Concomitant Medications............................................................51
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5.9.1. Permitted Other Concomitant Medications ................................................51
6. STUDY PROCEDURES .....................................................................................................52
6.1. Screening – Day -30 to Day -2................................................................................52
6.2. Study Period ............................................................................................................54
6.2.1. Visit 1 (Randomization) .............................................................................55
6.2.2. Visit 2 (Day 7) ............................................................................................56
6.2.3. Visit 3 (Day 14) ..........................................................................................57
6.2.4. Visit 4 (Day 21) ..........................................................................................57
6.2.5. Visit 5 (Day 28, Phone Visit) .....................................................................58
6.2.6. Visit 6 (Day 35) ..........................................................................................58
6.2.7. Visit 7 (Day 42, Phone Visit) .....................................................................59
6.2.8. Visit 8 (Day 49) ..........................................................................................60
6.2.9. Visit 9 (Day 56, Phone Visit) .....................................................................60
6.2.10. Visit 10 (Day 63) ......................................................................................61
6.2.11. Visit 11 (Day 70, Phone Visit) .................................................................62
6.2.12. Visit 12 (Day 84) ......................................................................................63
6.2.13. Visit 13 (Day 98, Phone Visit) .................................................................63
6.2.14. Visit 14 or Early Termination Visit (Day 105).........................................64
6.3. Follow Up Period ....................................................................................................65
6.3.1. Visit 15 – (Day 119) ...................................................................................65
6.3.2. Visit 16 – (Day 133, Phone Visit) ..............................................................65
6.4. Unplanned Visits.....................................................................................................65
6.4.1. Unplanned Phone Visits .............................................................................66
6.4.2. Unplanned Clinic Visits..............................................................................66
6.4.2.1. Unplanned Clinic Visit during the Dose Optimization 
Period.................................................................................................66
6.4.2.2. Unplanned Clinic Visit during the Maintenance Period ...........67
6.5. Subject Withdrawal (Early Termination)................................................................67
7. ASSESSMENTS..................................................................................................................68
7.1. Eligibility.................................................................................................................69
7.1.1. Review of Inclusion/Exclusion Criteria......................................................69
7.1.2. Medical History/Prior Medications/Procedures .........................................69
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7.1.3. Diagnostic Criteria for Parkinson’s Disease...............................................69
7.1.4. Mini Mental State Examination (MMSE) ..................................................69
7.1.5. Hoehn & Yahr (HY)...................................................................................69
7.1.6. Patient Health Questionnaire (PHQ-8) .......................................................70
7.2. Safety.......................................................................................................................70
7.2.1. Laboratory Tests .........................................................................................70
7.2.2. Pregnancy Testing ......................................................................................72
7.2.3. Physical Examinations................................................................................72
7.2.4. Neurological Examinations ........................................................................72
7.2.5. Blood Pressure and Heart Rate...................................................................73
7.2.6. Electrocardiogram.......................................................................................73
7.2.7. Questionnaire for Impulsive-Compulsive Disorder in Parkinson’s 
Disease Rating Scale (QUIP-RS).....................................................................74
7.2.8. Physician Withdrawal Checklist (PWC-20)...............................................75
7.2.9. Additional Laboratory Testing for Suspected Vascular Inflammation.......75
7.3. Assessment of Suicidal Ideation and Behavior.......................................................75
7.3.1. Columbia Suicide Severity Rating Scale (C-SSRS)...................................75
7.4. Efficacy Measures...................................................................................................76
7.4.1. Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).......................76
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7.7. Blood Volume .........................................................................................................81
8. ADVERSE EVENT REPORTING......................................................................................82
8.1. Adverse Events........................................................................................................82
8.2. Reporting Period .....................................................................................................83
8.3. Definition of an Adverse Event...............................................................................83
8.4. Medication Errors....................................................................................................84
8.5. Abnormal Test Findings..........................................................................................84
8.6. Serious Adverse Events...........................................................................................85
8.6.1. Protocol-Specified Serious Adverse Events...............................................85
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................85
8.7. Hospitalization ........................................................................................................86
8.8. Severity Assessment................................................................................................88
8.9. Causality Assessment..............................................................................................88
8.10. Exposure During Pregnancy..................................................................................88
8.11. Occupational Exposure .........................................................................................90
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal (Early Termination))..............................................................................90
8.13. Eliciting Adverse Event Information ....................................................................90
8.14. Reporting Requirements........................................................................................90
8.14.1. Serious Adverse Event Reporting Requirements .....................................90
8.14.2. Non serious Adverse Event Reporting Requirements ..............................91
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................91
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................91
9.1. Sample Size Determination.....................................................................................91
9.2. Efficacy Analysis ....................................................................................................92
9.2.1. Analysis of the Primary Endpoint...............................................................92
9.2.2. Analysis of Secondary/
 Endpoints...........................................93
9.4. Safety Analysis........................................................................................................94
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9.5. Interim Analysis ......................................................................................................94
9.6. Data Monitoring Committee ...................................................................................94
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................94
11. DATA HANDLING AND RECORD KEEPING .............................................................95
11.1. Case Report Forms/Electronic Data Record .........................................................95
11.2. Record Retention...................................................................................................95
12. ETHICS..............................................................................................................................96
12.1. Institutional Review Board/Ethics Committee......................................................96
12.2. Ethical Conduct of the Study ................................................................................96
12.3. Subject Information and Consent..........................................................................96
12.4. Subject Recruitment ..............................................................................................97
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................97
13. DEFINITION OF END OF TRIAL...................................................................................97
13.1. End of Trial in the United States...........................................................................97
13.2. End of Trial in a Member State.............................................................................98
13.3. End of Trial in All Other Participating Countries.................................................98
14. SPONSOR DISCONTINUATION CRITERIA ................................................................98
15. PUBLICATION OF STUDY RESULTS..........................................................................98
15.1. Communication of Results by Pfizer ....................................................................98
15.2. Publications by Investigators ................................................................................99
16. REFERENCES ................................................................................................................101
LIST OF TABLES
Table 1.
Steady State Exposures of PF-06649751 after Multiple Dosing in 
Parkinson’s Disease Patients with Motor Fluctuations ........................................30
Table 2.
Titration Scheme of PF-06649751 and Placebo ...................................................46
LIST OF FIGURES
Figure 1.
Decision Flow.......................................................................................................48
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APPENDICES
Appendix 1. Abbreviations....................................................................................................104
Appendix 2. Permitted/Prohibited Concomitant Medications...............................................108
Appendix 3. Moderate or Strong CYP3A Inhibitors and Inducers........................................109
Appendix 4. UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria*.....111
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PROTOCOL SUMMARY
Background and Rationale
In Parkinson’s disease, motor dysfunction can be mitigated via pharmacologic activation of 
direct striatal output pathways containing dopamine-1 receptors (D1R) and/or indirect striatal 
output pathways containing dopamine-2 receptors (D2R).  L-Dopa therapy acts through both 
pathways and effects an improvement in motor symptoms, which unfortunately diminishes 
over time.1 As Parkinson’s disease progresses, motor fluctuations reflect this diminished 
effectiveness, while dyskinesias emerge as manifestations of excessive dopaminergic 
stimulation.  As a consequence, the clinical response to L-Dopa is gradually confined to a 
relentlessly narrowing therapeutic window. Agonists at the D2 and D3 receptors (D2/D3R), 
such as pramipexole, ropinirole, and rotigotine, are also approved for the symptomatic 
treatment of Parkinson’s disease.2 However, the maximal efficacy observed is considered 
inferior to L-Dopa.  Efforts to develop selective D1R agonists have been ongoing for 
decades.  Unlike D2/D3R agonists, D1R agonists may produce L-Dopa like efficacy through 
selective stimulation of the direct pathway.  Development of a novel pharmaceutical agent 
that improves motor function without associated motor fluctuations or dyskinesias will 
provide an important new treatment option for patients with Parkinson’s disease who are at 
increasing risk of experiencing these manifestations of the condition like the patients at early 
stage of the disease. 
PF-06649751 is a potent and highly selective dopamine D1/D5 receptor partial agonist being 
evaluated for the symptomatic treatment of Parkinson’s disease.  PF-06649751 
(0.02-0.15 mg/kg, subcutaneous administration (SC)) was tested for its ability to improve 
parkinsonian symptoms in the 1-methyl-4-phenyl-1 2, 3, 6-tetrahydropyridine (MPTP) model 
of Parkinson’s disease in monkeys.  Treatment with PF-06649751 dose-dependently 
improved both parkinsonian disability and bradykinesia scores, and this effect was 
maintained over three consecutive days of dosing.  In monkeys primed to exhibit dyskinesias 
by prior chronic treatment with L-Dopa, PF-06649751 (0.1 and 0.15 mg/kg) reduced 
disability as effectively as an optimal dose of L-Dopa but with a longer duration of action 
and a lower level of dyskinesia. 
A total of 104 healthy subjects (88 receiving PF-06649751) have participated in the 
completed single ascending dose (B7601001; n=18), multiple ascending dose 
(B7601002; n=77), and single dose plus trimethobenzamide hydrochloride (TMB; 
B7601007, n=9) Phase 1 trials.
Additionally PF-06649751 has been administered to 45 Parkinson’s disease patients in one 
open-label multiple ascending dose study (B7601005) and 18 Parkinson’s disease patients 
have been assigned to study treatment with PF-06649751 or placebo in one double-blind, 
single ascending dose study (B7601009).
The results of study B7601001, B7601002, and B7601007 and the possible risks associated 
with the administration of PF-06649751 are summarized in the Investigator’s Brochure (IB). 
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This study is intended to complement other Phase 1 and 2 clinical investigations, by 
providing safety and efficacy experience in a population of patients with early stage 
Parkinson’s disease.
Study Objectives
Primary Objective

To evaluate the effect of PF-06649751 administered once daily on motor symptoms
in subjects with early stage Parkinson’s disease.
Secondary Objectives

To evaluate the safety and tolerability of PF-06649751 administered once daily in 
subjects with early stage Parkinson’s disease. 
 
 
 
 
Endpoints
Primary Endpoint (Efficacy)

Change from baseline in the Modified Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) Score Part III at Week 15.
Safety and Tolerability

Adverse events.

Clinical laboratory parameters.

Vital signs.

Electrocardiogram (ECG) parameters.
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
Columbia Suicide Severity Rating Scale (C-SSRS).

Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating 
Scale (QUIP-RS).

Physician Withdrawal Checklist (PWC-20).
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Study Design
The study has a randomized, double-blind, placebo-controlled, flexible-dose design.  
Approximately 88 subjects from approximately 30 centers in up to 5 countries will be 
randomized to 2 treatment groups (PF-06649751 or placebo) in a 1:1 ratio using a central 
randomization system. Each subject will undergo 15 weeks of double-blind treatment 
(including 9 weeks of Dose Optimization Period and 6 weeks of stable dosing during the
Dose Maintenance Period).  During the initial up titration, subjects will gradually increase 
the dose of investigational product at weekly intervals, as tolerated, until Parkinsonian 
symptoms are optimally controlled.  Investigational product will be self-administered once 
daily.  The target dose range for PF-06649751 is 3 mg to 15 mg once daily (Stage 4 – Stage 8 
in Table 2).  Adjustments to the up-titration schedule are permitted during the Dose 
Optimization Period based on clinical judgment to mitigate adverse events or symptoms of 
suspected dopaminergic overstimulation.
The 15 weeks of double-blind treatment will be preceded by a 30 day screening period.  
There will be an additional follow-up period of 28 days following discontinuation of 
investigational product, for total study duration of up to 23 weeks.
Statistical Methods
The primary endpoint is the change from baseline in the MDS-UPDRS score Part III at 
Week 15.  The details of the statistical model will be specified in the Statistical Analysis Plan 
(SAP).
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the subject.  Study visit times are relative to Visit 1
(Randomization), and not relative to when the previous visit actually occurred.  The indicated visit windows are only intended 
to mitigate scheduling conflicts for study visits.
Visit Identifier
Protocol Activity
Screening
Visit 
Dose Optimization Period
Dose Maintenance Period
Follow Up 
Period
Visit 1 Visit 2 Visit 3 Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9 Visit 
10
Visit 11 
Visit
12
Visit 13
Visit 14 or 
Early 
Termination
Visit
15
Visit 16 
D -30
to -2
D -1/
RAND
D 7 
+3
D 14 
+3
D 21 
+3
D 28 
+3
D 35 
+3
D 42 
+3
D 49 
+3
D 56 
+3
D 63 
3
D 70
3
D 84
3
D 98 
3
D 105 -3
D 119
3
D 133
3
Wks 1 – 9 
Wk 10
Wk 12 Wk 14
Wk 15
Wk 17 Wk 19
Informed consent
X1
Demographics2
X
Medical history 
X
X3
Prior/Concomitant 
medications assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full physical and 
neurological examination
X
X
X
Brief physical and 
neurological examination4
X
X
X
X
Mini Mental State 
Examination (MMSE)
X
UK Parkinson’s Disease 
Society Brain Bank 
Clinical Diagnostic 
Criteria
X
Hoehn & Yahr Stage
X
Height and weight, BMI5
X
X
X
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Visit Identifier
Protocol Activity
Screening
Visit 
Dose Optimization Period
Dose Maintenance Period
Follow Up 
Period
Visit 1 Visit 2 Visit 3 Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9 Visit 
10
Visit 11 
Visit
12
Visit 13
Visit 14 or 
Early 
Termination
Visit
15
Visit 16 
D -30
to -2
D -1/
RAND
D 7 
+3
D 14 
+3
D 21 
+3
D 28 
+3
D 35 
+3
D 42 
+3
D 49 
+3
D 56 
+3
D 63 
3
D 70
3
D 84
3
D 98 
3
D 105 -3
D 119
3
D 133
3
Wks 1 – 9 
Wk 10
Wk 12 Wk 14
Wk 15
Wk 17 Wk 19
Contraception check 
(Serum Pregnancy)/FSH 
Test6
X
Serological Testing7
X
Urine drug screening8
X
X
Safety laboratory9
X
X10
X
X
X
X
X10
 
 
 
 
ECG14
X
X
X
X
X
X
X
X
X
X
X
Supine and standing 
blood pressure and heart
rate
X15
X
X
X
X
X
X
X
X
X
X
Columbia Suicidality 
Severity Rating Scale 
(C-SSRS)16
X
X
X
X
X
X
X
X
X
X
X
Patient Health 
Questionnaire (PHQ-8)
X





Questionnaire for 
Impulsive-Compulsive 
Disorders in Parkinson’s 
Disease – Rating Scale 
(QUIP-RS)
X




X
X

X
Inclusion/exclusion 
criteria verification
X
X





Randomization
X





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Visit Identifier
Protocol Activity
Screening
Visit 
Dose Optimization Period
Dose Maintenance Period
Follow Up 
Period
Visit 1 Visit 2 Visit 3 Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9 Visit 
10
Visit 11 
Visit
12
Visit 13
Visit 14 or 
Early 
Termination
Visit
15
Visit 16 
D -30
to -2
D -1/
RAND
D 7 
+3
D 14 
+3
D 21 
+3
D 28 
+3
D 35 
+3
D 42 
+3
D 49 
+3
D 56 
+3
D 63 
3
D 70
3
D 84
3
D 98 
3
D 105 -3
D 119
3
D 133
3
Wks 1 – 9 
Wk 10
Wk 12 Wk 14
Wk 15
Wk 17 Wk 19
Subject training on 
management of 
investigational product 
and dosing diary
X
X


X


Investigational product 
accountability
X
X
X
X
X

X

X
X
Dosing compliance 
verification via phone17
X
X
X
X
X
Subject investigational 
product dosing diary18
X












X
Decision tree review19
X
X
X
X
X
X
X
X
X

Dispensing of 
Investigational product
X
X
X
X
X
X

X

X
Administration of 
Investigational product20
X20












X
MDS-UPDRS III21
X
X


X

X
X
X
X
X
 
 
 
 
 
 
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Visit Identifier
Protocol Activity
Screening
Visit 
Dose Optimization Period
Dose Maintenance Period
Follow Up 
Period
Visit 1 Visit 2 Visit 3 Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9 Visit 
10
Visit 11 
Visit
12
Visit 13
Visit 14 or 
Early 
Termination
Visit
15
Visit 16 
D -30
to -2
D -1/
RAND
D 7 
+3
D 14 
+3
D 21 
+3
D 28 
+3
D 35 
+3
D 42 
+3
D 49 
+3
D 56 
+3
D 63 
3
D 70
3
D 84
3
D 98 
3
D 105 -3
D 119
3
D 133
3
Wks 1 – 9 
Wk 10
Wk 12 Wk 14
Wk 15
Wk 17 Wk 19
 
 
 
 
 
 
Physician Withdrawal 
Checklist (PWC-20)
X
Abbreviations: = ongoing/continuous event; AE = adverse event; BMI = body mass index; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HIV = human immunodeficiency virus; HR = heart rate; MDS-UPDRS = Movement Disorder Society – Unified Parkinson’s Disease Rating Scale; 
PK = pharmacokinetics; RAND: Randomization; THC = tetrahydrocannabinol; UK = United Kingdom; Wk = week.
*
= Phone Visit (Visits 5, 7, 9, 11, 13, and 16).
1.
Informed consent will be completed prior to any screening assessments and prior to initiating any treatment washout period, if applicable.
2.
Current employment status will be collected as part of Demographics at Screening.
3.
Medical history assessed at Visit 1 (Randomization) to confirm no change in history post screening visit, deemed relevant to study participation.
4.
Brief physical will be focused on general appearance, the cardiovascular, respiratory, pulmonary, abdominal exams, as well as directed towards any subject 
reported symptoms.  The brief neurological exam includes observation for cerebellar (intention) tremor and for no cerebellar tremors (eg, resting or 
positional), finger to nose, heel to shin, Romberg, gait and tandem walking, positional and gaze evoked nystagmus.
5.
Height and BMI will only be assessed at Screening.
6.
FSH test at Screening is mandatory for female subjects that do not have documented hysterectomy, bilateral oophorectomy or medically confirmed ovarian 
failure, to confirm non-childbearing potential (see Section 4.1, Inclusion Criteria #5).
7.
HIV testing, Hepatitis B antigen, and Hepatitis C antibody.  In the case of anti-HCV positive result, a qualitative HCV-RNA follow up test is to be 
performed.
8.
Urine test for drugs of abuse (including THC) by central laboratory at Screening and by dipstick at site at Day -1 (Randomization).
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9.
Includes hematology, biochemistry, and urinalysis. Urinalysis will be performed by dipstick at site, and if positive, additional urine should be collected and 
sent to the central lab.
10. Refer to Section 7.2.1 for additional safety laboratory tests to be completed at Screening and Visit 15, and/or as necessary throughout the study after 
consultation with the Medical Monitor/Sponsor per Section 7.2.9.
11.
12.
13.
 
14. Triplicate ECG at all sampling time points (centrally read), except Screening.  Single ECG permitted at Screening if subject meets eligibility criteria after 
initial measurement (refer to Exclusion Criteria #21).
15. Triplicate vital signs (HR and blood pressure) at Screening, if needed, if subject does not meet eligibility criteria after initial measurement.
16. Columbia Suicidality Severity Rating Scale (C-SSRS) “Past five years” evaluation at Screening, and Columbia Suicidality Severity Rating Scale “Since last 
visit” at all other time points.
17. In addition to compliance verification, subjects will be instructed on which blister card to use for following the week at each phone visit.  The verification of 
blister card may be performed the day following the phone visits during Dose Optimization period (Visit 5 and 7).
18. Dosing diary should be started on Day 1 (first dose of investigational product) and filled in during the time course of the entire double blind treatment
period.
19. At each visit, when reviewing the decision tree (Figure 1, Section 5.5.1), evaluate, if the current dose level is well tolerated and, if the degree of motor 
symptom control can be considered satisfactory.
20. Visits should be scheduled at approximately the same time of day throughout the study.  Subjects take their morning dose at home.  Subjects will document 
the timing of investigational product dose on study visit days via the dosing diary.
21. MDS-UPDRS Part III should be assessed approximately 2 to 4 hours following the administration of the investigational product (except at screening visit). 
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1. INTRODUCTION
1.1. Indication
PF-06649751 is a D1/D5 receptor partial agonist that is being developed for the treatment of 
the signs and symptoms of Parkinson’s disease.
1.2. Purpose of Study
This study will evaluate the efficacy, safety, and tolerability of PF-06649751 in subjects with 
early stage Parkinson’s disease.
1.3. Background and Rationale
1.3.1. Parkinson’s Disease
Parkinson’s disease is a neurodegenerative disease affecting over 1 million patients in the 
United States, 1.2 million in Europe and 6.3 million worldwide.  Over 65 years of age, the 
prevalence of Parkinson’s disease is approximately 1%, increasing to 3% for individuals in 
their 80s.  The lifetime risk for developing Parkinson’s disease may be as high as 1 in 40.3
Parkinson’s disease is characterized early on by the classic motor symptom triad of 
bradykinesia (slow and reduced amplitude of movement), rigidity (resistance to passive 
movement), and resting tremor.  Key neuropathological features of Parkinson’s disease 
include dopaminergic neuronal loss and regional intracellular aggregation of the protein 
alpha-synuclein.4 Lesions in the substantia nigra result in loss of pre-synaptic 
dopamine-producing axon terminals in the striatum (putamen and caudate) and disruption of 
the physiological function of the direct and indirect basal ganglionic pathways leading to the 
clinical expression of Parkinson’s disease.5
Currently available pharmacological treatment strategies for Parkinson’s disease may be 
roughly grouped into approaches that: A) provide an exogenous source of a dopamine 
precursor (L-Dopa), B) increase the amount of dopamine in the brain (eg, by preventing 
degradation of endogenous dopamine [monoamine oxidase B inhibitors; MAO-Bi] or 
exogenous dopamine [catechol-O methyltransferase (COMT) inhibitors]), and C) are direct 
agonists of D2/D3 receptors (D2/D3R).
L-Dopa therapy provides increased dopamine levels in a transient and highly variable pulse 
and affords rapid onset improvement of motor symptoms for a limited duration.6 However, 
chronic L-Dopa therapy is associated with significant complications.  More than 40% of 
patients on L-Dopa experience motor fluctuations and dyskinesias after more than 3 to 
5 years of therapy.  These phenomena can be as troublesome as the disease itself.7  The initial 
consistent relief of symptoms resulting from dopamine replacement is ultimately replaced by 
a relentlessly narrowing therapeutic window.  Other pharmacologic strategies, including 
D2/3R agonists, do not appear to provide the same degree of symptomatic relief as patients 
experience with L-Dopa. 
Unlike D2/D3R agonists, D1R agonists may produce L-Dopa like efficacy through selective 
stimulation of the direct pathway.  Efforts to develop selective D1R agonists have been 
ongoing for decades.  In small clinical studies in Parkinson’s disease subjects, the selective 
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full D1/D5R agonists dihydrexidine,7 ABT-431,8,9 and CY 208 24310 showed L-Dopa-like 
relief of parkinsonian symptoms but also induced dyskinesias comparable to those caused by 
L-Dopa. 
In contrast to available D2/D3R agonists, D1/D5R agonists have demonstrated efficacy 
similar to L-Dopa in the MPTP-lesioned nonhuman primate model of Parkinson’s disease 
(see Investigator’s Brochure Section 5.1.3.2 In Vivo Pharmacodynamics).  Severely lesioned 
MPTP-treated monkeys showed no response to D2R agonists and modest improvement with 
L-Dopa treatment, but showed marked improvement with D1R agonist treatment.11
1.3.2. PF-06649751 Mechanism of Action
PF-06649751 is a highly selective partial agonist at dopamine D1 like receptors (D1 and D5 
receptors, abbreviated as D1Rs) which is being developed for the treatment of the signs and 
symptoms of Parkinson’s disease.  The compound is differentiated from other D1R agonists 
compounds that have been reported in the literature and tested in the clinic (eg, ABT 431 and 
dihydrexidine) in that PF-06649751 has a non-catechol chemical structure.  PF-06649751
showed a similar binding affinity for native D1Rs in brain membranes prepared from 
monkey striatal tissue (Ki = 7 nM).  In vitro binding studies demonstrated that PF-06649751
(MW = 391.35 g/mol) displayed high binding affinity for recombinant hD1 (Ki = 9 nM) and 
hD5 (Ki = 13 nM) dopamine receptors.  The binding potency of PF-06649751 for the 
recombinant rD1 receptor was 84 nM and ~10-fold lower than the hD1 receptor.  In vitro 
functional testing against recombinant hD1 and hD5 receptors established that the compound 
is an agonist, which stimulates cAMP formation with EC50 values of 19 nM and 17 nM, 
respectively.  Comparison of the cAMP response to the full agonist dopamine indicated that 
PF-06649751 is a partial agonist at D1Rs with intrinsic activity values of 65% and 81% for 
the hD1 and hD5 receptors, respectively.
The functional activity of the compound was demonstrated in vivo.  In mice, PF-06649751
increased locomotor activity (LMA).  Polysomnography and quantitative 
electroencephalography (qEEG) recordings in rats indicate that PF-06649751 approached 
significance to increase latency to enter rapid eye movement (REM) sleep and had no effect 
on overall sleep pattern, including REM and slow wave sleep (SWS).  PF-06649751 also 
induced transient changes in qEEG.  In monkeys, PF-06649751 increased eye blink rate 
(EBR) demonstrating that the compound was functionally active in vivo.  A positron 
emission tomography (PET) imaging study confirmed that the compound is brain penetrant 
and the in vivo receptor occupancy (RO) is in agreement with the calculated RO based on in 
vitro binding affinity. 
PF-06649751 (0.02-0.15 mg/kg, subcutaneous administration (SC)) was tested for its ability 
to improve parkinsonian symptoms in the MPTP model of Parkinson’s disease in monkeys.  
Treatment with PF-06649751 dose-dependently improved parkinsonian behaviors, and this 
effect was maintained over three consecutive days of dosing.  In monkeys primed to exhibit 
dyskinesias by prior chronic treatment with L-Dopa, PF-06649751 reduced disability as 
effectively as an optimal dose of L-Dopa but with a longer duration of action and a lower 
level of dyskinesia. 
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A predicted human plasma efficacious concentration (Ceff) of PF-06649751 has been derived, 
based upon the experience with PF-06649751 in the MPTP-induced monkey model of 
Parkinson’s disease.  The total and unbound human Ceff of PF-06649751 in plasma are 
predicted to be 27.6 ng/mL and 1.7 ng/mL, respectively, corresponding to approximately 
32% receptor occupancy. 
In an evaluation of secondary (off target) pharmacology in vitro, PF-06649751 at 10 M did 
not inhibit ligand binding by more than 50% at any of the receptors, transporters, and ion 
channels and enzyme and uptake assays evaluated except the primary pharmacologic target, 
D1R.  Therefore, the potential for secondary pharmacology is considered low at clinically 
relevant exposures. 
1.3.3. Summary of Preclinical Toxicology
PF-06649751 was administered to rats and monkeys in oral studies up to 15 weeks in 
duration.  PF-06649751 was negative in genetic toxicity testing.  Dose-limiting toxicity 
consisting of persistent decreased activity (3 days) and 2 days of low (<25% total ration) 
food consumption was observed in an exploratory study in monkeys following a single dose 
(15 mg/kg); no dose-limiting toxicity has been observed in rats.  The primary target organs 
identified in the safety pharmacology and toxicity studies were the central nervous system 
(monkeys and rats), reproductive system (female rats), and cardiovascular system (monkeys).  
Nonadverse central nervous system (CNS)-related findings associated with PF-06649751 
administration included behavioral observations in monkeys, and decreased activity and 
inappetance in rats and monkeys.  Minimal renal tubular necrosis was observed in an 
exploratory rat study that did not repeat in the definitive 1-month and 15-week studies.  Other 
findings included nonadverse gastrointestinal (GI), dermal, adrenal, thyroid and hepatic 
effects, minor changes in clinical pathology parameters (eg, decreased red cell mass, 
increased cholesterol, serum electrolytes, or urine volume), and nonadverse respiratory 
parameter changes.
In single-dose safety pharmacology studies in monkeys, cardiovascular effects included 
decreased blood pressure (within 0.75 to 8.5 hours post dose [HPD]), followed by increased 
blood pressure during later time periods (within 9 to 20 HPD), and increased heart rate, 
corrected QT (QTc) interval, and cardiac contractility.  Results of an in vitro hERG study and 
a monkey isolated heart (Langendorff) study suggested that the effects on heart rate, QTc, 
and contractility were not mediated by direct PF-06649751 effects on the heart, including 
hERG channel inhibition, as the IC50 in the hERG assay (64.9 M, 25400 ng/mL) is 940x to 
9700x the unbound Cmax range in monkeys at doses where QTc interval increases were 
observed. 
The no observed adverse effect level (NOAEL) in the 15-week monkey study of 5 mg/kg/day 
was associated with a combined sex mean total Cmax and AUC24 of 1350 ng/mL and 
11,800 ng•h/mL (78.3 ng/mL and 684 ng•h/mL, unbound), respectively.  These NOAEL 
exposures are 4.0x and 1.8x the unbound human Cmax (19.8 ng/mL) and AUCtau
(370 ng•h/mL), respectively, at a dose of 15 mg (Section 1.4.3).  In the 15-week study in 
male and female rats, the NOAEL for males was 60 mg/kg/day and was associated with a 
mean total Cmax and AUC24 of 7220 ng/mL and 79,700 ng•h/mL (505 ng/mL and 
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5580 ng•h/mL, unbound), respectively.  These NOAEL exposures in males are 25x and 
15x the unbound human Cmax and AUCtau, respectively, at 15 mg.  An NOAEL for females 
could not be determined in this study.  Except for the female reproductive tract changes
(ovarian findings consisting of follicular cysts, decreased/absent corpus luteum, and/or 
interstitial cell hypertrophy), there were no other adverse effects in female rats up to the high 
dose of 60 mg/kg/day for 15 weeks (Cmax 9050 ng/mL, AUC24 77,900 ng•h/mL [634 ng/mL 
and 5450 ng•h/mL, unbound]). The exposures in female rats at 60 mg/kg/day are 32x and 
15x the unbound human Cmax and AUCtau, respectively, at 15 mg.  In a subsequent 15-week 
study in female rats, the NOAEL for alterations in estrous cycles and the ovary indicating 
impaired ovulation was 0.2 mg/kg/day (Cmax 131 ng/mL, AUC24 1830 ng•h/mL, [9.17 ng/mL 
and 128 ng•h/mL, unbound]). The exposures at the NOAEL in female rats are <1x the 
human exposures at 15 mg.  The nonclinical safety profile of PF-06649751 is considered to 
be adequately characterized to support progression into human clinical trials of up to 
15 weeks in duration for men and for women of non-childbearing potential. 
At the end of the 26-week dosing phase in Study 8001294 (Pfizer Reference 15GR272), 
PF-06649751-related vascular/perivascular inflammation was noted microscopically in liver 
at the intermediate (20 mg/kg/day) and high (100 mg/kg/day) dose in male rats, as well as in 
the stomach, pancreas, or urinary bladder in males at 100 mg/kg/day. Based on these results, 
the preliminary NOAEL for vascular findings only following 26 weeks of administration of 
PF-06649751 was 5 mg/kg/day in male rats, and was 120 mg/kg/day in female rats.  At the 
NOAEL of 5 mg/kg/day for vascular inflammation in males, the mean total plasma Cmax was 
1610 ng/mL, and AUC24 was 11,000 ng•h/mL. The predicted exposures of PF-06649751 for 
chronic dosing (beyond 15 weeks) in future clinical studies are expected to continue to 
maintain an approximately 2-fold AUC-related safety margin for the vascular findings based 
on the preliminary NOAEL of 5 mg/kg/day following 26 weeks of administration of 
PF-06649751 in male rats.
Detailed information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator Brochure.
1.4. Previous Human Clinical Experience
1.4.1. Clinical Studies
PF-06649751 has been evaluated in 3 completed clinical studies in 104 healthy subjects 
which are described in the Investigator’s Brochure: 

Protocol B7601001 (n=18) was a Phase 1, first-in-human, placebo-controlled, 
randomized, single ascending dose study to evaluate the safety, tolerability and 
pharmacokinetics (PK) of PF-06649751 in healthy subjects.  This study was 
conducted in two sequential cohorts of healthy subjects (ie, the first 3 doses given to 
Cohort 1, the second 3 doses given to Cohort 2), and evaluated single oral 0.25 mg, 
0.75 mg, 0.75 mg fed, 1.5 mg and 2.5 mg (split over 8 hours) doses of PF-06649751. 
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
Protocol B7601002 (n=77) was a Phase 1, placebo controlled, randomized, multiple 
ascending dose trial to evaluate the safety and tolerability of PF-06649751 following 
multiple oral doses (with and without titration) with once daily dosing in healthy 
Western and Japanese subjects.  This study consisted of eight cohorts of healthy 
subjects run sequentially in a dose escalating manner, with repeated doses of 0.15 to 
5.0 mg of PF-06649751 given once daily for a total of 14, 21 or 28 days that included 
a titration period for doses >0.5 mg. 

Protocol B7601007 (n=9) was a Phase 1, placebo controlled, randomized, single dose 
study in healthy volunteers to evaluate the impact of prophylactic use of
trimethobenzaminde (TMB) on severity of nausea and emesis in healthy subjects.  
This study consisted of a single cohort of 9 healthy subjects who were administered 
three single doses of PF-06649751 (0.75 mg, 0.25 mg and 0.75 mg) along with TMB 
with at least a week long washout between each dosing. 
To date, PF-06649751 has been administered to 45 Parkinson’s disease patients in one
open-label multiple ascending dose study:

Protocol B7601005 was a Phase 1b, 2-period, open label, multicenter, dose escalation 
study of PF-06649751 in subjects with Parkinson’s disease experiencing motor 
fluctuations and, in Cohort 5, in subjects with Parkinson’s disease experiencing 
levodopa-induced dyskinesia.  In the beginning of the study, L-Dopa was
administered at one day for the evaluation of L-Dopa responsiveness.  In the 
following, PF-06649751 was up-titrated with parallel reduction of concomitant 
levodopa if clinically possible based on the discretion of the investigator.  The 
objective of the study was to evaluate the safety, tolerability and pharmacokinetics 
(PK) of multiple doses of PF-06649751.  
 pharmacokinetics
 
Additionally, 18 Parkinson’s disease patients have been assigned to study treatment with 
PF-06649751 or placebo in one double-blind, single ascending dose study (B7601009):

Protocol B7601009 was a double-blind, placebo-controlled, randomized, Phase 1b, 
2-cohort study to evaluate the safety, tolerability and pharmacokinetics of single 
ascending doses of PF-06649751 in Parkinson’s disease subjects. In the first cohort 
of the study (n=9), subjects received single administrations of placebo and 
PF-06649751 0.75 mg, 1.5 mg and 3 mg.  In the second cohort (n=9), subjects 
received single administrations of placebo and PF-06649751 3 mg, 6 mg and 9 mg.  
Overall, n=17 subjects were evaluated in the placebo dose group; n=6 subjects in 
each of the PF-06649751 0.75 mg, 1.5 mg, 6 mg and 9 mg dose groups; and 
n=12 subjects in the 3 mg dose groups. 
In addition to the current study, one Phase 2 clinical study (B7601003) is ongoing to evaluate 
the efficacy, the safety and tolerability in Parkinson’s disease subjects with Motor 
Fluctuations.  The B7601003 study is a 15 week randomized, double-blind, 
placebo-controlled parallel group study whose dose maintenance period includes 5 week 
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adjunctive treatment to stable L-Dopa and 5 week down titration of L-Dopa.  Approximately 
200 subjects from approximately 50 centers in up to 5 countries will be randomized to 
5 treatment groups (15 mg QD, 7 mg QD, 3 mg QD, 1 mg QD, or placebo).  The primary 
endpoint is the change from baseline in daily OFF time (based on patient reported Hauser 
diary) at the end of the 5 week adjunctive treatment to stable L-Dopa.
1.4.2. Safety
B7601001
One single ascending dose study in healthy subjects (B7601001) has been completed.  In 
study B7601001, PF-06649751 was determined to be well tolerated in healthy subjects for 
doses up to 0.75 mg.  Mild-to-moderate instances of nausea and emesis were observed in 
most subjects for doses above 0.75 mg.  The nausea and emesis observed after administration 
of a single dose of 1.5 mg (nausea in 5 of 5, and emesis in 4 of 5 subjects) precluded the 
ability to administer single doses of PF-06649751 above 1.5 mg. The tolerability of a split 
dose (with a two hour interval) was evaluated in Cohort 2.  The tolerability of a split dose of 
2.5 mg (nausea and vomiting in 4 of 4 subjects) precluded further titration to higher split 
doses.  One subject was removed from Cohort 1 after a single dose of 0.25 mg due to a mild 
drug related angioedema of the face.  No death occurred during this study.  No subjects 
experienced a severe adverse event (AE), or a dose reduction or a temporary discontinuation 
due to an AE, or a serious adverse event (SAE).  Sixty-seven AEs were reported (40 AEs in 
Cohort 1; 27 AEs in Cohort 2).  In Cohort 1, 33 AEs were mild in severity, and 7 moderate 
AEs were reported in the PF-06649751 1.5 mg treatment group.  In Cohort 2, 21 AEs were 
mild and 6 moderate AEs were reported in the PF-06649751 0.25-0.75-1.5 mg treatment 
group.  All moderate AEs, except for 1 AE of abdominal pain reported in the PF-06649751 
0.25-0.75-1.5 mg treatment group in Cohort 2, were considered treatment-related.
B7601002
One multiple ascending dose study in healthy subjects (B7601002) has been completed
within the reporting period.  This study was a randomized, double-blind, placebo-controlled, 
parallel-dose escalation, repeated dose study which evaluated the safety, tolerability and 
 
of ascending doses of PF-06649751.  Western healthy subjects were enrolled in 7 cohorts, 
and one cohort was conducted in Japanese healthy subjects.  In study B7601002, 
PF-06649751 using initial titration to the target dose, was determined to be well tolerated in 
healthy subjects for doses up to 5 mg QD.  Dose related mild-to-moderate instances of 
nausea and emesis were observed.  A dose proportional increase in the incidence of nausea 
was the most frequent AE reported in this study.  There was no notable difference in the 
incidence of nausea and vomiting between Western and Japanese subjects in the 1.5 mg QD 
dose group.  Other AEs reported by 3 or more subjects within any dose group included
gastrointestinal discomfort, abdominal pain upper, diarrhoea, and vomiting in the 
Gastrointestinal Disorders body system.  In the Nervous System, dizziness and headache 
were the most common AEs and appeared to be dose related.  Abnormal dreams were 
reported by 3 subjects receiving placebo, and 6 subjects receiving PF-06649751.
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B7601007
Nine healthy subjects participated in study B7601007, a single dose cross-over study.  
During study Period 1 and Period 3, 3 subjects received placebo and 6 subjects received 
PF-06649751 0.75 mg.  During Period 2, 3 subjects received placebo and 6 subjects received 
PF-06649751 0.25 mg.  A total of 47 all-causality AEs were reported (7 AEs in Placebo 
group; 28 AEs in PF-06649751 0.75 mg Period 1; 3 AEs in PF-06649751 0.25 mg; 9 AEs in 
PF-06649751 0.75 mg Period 3).  The most frequently reported AEs were headache 
(4 subjects in the placebo group, 4 subjects in PF-06649751 0.75 mg Period 1 and 1 subject
in Period 3), nausea (4 subjects in PF-06649751 0.75 mg Period 1 and 2 subjects in Period 3) 
and hot flush (1 subject in the placebo group, 3 subjects in PF-06649751 0.75 mg Period 1 
and 2 subjects in Period 3); all of these AEs were considered to be treatment-related.  The 
majority of the AEs (39/47) were mild in severity.  Eight subjects reported AEs that were 
moderate in severity, including nausea (1 subject), vomiting (3 subjects), fatigue (1 subject), 
headache (1 subject), hot flush (1 subject) and orthostatic hypotension (1 subject).  All 
moderate AEs were reported during PF-06649751 0.75 mg Period 1; they were considered to 
be treatment-related and resolved by end of study.  Prophylactic or concomitant use of the 
antiemetic trimethobenzamide hydrochloride did not reduce the incidence and severity of 
nausea and emesis observed in the single dose first in human (FIH) study (B7601001).
B7601005
The B7601005 included 4 completed cohorts:  

Cohort 3: 5 mg QD (n= 9 subjects).

Cohort 4: 15 mg QD (n=11 subjects).

Cohort 5: 15 mg QD, (n=6 subjects with levodopa-induced dyskinesia).

Cohort 6: 25 mg QD (n=19).
Based on safety data from the multiple-ascending dose study in healthy subjects (B7601002), 
Cohorts 1 and 2 of the study were not conducted.
There were no deaths, n=1 serious adverse events, n=6 severe adverse events and 
n=11 discontinuations due to adverse events.  The majority of AEs occurred during the 
up-titration period of PF-06649751 (Days 3 – Day 14) but the timing and dose level at which
AEs occurred were variable.
Preliminary safety results from Cohort 3, Cohort 4, Cohort 5, and Cohort 6 are summarized 
in the following: 
In Cohort 3 (titration to 5 mg QD), 43 AEs were observed in n=9 of n=9 subjects treated 
with PF-06649751, all of which were mild to moderate.  AEs resulting in treatment 
discontinuation and SAEs were not observed.  The most common AEs observed in 2 or more 
subjects in Cohort 3 were headache in n=6 subjects (66.7%), insomnia in n=3 subjects 
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(33.3%), abnormal dreams in n=3 subjects (33.3%), somnolence in n=2 subjects (22.2%), 
and hyperhidrosis in n=2 subjects (22.2%). 
In Cohort 4 (titration to 15 mg QD), 26 AEs were observed in n=7 of n=11 subjects treated 
with PF-06649751 with n=2 subjects discontinued due to AEs.  Most of them were mild.  
The most common AEs observed in 2 or more subjects in Cohort 4 were headache in 
n=7 subjects (63.6%), nausea in n=3 subjects (27.3%), dizziness in n=2 subjects (18.2%), and 
abnormal dreams in n=2 subjects (18.2%).  Severe AEs were 1 event of headache at a dose 
level of 9 mg QD, and 1 event of nausea at a dose level of 12 mg QD.
In Cohort 5 (titration to 15 mg QD), 27 AEs were observed in n=5 of n=6 subjects with 
levodopa-induced dyskinesia treated with PF-06649751 with n=2 subjects discontinued due 
to AEs.  Most of them were mild to moderate.  The most common AEs observed in 2 or more 
subjects in Cohort 5 were headache in n=3 subjects (50.0%), nightmare in n=2 subjects 
(33.3%), nausea in n=2 subjects (33.3%), dizziness in n=2 subjects (33.3%), abdominal 
discomfort in n=2 subjects (33.3%), anxiety in n=2 subjects (33.3%), neck pain in 
n=2 subjects (33.3%) and somnolence in n=2 subjects (33.3%).  Severe AEs were 1 event of 
nightmare at a dose level of 4 mg QD. 
In Cohort 6 (titration to 25 mg QD), 63 AEs were observed in n=15 of n=19 subjects treated 
with PF-06649751 with n=7 subjects discontinued due to AEs.  Most of them were mild to 
moderate.  The most common AEs observed in 2 or more subjects in Cohort 6 were nausea in 
n=8 subjects (42.1%), headache in n=8 subjects (42.1%), dizziness in n=5 subjects (26.3%), 
vomiting in n=4 subjects (21.1%), abnormal dreams in n=3 subjects (15.8%), agitation in 
n=2 subjects (10.5%), constipation in n=2 subjects (10.5%), and nightmare in n=2 subjects 
(10.5%).  Serious AEs were one event of event of palpitations (severe AE) not considered 
related to study drug by the investigator leading to discontinuation on the first day of study 
drug administration (Day 3) at a dose level of 1 mg.  Further severe AEs were 1 event of 
vomiting at a dose level of 12 mg QD and 1 event of dry mouth at a dose level of 18 mg QD. 
Across cohorts there were no apparent trends or clinically meaningful values for laboratory 
results, vital signs or ECG recordings.
In summary, multiple ascending-doses of PF-06649751 up to 25 mg QD were safe and well 
tolerated by subjects with Parkinson’s disease.
B7601009
Preliminary safety results from Cohort 1 and Cohort 2 are summarized in the following: 
There were no deaths, no serious adverse events, no severe adverse events and no 
discontinuations due to adverse events.  The number of adverse events in subjects who 
reported at least one adverse event was 9 events in n=6 out of n=17 subjects (placebo), 
1 event in n=1 out of n=6 subjects (0.75 mg), 2 events in n=2 out of n=6 subjects (1.5 mg), 
15 events in n=7 out of n=12 subjects (3 mg), 14 events in n=4 out of n=6 subjects (6 mg) 
and 5 events in n=4 out of n=6 subjects (9 mg). 
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Adverse events reported more than once in any dose group included mild or moderate 
headache (incidence of 35.3% in the placebo group, 0 in the 0.75 mg group, 16.7% in the 
1.5 mg group, 25% in the 3 mg group, 16.7% in the 6 mg group, and 50% in the 9 mg group).  
Mild or moderate nausea was reported with an incidence of 16.7% in the 3 mg group, 
33.3% in the 6 mg group 16.7% in the 9 mg group.  The incidence of vomiting (mild or 
moderate in severity) was 8.3% in the 3 mg group, 83.3% in the 6 mg group and 50% in the 
9 mg group.  Mild orthostatic hypotension was observed with an incidence of 5.9% in the 
placebo group, 8.3% in the 3 mg group, and 33.3% in the 6 mg group. 
No clinically meaningful lab abnormalities were observed.
The maximum increase of pulse rate from baseline was slightly higher in the high dose 
groups, with a mean of the maximum increase of standing pulse rate being 12.4, 13.5, 10.0 in 
the placebo, 0.75 mg and 1.5 mg groups, and of 18.1, 18.7 and 20.8 in the 3 mg, 6 mg and 
9 mg dose groups; and the mean of the maximum increase of supine pulse rate being 
9.5, 14.3, 7.2 and 14.0 in the placebo, 0.75, 1.5 and 3 mg dose groups, and of 17.3 and 
18.2 in the 6 mg and 9 mg dose groups.  No subjects had a standing or supine pulse rate 
>120 bpm.
The maximum decrease from baseline in systolic or diastolic blood pressure was similar 
between the dose groups.  N=2 (33.3%) subjects in the 1.5 mg dose group, n=1 (8.3%) in the 
3 mg group, n=2 (33.3%) in the 6 mg group and n=2 (33.3%) in the 9 mg group had a 
standing systolic blood pressure <90 mmHg, and n=1 (5.9%) in the placebo group and 
n=1 (16.7%) in the 9 mg group had a standing diastolic blood pressure <50 mmHg.
There appeared to be a small dose-related increase of the QTcF interval at the 2 h, 4 h and 
8 h post dose time points.  At 2 hours post dose, mean changes from baseline were 2.  5 msec 
in the placebo group, ranged from -1.0 to +3.1 msec in the 0.75, 1.5 and 3 mg groups, and 
were 10.6 msec in the 6 mg dose group and 11.7 in the 9 mg dose group.  At 4 hours post 
dose, changes from baseline were -1.9 in the placebo group, ranged from 3.0 to +5.4 msec in 
the 0.75, 1.5 and 3 mg groups, and were 8.4 msec in the 6 mg dose group and 10.7 msec in 
the 9 mg dose group.  At 8 hours post dose, changes from baseline were -1.1 in the placebo 
group, ranged from -1.6 to +2.7 msec in the 0.75, 1.5 and 3 mg groups, and were 9.0 msec in 
the 6 mg dose group and 6.1 msec in the 9 mg dose group.  The maximum change from 
baseline in QTcF was higher in the 3 mg, 6 mg and 9 mg dose groups, with mean values of 
14.3 msec in the placebo group, 11.3 msec, 13.9 msec, 18.1, 18.6 and 17.1 msec in the 
0.75 mg, 1.5 mg, 3 mg, 6 mg and 9 mg dose groups, respectively.  No subjects had QTcF 
values 500 msec, one subject in the 6 mg group had a maximum value 450 but <480 msec.  
No subject had an increase of QTcF from baseline 60 msec, n=1 subject in the 6 mg group 
had an increase of 30 but <60 msec.
In summary, single doses of PF-06649751 up to 9 mg were safe and well tolerated by 
subjects with Parkinson’s disease.  There were no deaths, serious adverse events, no severe 
adverse events and no discontinuations due to adverse events.  The most common mild to 
moderate adverse events were headache, nausea, vomiting and orthostatic hypotension.  
Nausea, vomiting and orthostatic hypotension appeared to be more common in the higher 
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dose groups (3 mg, 6 mg and 9 mg PF-06649751).  There appeared to be a small dose related 
increase in heart rate without consistent changes in blood pressure, except for the 
observations of orthostatic hypotension.  There was an increase of QTcF in the higher dose 
groups between 2 and 8 hours post dose, but no subject had a QTcF 500 msec or an increase 
of QTcF of 60 msec.
To date, nausea and emesis have been identified as Adverse Drug Reactions (ADR) for 
PF-06649751. 
1.4.3. Pharmacokinetics
The pharmacokinetic behavior of PF-06649751 following single doses is characterized by 
rapid absorption followed by bi-phasic decline in plasma concentrations.  PF-06649751 
reached peak concentration at approximately 1.0 to 2.0 hours following single oral doses.  
Both Cmax and AUCinf increased proportionally with increasing dose from 0.25 mg to 1.5 mg. 
Mean t½ were 21.0 to 22.4 hours. Food did not seem to alter Tmax, however, food decreased
AUCinf and Cmax by about 9% and 13%, respectively, at the 0.75 mg PF-06649751 dose.  
Co-administration of TMB did not have a noticeable impact on PF-06649751 exposures in 
healthy subjects.  Increase in steady state PF-06649751 exposures following multiple oral 
doses appeared to be approximately dose-proportional across the B7601002 and B7601005 
studies.  Evaluation of PF-06649751 pharmacokinetics in healthy Japanese subjects at 
1.5 mg QD dose suggests no meaningful difference between Japanese and Western subjects.
Based on preliminary data following single ascending doses in Parkinson disease (PD) 
patients (B7601009), peak PF-06649751 concentrations (Cmax) occurred at approximately 
3.0 to 4.0 hours post dose.  Increase in PF-06649751 Cmax and AUClast values was roughly 
dose proportional with in the dose range of 0.75-9 mg.  Exposures were observed to be in 
similar ranges for healthy subjects and PD patients at PF-06649751 doses of 0.75 mg and 
1.5 mg. 
Preliminary PF-06649751 steady state exposures in Parkinson’s disease patients at different 
doses from an on-going study (B7601005) are presented in Table 1.  Final parameters will be 
available upon finalization of the clinical study report.  PF-06649751 exposures at 5 mg QD 
were slightly higher than those observed in healthy subjects.  At steady state, both AUCtau
and Cmax increased in a roughly dose proportional manner with dose over the dose range of 
5 mg to 15 mg QD.  Increase in exposures from 15 mg QD to 25 mg QD was less than dose 
proportional.  Median Tmax was 2.0 hours for the 5 mg dose group, and approximately 
4.0 hours at 15 mg and 25 mg.  Based on a limited number of subjects, PF-06649751 Cmax
and AUCtau values appear to have higher variability at doses greater than the 5 mg dose 
group. 
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Table 1.
Steady State Exposures of PF-06649751 after Multiple Dosing in 
Parkinson’s Disease Patients with Motor Fluctuations
Dose
Cmax,ss (ng/mL)
Tmax (hrs)
AUC24,ss (ng*hr/ml)
5 mg QD (n=9)
118.5 (33)
2.0 (1.0-4.0)
2105 (35.0)
15 mg QD (n=7)a
325.4 (46)
4.0(2.0-12.0)
5993 (61.0)
25 mg QD (n=7)
401.6 (41)
4.03 (1.97-8.00)
7182 (52)
Values for Cmax,ss and AUC24,ss are presented as geometric means (%CV).  Median values (range) are 
presented for Tmax
a. Values represent Cohort 4.
1.5. Rationale
1.5.1. Study Rationale
It is hypothesized that if an oral therapy were to demonstrate improvements in motor control 
over available therapies, but without inducing the complications of available therapies, it 
would represent a substantial advance in the symptomatic treatment paradigm in Parkinson’s 
disease.  This Phase 2 study will evaluate the efficacy, safety, and tolerability of
PF-06649751 as a potential novel therapeutic agent in subjects with early stage Parkinson’s 
disease.  PF-06649751 is a novel D1 and D5 specific dopamine agonist and has the potential 
to improve motor symptoms in subjects with early Parkinson’s disease.  There is diversity in 
the therapeutic approach to this population among prescribers as well as experts in the field, 
with several treatment options available.  The study population will include male and female 
subjects of non-childbearing potential diagnosed with Parkinson’s disease, in the early stage 
of the disease, and who have no or limited history of exposure to L-Dopa and/or dopamine 
agonists.  
exploratory
 
 
1.5.2. Dose Rationale
PF-06649751 is a potent D1R agonist with terminal half-life long enough to facilitate 
once-daily dosing.  In vitro data suggest CYP3A4 as the primary enzyme responsible for the 
majority of PF-06649751 metabolism.  Data also indicates that overall risk of PF-06649751 
to perpetrate drug interactions due to inhibition of P-glycoprotein, breast cancer resistance 
protein (BCRP), organic cation transporter (OCT1), and/or multidrug and toxin extrusion 
protein (MATE1) at the 15 mg dose level is low and clinically relevant drug-drug 
interactions are not anticipated (further information is available in the Investigator Brochure).
Phase 1 studies demonstrate poor tolerability at single oral doses greater than 1.5 mg in 
healthy subjects and titration improves tolerability at higher doses.  The intent of the study is 
to investigate the safety, tolerability and efficacy in early Parkinson’s disease patients.  Due 
to the heterogeneity in disease severity in the patient population, a flexible dosing scheme is 
being implemented in the study with an aim to get each subject to his/her optimal dose for 
management of motor symptoms.  Such a dosing paradigm would mimic the usage of 
PF-06649751 in a real-world clinical setting.
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Subjects will be titrated to a dose that is deemed optimum by the investigator based on the 
subject’s response with respect to motor control and tolerability.  Based on all the PK, safety 
and tolerability data available to-date, a dose of 15 mg QD is set as the upper limit of daily 
dose that a subject can achieve in this study.  A dose of 3 mg QD is expected to result in 
average concentrations similar Ceff values established using MPTP monkeys.  Based on the 
observed exposures from study B7601005 (Table 1), a 15 mg QD dose is expected to provide 
exposures ~1.8 – 4 fold lower than the PK stopping criteria from the 15-week monkey 
toxicological study.  The ~1.8 – 4 fold exposure window provides sufficient margin for a 
potential increase in PF-06649751 exposures when co-administered with weak inhibitors of 
CYP3A4.  To prevent accidental exposure increases greater than toxicological limits, 
subjects on moderate or strong CYP3A4 inhibitors will be excluded from the trial until the 
magnitude of CYP3A4 interaction is defined within a drug-drug interaction study.
Based on previous experience in healthy subjects (study B7601002), subjects will be titrated 
to their optimum dose using a titration scheme presented in Section 5.5.1.  Briefly, a 
PF-06649751 dose of 0.25 mg QD will be the starting dose in this study.  This dose has been 
shown to be well tolerated and safe in all healthy subject Phase 1 studies, to-date.  
PF-06649751 doses will be increased at weekly intervals to reach the maximum allowed dose 
of 15 mg QD in 8 weeks.  Due to the flexible nature of the study, some subjects may reach
optimal dose before Visit 10.  Specific instructions around up-titration and down-titrations, in 
case of tolerability issues, are provided in Section 5.5.1.  The approximately 8 week titration 
scheme is similar to other dopamine agonists currently marketed for treatment of Parkinson’s 
disease, and also allows subjects to be at stable dose for at least 6 weeks before the primary 
endpoint collection. 
1.5.3. Summary of Benefit-Risk Assessment
The study is designed to assess the efficacy, safety and tolerability of PF-06649751 in 
subjects with early stage Parkinson’s disease. Based on the clinical safety data available 
to-date, PF-06649751 dose levels in this study do not pose any specific risk to study
participants. The study will attempt to mitigate mild-to-moderate instances of nausea, emesis 
and abdominal discomfort seen in prior studies in healthy subjects and subjects with 
Parkinson’s disease by slow dose escalation, flexible dose optimization, and permitted 
concomitant use of anti-emetics for symptomatic treatment at the discretion of the 
investigator. Any potential risks will be further minimized by safety monitoring during the 
study and follow up for the subjects’ well-being.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Study Objectives
2.1.1. Primary Objective

To evaluate the effect of PF-06649751 administered once daily on motor symptoms 
in subjects with early stage Parkinson’s disease.
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2.1.2. Secondary Objectives

To evaluate the safety and tolerability of PF-06649751 administered once daily in 
subjects with early stage Parkinson’s disease. 
 
 
 
 
2.2. Endpoints
2.2.1. Primary Endpoint (Efficacy)

Change from baseline in the Modified Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) Score Part III at Week 15.
2.2.2. Safety and Tolerability

Adverse events.

Clinical laboratory parameters.

Vital signs.

ECG parameters.

Columbia Suicide Severity Rating Scale (C-SSRS).

Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating 
Scale (QUIP-RS).

Physician Withdrawal Checklist (PWC-20).
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3. STUDY DESIGN
3.1. Study Overview
The study has a randomized, double-blind, placebo-controlled, flexible-dose design.  
Approximately 88 subjects from approximately 30 centers in up to 5 countries will be 
randomized to 2 treatment groups (PF-06649751 or placebo) in a 1:1 ratio using a central 
randomization system.
Each subject will undergo 15 weeks of double-blind treatment (including 9 weeks of Dose 
Optimization Period and 6 weeks of stable dosing during the Dose Maintenance Period).  The 
15 weeks of double-blind treatment will be preceded by a 30 day screening period.  There 
will be an additional follow-up period of 28 days following discontinuation of investigational 
product.  The overall study duration will be up to 23 weeks.
C
C
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During the initial up titration, subjects will gradually increase the dose of investigational 
product at weekly intervals, as tolerated, until Parkinsonian symptoms are optimally 
controlled.  Investigational product will be self-administered once daily.  The target dose 
range for PF-06649751 is 3 mg to 15 mg once daily (Stage 4 – Stage 8 in Table 2).  
However, a maintenance dose less than 3 mg may be selected, based on clinical response.  
Adjustments to the up-titration schedule are permitted during the Dose Optimization Period
based on clinical judgment to mitigate adverse events or symptoms of suspected 
dopaminergic overstimulation.  Thereafter, any dose adjustment during the Maintenance 
Period (after Visit 10) may only be performed after discussion with the Sponsor Medical 
Monitor/Study Clinician.  For both the PF-06649751 and placebo treatment arms, 
investigational product will be discontinued at Visit 14.
3.1.1. Screening
Informed consent will be completed prior to any screening assessments to initiate any 
treatment washout period, if applicable.  All other screening assessments will occur within 
30 days prior to Visit 1 (Randomization).  Rescreening may be permitted after discussion 
with the Sponsor Medical Monitor/Study Clinician.
3.1.2. Double Blind Period 
Eligible subjects will enter the 15 week double blind treatment phase, consisting of:

A 9 week Dose Optimization Period including:

Up titration of investigational product (PF-06649751 or placebo) administered 
once daily;

Period for stabilization after reaching an optimized dose.

A stable treatment period (Dose Maintenance Period) for 6 weeks. 
Subjects will return to the clinic each week during Visit 1 through Visit 4, and every other 
week thereafter during the Dose Optimization Period.  Alternating phone visits will occur at 
every other week after Visit 4.  During the Dose Maintenance Period, subjects will return to 
the clinic twice, at Visit 12 and Visit 14.  Phone visits will be performed at Visit 11 and 13. 
Each subject is planned to be up-titrated in a double-blind fashion to the clinically 
appropriate dose level of investigational product according to Dose optimization of 
Investigational Product, Section 5.5.1.
Following Visit 14, treatment with investigational product will be discontinued. 
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3.1.3. Follow-up Period
A follow-up clinic visit approximately two weeks after discontinuation of investigational 
product (Visit 15) will take place for the assessment of subject safety.  A follow-up phone 
visit will occur approximately 28 days after discontinuation of investigational product
(Visit 16) for a final subject safety assessment.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
The sponsor or designee will verify critical elements of the screening and enrollment process 
and provide written authorization (eg, e-mail) concurring with the investigator assessment 
that the subject is eligible to return for Visit 1 (Randomization) assessments.  Eligibility may 
also be documented via telephone authorization followed by written confirmation.  The key 
elements to be reviewed by the sponsor may include Parkinson’s disease diagnosis, 
MDS-UPDRS Part III, medical history, concomitant medications, and select screening safety 
assessments including C-SSRS, PHQ-8, MMSE, labs, ECGs, and vital signs (See 
Section 7.1.1, regarding Review of Inclusion/Exclusion Criteria).
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
General and Administrative:
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
3. Females of non-childbearing potential and/or male subjects between the ages of 
45 and 80 years, inclusive. 
4. Male subjects able to father children must agree to use a highly effective method of 
contraception throughout the study and for at least 28 days after the last dose of 
assigned treatment. 
5. Female subjects of non-childbearing potential (ie, meet at least 1 of the following 
criteria):
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
Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) level
confirming the post-menopausal state.
Parkinson’s Diagnosis:
6. Clinical diagnosis of Parkinson’s disease consistent with the United Kingdom (UK)
Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria (Appendix 4).
7. Parkinson’s Disease Hoehn & Yahr Stage I-III inclusive.
8. Parkinson’s disease subjects deemed appropriate for treatment of motor symptoms
with a MDS-UPDRS Part III score 10.
Concomitant Parkinson’s Disease Medications:
9. Treatment naïve or history of prior incidental treatment with dopaminergic agents
(including L-Dopa and dopamine receptor agonist medications) for no more than 
28 days and not within at least 7 days prior to Visit 1 (Randomization) as outlined in 
Section 5.8, Concomitant Treatment(s), and Appendix 2.
10. Willing and able to refrain from any Parkinson’s disease medication not permitted by 
the protocol (including dopaminergic agents) throughout participation in the study as 
outlined in Appendix 2. 
Screening assessments:
11. A score of 26 on the Mini Mental State Examination (MMSE). 
12. Body Mass Index (BMI) of 17.5 to 35 kg/m2; and a total body weight 45 kg. 
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
Parkinson’s Diagnosis:
1. History or clinical features consistent with an atypical Parkinsonian syndrome
(including but not limited to Progressive Supranuclear Palsy, Multiple System 
Atrophy, Cortico-Basal Degeneration, etc).
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2. Any Parkinson’s disease-related feature or symptom that could interfere with the 
study conduct and results as assessed by the sponsor or Investigator. 
Medical History:
3. Presence of acute or chronic clinically significant medical, including fever, or 
psychiatric condition or cognitive impairment or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
4. Presence or history of brain tumor, past history of hospitalization for head trauma 
with loss of consciousness, epilepsy (as defined by the International League Against 
Epilepsy),31 conditions that lower seizure threshold, seizures of any etiology 
(including substance or drug withdrawal), or known increased risk of seizures. 
5. Any significant AXIS I psychiatric disease as defined by the Diagnostic and 
Statistical Manual of Mental Disorders, 4th edition-Revised (DSM IV-TR, American 
Psychiatric Association, 2000) including subjects with clinically significant 
depression (PHQ-8 total score 15) (refer to Section 7.1.6, Depression Assessment 
(PHQ-8).  Presence of minor depression or treated, stable depressive disorder is 
acceptable. 
6. Subjects who have made a suicide attempt within the last 5 years.  Subjects who, in
the investigator’s judgment, pose a significant suicide risk.  Subjects who have
suicidal ideation associated with actual intent and a method or plan in the past
6 months (ie, “Yes” answers on items 4 or 5 of the C-SSRS; refer to Section 7.3
Assessment of Suicidal Ideation and Behavior (C-SSRS). 
7. History of clinically significant alcohol or substance dependency (other than caffeine 
or nicotine), as defined in DSM IV-TR, within 1 year before Screening.
8. In the opinion of the investigator (or caregiver, as applicable), has signs/symptoms 
suggestive of clinically significant cognitive impairment that would interfere with the 
ability to comply with study procedures.
9. Any condition possibly affecting drug absorption, past surgery of the gastrointestinal
tract (eg, gastrectomy, colectomy), except cholecystectomy.
10. History of vasculitis.
11. History of Human Immunodeficiency Virus (HIV) infection.
12. History of malignancy other than:
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
Non-metastatic basal or squamous cell carcinoma of the skin or carcinoma in situ 
that was surgically removed in total >1 year before screening and has not 
recurred.  

Other type of malignancy which has been in remission 5 years or more before 
screening and has not recurred.  
13. Subjects with first degree family history of unexplained sudden death, or of Long QT 
syndrome (LQTS). 
14. Within 1 year of Screening or between Screening and Visit 1 (Randomization), any of 
the following: myocardial infarction; moderate or severe congestive heart failure, 
NYHA class III or IV; hospitalization for, or symptoms of, unstable angina; syncope 
due to orthostatic hypotension or unexplained syncope; known significant structural 
heart disease (eg, significant valvular disease, hypertrophic cardiomyopathy); or 
hospitalization for arrhythmia.
Concomitant Medications:
15. Currently receiving moderate or strong CYP3A4 inducers or CYP3A4 inhibitors 
(except for topical administration) as outlined in Section 5.8 Concomitant 
Treatment(s), Appendix 2, and Appendix 3. 
16. Currently receiving an antipsychotic, metoclopramide, reserpine, or amphetamine as 
outlined in Section 5.8 Concomitant Treatment(s) and Appendix 2.
17. Prohibited concomitant medications as outlined in Section 5.8, Concomitant 
Treatment(s), and Appendix 2. 
Screening Assessments:
18. Pregnant female subjects; breastfeeding female subjects; females of childbearing 
potential (assessed at Screening); male subjects with partners currently pregnant; 
male subjects able to father children who are unwilling or unable to use a highly 
effective method of contraception as outlined in this protocol for the duration of the 
study and for at least 28 days after the last dose of investigational product or longer 
based upon the compound’s half-life characteristics.
19. Screening supine blood pressure 160 mm Hg (systolic) or 95 mm Hg (diastolic), on 
a single measurement.  If abnormal, up to 2 repeats are permitted following at least 
5 minutes of rest.  The screening value in that case will be the average of the 2 values 
closest to the normal range. 
20. A decrease in systolic blood pressure (BP) of >20 mmHg or in diastolic BP of 
>10 mmHg measured 2 minutes after changing from a supine to standing position in 
the presence of symptoms of orthostasis.  In the absence of symptoms of orthostasis a 
decrease in systolic blood pressure (BP) of >30 mmHg or in diastolic BP of 
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>15 mmHg measured 2 minutes after changing from a supine to standing position 
(The mean of three independent sets of vital signs, taken at least 15 minutes apart at 
the screening visit, will determine eligibility).
21. 12-lead ECG demonstrating QTcF >450 msec (>470 msec for females) or a QRS 
interval >120 msec at screening.  If QTcF exceeds 450 msec (470 msec for females), 
or QRS exceeds 120 msec, the ECG should be repeated two more times and the 
average of the three values should be used to determine the subject’s eligibility. 
22. Subjects with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat, if deemed necessary:  

Aspartate transaminase (AST)/ serum glutamic oxaloacetic transminase (SGOT) 
or alanine transaminase (ALT)/ serum glutamic pyruvic transminase (SGPT) 
2 x upper limit of normal (ULN).

Total bilirubin 1.5 x ULN; subjects with a history of Gilbert's syndrome may 
have a direct bilirubin measured and would be eligible for this study provided the 
direct bilirubin is ULN.
23. A positive urine drug screen for drugs of abuse unless explained by medically 
indicated medication.
24. A positive test for hepatitis B surface antigen or hepatitis C antibody (if confirmed by 
positive hepatitis C virus-ribonucleic acid (HCV-RNA) test).
General and Administrative:
25. Subjects who are investigational site staff members directly involved in the conduct 
of the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the study.
26. Treatment with an investigational drug within 30 days (or as determined by the local 
requirement) or 5 half-lives preceding the first dose of study medication (whichever is 
longer).
27. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 56 days prior to Visit 1 (Randomization). 
28. Unwilling or unable to comply with the lifestyle requirements described in 
Section 4.4 this protocol.
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4.3. Randomization Criteria 
Subjects will be randomized into the study provided they have satisfied all subject selection 
criteria.  Using a central randomization system, eligible subjects will be randomized to one of 
two treatment groups (PF-06649751 or matching placebo) in a 1:1 ratio.  Randomization 
blocks will be stratified by region.
4.4. Lifestyle Guidelines
4.4.1. Meals and Dietary Restrictions

Subjects will not be permitted to eat or drink grapefruit or grapefruit-related citrus 
fruits (eg, Seville oranges, pomelos, star fruit) from 7 days prior to the first dose of 
study medication until the end of double blind study medication.
4.4.2. Alcohol, Caffeine, and Tobacco

Subjects will abstain from alcohol for at least 12 hours prior to every study visit. 

Subjects may undergo an alcohol breath test or blood alcohol test at the discretion of 
the investigator.

Coffee and caffeine containing products are permitted throughout the study.

Tobacco and tobacco containing products are permitted throughout the study.
4.4.3. Activity

Subjects should abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. 
4.4.4. Contraception – Females
Females of childbearing potential are excluded from this study.
4.4.5. Contraception – Males
All male subjects who are able to father children and are sexually active must agree to use a 
highly effective method of contraception consistently and correctly for the duration of the 
active treatment period and for at least 28 days after the last dose of investigational product.  
The investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected an appropriate method of contraception for the individual subject and his 
partner from the permitted list of contraception methods (see below) and instruct the subject 
in its consistent and correct use.  Subjects need to affirm that they meet the criteria for correct 
use of at least 1 of the selected methods of contraception.  The investigator or his/her 
designee will discuss with the subject the need to use highly effective contraception 
consistently and correctly according to the Schedule of Activities and document such 
conversation in the subject’s chart.  In addition, the investigator or his or her designee will 
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instruct the subject to call immediately if the selected contraception method is discontinued 
or if pregnancy is known or suspected in the subject’s partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the subject plans to remain on the same 
treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness.
2. Correctly placed copper -containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository). For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
6. Female partner who meets the criteria for non-childbearing potential, as described 
below:
Female subjects of non-childbearing potential must meet at least one of the following 
criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle stimulating hormone (FSH) level 
confirming the post-menopausal state.
All other females (including females with tubal ligations) will be considered to be of 
childbearing potential.
All sexually active male subjects must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose of investigational product.
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4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study SharePoint site.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigational site.
4.6. Rater Qualifications
Only qualified individuals who have been certified and/or trained through the Pfizer rater 
qualification program will be permitted to perform those evaluations for which they have
been trained and/or certified.  Prior to the study, the sites will be informed of the overall rater 
qualification methodology including the minimum qualifications and/or training requirement 
a rater must fulfill.  Raters performing certain assessments will require certification by a 
vendor designated by the Sponsor prior to rating in this study.
The level of education, experience with the target population (or equivalent), and specific 
scale experience (or equivalent), scale-specific certification required (if applicable, 
eg, C-SSRS, MDS-UPDRS) will be documented and used to determine whether a rater is 
approved for a given assessment.  Proposed raters who do not meet specific criteria but who 
may be qualified based on unique circumstances may be individually reviewed by the study 
clinical team to determine whether alternative experience or training may be equivalent to the 
specific criteria for a given assessment.  If approval is granted, details of the relevant 
experience or training and the detailed rationale for judging them to be equivalent to the 
specified criteria will be documented in the rater tracking spreadsheet or equivalent. 
All raters must be certified and/or trained on the selected study assessments as defined in the 
rater qualification documentation before he/she can participate in the administration of the 
assessments in the study.  For specifically defined assessments, rater training and 
standardization exercises (when deemed necessary by the clinical study team) may be 
conducted.  Each site will be provided written documentation outlining each rater’s 
certification for specific study assessments.  Recertification and/or retraining may be required 
at periodic intervals during the study, at the discretion of the study clinical team or designee.
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The raters who administer specific study assessments may be documented in a centralized 
location and all site staff who administer ratings may be verified in the site study 
documentation during the conduct of the study. 
Raters performing certain assessments will require certification by a vendor designated by 
the Sponsor prior to rating in this study. 
5. STUDY TREATMENTS
Investigational Product (IP) for the purpose of this study includes:

PF-06649751 or placebo.
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference in a clinical trial, including a 
product with a marketing authorization when used or assembled (formulated or packaged) in 
a way different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use (ICH E6 1.33).
5.1. Allocation to Treatment
Allocation of subjects to treatment groups will proceed through the use of an interactive 
response technology (IRT) system.  The site personnel (study coordinator or specified 
designee) will be required to enter or select information including but not limited to the 
user’s identification (ID) and password, the protocol number, the subject number and the date 
of birth of the subject.  The site personnel will then be provided with a treatment assignment 
and dispensable unit (DU) or container number when drug is being supplied via the IRT 
system.  The IRT system will provide a confirmation report containing the subject number 
and DU or container number assigned.  The confirmation report must be stored in the site’s 
files. 
There is a 24-hour-a-day, 365-days-a-year IRT helpdesk available for any questions or 
issues.  The study specific IRT reference manual will provide the contact information and 
further details on the use of the IRT system. 
5.2. Breaking the Blind
Treatment assignment will be blinded to the sponsor study team, subject and investigator.  At 
the initiation of the study, the study site will be instructed on the method for breaking the 
blind.  The method will be either a manual or an electronic process.  Blinding codes should 
be broken only in emergency situations for reasons of subject safety. Whenever possible, the 
investigator or sub-investigator will consult with a member of the study team prior to 
breaking the blind.  When the blinding code is broken, the reason must be fully documented 
and entered on the case report form (CRF), and the subject is to be discontinued from the 
study.
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5.3. Subject Compliance
Investigational product will be administered by the subject in the outpatient setting (each 
morning, daily for the duration of the treatment period).  A dosing diary will be given to the 
subject with instructions on how to record the blister card being used and also the daily times 
of investigational product administration.  The subject will bring all blister cards, used and 
un-used, back to the clinic at each visit. At each visit, a tablet count will be done by the 
research staff, and the subject will be questioned about any missed or extra doses taken. Site 
personnel will assess administration compliance based on the drug accountability of the 
blister packs, review of the dosing diary, and discussion with the subject.  In cases where 
tablets are unaccounted for by the dosing diary and/or questioning of subjects, the site will 
consider the drug accountability to be a source for missed or additional doses.  A subject will 
be considered compliant with the protocol at a study treatment compliance range of 
80%-120%.
In cases where the subject is outside the compliance range, a protocol deviation will be 
captured and the site is expected to take appropriate actions depending on the reason for 
non-compliance (eg, if a subject did not have a valid reason for not taking investigational 
product, that the subject is re-educated on investigational product administration 
requirements and expectation to adhere to the requirements).  Cases of repeated 
non-compliance may result in discontinuation of the subject from the study, if deemed 
necessary by the investigator and/or sponsor.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Blinded PF-06649751 and its matched placebo will be provided as tablets for oral 
administration.  PF-06649751 0.25 mg, 1 mg, 5 mg and their matching placebo will be 
supplied in blister cards.  At each dispensing visit, subjects will receive sufficient quantity of 
investigational product to last until their next scheduled visit.  Each blister card will be 
labeled according to local regulatory requirements.
5.4.2. Preparation and Dispensing
The PF-06649751 0.25 mg, 1 mg, 5 mg tablets, and matching placebo are to be dispensed 
using a drug management system at each visit.  A qualified staff member will dispense the 
investigational product via unique container numbers in the blister card(s) provided per the 
study visit schedule.  The subject/caregiver are to be instructed to maintain the product in the 
blister cards provided throughout the course of dosing and return all blister cards, used and 
unused, to the site at the next study visit for accountability.
5.5. Administration
For investigational product administration, subjects (and caregivers, as applicable) should be 
instructed as follows:

Take 3 tablets at approximately the same time each morning. 
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
Swallow each tablet whole, with water.

Do not manipulate or chew the tablet prior to swallowing.

All tablets should be taken within approximately 5 minutes.

The tablets may be taken with or without food.

Subjects will document the timing of investigational product administration on each 
day of the double-blind treatment via the subject dosing diary.
5.5.1. Dose Optimization of Investigational Product
Each subject is planned to be up-titrated in a double-blind fashion to an optimal dose level of 
investigational product according to a flexible dose titration scheme.  Reaching of the 
maximum allowed dose level (15 mg, Stage 8) is not mandatory; subjects may achieve a 
satisfactory clinical response at a lower dose level. 
Modifications to the upward titration of investigational product can be made to achieve an 
optimized dose level.  Dose escalation will continue, as tolerated, to a response level judged 
satisfactory by the investigator.  The target dose is the dose at which the individual subject 
has achieved an optimal clinical balance of motor symptom control and tolerability, based on 
the judgment of the investigator.  The target dose range for PF-06649751 is expected to be 
between 3 mg to 15 mg once daily.
Dose optimization is to be completed no later than Visit 10; thereafter the achieved dose
level will be maintained for the remainder of the double-blind treatment period.  Dose
adjustments after Visit 10 may be performed only after consultation with the Sponsor 
Medical Monitor/Study Clinician. 
The titration scheme for this study is presented in Table 2.
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Table 2.
Titration Scheme of PF-06649751 and Placebo
Stage #
Start Day of Dose Level a,b
PF-06649751 (QD mg)
Placebo
Stage 1/from day 1a
0.25
P
Stage 2/from day 8c
0.75
P
Stage 3/from day 15
1.5
P
Stage 4/from day 22
3
P
Stage 5/from day 29
5
P
Stage 6/from day 36
7
P
Stage 7/from day 43
11
P
Stage 8/from day 50
15
P
a. Subjects will initiate the first dose and subsequent dose level increases the day after the corresponding 
phone/clinic visit (eg, Day 1 is the day after Visit 1).
b. For subjects who will not achieve their individual optimal dose level on the day following Visit 8, dose 
escalation is permitted, however the final dose level increase must be completed before Visit 10.
c. The increase in dose level from Stage 1 to Stage 2 is a mandatory step at Visit 2 (from Day 8).
5.5.1.1. Dose Optimization Period 

Stage 1 (Day 1 to Day 7): Subjects who experience intolerable adverse events during 
the first week of the study will need to discontinue the investigational product. 

Stage 2 onward: Dose level increases are permitted on a weekly basis.
At each planned visit and as necessary at unplanned visits during the Dose Optimization 
Period, the investigator will evaluate:

If the current dose level is well tolerated; and

If the degree of motor symptom control can be considered satisfactory.
Based on this evaluation and investigator discretion, a decision will be made to:

Decrease the dose to the previous dose level to address potential tolerability findings.

Stay at the current dose level to address potential tolerability findings, if needed for 
further clinical stabilization or when the individual subject has achieved an optimal 
balance of motor symptom control and tolerability.

Increase the dose to the next higher dose level to evaluate if further clinical benefit 
can be achieved.
For subjects who have achieved an optimal balance of motor symptom control and 
tolerability, the investigator should consider an attempt to increase the dose to the next higher 
dose level in order to evaluate if further clinical benefit can be achieved.
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Efforts should be made to reach the minimum targeted dose of 3 mg or placebo (Stage 4).  
Subjects who have not reached Stage 4 by Visit 10 will stay at their current dose for the 
remainder of the study.
Subjects whose dose had been reduced to the previous dose level and who still do not tolerate 
the reduced dose level or who do not tolerate a re-challenge at the previously attempted dose 
level should be returned to the next lower/previous dose level and stay at this dose level for 
the remainder of the double-blind treatment period.
It is possible that a stable dose can be reached by or before Visit 8.  However, continued dose 
adjustments for efficacy and tolerability may occur until Visit 10.
Figure 1 (below) lists the decision flow that should occur at each phone and clinic visit 
during the Dose Optimization Period: 
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Figure 1.
Decision Flow
Is the current dose 
level sufficiently well 
tolerated? 
Will remaining at the 
current dose level 
potentially improve 
tolerability?  
Has the dose 
level been 
reduced
before?
Is motor control 
optimized? 
Remain at the current 
dose level until next 
phone or 
clinic visit 
1
Remain at the current 
dose level until next 
phone or clinic visit 
2
Return to the previous 
dose level for the 
remainder of the 
study
2
Return to the 
previous  dose 
level until next 
phone or clinic 
visit 
2
1.
Consider proceeding to the next higher dose level to evaluate if further clinical benefit can be achieved 
2.
Consider discontinuation if limited tolerability persists
Yes
Yes
No
No
Proceed to the next 
higher dose
level
Yes
Yes
No
No
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5.5.2. Dose Maintenance Period

The maintenance dose is reached when the individual subject has achieved an optimal 
balance of motor symptom control and tolerability, based on clinical judgment.

The target dose range is expected to be 3 mg to 15 mg once daily (Stage 4 – Stage 8).  
However, a maintenance dose less than 3 mg may be selected, based on tolerability 
and clinical response.

Any dose adjustment during the Maintenance Period (after Visit 10) may only be 
performed after consultation with the Sponsor Medical Monitor/Study Clinician.
5.6. Investigational Product Storage 
The investigator, or an approved designee, eg, pharmacist, will ensure that all investigational 
products are stored in a secured area with controlled access under required storage conditions 
and in accordance with applicable regulatory requirements.  An Investigational Product 
Manual will be supplied to the pharmacy prior to initiation of the study and will provide 
further information regarding storage conditions of the product.
Investigational product should be stored in its original container and in accordance with the 
label.  Site staff will instruct subjects on the proper storage requirements for take home 
investigational products, including how to report temperature excursions.  See the single 
reference safety document (SRSD), which for this study is the Investigator’s Brochure.
However, storage conditions stated in the single reference safety document 
(eg, Investigator’s Brochure and package insert) will be superseded by the storage conditions 
stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  Once an 
excursion is identified, the investigational product must be quarantined and not used until the 
sponsor provides documentation of permission to use the investigational product.  It will not 
be considered a protocol deviation if the sponsor approves the use of the investigational 
product after the temperature excursion.  Use of the investigational product prior to sponsor 
approval will be considered a protocol deviation.
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Specific details regarding information the site should report for each excursion will be 
provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products. 
5.7. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  Subjects will return Investigational 
Product to the site per the Schedule of Activities.  Additional details regarding the process for 
accountability will be provided prior to initiation of the study.
5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Concomitant Treatment(s)
Subjects will abstain from all concomitant medications as outlined in Appendix 2 and 
Appendix 3, except for the treatment of adverse events.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All subjects will be questioned about 
concomitant treatment at each phone or clinic visit.
Medications taken within 60 days before the first dose of study investigational product will 
be documented as a prior medication.  Medications taken after the first dose of study
investigational product will be documented as concomitant medications.
5.8.1. Medications for Parkinson’s Disease
Permitted Parkinson’s disease medications: 

MAO-B inhibitors, amantadine and anticholinergic drugs are permitted.  Subjects 
must be on a stable dose of these anti-parkinsonian medications for at least 42 days 
prior to Visit 1 (Randomization).
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Prohibited Parkinson’s disease medications:

Prior exposure or history of treatment with L-dopa for more than 28 days; and any 
treatment with L-Dopa within 7 days prior to Visit 1 (Randomization).

Prior exposure or history of treatment with dopamine receptor agonists including 
pramipexole, ropinirole, rotigotine and apomorphine for more than 28 days; and 
within 7 days prior to Visit 1 (Randomization).

Rescue Parkinson’s disease medications taken after the first dose of investigational 
product are not permitted.
5.9. Other Prohibited Concomitant Medications
The following medications will not be permitted within 28 days prior to Visit 1
(Randomization):

CYP3A4 inducers: the use of moderate and strong inducers of CYP3A4 is not 
permitted, since they may decrease the levels of the study drug.  A list of potential 
drug inducers is provided in Appendix 3. 

CYP3A4 inhibitors: the use of moderate or strong inhibitors of CYP3A4 is not 
permitted, since concomitant use these may lead to increased levels of the study drug.  
A list of potential CYP3A4 inhibitors is provided in Appendix 3.
The use of marijuana is not permitted from Screening through the end of the double blind 
treatment period.
The following medications will not be permitted within 42 days prior to Visit 1
(Randomization):

Amphetamines, methylphenidate or other stimulants. 

Antipsychotics, metoclopramide, or reserpine are not permitted.

Lithium, tricyclic antidepressants, irreversible MAO-A/B inhibitor antidepressants 
(including moclobemide, tranylcypromine, and phenelzine).

Antiepileptics are not permitted except if used for chronic painful conditions at steady 
doses (for example, gabapentin or pregabalin).
5.9.1. Permitted Other Concomitant Medications
Stable doses of other concomitant medications are permitted during the course of the study, 
including antihypertensives, antidepressants (other than irreversible MAO-A/B inhibitors), 
anticoagulants, lipid lowering agents, oral antidiabetics, thyroid replacement hormones, and 
antacids.  For symptomatic treatment of nausea and/or emesis, the use of an anti-emetic may 
be considered.
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Stable low dose opioids for chronic painful medical conditions may be permitted based on a 
consultation with the medical monitor.
The potential risk for drug-drug-interactions with PF-06649751 and primary substrates of 
CYP3A4 (especially those with narrow therapeutic index, vinca alkaloids), and BCRP is 
considered low but cannot be excluded as it has not been fully been evaluated at this time.  
Therefore, caution is recommended when PF-06649751 is combined with BCRP 
(eg, rosuvastatin, methotrexate, mitoxantrone, etc.) or CYP3A substrate (eg, alfentanil, 
ergotamine, irinotecan, ticagrelor, simvastatin, etc.). 
 
6. STUDY PROCEDURES 
6.1. Screening – Day -30 to Day -2
Subjects will be screened within 30 days prior to administration of investigational product to 
confirm they meet the subject selection criteria for the study.  The investigator (or an 
appropriate delegate at the investigator site) will obtain informed consent from each subject 
in accordance with the procedures described in Section 12.3. Informed consent may be 
obtained up to 60 days prior to Visit 1 (Randomization).
Rescreening may be permitted after discussion with the study Sponsor clinician or medical 
monitor or under the specific circumstance of HCV positive laboratory test in order to 
perform follow up a follow up qualitative HCV RNA test.
At any given time, the sponsor or designee will verify critical elements of the screening and 
enrollment process and, in cases where verification is required, will provide written 
authorization (eg, e-mail) concurring (or disagreeing, if necessary, dependent on outcome) 
with the investigator assessment that the subject is eligible for enrollment into the study.  
Eligibility may also be documented via telephone authorization followed by written 
confirmation.  The key elements to be reviewed by the sponsor may include Parkinson’s 
disease diagnosis, MDS-UPDRS scores, medical history, concomitant medications, and 
select screening safety assessments including labs, ECGs, and vital signs.  Full instructions 
on the Screening Verification process will be provided as part of training.  It is critical that 
the sponsor be provided with all requested data in a timely fashion in advance of enrollment, 
as will be instructed during study training. 
The following procedures will be completed:

Obtain written informed consent.  For subjects needing further adjustment of 
concomitant medications, informed consent should be obtained prior to any 
adjustments and prior to the Screening visit.

Register subject as Screened in interactive web response (IWR) system.  Subjects will 
be assigned unique, 8-digit number, which will be retained throughout duration of 
study participation.
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
Obtain prior medical history and demography.

Assess prior/concomitant medications including Parkinson’s disease medications.

Review and assess adverse events (AEs).

Perform full physical and neurological examination.

Perform Mini Mental State Examination (MMSE).

Verify Parkinson’s disease diagnosis using the UK Parkinson’s Disease Society Brain 
Bank Clinical Diagnostic Criteria (Appendix 4).

Perform Hoehn & Yahr Stage assessment.

Collect height, weight, and BMI.

Collect blood and urine specimens for the following:

Serum pregnancy test for all females.  A negative pregnancy result (contraception 
check) is required before the subject may receive investigational product.

FSH test for female subjects that are amenorrheic for at least 12 months.  This is 
is mandatory for female subjects that do not have documented hysterectomy, 
bilateral oophorectomy or medically confirmed ovarian failure, to confirm 
non-childbearing potential (see Section 4.1, Inclusion Criteria #5).

Serological testing (HIV, Hepatitis B antigen, and Hepatitis C antibody).

Urine drug screening test for drugs of abuse (including tetrahydrocannabinol 
(THC) to be performed at the central lab.

Safety laboratory tests (including additional specific tests to monitor for vascular 
inflammation).  Urinalysis will be performed by dipstick at site, and if positive, 
additional urine should be collected and sent to the central lab.

Perform standard supine 12-lead electrocardiogram (ECG). If QTcF exceeds 
450 msec for males or 470 msec for females, or QRS interval exceeds 120 msec, the 
ECG should be repeated two more times and the average of the three values should be 
used to determine the subject’s eligibility. 

Perform supine and standing vitals (HR and blood pressure).  If the subject does not 
meet the eligibility criteria for vitals (HR and blood pressure) after initial 
measurement, perform triplicate vital signs to determine eligibility.

Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Past 5 years” 
Evaluation.
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
Perform the Patient Heath Questionnaire (PHQ-8).

Perform Movement Disorder Society-sponsored revision of the Unified Parkinson’s 
Disease Rating Scale (MDS-UPDRS) Parts I, II, III, and IV.

Review Inclusion and Exclusion criteria.
To prepare for study participation, subjects will be instructed on the use of the Lifestyle 
Guidelines (Section 4.4) and Concomitant Medications (Section 5.8) of the protocol.
6.2. Study Period
For the study period described below, there is a +3 day visit window for scheduling of visits 
during Dose Optimization Period from Visit 2 until Visit 9 (inclusive).
From Visit 10 to Visit 16, the visit window will be 3 days except for Visit 14 where the visit 
window to be -3 days to ensure discontinuation of investigational product after 15 weeks of 
treatment. 
If deemed necessary for the clarification of dosing decisions or further clinical assessments 
which cannot be completed during the phone visit an additional unplanned clinic visit may be 
scheduled (Section 6.4.2, Unplanned Clinic Visits).
Study visit times are based relative to Visit 1 (Randomization), and not relative to the 
previous visit.  The indicated visit windows are only intended to mitigate scheduling 
conflicts for study visits.
For each visit, when multiple procedures are scheduled, the following chronology of events 
should be adhered to, where possible:

 
 
 
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
Other procedures may be obtained between or concurrent to those listed above.
6.2.1. Visit 1 (Randomization)

Assess prior/concomitant medications.

Confirm no change in medical history since screening visit.

Review Inclusion and Exclusion criteria.

Instruct eligible subjects to complete the following PROs (recommended in this order, 
whenever possible): 


Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–
Rating Scale (QUIP-RS);

.

Perform brief physical and neurological examination.

Urine drug screening in the form of a dipstick performed at the site.


Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard supine and standing vitals (HR and blood pressure).

Collect blood and urine for safety lab tests.  Screening labs must have no clinically 
significant findings, as judged by the investigator, in order for the subject to be 
randomized.  Urinalysis will be performed by dipstick at site, and if positive, 
additional urine should be collected and sent to the central lab.
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
Collect blood and urine biospecimen samples.  
 
 


Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.

Review and assess adverse events (AEs).


Register subject as Randomized in IRT in order to obtain randomization number.

Provide written and verbal instructions on the storage, management, and return of 
investigational product, and on the use of subject dosing diary to track investigational 
product blister cards and the daily investigational product dosing time (Sections 5.3, 
5.4, 5.5, and 5.6).

Dispense Investigational Product.

Instruct subjects on which blister card to dose from and start of daily dosing of 
investigational product in accordance with the flexible dose up-titration scheme 
(Section 5.5.1).  Subjects will begin dosing the following morning (Day 1).
6.2.2. Visit 2 (Day 7)

Assess concomitant medications.

Review and assess adverse events (AEs).

Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard supine and standing vitals (HR and blood pressure).

Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last visit”.

Investigational Product Accountability.

Review the dosing diary information recorded by the subject to ensure documentation 
of investigational product blister cards, and dosing compliance (ie, ensure daily 
dosing time was recorded and assess situations such as missed/additional doses).

Evaluate and document status of dose optimization using the Decision Flow 
(Figure 1).
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
Dispense investigational product.

Instruct subjects which blister card to dose from and on continued daily dosing of 
investigational product in accordance with the flexible dose arm up-titration scheme
(see Section 5.5.1 Dose optimization of Investigational Product).
6.2.3. Visit 3 (Day 14)

Assess concomitant medications.

Review and assess adverse events (AEs).

Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard supine and standing vitals (HR and blood pressure).

Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last visit”. 

Investigational Product Accountability.

Review the dosing diary information recorded by the subject to ensure documentation 
of investigational product blister cards, and dosing compliance (ie, ensure daily 
dosing time was recorded and assess situations such as missed/additional doses).

Evaluate and document the status of dose optimization using the Decision Flow 
(Figure 1).

Dispense investigational product.

Instruct subjects which blister card to dose from and on continued daily dosing of 
investigational product in accordance with the flexible dose arm up-titration scheme
(see Section 5.5.1 Dose optimization of Investigational Product). 
6.2.4. Visit 4 (Day 21)

Perform MDS-UPDRS Part III.

Assess concomitant medications.

Review and assess adverse events (AEs).

Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard supine and standing vitals (HR and blood pressure).

Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last visit”.
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
Retrain subjects on the storage, management, and return of investigational product, 
and on the use of subject dosing diary to track investigational product blister cards 
and the daily investigational product dosing time (Sections 5.3, 5.4, 5.5, and 5.6).

Collect blood sample for evaluation of PF-06649751 pharmacokinetics.  Document 
the date, time and amount of latest dose subject administered.

Investigational Product Accountability.

Review the dosing diary information recorded by the subject to ensure documentation 
of investigational product blister cards, and dosing compliance (ie, ensure daily 
dosing time was recorded and assess situations such as missed/additional doses).

Evaluate and document the status of dose optimization using the Decision Flow 
(Figure 1).

Dispense Investigational Product.

Instruct subjects which blister card to dose from and on continued daily dosing of 
investigational product in accordance with the flexible dose arm titration scheme (see 
Section 5.5.1 Dose optimization of Investigational Product).
6.2.5. Visit 5 (Day 28, Phone Visit)

Assess concomitant medications.

Review and assess adverse events (AEs).

Review during the phone call dosing diary information with subject to ensure 
documentation of investigational product blister cards, and dosing compliance 
(ie, ensure daily dosing time was recorded and assess situations such as 
missed/additional doses. 

Evaluate and document the status of dose optimization using the Decision Flow 
(Figure 1).

Instruct subjects which blister card to dose from and on continued daily dosing of 
investigational product in accordance with the flexible dose arm titration scheme (see 
Section 5.5.1 Dose optimization of Investigational Product).

Inform the subject that the verification of blister card will be performed the day 
following the phone visit by the site staff by text, phone or email depending on the 
site/subject’s preference.
6.2.6. Visit 6 (Day 35)

Perform MDS-UPDRS Part III.
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
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease– Rating 
Scale (QUIP-RS). 

Assess concomitant medications.

Review and assess adverse events (AEs).

Perform brief physical and neurological examination.

Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard supine and standing vitals (HR and blood pressure).

Collect blood samples for safety laboratory tests.  Urinalysis will be performed by 
dipstick at site, and if positive, additional urine should be collected and sent to the 
central lab.

Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last visit”.

Collect blood sample for evaluation of PF-06649751 pharmacokinetics.  Document 
the date, time and amount of latest dose subject administered.

Investigational Product Accountability. 

Review the dosing diary information recorded by the subject to ensure documentation 
of investigational product blister cards, and dosing compliance (ie, ensure daily 
dosing time was recorded and assess situations such as missed/additional doses).

Evaluate and document the status of dose optimization using the Decision Flow 
(Figure 1).

Dispense Investigational Product.

Instruct subjects which blister card to dose from and on continued daily dosing of 
investigational product in accordance with the flexible dose arm titration scheme (see 
Section 5.5.1 Dose optimization of Investigational Product). 
6.2.7. Visit 7 (Day 42, Phone Visit)

Assess concomitant medications.

Review and assess adverse events (AEs).

Review during the phone call dosing diary information with subject to ensure 
documentation of investigational product blister cards, and dosing compliance 
(ie, ensure daily dosing time was recorded and assess situations such as 
missed/additional doses. 
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
Evaluate and document the status of dose optimization using the Decision Flow 
(Figure 1).

Instruct subjects which blister card to dose from and on continued daily dosing of 
investigational product in accordance with the flexible dose arm titration scheme (see 
Section 5.5.1 Dose optimization of Investigational Product).

Inform the subject that the verification of blister card will be performed the day 
following the phone visit by the site staff by text, phone or email depending on the 
site/subject’s preference.
6.2.8. Visit 8 (Day 49)

Perform MDS-UPDRS Part III.

Assess concomitant medications.

Review and assess adverse events (AEs).

Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard supine and standing vitals (HR and blood pressure).

Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last visit”.

Investigational Product Accountability. 

Review the dosing diary information recorded by the subject to ensure documentation 
of investigational product blister cards, and dosing compliance (ie, ensure daily 
dosing time was recorded and assess situations such as missed/additional doses).

Evaluate and document the status of dose optimization using the Decision Flow 
(Figure 1).

Dispense Investigational Product.

Instruct subjects which blister card to dose from and on continued daily dosing of 
investigational product in accordance with the flexible dose arm titration scheme (see 
Section 5.5.1 Dose optimization of Investigational Product). 
6.2.9. Visit 9 (Day 56, Phone Visit)

Assess concomitant medications.

Review and assess adverse events (AEs).

Review during the phone call dosing diary information with subject to ensure 
documentation of investigational product blister cards, and dosing compliance 
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(ie, ensure daily dosing time was recorded and assess situations such as 
missed/additional doses.

Evaluate and document the status of dose optimization using the Decision Flow 
(Figure 1).

Instruct subjects which blister card to dose from and on continued daily dosing of 
investigational product in accordance with the flexible dose arm titration scheme (see 
Section 5.5.1 Dose optimization of Investigational Product).

Inform the subject that the verification of blister card will be performed the day 
following the phone visit by the site staff by text, phone or email depending on the 
site/subject’s preference.
6.2.10. Visit 10 (Day 63)

Instruct subject to complete the following patient reported outcomes: 


Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating 
Scale (QUIP-RS);



Assess concomitant medications.

Review and assess adverse events (AEs).

Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last visit”.

Perform full physical and neurological examination.
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
Collect weight.

Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard supine and standing vitals (HR and blood pressure).

Collect blood samples for safety laboratory tests.  Urinalysis will be performed by 
dipstick at site, and if positive, additional urine should be collected and sent to the 
central lab.

 

Retrain subjects on the storage, management, and return of investigational product, 
and on the use of subject dosing diary to track investigational product blister cards 
and the daily investigational product dosing time (Sections 5.3, 5.4, 5.5, and 5.6).

Investigational Product Accountability. 

Review the dosing diary information recorded by the subject to ensure documentation 
of investigational product blister cards, and dosing compliance (ie, ensure daily 
dosing time was recorded and assess situations such as missed/additional doses).

Dispense Investigational Product.

Instruct subjects on continued daily dosing of investigational product (see 
Section 5.5.2 Dose Maintenance Period).
6.2.11. Visit 11 (Day 70, Phone Visit) 

Assess concomitant medications.

Review and assess adverse events (AEs).

Review during the phone call dosing diary information with subject to ensure 
documentation of investigational product blister cards, and dosing compliance 
(ie, ensure daily dosing time was recorded and assess situations such as 
missed/additional doses. 

Instruct subjects on continued daily dosing of investigational product (see 
Section 5.5.2 Dose Maintenance Period).
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6.2.12. Visit 12 (Day 84)

Perform MDS-UPDRS Part III.

Assessment of concomitant medications.

Review and assess adverse events (AEs).

Perform brief physical and neurological examination.

Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard supine and standing vitals (HR and blood pressure).

Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last visit”.

 
 

Collect blood sample for evaluation of PF-06649751 pharmacokinetics.  Document 
the date, time and amount of latest dose subject administered.

Investigational Product Accountability.

Review the dosing diary information recorded by the subject to ensure documentation 
of investigational product blister cards, and dosing compliance (ie, ensure daily 
dosing time was recorded and assess situations such as missed/additional doses).

Dispense Investigational Product.

Instruct subjects on continued daily dosing of investigational product (see 
Section 5.5.2 Dose Maintenance Period).
6.2.13. Visit 13 (Day 98, Phone Visit)

Assess concomitant medications.

Review and assess adverse events (AEs).

Review during the phone call dosing diary information with subject to ensure 
documentation of investigational product blister cards, and dosing compliance 
(ie, ensure daily dosing time was recorded and assess situations such as 
missed/additional doses. 

Instruct subjects on continued daily dosing of PF-06649751 or placebo (see 
Section 5.5.2 Dose Maintenance Period).
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
Instruct subjects that the last dose of investigational product will be the morning of
Day 105.
6.2.14. Visit 14 or Early Termination Visit (Day 105)

Instruct subject to complete the following patient reported outcomes:


Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating 
Scale (QUIP-RS);









Assess concomitant medications.

Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last visit”. 

Review and assess adverse events (AEs).

Perform full physical and neurological exam.

Collect weight.

Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard supine and standing vitals (HR and blood pressure).

Collect blood samples for safety laboratory tests.  Urinalysis will be performed by 
dipstick at site, and if positive, additional urine should be collected and sent to the 
central lab.
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
 

Investigational Product Accountability.

Review the dosing diary information recorded by the subject to ensure documentation 
of investigational product blister cards, and dosing compliance (ie, ensure daily 
dosing time was recorded and assess situations such as missed/additional doses).

Discontinuation of daily dosing of investigational product.
6.3. Follow Up Period
6.3.1. Visit 15 – (Day 119)

Assess concomitant medications.

Review and assess adverse events (AEs).

Perform brief physical and neurological exam.

Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard supine and standing vitals (HR and blood pressure).

Collect blood samples for safety laboratory tests (including additional specific tests to 
monitor for vascular inflammation). Urinalysis will be performed by dipstick at site, 
and if positive, additional urine should be collected and sent to the central lab.

Collect blood and urine biospecimen samples.

Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last visit”.

Perform Physician Withdrawal Checklist (PWC-20).
6.3.2. Visit 16 – (Day 133, Phone Visit)

Review and assess adverse events (AEs).
6.4. Unplanned Visits
Unplanned visits for adjustments of investigational product or for other purposes (eg, for 
safety reasons) may occur.
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6.4.1. Unplanned Phone Visits
During an unplanned phone visit, the following assessments should occur (at a minimum):

Review and assess adverse events (AEs).

Assess concomitant medications.

Review during the phone call dosing diary information with subject to ensure 
documentation of investigational product blister cards, and dosing compliance 
(ie, ensure daily dosing time was recorded and assess situations such as 
missed/additional doses. 

Instruct subjects on continued daily dosing of investigational product (see as 
applicable Section 5.5.1 Dose optimization of Investigational Product or 5.5.2 Dose 
Maintenance Period).
6.4.2. Unplanned Clinic Visits 
6.4.2.1. Unplanned Clinic Visit during the Dose Optimization Period
During an unplanned clinic visit, the following assessments should occur (at a minimum),
except MDS -UPDRS Part III (which is optional):

Review and assess adverse events (AEs).

Assess concomitant medications.

Perform MDS-UPDRS Part III (optional).

Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard single supine and standing vitals (HR and blood pressure).

Investigational Product Accountability. 

Review the dosing diary information recorded by the subject to ensure documentation 
of investigational product blister cards, and dosing compliance (ie, ensure daily 
dosing time was recorded and assess situations such as missed/additional doses).

Evaluate and document the status of dose optimization using the Decision Flow 
(Figure 1).

Dispense Investigational Product, if applicable.

Instruct subjects which blister card to dose from and on continued daily dosing of 
investigational product in accordance with the flexible dose arm titration scheme (see 
Section 5.5.1 Dose optimization of Investigational Product). 
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6.4.2.2. Unplanned Clinic Visit during the Maintenance Period
An unplanned clinic visit must occur if the sponsor is contacted during the Maintenance 
Period for a dose adjustment.  The following assessments should occur (at a minimum),
except MDS -UPDRS Part III (which is optional):

Review and assess adverse events (AEs).

Assess concomitant medications.

Perform MDS-UPDRS Part III (optional).

Perform standard supine triplicate 12-lead electrocardiogram (ECG).

Perform standard single supine and standing vitals (HR and blood pressure).

Investigational Product Accountability.

Review the dosing diary information recorded by the subject to ensure documentation 
of investigational product blister cards, and dosing compliance (ie, ensure daily 
dosing time was recorded and assess situations such as missed/additional doses).

Consult with the sponsor on discontinuation or dose adjustment. 

Dispense Investigational Product if authorization received from the sponsor to 
proceed with a dose adjustment.

Instruct subjects on continued daily dosing of investigational product (see 
Section 5.5.2 Dose Maintenance Period).
6.5. Subject Withdrawal (Early Termination)
Withdrawal of consent: Subjects who request to discontinue study treatment will remain in 
the study and must continue to be followed for protocol specified follow-up procedures.  The 
only exception to this is when a subject specifically withdraws consent for any further 
contact with him or her or persons previously authorized by the subject to provide this 
information.  Subjects should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible.  The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of investigational product or also from study procedures and/or post 
treatment study follow-up, and entered on the appropriate CRF page.  In the event that vital 
status (whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up: All reasonable efforts must be made to locate subjects to determine and 
report their ongoing status.  This includes follow-up with persons authorized by the subject 
as noted above.  Lost to follow-up is defined by the inability to reach the subject after a 
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minimum of 2 documented phone calls, faxes, or e-mails as well as lack of response by the 
subject to 1 registered mail letter.  All attempts should be documented in the subject’s 
medical records.  If it is determined that the subject has died, the site will use permissible 
local methods to obtain the date and cause of death.  If the investigator’s use of a third-party 
representative to assist in the follow-up portion of the study has been included in the 
subject’s informed consent, then the investigator may use a sponsor-retained third-party 
representative to assist site staff with obtaining the subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study.  The site 
staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If, after all attempts, 
the subject remains lost to follow-up, then the last-known-alive date as determined by the 
investigator should be reported and documented in the subject’s medical records.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return all unused investigational 
product(s), request that the subject return for a final visit, if applicable, and follow up with 
the subject regarding any unresolved adverse events (AEs).
Every effort should be made to have the subject return to the clinic for final safety 
assessments and to be questioned regarding their reason for withdrawal.  At the early 
termination visit, every effort must be made to complete the assessments outlined in the 
Schedule of Activities.
Lack of completion of all or any of the early termination procedures will not be viewed as 
protocol deviations so long as the subject’s safety was preserved.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
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he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
7.1. Eligibility
7.1.1. Review of Inclusion/Exclusion Criteria
All inclusion and exclusion criteria must be carefully reviewed and compared against the 
screening data for the subject.  Protocol deviations related to subject eligibility are of 
particular concern and will be specifically monitored by the sponsor via screening 
verification in addition to the capture and review of protocol deviations through routine 
monitoring.
7.1.2. Medical History/Prior Medications/Procedures
Investigators should make all reasonable efforts to obtain an accurate and complete medical 
history and history of prior medication use when evaluating whether a subject is eligible for 
the study.  If the status of a subject’s medical history is in doubt or information pertaining to 
a critical variable is conflicting, every reasonable step to secure proper documentation of 
correct medical status should be attempted.  Documentation of the medical and medication
histories over the protocol defined time periods should be available for sponsor review 
during the source data verification process.  Questions about prior medications or eligibility 
should be directed to the sponsor Medical Monitor or designate.
7.1.3. Diagnostic Criteria for Parkinson’s Disease
Investigators must confirm and thoroughly document the diagnosis of Parkinson’s disease.  
Parkinson’s disease must be consistent with the UK Brain Bank Criteria12 and will be 
verified by a central enrollment committee prior to enrollment.  It is critically important that 
the investigator document the basis for confirming the diagnosis of Parkinson’s disease and 
have this information available for sponsor verification prior to enrollment.  The UK Brain 
Bank Criteria is supplied in Appendix 4 for reference.
7.1.4. Mini Mental State Examination (MMSE)
The MMSE is a brief 30 point questionnaire test that is used to assess cognition.13  It is 
commonly used to screen for dementia.  In the time span of about 10 minutes, it samples 
various functions, including arithmetic, memory and orientation.  Scores range from 0-30.  
Administration and scoring guidelines will be provided to the investigator site prior to 
initiation of the study.
7.1.5. Hoehn & Yahr (HY)
The HY is widely used to define broad categories of function in Parkinson’s disease.24 The 
HY is commonly used for describing, in broad terms, how Parkinson’s symptoms progress 
and the relative level of disability.  See Inclusion Criteria #5 (Section 4.1) for HY definition 
for this study.
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7.1.6. Patient Health Questionnaire (PHQ-8)
PHQ-8 is a self-report 8-item PRO used to assess depression and severity of depressive 
disorder and takes about 5 minutes to complete.  The PHQ-8 consists of eight of the nine 
criteria on which the DSM-IV diagnosis of depressive disorders is based.28 29 The scores for 
each item are summed to produce a total score between 0 and 24 points.  A total score of 0 to 
4 represents no significant depressive symptoms.  A total score of 5 to 9 represents mild 
depressive symptoms; 10 to 14, moderate; 15 to 19, moderately severe; and 20 to 24, 
severe.30 The PHQ-8 will be performed only at screening.  Subjects with clinically 
significant depression, as marked by a PHQ-8 total score 15 are excluded per Section 4.2
(Exclusion Criteria).
7.2. Safety
7.2.1. Laboratory Tests
The following safety laboratory tests will be performed at times defined in Study Procedures
(Section 6) of this protocol.  Additional laboratory results may be reported on these samples 
as a result of the method of analysis or the type of analyzer used by the clinical laboratory; or 
as derived from calculated values.  These additional tests would not require additional 
collection of blood.  Unscheduled clinical labs may be obtained at any time during the study 
to assess any perceived safety concerns.
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Hematologyf
Chemistryf
Urinalysisf
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
(w/differential)
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea and Creatinine
Glucose 
Calcium
Sodium
Potassium
Chloride
Total CO2 (Bicarbonate)
AST, ALT
Total Bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
Specific Gravity
Urine creatinine
FSHb
Urine drug screeningc
Human 
immunodeficiency virusd
Hepatitis B antigend
Hepatitis C antibodyd
HCV-RNA test
Anti-neutrophil 
cytoplasmic antibody 
panel (C-ANCA and 
P-ANCA)e,f
Antinuclear antibody 
(ANA)e,f
Fibrinogene,f
C-Reactive Protein 
(CRP)e,f
Erythrocyte
Sedimentation Rate
(ESR)e, f
Complement (C3, C4, 
and CH50/CH100)e,f
Rheumatoid Factore,f
Immunoglobulin panel 
(IgG, IgA, and IgE)e,f
Additional Tests (Needed 
for Hy’s law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
a Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b At Screening only, in females who are amenorrheic for at least 12 consecutive months. 
c At Screening and Day -1 (Randomization) only.
d At Screening only and in case of anti-HCV positive result, a qualitative HCV-RNA test to be performed.
e At Screening and Visit 15 only.
f Tests to be completed in the case of suspected concerning vasculitic process and after discussion with the 
Medical Monitor/ Sponsor Study Clinician per Section 7.2.9.

Minimum requirement for drug screening includes: cocaine, tetrahydrocannabinol 
(THC), opiates/opioids, benzodiazepines and amphetamines.

Subjects may undergo random urine drug screening at the discretion of the 
investigator.  Drug screening conducted prior to dosing must be negative for subjects 
to receive study medication. 
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7.2.2. Pregnancy Testing
Females of childbearing potential are excluded from the study.  All female subjects of 
non-childbearing potential will have a FSH test, if amenorrheic for at least 12 consecutive 
months.  Results will be obtained prior to investigational product dosing. 
Confirmation of non-childbearing potential is required before the subject may receive 
investigational product. 
7.2.3. Physical Examinations
Physical examinations must be conducted by a physician, or appropriately medically 
qualified person (eg, trained physician's assistant, nurse practitioner) in accordance with local 
(country and state) laws.  A full physical examination will include head, ears, eyes, nose, 
mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, 
and neurological systems.  The brief physical examination will be focused on general 
appearance, pulmonary, abdominal exams, the respiratory and cardiovascular systems, as 
well as towards subject reported symptoms.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface.  Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains.  They must also remove the contents of their 
pockets and remain still during measurement of weight.
7.2.4. Neurological Examinations
Full and brief neurological examinations should be conducted by a neurologist, a physician 
trained in conducting full neurological examinations as acceptable according to local 
(country and state) law.  Brief neurological examinations may be conducted by a neurologist 
or physician as acceptable according to local regulation. 
The complete/full neurological examination should include assessment of the cranial nerves; 
muscle strength, tone, abnormal movements; deep tendon reflexes; sensory exam, 
coordination, gait and station.  Higher cortical and motor function is considered part of the 
complete neurological exam.
The brief neurological exam includes observation for cerebellar (intention) tremor and for 
non-cerebellar tremors (eg, resting or positional), finger to nose, heel to shin, Romberg, gait 
and tandem walking, positional and gaze evoked nystagmus.  Any abnormal findings may be 
confirmed by consultation with a certified neurologist.
The neurological examination results will be recorded in a neurological examination case 
report form (CRF).  All the neurological examination results must be recorded on the source 
documents, which will be monitored at the clinical study site.  Abnormal neurological 
examination results deemed to be clinically significant and occurring after Day -1 
(Randomization) will be captured as an AE.
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7.2.5. Blood Pressure and Heart Rate
Blood pressure and heart rate will be measured at times specified in the Study Procedures
(Section 6) of this protocol.  Additional collection times, or changes to collection times of 
blood pressure and heart rate will be permitted, as necessary, to ensure appropriate collection 
of safety data.
The same arm (preferably the dominant arm) should be used if possible throughout the study.  
Subjects should be instructed not to speak during measurements. 
The same properly sized and calibrated blood pressure cuff will be used to measure blood 
pressure each time.  The use of an automated device for measuring BP and heart rate is 
acceptable, although, when done manually, heart rate will be measured in the brachial/radial 
artery for at least 30 seconds.  When the timing of these measurements coincides with a 
blood collection, blood pressure and heart rate should be obtained prior to the nominal time 
of the blood collection.
At screening, if initial vital sign measurement does not meet eligibility criteria, the 
subsequent two measurements will be conducted following at least 5 minutes of rest.  The 
procedure for collecting postural or orthostatic data will be:

Assess BP after subject is in supine position for a minimum of 5 minutes;

Stand subject up for 2 minutes;

Assess BP after subject is in the standing position for approximately 2 minutes.
Orthostatic hypotension is defined as a decrease of 20 mmHg for systolic blood pressure or 
10 mmHg for diastolic blood pressure 2 minutes after standing from a supine position.  
Orthostatic hypotension may be symptomatic or asymptomatic.  Symptoms of orthostatic 
hypotension are those that develop upon assuming the erect posture from a supine position 
and may include: lightheadedness, dizziness, blurred vision, weakness, fatigue, cognitive 
impairment, nausea, palpitations, tremulousness, headache and/or neck ache.
If a subject has symptoms suggestive of orthostasis, but not documented orthostatic 
hypotension, repeated measurements of supine/standing blood pressure should be obtained at 
the investigator’s discretion.  Lesser degrees of blood pressure reduction may still be 
considered clinically significant if the subject becomes symptomatic upon standing, 
especially in the presence of a significant increase in heart rate (30 beats per minute (BPM).
7.2.6. Electrocardiogram
Electrocardiograms (ECGs) should be collected at times specified in the Study Procedures
(Section 6) of this protocol.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. 
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Triplicate 12-lead ECGs will be obtained approximately 2-4 minutes apart; the average of the 
triplicate ECG measurements collected predose on Day -1 (Randomization) will serve as 
each subject’s baseline QTcF value.  When the timing of these measurements coincides with 
a blood collection, the ECG should be obtained prior to the nominal time of the blood 
collection, blood pressure and heart rate. 
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements. 
If the average of QTcF values from the triplicate measurements are above the threshold value 
(45 msec from the baseline; or is 500 msec), then a single ECG must be repeated at least 
hourly until QTcF values from 2 successive ECGs fall below the threshold value that 
triggered the repeat measurement.
If QTcF values remain 500 msec (or 45 msec from the baseline) for greater than 4 hours 
(or sooner at the discretion of the investigator); or QTcF intervals get progressively longer, 
the subject should undergo continuous ECG monitoring and sponsor should be notified.  A 
cardiologist should be consulted if QTcF intervals do not return to less than 500 msec (or to 
<45 msec above the baseline) after 8 hours of monitoring (or sooner at the discretion of the 
investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified physician’s interpretation determines that the QTcF values are in the acceptable 
range.
7.2.7. Questionnaire for Impulsive-Compulsive Disorder in Parkinson’s Disease Rating 
Scale (QUIP-RS)
The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating 
Scale (QUIP-RS) is a PD-specific PRO designed to assess the severity of impulse control 
disorders in Parkinson’s disease.  The estimated timeframe for completion is approximately 
5 minutes.
The QUIP-RS has 4 primary questions pertaining to commonly reported thoughts, 
urges/desires, and behaviors associated with impulsive-compulsive disorder, each applied to 
the 4 impulsive-compulsive disorders (compulsive gambling, buying, eating, and sexual 
behavior) and 3 related disorders (medication use, punding, and hobbyism).  It uses a 5-point 
Likert scale (score 0–4 for each question) to gauge the frequency of behaviors, and instructs 
patients to answer questions based on behaviors that occurred in the preceding 4 weeks (or 
any 4-week period in a designated time frame).  The QUIP-RS is valid and reliable as a 
rating scale for impulse control disorders and related disorders in Parkinson’s disease, and 
can be used to support a diagnosis of these disorders, as well as to monitor changes in 
symptom severity over time.14
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7.2.8. Physician Withdrawal Checklist (PWC-20)
The PWC-20 is a 20-item reliable and sensitive instrument for the assessment of BZ-like 
discontinuation symptoms.  It correlates extremely highly with the PWC-35, its parent scale 
(r=0.980).  Since most items are also complaints commonly reported by patients as 
symptoms of anxiety, it is not surprising that the PWC-20 and the Hamilton Anxiety Rating 
Scale (HAM-A) correlate highly (r=0.80) with each other.  Therefore, a combination of 
symptoms and time course, not type of symptoms alone, best differentiate between 
discontinuation symptoms of rebound/withdrawal and return of anxiety.  Discontinuation 
symptoms occur early and disappear rather swiftly, depending upon speed of taper, daily 
medication dose, and drug elimination half-life.16
7.2.9. Additional Laboratory Testing for Suspected Vascular Inflammation
During the study, if there is suspicion of the development of a concerning vasculitic process,
the subject should discontinue investigational product and the investigator will contact the 
designated Medical Monitor/Sponsor Study Clinician immediately, and should collect the 
vasculitis panel of tests in addition to the other Safety Laboratory Tests (Hematology, 
Chemistry, and Urinalysis) before any therapy for vasculitis is initiated (refer to Section 7.2.1
for the list of specific laboratory tests included). 
7.3. Assessment of Suicidal Ideation and Behavior
7.3.1. Columbia Suicide Severity Rating Scale (C-SSRS)
The Columbia Suicide Severity Rating Scale (C-SSRS) is an interview based rating scale to 
systematically assess suicidal ideation and suicidal behavior.17 Versions are available for 
“lifetime” and “since last evaluation”.  The “lifetime” evaluation is done at screening, and the 
“since last evaluation” is done at all other time points.
The C-SSRS is to be collected at times specified in the Study Procedures (Section 6) of this 
protocol by an appropriately trained clinical site staff member.  The C-SSRS can also be 
administered at any time in the study at the discretion of the investigator based on any 
reasonable concern.
At each suicidality assessment as per Study Procedures, subjects felt to have significant 
suicidal ideation with actual plan and intent or suicidal behavior, must be evaluated by a 
clinician/mental health professional (MHP) skilled in the evaluation of suicidality in the 
subjects by virtue of training or experience (eg, psychiatrist, licensed clinical psychologist) 
who will determine if it is safe for the subject to participate/continue in the trial.  Specific 
criteria that indicate a need for such an assessment are:

Suicidal ideation associated with actual intent and/or plan in the past 6 months; (a 
“YES” answer to C-SSRS questions 4 “some intent to act without specific plan” or 
5 “specific plan and intent”).

Previous history of suicide behaviors in the past 5 years (a “YES” answer to any of 
the suicidal behavior items of the C-SSRS with the behavior occurring in the past 
5 years).
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
In the investigators judgment a risk assessment or exclusion is warranted.
A written copy of the risk assessment should be included in the subject's clinical record 
(source documentation).
Other possible suicidality adverse events or other clinical observations may, based on the 
judgment of the investigator, also trigger a risk assessment and require a narrative.
Suicidality adverse events or other clinical observations may, based on the judgment of the 
investigator and clinician/MHP, also trigger a risk assessment and a narrative using 
information from the C-SSRS, and available information, prior to screening and baseline 
information, and the clinician/MHP assessment.  When there is a positive response to any 
question on the C-SSRS, the investigator should determine whether an adverse event has 
occurred.
At the baseline visit (Visit 1 (Randomization)), a risk assessment will be done by qualified 
staff at the clinical site to determine whether it is safe for the subject to be enrolled or to 
continue to participate in the trial.
Subjects who respond “YES” to items 4, 5 or to any behavioral question of the C-SSRS at 
any time after the baseline visit (Visit 1 (Randomization)) will be assessed by clinician/MHP 
to determine whether it is safe for the subject to continue in the trial.
Subjects who respond “YES” to items 4, 5 or to any behavioral question of the C-SSRS on 
more than one occasion during a trial must have their suicidality managed appropriately by 
the investigator together with the clinician/MHP (or the investigator alone if the investigator 
is a qualified mental health professional).  Depending on the specifics of the subject as 
assessed by the investigator and/or clinician/MHP, the subject may be discontinued from the 
trial.
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
7.7. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 
217 mL.  The table below reflects the approximate sample volumes needed for each 
measured endpoint.  The actual collection times of blood sampling may change, but the total 
blood volume collected will not increase.  Additional blood samples may be taken for safety 
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assessments at times specified by Pfizer, provided the total volume taken during the study
does not exceed 550 mL during any period of 30 consecutive days.
Sample Type
Sample 
Volume (mL)
Number of Sampling Times
Total Volume 
(mL)
Screening
Study Period
Follow-Up
Safety Labs 
8
1
5
1
56
ANCA Testing
4
1
1
8
ANA
2
1
1
4
Fibrinogen
2.7
1
1
5.4
ESR
2
1
1
4
Complement (C3, C4, 
CH50/CH100)
4
1
1
8
Rheumatoid factor
2
1
1
4
Immunoglobulin panel 
(IgG, IgA, IgE)
3
1
1
6
HIV/Hepatitis Panel
5
1
5
TOTAL
216.4
This total volume does not include discarded blood from pre-draws used to remove fluid from flushed 
catheters, if applicable.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
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8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the subject has taken at least 1 dose of investigational product through the subject’s last 
visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;
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
Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
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8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject, or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to run LFTs because of clinical 
sign/symptom presentation in a subject, such LFT results should be handled and followed up
as described below. 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:
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
Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 × ULN, or 
8 × ULN (whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN or
if the value reaches 3 × ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug, and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for LFT abnormalities identified at the time, should be 
considered potential Hy’s law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
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Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
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8.8. Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, 
or SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, 
these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
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2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure. The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
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8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject Withdrawal
(Early Termination))
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject.  In addition, each study subject will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
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For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by the 
Sponsor.  This document may modify the plans outlined in the core protocol elements; 
however, any major modifications of the primary endpoint definition and/or its analysis will 
also be reflected in a protocol amendment.
9.1. Sample Size Determination
The sample size is based on the primary endpoint, the change from baseline in the 
MDS-UPDRS score Part III at Week 15.  The comparisons will be of PF-06649751 against 
placebo, and the decision criteria for efficacy are given below:

C1: At least 50% confident that PF-06649751 effect is 3.6 units better than placebo.

C2: at least 95% confident that PF-06649751 effect is better than placebo effect.
Better is defined as a reduction in the MDS-UPDRS score Part III.
The sample size indicates that 34 subjects per arm will give sufficient precision for a 
comparison of PF-06649751 versus placebo to meet criterion C2 with observed effects of at 
least 3.6 units (Criterion C1).  It is estimated that the probability of passing both criteria for a 
true effect of 5.4 units would be 81%, and the probability of passing the criteria for a true 
null effect (0 unit) would be 4%.
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Assuming that 23% of the subjects will fail to complete the study or optimize the dose 
44 subjects per arm (a total of 88 subjects) will be randomized for the study. 
A conservative estimate of the between-subject standard deviation of 8.4 units has been used 
based on historical early Parkinson’s disease trials.
9.2. Efficacy Analysis
All efficacy analyses will be based on the Full Analysis Set (FAS) which is defined as all 
subjects who are randomized to the study, receive at least 1 dose of study medication, and 
have a baseline and at least one post-baseline MDS-UPDRS score Part III.  Analyses may be 
repeated using a Per Protocol Set (PPS) as appropriate, which will exclude subjects who are 
major protocol deviators from the FAS.
9.2.1. Analysis of the Primary Endpoint
The primary analysis will be conducted on the primary endpoint, the change from baseline in 
the MDS-UPDRS score Part III at Week 15, based on the FAS population.  The primary 
analysis will utilize a restricted maximum likelihood (REML)-based mixed model for 
repeated measures (MMRM).  The response variable in the model will be the change from 
baseline to each post baseline visit, and the following fixed effects will be included in the 
model:

Treatment (with 2 levels: PF-06649751 and placebo), a categorical factor.

Visit, a categorical factor.

Treatment-by-visit interaction.

Baseline MDS-UPDRS score Part III, a continuous covariate.

Baseline-by-visit interaction.

Geographic region as appropriate.
An unstructured variance-covariance structure will be used to model the within-subject 
errors.  In the unlikely event that the computational algorithm fails to converge, the following 
structures will be executed in the order specified (essentially in decreasing order of 
complexity) until convergence is achieved: heterogeneous Toeplitz, heterogeneous first-order 
autoregressive, autoregressive, heterogeneous compound symmetry, compound symmetry, 
and variance components.  The first structure yielding convergence will be used as the 
primary analysis.  The Kenward and Roger method for calculating the denominator degrees 
of freedom for tests of fixed effects will be used.
The efficacy comparisons for this MMRM model will be based on the treatment difference 
vs. placebo estimated at Week 15 using least-squares means.  Their point estimates, standard 
errors, and two-sided 90% CIs will be reported.
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Subgroup analysis will be conducted based on the level of subjects’ maintenance doses 
(<3 mg or 3 mg).  All other secondary and sensitivity analyses for the primary endpoint will 
be detailed in the SAP.
9.2.2. Analysis of Secondary/
 Endpoints
All secondary/
 endpoint analyses will be detailed in the SAP.
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
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9.4. Safety Analysis
Adverse events, ECGs, blood pressure, heart rate, C-SSRS, QUIP-RS, PWC-20, and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of subjects.  Any clinical laboratory, ECG, BP, and HR abnormalities of 
potential clinical concern as defined in Pfizer Data Standards will be described.  Safety data 
will be presented in tabular and/or graphical format and summarized descriptively, where 
appropriate.
9.5. Interim Analysis 
Up to one interim analysis will be performed when approximately 28 randomized subjects 
(32% total sample size) have finished their double-blind treatment period in the study, and 
efficacy data have been collected, databased and cleaned.  The purpose of this interim 
analysis will be to assess study futility and to aid future development planning.  If an interim 
analysis is performed, the study will continue whilst the analysis is being conducted. 
Before any interim analysis is initiated, the details of the objectives, decision criteria, 
unblinding, dissemination plan and method of maintaining the study blind as per Pfizer’s 
standard operating procedures (SOPs) will be documented and approved in an internal review 
committee (IRC) charter.  In addition, the analysis details will be documented and approved 
in the statistical analysis plan (SAP) or an interim analysis SAP.
9.6. Data Monitoring Committee
Unblinded safety data of the study will be periodically reviewed by an external, independent 
data safety monitoring committee (eDMC).
The eDMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the charter.  The recommendations made by the eDMC to alter the conduct of 
the study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
that are not endpoints, to regulatory authorities, as appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
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The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
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correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008.
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study subjects.  The study site 
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will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
12.4. Subject Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used. 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in the United States
Last Subject Last Visit (LSLV) is defined as the date the investigator reviews the last 
subject’s final safety data and determines that no further evaluation is required for the subject 
to complete the trial.
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13.2. End of Trial in a Member State
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State. End of trial in a Member State of the European Union is defined as last 
subject last visit (LSLV) based on the total of randomized subjects in accordance with 
protocol Section 9.1, Sample Size Determination. Poor recruitment (recruiting less than the 
anticipated number in the CTA) by a Member State is not a reason for premature termination 
but is considered a normal conclusion to the study in that Member State.
13.3. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as last subject last visit (LSLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-06649751 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 7 days.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
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Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the primary completion date for studies in adult populations or 
within 6 months of the primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
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Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.
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16. REFERENCES
1.
Yamamoto, M. and Schapira, A. H. (2008). Dopamine agonists in Parkinson's disease. 
Expert Rev Neurother 8(4): 671-677.
2.
Pinter, M. M., Rutgers, A. W. and Hebenstreit, E. (2000). An open-label, multicentre 
clinical trial to determine the levodopa dose-sparing capacity of pramipexole in patients
with idiopathic Parkinson's disease. J Neural Transm 107(11): 1307-1323.
3.
Nussbaum, R. L. and Ellis, C. E. (2003). Alzheimer's disease and Parkinson's disease. N 
Engl J Med 348(14): 1356-1364.
4.
Papapetropoulos, S., Adi, N., Mash, D. C., Shehadeh, L., Bishopric, N. and Shehadeh, 
L. (2007). Expression of alpha-synuclein mRNA in Parkinson's disease. Mov Disord 
22(7): 1057-1059; author reply 1057.
5.
Schiffmann, S. N., Dassesse, D., d'Alcantara, P., Ledent, C., Swillens, S. and Zoli, M. 
(2003). A2A receptor and striatal cellular functions: regulation of gene expression, 
currents, and synaptic transmission. Neurology 61(11 Suppl 6): S24-29.
6.
Olanow, C. W., et al. (2001). "An algorithm (decision tree) for the management of 
Parkinson’s disease (2001): treatment guidelines." Neurology 56(suppl 5): S1-S88.
7.
Blanchet, P. J., Fang, J., Gillespie, M., Sabounjian, L., Locke, K. W., Gammans, R., 
Mouradian, M. M. and Chase, T. N. (1998). Effects of the full dopamine D1 receptor 
agonist dihydrexidine in Parkinson's disease. Clin Neuropharmacol 21(6): 339-343.
8.
Rascol, O., Blin, O., Thalamas, C., Descombes, S., Soubrouillard, C., Azulay, P., Fabre, 
N., Viallet, F., Lafnitzegger, K., Wright, S., Carter, J. H. and Nutt, J. G. (1999). 
ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson's disease. Ann 
Neurol 45(6): 736-741.
9.
Rascol, O., Nutt, J. G., Blin, O., Goetz, C. G., Trugman, J. M., Soubrouillard, C., 
Carter, J. H., Currie, L. J., Fabre, N., Thalamas, C., Giardina, W. W. and Wright, S. 
(2001). Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to 
levodopa in patients with Parkinson disease. Arch Neurol 58(2): 249-254.
10.
Emre, M., Rinne, U. K., Rascol, A., Lees, A., Agid, Y. and Lataste, X. (1992). Effects 
of a selective partial D1 agonist, CY 208-243, in de novo patients with Parkinson 
disease. Mov Disord 7(3): 239-243.
11.
Nichols, D. E. and Lewis, M. M. (2004). Mechanisms and issues relating to the use of 
D1-like dopamine receptor agonists for age-related illnesses: Parkinson's disease and 
memory and cognition. Med Chem Res 13(1-2): 105-114.
12.
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Parkinson’s disease. A clinico-pathological study of 100 cases. JNNP 1992; 
55:181-184.
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13.
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for 
grading the cognitive state of patients for clinician. J Psychiatr Res 1975; 12(3):189-98.
14.
Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire 
for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating Scale. Mov Disord. 
2012;27(2):242-247.
15.
 
16.
Rickels K, Garcia-Espana F, Mandos L, Case GW. Physician Withdrawal Checklist 
(PWC-20). Journal of Clinical Psychopharmacology. 2008; 28(4):447-451.
17.
Posner, K., et al. (2011). "The Columbia-Suicide Severity Rating Scale: initial validity 
and internal consistency findings from three multisite studies with adolescents and 
adults." Am J Psychiatry 168(12): 1266-1277.
18.
Osman A, Bagge CL, Gutierrez PM, et al. The Suicidal Behaviors Questionnaire-
Revised (SBQ-R): validation with clinical and nonclinical samples. Assessment 2001; 
8(4):443-54.
19.
Goetz CG, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored 
revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): process, 
format, and clinimetric testing plan. Mov Disord 2007; 22(1):41-7.
20.
Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories -
IA and -II in psychiatric outpatients. Journal of Personality Assessment . 1996; 67(3): 
588–97. 
21.
 
22.
 
23.
 
24.
Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 
1967; 17(5):427-42.
25.
Gayed I, et al. The Impact of DaTscan in the Diagnosis of Parkinson Disease. Clinical 
Nuclear Medicine. 2015;40(5):390-393.
26.
Chaudhuri, KR. King's Parkinson's disease pain scale, the first scale for pain in PD: An 
international validation. Mov Disord. 2015;30(12):1623-31.
CCI
CCI
CCI
CCI
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27.
Trenkwalder C, Kohnen R, Högl B, Metta V, Sixel-Döring F, Frauscher B,Hülsmann J, 
Martinez-Martin P, Chaudhuri KR. Parkinson's disease sleepscale--validation of the 
revised version PDSS-2. Mov Disord. 2011; 26(4):644-52.
28.
Kroenke K, Spitzer RL. The PHQ-9: A new depression diagnostic and severity measure. 
Psychiatric Ann. 2002; 32(9) 509–521.
29.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental 
Disorders, 4th Edition. American Psychiatric Association, Washington, DC. 1994.
30.
Kroenke K, Spitzer RL, Williams JBW. The PHQ-9: validity of a brief depression 
severity measure. J. Gen. Intern. Med. 2001; 16: 606–613.
31.
Fisher RS, et al. ILAE official report: a practical clinical definition of epilepsy. 
Epilepsia, 55(4): 475-82, 2014.
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Appendix 1. Abbreviations
This is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ADR
adverse drug reaction
AE
adverse event
ALT
alanine aminotransferase
ANA
Anti-Nuclear antibody
AST
aspartate aminotransferase
AUC
area under the curve
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to the time of 
the last quantifiable concentration
BCRP
breast cancer resistance protein
BMI
body mass index
BP
blood pressure
BPM
beats per minute
BUN
blood urea nitrogen
C-ANCA
Cytoplasmic Anti-Neutrophil Cytoplasmic Antibody
Cavg
average concentration
CDS
core data sheet
Ceff
human plasma efficacious concentration
CI
confidence interval
CNS
central nervous system
Cmax
maximum (peak) observed concentration
COMT
catechol-O methyltransferase
CRF
case report form
CRP
C-Reactive Protein
CSA
clinical study agreement
CSF
cerebrospinal fluid
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
D1R
D1 receptor
DAI
dosage and administration instructions
DaT
dopamine transporter
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DU
dispensable unit
EBR
eye blink rate
EC
ethics committee
CCI
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Abbreviation
Term
ECG
electrocardiogram
EDMC
external data monitoring committee 
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EOT
end of trial
ESR
Erythrocyte Sedimentation Rate
EU
European Union
EudraCT
European Clinical Trials Database
FAS
full analysis set
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FIH
first in human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
HAM-A
Hamilton Anxiety Rating Scale
HCV-RNA
hepatitis C virus-ribonucleic acid
hERG
Human ether-a-go-go-related gene
HIV
human immunodeficiency virus
HPD
hours post dose
HR
heart rate
HRQL
health-related quality of life
HY
Hoehn & Yahr
IB
investigator’s brochure
IC50
half maximal inhibitory concentration
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IVR
interactive voice response
IWR
interactive web response
L-Dopa
levodopa
LFT
liver function test
LMA
locomotor activity
LPD
local product document
LQTS
long QT syndrome 
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Abbreviation
Term
LSLV
last subject last visit 
MAD
multiple ascending dose
MAO-B
monoamine oxidase B
MATE1
multidrug and toxin extrusion protein
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
 
MED
Minimal Efficacious Dose
MHP
mental health professional
MMRM
mixed model for repeated measures
MMSE
Mini Mental State Examination
MPTP
1-methyl-4-phenyl-1 2, 3, 6-tetrahydropyridine
MTD
Maximum Tolerated Dose
N/A
not applicable
NOAEL
No observed adverse effect level
OCT1
organic cation transporter
P-ANCA
Perinuclear Anti-Neutrophil Cytoplasmic Antibody
PBMC
Peripheral Blood Mononuclear Cell
PCD
primary completion date
PD
pharmacodynamics
PET
positron emission tomography
PFS
pre-filled syringe
PHQ-8
Patient Health Questionnaire
PPS
per protocol set
PRO
patient reported outcome
PT
prothrombin time
PWC-20
Physician Withdrawal Checklist
QD
“quaque die”, once per day
QID
“quarter in die”, four times per day
qEEG
polysomnography and quantitative electroencephalography
QTcF
corrected QT (Fridericia correction)
QUIP-RS
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease – Rating Scale
RAND
Randomization
RBC
red blood cell
CCI
CCI
CCI
CCI
CC
I
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Abbreviation
Term
REM
rapid eye movement
REML
restricted maximum likelihood
RNA
ribonucleic acid
RO
receptor occupancy  
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCL
Supply Chain Lead
SGOT
serum glutamic oxaloacetic transminase
SGPT
serum glutamic pyruvic transminase
SIB
suicidal ideation and behavior
SOP
standard operating procedure
SPC
summary of product characteristics
SRSD
single reference safety document
SWS
slow wave sleep
T1/2
half-life
THC
tetrahydrocannabinol
TMB
trimethobenzaminde
UK
United Kingdom
ULN
upper limit of normal
US
United States
USPI
United States package insert
WBC
white blood cell
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Appendix 2. Permitted/Prohibited Concomitant Medications
Use Category
Type of Medication
Guidance
Permitted
Any previous, current or new 
medications for medical illness 
not listed under the prohibited 
medication section below.
As needed based on investigator’s judgment and subject’s 
medical needs.1
Hypnotics, sedatives, anxiolytics
Stable low doses of benzodiazepines are permitted. The 
planned prescription of benzodiazepines for P.r.n. (“as 
needed”) use throughout the study should be discussed with 
the medical monitor/Pfizer Clinician. For insomnia, 
non-benzodiazepines are permitted.
Anticholinergics
Permitted if at a stable dose for at least 42 days prior to 
Visit 1 (Randomization).  No dose changes should be 
anticipated for the duration of the study.
MAO-B inhibitors (Parkinson’s 
disease medication)
Permitted if at a stable dose for at least 42 days prior to 
Visit 1 (Randomization).  No dose changes should be 
anticipated for the duration of the study.
Amantadine
Permitted if at a stable dose for at least 42 days prior to 
Visit 1 (Randomization).  No dose changes should be 
anticipated for the duration of the study.
Prohibited
L-Dopa and dopamine receptor 
agonist medications including 
pramipexole, ropinirole, rotigotine 
and apomorphine
Prohibited if prior exposure or history of treatment with 
dopaminergic agents for more than 28 days and within at 
least 7 days prior to Visit 1 (Randomization) and throughout 
the study.
Amphetamines, methylphenidate 
or other stimulants
Prohibited at least 42 days prior to Visit 1 (Randomization),
Antipsychotics or neuroleptics
Antipsychotics, metoclopramide, or reserpine are prohibited 
at least 42 days prior to Visit 1 (Randomization).
Antiepileptics
Antiepileptics are prohibited at least 42 days prior to Visit 1
(Randomization), except if used for chronic painful 
conditions at steady doses (for example, gabapentin or 
pregabalin).
Lithium, irreversible MAO-A/B 
inhibitor antidepressants 
(including moclobemide, 
tranylcypromine, and phenelzine)
Prohibited at least 42 days prior to Visit 1 (Randomization).  
Stable low dose opioids for chronic painful medical 
conditions may be permitted based on a consultation with the 
medical monitor.
Moderate or Strong CYP3A 
Inhibitors and Inducers
Prohibited at least 28 days prior to Visit 1 (Randomization).  
Drugs that induce or inhibit the hepatic metabolizing 
cytochrome 3A4 enzymes.
Marijuana
Prohibited from Screening through the end of the double 
blind treatment period.
Herbal Supplements
Herbal supplements must be discontinued at least 28 days 
period to Visit 1 (Randomization).  However, Melatonin is 
permitted if at a stable dose for at least 42 days prior to 
Visit 1 (Randomization).
1. Investigator to discuss with sponsor as needed.
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Appendix 3. Moderate or Strong CYP3A Inhibitors and Inducers
CYP 3A Inhibitors
CYP 3A 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 wort3
Ciprofloxacin
Troglitazone
Anti-infectives
Bosentan
Itraconazole
Nafcillin
Ketoconazole
Avasimibe4
Fluconazole
Posaconazole
Voriconazole
Anti-anginal therapy
Diltiazem
Verapamil
Anti-cancer therapy
Crizotinib
Imatinib
Miscellaneous
Nefazodone
Aprepitant
Grapefruit juice1
Conivaptan
Mibefradil2
1.  The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation 
dependent.  Studies 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).
2.  Withdrawn from the United States market.
3.  The effect of St. John’s wort varies widely and is preparation-dependent.
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4.  Not a marketed drug.
Reference: 
U.S. Food and Drug Administration.  Guidance for Industry.  Drug Interaction Studies -
Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. 
2012. Available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/ucm292362.pdf
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Appendix 4. UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria*
Step 1. Diagnosis of Parkinsonian Syndrome

Bradykinesia.

At least one of the following:

Muscular rigidity;

4-6 Hz rest tremor;

Postural instability not caused by primary visual, vestibular, cerebellar, or 
proprioceptive dysfunction. 
Step 2. Exclusion criteria for Parkinson’s disease 

History of repeated strokes with stepwise progression of parkinsonian features.

History of repeated head injury.

History of definite encephalitis.

Oculogyric crises.

Neuroleptic treatment at onset of symptoms.

More than one affected relative.

Sustained remission.

Strictly unilateral features after 3 years.

Supranuclear gaze palsy.

Cerebellar signs.

Early severe autonomic involvement.

Early severe dementia with disturbances of memory, language, and praxis.

Babinski sign.

Presence of cerebral tumor or communication hydrocephalus on imaging study.

Negative response to large doses of levodopa in absence of malabsorption.
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
MPTP exposure.
Step 3. supportive prospective positive criteria for Parkinson’s disease 
Three or more required for diagnosis of definite Parkinson’s disease in combination with step 
one

Unilateral onset.

Rest tremor present.

Progressive disorder.

Persistent asymmetry affecting side of onset most.

Excellent response (70-100%) to levodopa.

Severe levodopa-induced chorea.

Levodopa response for 5 years or more.

Clinical course of ten years or more.
*  Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Parkinson’s disease. A clinico-pathological study of 100 cases. JNNP 1992;55:181-184.
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SAP_001.pdf: 
Protocol B7601011 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 1
TMF Doc ID: 98.03
Protocol B7601011
A 15-WEEK, PHASE 2, DOUBLE BLIND, RANDOMIZED,
PLACEBO-CONTROLLED, FLEXIBLE DOSE STUDY TO INVESTIGATE THE
EFFICACY, SAFETY AND TOLERABILITY OF PF-06649751 IN SUBJECTS WITH
EARLY STAGE PARKINSON’S DISEASE
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
04-AUG-2016
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Protocol B7601011 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 2
TMF Doc ID: 98.03
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives .......................................................................................................7
2.1.1. Primary Objective.........................................................................................7
2.1.2. Secondary Objectives ...................................................................................7
2.2. Study Design .............................................................................................................8
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9
3.1. Primary Endpoint(s) ..................................................................................................9
3.2. Secondary Endpoint(s) ............................................................................................10
3.3.
 
3.4. Baseline Variables...................................................................................................17
3.5. Safety Endpoints .....................................................................................................18
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3.5.1. Adverse Events...........................................................................................18
3.5.2. Laboratory Data..........................................................................................19
3.5.3. Vital Signs (Blood Pressure and Pulse Rate)..............................................19
3.5.4. Electrocardiogram (ECG)...........................................................................19
3.5.5. Physical Examination .................................................................................20
3.5.6. Neurological Examination..........................................................................20
3.5.7. Columbia Suicide Severity Rating Scale (C-SSRS)...................................20
3.5.8. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease – Rating Scale (QUIP-RS)..................................................................23
3.5.9. Physician Withdrawal Checklist (PWC-20)...............................................24
4. ANALYSIS SETS ...............................................................................................................24
4.1. Full Analysis Set .....................................................................................................25
4.2. Per Protocol Analysis Set........................................................................................25
4.3. Safety Analysis Set..................................................................................................25
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................26
5.1. Hypotheses and Decision Rules ..............................................................................26
5.2. General Methods .....................................................................................................26
5.2.1. Analyses for Binary Data............................................................................26
5.2.2. Analyses for Continuous Data....................................................................26
5.2.2.1. Restricted Maximum Likelihood (REML)-based Mixed 
Model for Repeated Measures (MMRM)..........................................27
5.2.3. Analyses for Categorical Data....................................................................27
5.3. Methods to Manage Missing Data ..........................................................................28
6. ANALYSES AND SUMMARIES ......................................................................................28
6.1. Primary Endpoint(s) ................................................................................................29
6.1.1. MDS-UPDRS score Part III........................................................................29
6.1.1.1. Primary Analysis.......................................................................29
6.1.1.2. Sensitivity/Robustness Analyses...............................................29
6.2. Secondary Endpoint(s) ............................................................................................30
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6.3. Other Endpoint(s)....................................................................................................30
6.4. Subset Analyses.......................................................................................................33
6.5. Baseline and Other Summaries and Analyses.........................................................33
6.5.1. Baseline Summaries....................................................................................33
6.5.2. Study Conduct and Subject Disposition .....................................................34
6.5.3. Study Treatment Exposure .........................................................................34
6.5.4. Concomitant Medications and Non-Drug Treatments................................34
6.6. Safety Summaries and Analyses .............................................................................34
6.6.1. Adverse Events...........................................................................................35
6.6.2. Laboratory Data..........................................................................................35
6.6.3. Vital Signs (Blood Pressure and Pulse Rate)..............................................36
6.6.4. Electrocardiogram.......................................................................................36
6.6.5. Physical Examination .................................................................................37
6.6.6. Neurological Examination..........................................................................37
6.6.7. Columbia Suicide Severity Rating Scale (C-SSRS)...................................37
6.6.8. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease – Rating Scale (QUIP-RS)..................................................................37
6.6.9. Physician Withdrawal Checklist (PWC-20)...............................................37
7. INTERIM ANALYSES.......................................................................................................38
7.1. Introduction .............................................................................................................38
7.2. Interim Analyses and Summaries............................................................................38
8. REFERENCES ....................................................................................................................39
9. APPENDICES .....................................................................................................................40
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ................................................6
Table 2.
Titration Scheme of PF 06649751 and Placebo .....................................................9
Table 3.
C-SSRS Mapped to C-CASA - Suicidality Events and Codes.............................21
Table 4.
C-SSRS Mapped to C-CASA – Examples of Worsening/New Onset .................23
Table 5.
Safety QTcF..........................................................................................................36
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APPENDICES
Appendix 1. SUMMARY OF EFFICACY ANALYSES........................................................40
Appendix 2. DATA DERIVATION DETAILS ......................................................................41
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B7601011 is based on the protocol approved 
by 27JUL2016 (protocol dated 20JUL2016).  
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1
Not Applicable
Not Applicable
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B7601011.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment
Text taken directly from the protocol is italicized.
PF-06649751 is a highly selective partial agonist at dopamine D1 like receptors (D1 and D5
receptors, abbreviated as D1Rs) which is being developed for the treatment of the signs and
symptoms of Parkinson’s disease. The compound is differentiated from other D1R agonists
compounds that have been reported in the literature and tested in the clinic (eg, ABT 431 and
dihydrexidine) in that PF-06649751 has a non-catechol chemical structure. PF-06649751
showed a similar binding affinity for native D1Rs in brain membranes prepared from monkey 
striatal tissue (Ki = 7 nM). In vitro binding studies demonstrated that PF-06649751 (MW = 
391.35 g/mol) displayed high binding affinity for recombinant hD1 (Ki = 9 nM) and hD5 (Ki 
= 13 nM) dopamine receptors. The binding potency of PF-06649751 for the recombinant 
rD1 receptor was 84 nM and ~10-fold lower than the hD1 receptor. In vitro functional 
testing against recombinant hD1 and hD5 receptors established that the compound is an 
agonist, which stimulates cAMP formation with EC50 values of 19 nM and 17 nM, 
respectively. Comparison of the cAMP response to the full agonist dopamine indicated that 
PF-06649751 is a partial agonist at D1Rs with intrinsic activity values of 65% and 81% for 
the hD1 and hD5 receptors, respectively.
The functional activity of the compound was demonstrated in vivo. In mice, PF-06649751
increased locomotor activity (LMA). Polysomnography and quantitative
electroencephalography (qEEG) recordings in rats indicate that PF-06649751 approached
significance to increase latency to enter rapid eye movement (REM) sleep and had no effect
on overall sleep pattern, including REM and slow wave sleep (SWS). PF-06649751 also
induced transient changes in qEEG. In monkeys, PF-06649751 increased eye blink rate
(EBR) demonstrating that the compound was functionally active in vivo. A positron emission 
tomography (PET) imaging study confirmed that the compound is brain penetrant and the in 
vivo receptor occupancy (RO) is in agreement with the calculated RO based on in vitro 
binding affinity.
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PF-06649751 (0.02-0.15 mg/kg, subcutaneous administration (SC)) was tested for its ability
to improve parkinsonian symptoms in the MPTP model of Parkinson’s disease in monkeys.  
Treatment with PF-06649751 dose-dependently improved parkinsonian behaviors, and this
effect was maintained over three consecutive days of dosing. In monkeys primed to exhibit
dyskinesias by prior chronic treatment with L-Dopa, PF-06649751 reduced disability as
effectively as an optimal dose of L-Dopa but with a longer duration of action and a lower
level of dyskinesia.
A predicted human plasma efficacious concentration (Ceff) of PF-06649751 has been 
derived, based upon the experience with PF-06649751 in the MPTP-induced monkey model 
of Parkinson’s disease. The total and unbound human Ceff of PF-06649751 in plasma are
predicted to be 27.6 ng/mL and 1.7 ng/mL, respectively, corresponding to approximately
32% receptor occupancy.
In an evaluation of secondary (off target) pharmacology in vitro, PF-06649751 at 10 μM did
not inhibit ligand binding by more than 50% at any of the receptors, transporters, and ion
channels and enzyme and uptake assays evaluated except the primary pharmacologic target,
D1R. Therefore, the potential for secondary pharmacology is considered low at clinically
relevant exposures.
2.1. Study Objectives
2.1.1. Primary Objective
•
To evaluate the effect of PF-06649751 administered once daily on motor symptoms in 
subjects with early stage Parkinson’s disease.
2.1.2. Secondary Objectives
•
To evaluate the safety and tolerability of PF-06649751 administered once daily in
subjects with early stage Parkinson’s disease.
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2.2. Study Design
The study has a randomized, double-blind, placebo-controlled, flexible-dose design.  
Approximately 88 subjects from approximately 30 centers in up to 5 countries will be
randomized to 2 treatment groups (PF-06649751 or placebo) in a 1:1 ratio using a central
randomization system. 
Each subject will undergo 15 weeks of double-blind treatment (including 9 weeks of Dose 
Optimization Period and 6 weeks of stable dosing during the Dose Maintenance Period). 
The 15 weeks of double-blind treatment will be preceded by a 30 day screening period. 
There will be an additional follow-up period of 28 days following discontinuation of 
investigational product. The overall study duration will be up to 23 weeks.
During the initial up titration, subjects will gradually increase the dose of investigational
product at weekly intervals, as tolerated, until Parkinsonian symptoms are optimally
controlled. Investigational product will be self-administered once daily. The target dose
range for PF-06649751 is 3 mg to 15 mg once daily (Stage 4 – Stage 8 in Table 2).
However, a maintenance dose less than 3 mg may be selected, based on clinical response.  
Adjustments to the up-titration schedule are permitted during the Dose Optimization Period
based on clinical judgment to mitigate adverse events or symptoms of suspected
dopaminergic overstimulation. Thereafter, any dose adjustment during the Maintenance
Period (after Visit 10) may only be performed after discussion with the Sponsor Medical
Monitor/Study Clinician. For both the PF-06649751 and placebo treatment arms,
investigational product will be discontinued at Visit 14.  
Informed consent will be completed prior to any screening assessments to initiate any
treatment washout period, if applicable. All other screening assessments will occur within
30 days prior to Visit 1 (Randomization). Rescreening may be permitted after discussion
with the Sponsor Medical Monitor/Study Clinician. 
Eligible subjects will enter the 15 week double blind treatment phase, consisting of:

A 9 week Dose Optimization Period including:

Up titration of investigational product (PF-06649751 or placebo) administered
once daily;

Period for stabilization after reaching an optimized dose.

A stable treatment period (Dose Maintenance Period) for 6 weeks.
Subjects will return to the clinic each week during Visit 1 through Visit 4, and every other
week thereafter during the Dose Optimization Period. Alternating phone visits will occur at
every other week after Visit 4. During the Dose Maintenance Period, subjects will return to
the clinic twice, at Visit 12 and Visit 14. Phone visits will be performed at Visit 11 and 13.  
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Each subject is planned to be up-titrated in a double-blind fashion to the clinically
appropriate dose level of investigational product according to Dose optimization of
Investigational Product.
Following Visit 14, treatment with investigational product will be discontinued.
A follow-up clinic visit approximately two weeks after discontinuation of investigational
product (Visit 15) will take place for the assessment of subject safety. A follow-up phone
visit will occur approximately 28 days after discontinuation of investigational product
(Visit 16) for a final subject safety assessment.
Table 2.
Titration Scheme of PF 06649751 and Placebo
Stage #
Start Day of Dose Level a,b
PF-06649751 (QD mg)
Placebo
Stage 1/from day 1a
0.25
P
Stage 2/from day 8 c
0.75
P
Stage 3/from day 15
1.5
P
Stage 4/from day 22
3
P
Stage 5/from day 29
5
P
Stage 6/from day 36
7
P
Stage 7/from day 43
11
P
Stage 8/from day 50
15
P
a.
Subjects will initiate the first dose and subsequent dose level increases the day after the corresponding 
phone/clinic visit (eg, Day 1 is the day after Visit 1).
b.
For subjects who will not achieve their individual optimal dose level on the day following Visit 8, dose 
escalation is permitted, however the final dose level increase must be completed before Visit 10.
c.
The increase of dose level from stage 1 to stage 2 is a mandatory step at visit 2 (from day 8).
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Change from baseline in the Modified Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS) Score Part III at Week 15.
MDS-UPDRS Part III assesses the motor signs of Parkinson’s disease and is administered by 
the investigator.  It is comprised of 33 sub-scores based on 18 items, several with right, left 
or other body distribution scores.  Each question is anchored with five responses that are 
linked to commonly accepted clinical terms: 0 = normal, 1 = slight, 2 = mild, 3 = moderate, 
and 4 = severe.  Assessments will be done at times specified in the STUDY PROCEDURES 
section of the protocol.  Higher total scores indicate more severe motor signs of Parkinson’s 
disease.
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If more than 7 of the MDS-UPDRS Part III items are missing for a time point,1 the total score 
for that time point is missing; otherwise, the total score will be imputed as follows: sum of 
the non-missing item scores X (total number of items)/ (number of items non-missing).
Baseline will be the Day -1/Rand measurement.
3.2. Secondary Endpoint(s)
Safety and tolerability of PF-06649751 will be discussed under the Safety Endpoints (See 
Section 3.5).
 
 
 
 
 
 
 
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3.4. Baseline Variables
Baseline variables include:
•
Demographics.
•
Medical history.
•
Prior/current medication.
•
•
Primary diagnosis and duration.
•
Region (stratification factor).
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
Concomitant Parkinson's Disease Medication=NO/YES at randomization
(stratification factor).

Prior doparminergic anti-PD med exposure.
These data will be summarized as part of the baseline characteristics.
At any given time, the sponsor or designee will verify critical elements of the screening and
enrollment process and, in cases where verification is required, will provide written
authorization (eg, e-mail) concurring (or disagreeing, if necessary, dependent on outcome)
with the investigator assessment that the subject is eligible for enrollment into the study.
3.5. Safety Endpoints
Adverse events, ECGs, blood pressure, heart rate, C-SSRS, QUIP-RS, PWC-20, and safety
laboratory data will be reviewed and summarized on an ongoing basis during the study to
evaluate the safety of subjects. 
The final dose achieved will be determined for each subject.
3.5.1. Adverse Events
An adverse event is considered treatment emergent relative to a given treatment if:

the event occurs for the first time during the effective duration of treatment and was 
not seen prior to the start of treatment (for example, during the baseline or run-in 
period), or

the event was seen prior to the start of treatment but increased in severity during 
treatment.
The effective duration of treatment is determined by the lag time.  Any event occurring 
within the lag time, whether this occurs during a break in treatment or at the end of treatment, 
is attributed to the corresponding treatment period. An infinite lag will be used for the 
study. 
A 3-tier approach will be used to summarize AEs. Under this approach, AEs are classified 
into 1 of 3 tiers. Different analyses will be performed for different tiers (See Section 6.6.1). 
Tier-1 events: These are pre-specified events of clinical importance and are maintained in a 
list in the product’s Safety Review Plan (no Target Medical Events {TMEs} have been 
defined at this point in time).
Tier-2 events: These are events that are not tier-1 but are “common”. A MedDRA PT is 
defined as a Tier-2 event if there is at least a frequency ≥1% in any treatment group.
Tier-3 events: These are events that are neither Tier-1 nor Tier-2 events. Pfizer standard 
safety output where all AEs will be included (ie, no new outputs).
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3.5.2. Laboratory Data
Laboratory data will be measured at times specified in the STUDY PROCEDURES section 
of the protocol.
 
Baseline will be the Day -1/Rand measurement.
Determine if there are any laboratory data abnormalities of potential clinical concern as 
defined in Pfizer Data Standards. 
3.5.3. Vital Signs (Blood Pressure and Pulse Rate)
Blood pressure and pulse rate will be measured at times specified in the STUDY 
PROCEDURES section of this protocol.  Additional collection times, or changes to collection 
times of blood pressure and pulse rate will be permitted, as necessary, to ensure appropriate 
collection of safety data.
Orthostatic hypotension is defined as a decrease of ≥20 mmHg for systolic blood pressure or 
≥10 mmHg for diastolic blood pressure 2 minutes after standing from a supine position.  
Orthostatic hypotension may be symptomatic or asymptomatic.
Baseline will be the Day -1/Rand measurement.
Determine if there is any blood pressure or pulse rate data abnormalities of potential clinical 
concern as defined in Pfizer Data Standards.
3.5.4. Electrocardiogram (ECG)
Electrocardiograms (ECGs) should be collected at times specified in the Study Procedures
(Section 6) of this protocol.
All scheduled ECGs should be performed after the subject has rested quietly for at least
10 minutes in a supine position.
The average of the triplicate readings collected at each assessment time will be calculated 
prior to analyzing each ECG parameter.  If more than three readings are collected at one 
triplicate ECG assessment time, average across all readings will be calculated. If any of the 
three individual ECG tracings has a QTc value ≥500 msec, but the mean of the triplicates is 
not ≥500 msec, the data from the subject’s individual tracing will be described in a safety 
section of the study report in order to place the ≥500 msec value in appropriate clinical 
context.  However, values from individual tracings within triplicate measurements that are 
≥500 msec will not be included in the categorical analysis unless the average from the 
triplicate measurements is also ≥500 msec.  The mean measurement is reported.
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Baseline will be the average of the triplicate ECG measurements collected on Day -1/Rand.
Change and percent change from baseline will be calculated at each time point for each ECG 
parameter.
If not supplied, QTcF will be derived using Fridericia’s heart rate correction formula:
QTcF = QT / (RR)1/3
where RR = 60 bpm/HR (if not provided)
If QTcB is collected, then it should be listed only.
Determine if there are any ECG data abnormalities of potential clinical concern as defined in 
Pfizer Data Standards.
3.5.5. Physical Examination 
Physical Examination will be measured at times specified in the STUDY PROCEDURES 
section of the protocol. 
3.5.6. Neurological Examination 
Neurological Examination will be measured at times specified in the STUDY 
PROCEDURES section of the protocol.
3.5.7. Columbia Suicide Severity Rating Scale (C-SSRS)
The Columbia Suicide Severity Rating Scale (C-SSRS) is an interview based rating scale to 
systematically assess suicidal ideation and suicidal behavior.17 Versions are available for 
“lifetime” and “since last evaluation”. The “lifetime” evaluation is done at screening, and 
the “since last evaluation” is done at all other time points. The C-SSRS is to be collected at 
times specified in the Study Procedures (Section 6) of this protocol by an appropriately 
trained clinical site staff member. The C-SSRS can also be administered at any time in the 
study at the discretion of the investigator based on any reasonable concern. At each 
suicidality assessment as per Study Procedures, subjects felt to have significant suicidal 
ideation with actual plan and intent or suicidal behavior, must be evaluated by a 
clinician/mental health professional (MHP) skilled in the evaluation of suicidality in the 
subjects by virtue of training or experience (eg, psychiatrist, licensed clinical psychologist) 
who will determine if it is safe for the subject to participate/continue in the trial. Specific 
criteria that indicate a need for such an assessment are:

Suicidal ideation associated with actual intent and/or plan in the past 6 months; (a 
“YES” answer to C-SSRS questions 4 “some intent to act without specific plan” or 
5 “specific plan and intent”).

Previous history of suicide behaviors in the past 5 years (a “YES” answer to any of
the suicidal behavior items of the C-SSRS with the behavior occurring in the past 
5 years).
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
In the investigators judgment a risk assessment or exclusion is warranted. A written 
copy of the risk assessment should be included in the subject's clinical record (source 
documentation). Other possible suicidality adverse events or other clinical
observations may, based on the judgment of the investigator, also trigger a risk 
assessment and require a narrative.
Suicidality adverse events or other clinical observations may, based on the judgment of 
theinvestigator and clinician/MHP, also trigger a risk assessment and a narrative using 
information from the C-SSRS, and available information, prior to screening and baseline 
information, and the clinician/MHP assessment. When there is a positive response to any 
question on the C-SSRS, the investigator should determine whether an adverse event has 
occurred. 
At the baseline visits (Visit 1 (Randomization)), a risk assessment will be done by qualified 
staff at the clinical site to determine whether it is safe for the subject to be enrolled or to 
continue to participate in the trial. 
Subjects who respond “YES” to items 4, 5 or to any behavioral question of the C-SSRS at 
any time after the baseline visit (Visit 1 (Randomization)) will be assessed by clinician/MHP 
to determine whether it is safe for the subject to continue in the trial. 
Subjects who respond “YES” to items 4, 5 or to any behavioral question of the C-SSRS on 
more than one occasion during a trial must have their suicidality managed appropriately by 
the investigator together with the clinician/MHP (or the investigator alone if the investigator 
is a qualified mental health professional). Depending on the specifics of the subject as 
assessed by the investigator and/or clinician/MHP, the subject may be discontinued from the
trial.
C-SSRS responses will be mapped to the Columbia Classification Algorithm of Suicide 
Assessment (C-CASA).
Table 3.
C-SSRS Mapped to C-CASA - Suicidality Events and Codes
C-CASA 
Event Code
C-CASA Event
C-SSRS Response
1
Completed suicide
As captured in the safety database
2
Suicide attempt
“Yes” on “Actual Attempt”
3
Preparatory acts towards 
imminent suicidal behavior
“Yes” on any of the following:

”Aborted attempt”, or

“Interrupted attempt”, or

“Preparatory Acts or Behavior”
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C-CASA 
Event Code
C-CASA Event
C-SSRS Response
4
Suicidal ideation
“Yes” on any of the following:

“Wish to be dead”, or

“Non-Specific Active Suicidal Thoughts”, 
or

“Active Suicidal Ideation with Any 
Methods (Not Plan) without Intent to Act”, 
or

“Active Suicidal Ideation with Some Intent 
to Act, without Specific Plan”, or

“Active Suicidal Ideation with Specific 
Plan and Intent”
7
Self-injurious behavior, no 
suicidal intent
“Yes” on “Has subject engaged in Non-suicidal 
Self-Injurious Behavior?”
The following 3 endpoints are key endpoints for suicidality data analysis and evaluation: 

Suicidal Behavior;

Suicidal Ideation;

Suicidal Behavior or Ideation.
Suicidal behavior: A subject is said to have suicidal behavior if the subject has experienced 
any of the following events (C-CASA event codes 1-3): 

Completed suicide;

Suicide attempt; or

Preparatory acts toward imminent suicidal behavior.
Suicidal ideation: Any observed suicidal ideation maps to a single C-CASA category.  
Depending on the scale used, more granularity of observed ideation (sub-categories of 
C-CASA category 4) may be displayed. The C-SSRS, for example, includes five ideation 
questions (that map to C-CASA category 4) with increasing severity.   
Subjects with new onset suicidality: A subject will be considered to have a new onset of 
suicidality if the subject reported no ideation and no behavior at the baseline assessment 
(note that self-injurious behavior, no suicidal intent [C-CASA code 7] is not considered to be 
suicidal ideation or behavior) and reported any behavior or ideation post-baseline.  Data 
observed at screening is not considered in the definition of new onset.
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Subjects with worsening suicidality relative to baseline: A subject will be considered to have 
a worsening of suicidality if the subject moved to a lower numbered C-CASA category 
(observed in categories 1-4) than was reported at baseline.  Movement within C-CASA 
categories 5-9 would not be considered worsening.  In addition, worsening will be considered 
within the suicide ideation C-CASA category 4 if there is an increase in severity identified in 
the C-SSRS which captures additional granularity on suicide ideation. A subject who reports 
only ideation at baseline and who reports any behavior post-baseline is considered to have 
worsened.  Data observed at screening is not considered in the definition of worsening.
Table 4.
C-SSRS Mapped to C-CASA – Examples of Worsening/New Onset shows 
examples of new onset suicidality and worsening suicidality for C-SSRS after mapping to 
C-CASA.
Table 4.
C-SSRS Mapped to C-CASA – Examples of Worsening/New Onset
New Onset
Worsening
Baseline
Any post-baseline 
(or by Week)
Baseline
Any post-baseline 
(or by Week)
No ideation and no 
behavior
C-CASA code=4 
(any ideation) or
C-CASA code=1, 2, 
or 3 (any behavior)
Only C-CASA 
code=4 (Ideation 
only)
C-CASA code=3, 2, 
or 1 (any behavior) 
Lowest C-CASA 
code=4
C-CASA code=3, 2, 
or 1 (any behavior)
Lowest C-CASA 
code=3
C-CASA code=2, or 
1
Lowest C-CASA 
code=2
C-CASA code=1
With the C-SSRS, worsening may also be observed within suicidal ideation.  In this case, the 
order of suicidal ideations with increasing worsening is as follows: wish to be dead, non-
specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without 
intent to act, active suicidal ideation with some intent to act, without specific plan, and active 
suicidal ideation with specific plan and intent. All of these values will be considered 
worsening for reporting.
3.5.8. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease –
Rating Scale (QUIP-RS)
The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating
Scale (QUIP-RS) is a PD-specific PRO designed to assess the severity of impulse control
disorders in Parkinson’s disease.  The estimated timeframe for completion is approximately
5 minutes.
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The QUIP-RS has 4 primary questions pertaining to commonly reported thoughts,
urges/desires, and behaviors associated with impulsive-compulsive disorder, each applied to
the 4 impulsive-compulsive disorders (compulsive gambling, buying, eating, and sexual
behavior) and 3 related disorders (medication use, punding, and hobbyism). It uses a 5-point
Likert scale (score 0–4 for each question) to gauge the frequency of behaviors, and instructs
patients to answer questions based on behaviors that occurred in the preceding 4 weeks (or
any 4-week period in a designated time frame).
The QUIP-RS is valid and reliable as a
rating scale for impulse control disorders and related disorders in Parkinson’s disease, and
can be used to support a diagnosis of these disorders, as well as to monitor changes 
insymptom severity over time.
Each question is anchored with the following five responses: Never (0), Rarely (1), 
Sometimes (2), Often (3), and Very Often (4). The scoring range for each item (ie, disorder) 
is 0-16. If a subject has one to three missing items for an impulsive-compulsive disorder, the 
values for that disorder from their previous assessment will be carried forward and utilized; 
otherwise if the subject is missing all items for a disorder the score will be considered 
missing. The higher score indicates a greater level of the Impulsive-Compulsive Disorder. 
3.5.9. Physician Withdrawal Checklist (PWC-20)
The PWC-20 is a 20-item reliable and sensitive instrument for the assessment of BZ-like
discontinuation symptoms. It correlates extremely highly with the PWC-35, its parent scale
(r=0.980). Since most items are also complaints commonly reported by patients as
symptoms of anxiety, it is not surprising that the PWC-20 and the Hamilton Anxiety Rating
Scale (HAM-A) correlate highly (r=0.80) with each other. Therefore, a combination of
symptoms and time course, not type of symptoms alone, best differentiate between
discontinuation symptoms of rebound/withdrawal and return of anxiety. Discontinuation
symptoms occur early and disappear rather swiftly, depending upon speed of taper, daily
medication dose, and drug elimination half-life.
Determine the number of subjects with each symptom present (eg, mild or higher severity) 
and categorize each subject by severity (eg, mild, moderate, and severe). Only non-missing 
items are considered in summary presentations, and will establish the denominator.
The total PWC-20 score is the sum of 20 item-scores and ranges between 0 and 60.  The 
higher score indicates more frequent/severe symptoms. If more than 5 of the 20 individual 
items are missing then the total PWC-20 score will be set to missing; otherwise, the total 
PWC-20 score will be imputed as follows: sum of the non-missing item scores X (total 
number of items)/ (number of items non-missing).
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per standard operating procedures.
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4.1. Full Analysis Set
All efficacy analyses will be based on the Full Analysis Set (FAS) which is defined as all
subjects who are randomized to the study, receive at least 1 dose of study medication, and
have a baseline and at least one post-baseline MDS-UPDRS score Part III. The FAS is the 
primary population for efficacy.
The FAS subjects will be analyzed according to their randomized treatment regardless of  the 
actual treatment they received.
4.2. Per Protocol Analysis Set
The Per Protocol Analysis Set (PPAS) will be a subset of the FAS dataset.  This set will 
exclude subjects based on the following criteria:
•
Dose compliance is less than 80% during maintenance period;
•
Subjects who reach a maintenance dose; a maintenance dose is defined as the dose a 
subject has continued at least for the last 4 weeks during the maintenance period;
•
Any major protocol violations (including but not limited to the violation of entry 
criteria, use of excluded medication, errors in treatment assignment, loss to follow-up 
and missing data).
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations, and the precise reasons for excluding subjects from the PPAS will be fully 
defined and documented (Subject Evaluability Determination List) before breaking the blind 
for the final database release.
4.3. Safety Analysis Set
The safety analysis set will include all patients who received at least one dose of
PF-06649751 or placebo. The safety analysis set is the primary population for treatment 
administration/compliance and safety.
All subjects who receive at least one dose of study medication will be classified according to 
the actual study treatment received. A randomized but not treated subject will be excluded 
from the safety analyses.  A treated but not randomized subject or a randomized but took 
incorrect treatment subject will be reported under the treatment actually received.  
 
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5. GENERAL METHODOLOGY AND CONVENTIONS
See the Interim Analysis Plan (IAP) and Internal Review Committee (IRC) Charter for 
details on any unblinding for the interim analysis.
The blind for the study will be broken and the final analysis of the study data will be 
conducted once the last remaining subject has completed the study or is withdrawn from the 
study prior to completion, all data have been entered into the database, all data issues 
resolved, the per protocol population has been determined, and the database has been locked.
5.1. Hypotheses and Decision Rules
The sample size is based on the primary endpoint, the change from baseline in the MDS-
UPDRS score Part III at Week 15. The comparisons will be of PF-06649751 against
placebo, and the decision criteria for efficacy are given below:
•
C1: At least 50% confident that PF-06649751 effect is 3.6 units better than placebo.
•
C2: at least 95% confident that PF-06649751 effect is better than placebo effect.
Better is defined as a reduction in the MDS-UPDRS score Part III.
5.2. General Methods 
Descriptive summaries for the efficacy, safety, baseline, and other endpoints will be 
displayed by treatment group:
•
PF-06649751; and
•
Placebo
5.2.1. Analyses for Binary Data
Analyses for any binary data output will show the number and percentage of subjects in each 
response category, and the response rate and its 90% confidence interval (CI) will be 
calculated. The confidence interval of the response rate will be calculated based on the 
method of Agresti-Coull. Also, the difference of the response rates (with 90% CIs) between 
each PF-06649751 treatment group and placebo group will be presented.
5.2.2. Analyses for Continuous Data
Descriptive statistics n, mean, median, standard deviation, minimum, and maximum will be 
used to summarize the endpoints. The differences of each PF-06649751 treatment versus the 
placebo group with 90% confidence intervals from the fitted model will be reported.
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5.2.2.1. Restricted Maximum Likelihood (REML)-based Mixed Model for Repeated 
Measures (MMRM)
The primary analysis will utilize a restricted maximum likelihood (REML)-based mixed 
model for repeated measures (MMRM). The response variable in the model will be the 
change from baseline to each post baseline visit, and the following fixed effects will be 
included in the model:
•
Treatment (with 2 levels: PF-06649751 and placebo), a binary factor.
•
Visit, a categorical factor.
•
Treatment-by-visit interaction.
•
Baseline MDS-UPDRS score Part III, a continuous covariate.
•
Baseline-by-visit interaction.
•
Geographic region (stratification factor).
•
Concurrent anti- PD med Yes/No at randomization (stratification factor).
An unstructured variance-covariance structure will be used to model the within-subject
errors. In the unlikely event that the computational algorithm fails to converge, the following 
structures will be executed in the order specified (essentially in decreasing order of 
complexity) until convergence is achieved: heterogeneous Toeplitz, heterogeneous first-order 
autoregressive, autoregressive, heterogeneous compound symmetry, compound symmetry, 
and variance components. The first structure yielding convergence will be used as the 
primary analysis. The Kenward and Roger method for calculating the denominator degrees 
of freedom for tests of fixed effects will be used.
The efficacy comparisons for this MMRM model will be based on the treatment difference
vs. placebo estimated at Week 15 using least-squares means. Their point estimates, standard 
errors, and two-sided 90% CIs will be reported. 
5.2.3. Analyses for Categorical Data
Categorical data 
) will show the number and percentage of subjects 
for each category and include mean/median descriptive statistics similar to the continuous 
data (See Section 5.2.2). Analysis of the categorical data will use Cochran-Mantel-Haenszel 
methods, where row-mean-score-difference tests use ridit scores that yield nonparametric 
analyses. 
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5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied (eg, partial dates for AEs and concomitant medications will be imputed according to 
Pfizer standard algorithms).
For scales used in this study, scores will be imputed according to the imputation rules and 
algorithms for missing component scores that are provided in the data standard documents, or 
scale documentation. Details are included for each endpoint in Section 3. 
If baseline measures are missing, the last values prior to study treatment, provided that the 
data is collected on or after the screening visit will be used. This information is used as a 
reference for the measurements and observations made subsequent to the start of study 
treatment.
 
 
 
 
 
6. ANALYSES AND SUMMARIES
Both the FAS and PPAS populations will be used in the analyses of the primary efficacy 
endpoint, with the FAS being primary.  For all other efficacy endpoints, only the FAS 
analysis set will be utilized.
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6.1. Primary Endpoint(s)
6.1.1. MDS-UPDRS score Part III
6.1.1.1. Primary Analysis
Endpoints: MDS-UPDRS Part III total score

Analysis time points: Week 15.

Analysis population (method of imputation for missing data): FAS (See Section 3.1).

Analysis methodology: Change from baseline will be analyzed using the MMRM 
Analysis (See Section 5.2.2.1).

Supporting objective and Decision rule: Primary Objective (See Section 2.1.1).
Reporting results:

Raw data: The sample size, mean, standard deviation, median, minimum and 
maximum at baseline and post-baseline visits will be presented for each treatment 
arm.

Change from baseline:  The sample size, mean, standard deviation, median, minimum 
and maximum will be presented for each treatment arm. The point estimate, 90% 
confidence interval for the point estimate, difference from the placebo for each pair of 
treatment groups and the corresponding 90% confidence interval will be presented. 
Figures

Vertical bar chart of LS means and 90% confidence intervals at Week 15. 

Change from baseline time profile per MMRM for each treatment group.

Empirical cumulative distribution function showing % of subjects with change from 
baseline <= cutoff value at Week 15 by treatment group with missing values assigned 
to the worst outcome.
6.1.1.2. Sensitivity/Robustness Analyses
To support the interpretation of the primary analysis the following analyses will be 
performed:  
Endpoint: MDS-UPDRS Part III total score

Analysis time points: Week 15.

Analysis populations (method of imputation for missing data): PPAS (See
Section 3.1).
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•
Analysis methodology: Change from baseline will be analyzed using the MMRM 
Analysis (See Section 5.2.2.1).
Reporting results:
•
Raw data: The sample size, mean, standard deviation, median, minimum and 
maximum at baseline and post-baseline visits will be presented for each treatment 
arm.
•
Change from baseline: The sample size, mean, standard deviation, median, minimum 
and maximum will be presented for each treatment arm. The point estimate, 90% 
confidence interval for the point estimate, difference from the placebo for each pair of 
treatment groups and the corresponding 90% confidence interval will be presented.
6.2. Secondary Endpoint(s)
Safety and tolerability of PF-06649751 will be described under the safety summaries and 
analyses (See Section 6.6).
 
 
 
 
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•
 
 
 
 
 
 
 
 
 
 
 
 
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6.4. Subset Analyses 
The primary endpoint will also be analyzed respectively for subset of subjects:
•
in different geographic regions; 
•
concomitant Parkinson's Disease medication=NO/YES at randomization;
•
Subjects with prior doparminergic anti-PD med exposure;
•
Level of subjects’ maintenance doses (<3 mg or ≥3 mg).
Only subgroup that has >=10% of total subjects will be analyzed.  The MMRM analysis (See
Section 5.2.2.1) will be performed and similar reporting results as described in Section 6.1.1
will be presented for each of the subset analyses.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
A breakdown of demographic data will be provided for age, race, weight, body mass index 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ with tables and 
listings presented in accordance with the Pfizer Data Standards. Use geriatric age categories 
for the demographic summaries (<65, 65-74, 75-84, and ≥85).
Also, medical history and primary diagnosis will be tabulated and listed in in accordance 
with the Pfizer Data Standards.
 
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6.5.2. Study Conduct and Subject Disposition
Data will be reported in accordance with Pfizer Data Standards
6.5.3. Study Treatment Exposure
Duration of exposure will be presented in tables and listings in accordance with the Pfizer 
Data Standards.  
A maintenance dose is defined as the dose a subject has continued at least for the last 
4 weeks (see Section 4.2) during the maintenance period.  
A summary will be prepared for the number of subjects who discontinue the treatment before 
the dose maintenance period, their final dose, and reason for drop outs. 
For those who reached the dose maintenance period, a summary will be prepared of the 
number and percent of patients by final dose received, the maintenance dose, and the number 
of dose adjustments per patient until the final dose received.  Their disposition will also be 
summarized by the maintenance dose including all subjects who did not reach a maintenance 
dose. Time to reach the  maintenance dose (defined as 15+ weeks for subjects who never 
reached a maintenance dose) will be summarized by the maintenance dose within each 
treatment. A separate summary of disposition at the end of each subject’s titration (reached
the maintenance dose or not) will also be provided by their dose at the end of titration.
Compliance will be calculated and summarized across the whole double-blind treatment 
phase, and by visit. Compliance will be based on the dosing record, and calculated as:
Compliance = Actual Dosing / Expected dosing X 100%.
6.5.4. Concomitant Medications and Non-Drug Treatments
All prior and concomitant medication(s) as well as non-drug treatment(s) will be provided in 
tables and listings in accordance with the Pfizer Data Standards. Prior and concomitant anti-
PD medication use (including prior exposure to dopaminergic treatments) including prior 
exposure to dopaminergic treatments) will also be separately summarized.
6.6. Safety Summaries and Analyses
The safety analysis set is the primary population for the safety summaries and analyses.
C
C
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6.6.1. Adverse Events
Adverse events will be listed and summarized within treatment group in accordance with the 
Pfizer Data Standards.
The details of Tier-1, Tier-2 and Tier-3 AEs are described in Section 3.5.1.
Adverse events within Tier-1 and -2 will be summarized using Risk Differences between 
each PF-06649751 group and placebo, together with 95% CI. A graphical presentation of the 
percentage of subjects with each AE and Risk Difference (with 95% CI) ordered by 
decreasing risk difference will be shown for the Tier-1 and -2 AEs separately. Significance 
tests will be performed for the Tier-1 adverse events. There will be no multiplicity 
adjustment for these significance tests.
For Tier-1 and Tier-2 adverse event outputs, the following footnotes will be used: “P-values 
and confidence intervals are not adjusted for multiplicity and should be used for screening 
purpose only. The 95% Confidence intervals are provided to help gauge the precision of the 
estimates for Risk Difference. Risk Difference is computed as PF-06649751 versus 
Placebo.”
Tier-1 events for risk difference and relative risk will use unconditional exact methods (an 
approach proposed by Chan and Zhang, 19992) based on standardized statistics. For Tier-2 
events, an asymptotic approach will be performed.
The Tier-3 adverse events will be described as part of the overall AE summary.
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 
generally considered as an
 analysis and its purpose is to generate hypotheses for 
further investigation. The 3-tier approach facilitates this 
 analysis.
6.6.2. Laboratory Data
Laboratory data will be listed and summarized within treatment group in accordance with the 
Pfizer Data Standards.  
Incidence of laboratory test abnormalities (including without regard to baseline abnormality) 
will be summarized within each treatment group.
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6.6.3. Vital Signs (Blood Pressure and Pulse Rate)
For each planned time point, baseline values and change from baseline values within each 
treatment will be summarized with descriptive statistics (using Pfizer Data Standards). A 
plot of individual blood pressure versus plasma concentration will be generated.
Maximum decrease and increase values and changes from baseline for vital signs (for supine 
and standing) will also be summarized descriptively within treatment group using categories 
as defined in the Pfizer Data Standards. Numbers and percentages of subjects meeting the 
categorical criteria will be provided.  All planned and unplanned post-dose time points will 
be counted in these categorical summaries.  All values meeting the criteria of potential 
clinical concern will be listed.
Vital signs collected at additional positions will be listed only.
The following non-standard safety tables will be included:

A summary of postural change from supine to standing systolic and diastolic blood 
pressures.

Incidence of subjects with orthostatic hypotension (defined in Section 3.5.3 above), 
for each visit, last visit and any post-baseline incidence or orthostatic hypotension or 
minimum absolute change in postural blood pressure.
6.6.4. Electrocardiogram
For each planned time point, baseline values, raw values and change from baseline values 
within each treatment will be summarized with descriptive statistics for each ECG parameter 
(using Pfizer Data Standards). 
A plot of QTcF versus plasma concentration will be generated at nominal time points.  
Maximum decrease and increase values and changes from baseline for the ECG parameters 
QT interval, heart rate, QTc interval, PR interval and QRS interval will be summarized by 
treatment and time post dose using Pfizer Data Standards.
The number (%) of subjects with maximum post dose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment:
Table 5.
Safety QTcF
Borderline (msec)
Prolonged (msec)
Absolute Value
450 - <480
480
Absolute Change
30-<60
60
In addition, the number of subjects with corrected and uncorrected QT values 500 msec will 
be summarized. 
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ECG endpoints and changes from baseline (QTcF, PR, QRS) will also be summarized 
descriptively by treatment using categories as defined in Pfizer Data Standards (for QTc, 
these correspond to ICH E14). Numbers and percentages of subjects meeting the categorical 
criteria will be provided. All planned and unplanned post dose time points will be counted in 
these categorical summaries. All values meeting the criteria of potential clinical concern will 
be listed.
6.6.5. Physical Examination
Physical examination data will be listed and summarized within treatment group in 
accordance with the Pfizer Data Standards. Summary of new/intensified physical 
examination findings from Baseline to Week 15 will also be presented.
6.6.6. Neurological Examination
Summary of new/intensified neurological examination findings from Baseline to Week 15 
will be presented. Otherwise, neurological examination data will be presented in the listings.
6.6.7. Columbia Suicide Severity Rating Scale (C-SSRS)
In general, the denominator used in the percentages will be the number of subjects assessed 
for suicidality or worsening, the denominator would include the subset of subjects who had 
any level of suicidality reported at baseline.  For new onset, the denominator would include 
the subset of subjects with no suicidality reported at baseline.
A subject listing of C-CASA categories as well as the underlying C-SSRS scale data will be 
presented.  
In addition, a summary table with the number and percent of subjects within each C-CASA 
category by treatment group at screening, baseline, and at any time post-baseline without 
regard to baseline will be reported.
6.6.8. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease –
Rating Scale (QUIP-RS)
For each planned time point and item (ie, disorder), baseline values, raw values and change 
from baseline values within each treatment will be summarized with descriptive statistics.
6.6.9. Physician Withdrawal Checklist (PWC-20)
Summaries of the count and percentage of patients experiencing each symptom and severity
listed in the PWC-20 will be provided by treatment group. Follow the PDS used for reporting 
incidence and severity of Adverse Events.
The Total PWC-20 score will be presented by treatment group using continuous summary 
statistics for the raw data.
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7. INTERIM ANALYSES
7.1. Introduction
Up to one interim analysis will be performed when approximately 28 randomized subjects
(32% total sample size) have finished their double-blind treatment period in the study, and
efficacy data have been collected, databased and cleaned. The purpose of this interim
analysis will be to assess study futility and to aid future development planning. If an interim
analysis is performed, the study will continue whilst the analysis is being conducted.
7.2. Interim Analyses and Summaries
Before any interim analysis is initiated, the details of the objectives, decision criteria,
unblinding, dissemination plan and method of maintaining the study blind as per Pfizer’s
standard operating procedures (SOPs) will be documented and approved in an internal 
review committee (IRC) charter. 
In addition, the analysis details will be documented and approved in a separate interim 
analysis SAP.
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8. REFERENCES 
1.
Goetz, et al. Handling Missing Values in the MDS-UPDRS. Movement Disorders 
(2015).
2.
Chan ISF, Zhang Z. (1999). Test-based exact confidence intervals for the difference of 
two binomial proportions. Biometrics, 55:1201–1209.
3.
Agresti, Alan, and Brent A. Coull. "Approximate is better than “exact” for interval 
estimation of binomial proportions." The American Statistician 52.2 (1998): 119-126.
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9. APPENDICES 
Appendix 1. SUMMARY OF EFFICACY ANALYSES
Endpoint 
Analysis Set
Statistical 
Method 
Missing 
Data
Interpretation
MDS-UPDRS 
Parts III, Week 15
FAS
MMRM
OC
Primary 
Analysis
MDS-UPDRS 
Parts III, Week 15
FAS-by geographic region
MMRM
OC
Subset 
Analysis*
MDS-UPDRS 
Parts III, Week 15
FAS-by concomitant 
Parkinson's Disease 
medication at randomization 
(NO/YES)
MMRM
OC
Subset 
Analysis*
MDS-UPDRS 
Parts III, Week 15
FAS-by prior doparminergic 
anti-PD med exposure 
(NO/YES)
MMRM
OC
Subset 
Analysis*
MDS-UPDRS 
Parts III, Week 15
FAS-by level of subjects’ 
maintenance doses (<3 mg or 
≥3 mg)
MMRM
OC
Subset 
Analysis*
MDS-UPDRS 
Parts III, Week 15
PPAS
MMRM
OC
Sensitivity 
Analysis
MDS-UPDRS 
Parts III, All Other 
Visits
FAS
MMRM
OC
Secondary 
Analysis
MDS-UPDRS Parts I, 
II, IV, and total score, 
All Visits
FAS
MMRM
OC
Secondary 
Analysis
FAS
MMRM
OC
 
Endpoints
FAS
CMH
LOCF
 
Endpoints
*Only subgroups that have >=10% of total subjects will be analyzed.
CCI
CCI
CCI
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Protocol B7601011 (PF-06649751) Statistical Analysis Plan
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CCI
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