Conditions: Parkinson Disease
Keywords: Parkinson Disease Motor Fluctuation
Allocation: RANDOMIZED | Intervention model: 
Enrollment: 108
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 who experience motor-fluctuations.

Detailed description:
The study has a randomized, double-blind, placebo-controlled parallel group design. Approximately 198 subjects will be randomized to 5 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: Placebo arm 2: PF-06649751 low dose level (1 mg QD) arm 3: PF-06649751 lower middle dose 1 (3 mg QD) arm 4: PF-06649751 higher middle dose 2 (7 mg QD) arm 5: PF-06649751 high dose (15 mg QD)

Interventions: intervention 1: Placebo intervention 2: PF-06649751 low dose (1 mg QD) intervention 3: PF-06649751 middle dose 1 (3 mg QD) intervention 4: PF-06649751 middle dose 2 (7 mg QD) intervention 5: PF-06649751 high dose (15 mg QD)
Intervention descriptions: intervention 1: Placebo intervention 2: PF-06649751 low dose (1 mg QD) intervention 3: PF-06649751 lower middle dose 1 (3 mg QD) intervention 4: PF-06649751higher middle dose 2 (7 mg QD) intervention 5: PF-06649751 high dose (15 mg QD)

Protocol document:
Prot_001.pdf: 
PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 1
A 15-WEEK, PHASE 2, DOUBLE BLIND, RANDOMIZED,
PLACEBO-CONTROLLED, DOSE RANGING STUDY TO INVESTIGATE THE 
EFFICACY, SAFETY AND TOLERABILITY OF PF-06649751 IN SUBJECTS WITH 
MOTOR FLUCTUATIONS DUE TO 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:
2015-004912-39
Protocol Number:
B7601003
Phase:
2
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 2
Document History
Document
Version Date
Summary of Changes
Amendment 2
22 November 2016
1. Protocol Summary, Schedule Activities, 
Section 3.1, Section 3.1.2, Section 5.5, 
Section 5.5.2, and Section 5.5.3: Clarified 
Period A as “Primary Efficacy” and Period B 
as “Maintenance”.
2. Protocol Summary, Section 1.4.1, and 
Section 1.4.2: Clinical studies and safety data 
updated to include the completed Phase 1b 
studies (B7601005 and B7601009).
3.
4.
5. Protocol Summary, Schedule of Activities, 
Section 3.1 Figure 1, Section 3.1.1, and 
Section 6: Screening window increased from 
30 days to 45 days and clarified that 
Screening procedures may be split between 
multiple days/visits for feasibility and/or
subject comfort, as appropriate. Individual 
screening procedures should not be split 
between multiple days/visits (eg, all parts of 
the MDS-UPDRS exam to be completed on 
the same screening day).
6. Protocol Summary and Section 3.1: Number 
of countries updated to 6 and study duration 
updated to 25 weeks. 
7. Schedule of Activities: Added line for 
vasculitis laboratory panel.
8. Schedule of Activities: Deleted abbreviation 
text related to adjunct L-Dopa Treatment. 
9. Schedule of Activities: ‘(X)’ abbreviation 
added to denote procedure to be conducted in 
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 3
the case of a clinic visit.
10. Schedule of Activities and Section 1.5.1: 
Open Label Extension study added.
11.
12. Schedule of Activities, Section 3.1 Figure 1, 
Section 3.1.2, and Section 6: During the 
Titration Period, the Week 2 and 3 clinic 
visits may be conducted as phone visits
(excluding sites in Japan). 
13. Schedule of Activities, Section 3.1 Figure 1, 
Section 3.1.2, and Section 6: Period B, 
Week 11, 12, and 14 clinic visits removed.
14. Schedule of Activities, Section 3.1 Figure 1, 
Section 3.1.2, and Section 6: Week 13 clinic 
visit to be conducted as a phone visit.
15. Schedule of Activities and Section 6: Brief 
physical and neurological examination
deleted at Week 3 and Week 13.
16. Schedule of Activities and Section 6: 
MDS-UPDRS III deleted at Week 2, Week 3, 
Week 11, Week 12 and Week 13. 
17. Schedule of Activities and Section 6: OFF 
time diary dispensed at Screening, Day 7, 28, 
35, and 70. OFF time diary collected and 
reviewed at Day 0 (Randomization), 21 (in 
case of clinic visit), 28, 35, 70, and 105. “X” 
for Dispense OFF time diary deleted for 
Week 2, Week 12 and Week 13. “X” for OFF
time diary collection/review deleted for 
Week 3 and Week 13 visits.
18. Schedule of Activities, Footnote ‘a’ and 
Appendix 7: Week 2 and Week 3 visits during 
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 4
the Titration Period must be conducted as in 
clinic visits in Japan (see Appendix 7). 
19. Schedule of Activities, Footnote ‘b’ and 
Section 3.1.2: At the discretion of the 
investigator, the Week 2 and Week 3 visits 
may be conducted as phone visits, in which 
case investigational product will be dispensed 
by the site to secure courier and delivered to 
the subject following the phone visit. 
20. Schedule of Activities, Footnote ‘c’ and 
Section 6: The Week 10 visit (and associated 
procedures) may be used as screening for 
subjects eligible for the Open Label Extension 
study B7601017 (subject to availability), and 
the Week 15 visit may then be used as Visit 1 
of the extension study. The Week 17 and 
Week 19 visits will not be conducted in this 
case.
21. Schedule of Activities, Footnote #10, 
Section 6, and Section 7.2.5: Clarification that 
subject temperature must be assessed at 
Screening and Day 0 (Randomization) to 
confirm no symptoms of fever (see Exclusion 
Criteria #6).
22.
23. Schedule of Activities, Footnote #15 and 
Section 6: New footnote added. In addition to 
compliance verification, subjects will be 
instructed on which blister card to use for
following the week at each phone visit. 
24. Schedule of Activities, Footnote #20 and 
Section 7.3.1: Clarification that subjects must 
complete the OFF time diary (Hauser diary) 
for three consecutive days in the week prior to 
each diary review visit, including Day 0 
(Randomization) visit.
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 5
25. Section 1.3.3 and Section 1.5.1: Preclinical 
toxicology data updated.
26. Section 1.4.3, Table 1, and Section 1.5.2: 
Steady state exposure data and dose rationale 
updated. 
27. Section 3.1: Figure 1 updated to reflect 
updated visit schedule and screening window 
of 45 days.
28. Section 3.1.3 and Section 6.6: Clarification 
that all subjects (including Early Termination) 
who have received at least 1 dose of 
investigational product (except a subject who 
withdraws consent), will undergo a follow-up 
visit at least 28 calendar days, and up to 
35 calendar days after the last administration 
of the investigational product to capture any 
potential adverse events and to confirm 
appropriate contraception usage. This may be 
conducted as a phone visit.
29. Section 3.1.4, Open Label Extension Study 
added.
30. Section 3.1.1: Clarification that for the final 
Inclusion/Exclusion criteria verification on 
Day 0 (Randomization) by the investigator, 
subjects must have ≥2.5 hours OFF time each 
day, collected over 3 consecutive days during 
the week prior to Day 0 (Randomization), 
with fewer than 4 errors or missing entries in 
diary data per day.
31. Section 4.1, Inclusion Criteria #3: Male and 
female subjects of non-childbearing potential 
between 40 – 85 years are eligible. 
32. Section 4.1, Inclusion Criteria #9: L-Dopa 
dose must be stable at least 21 days prior to 
Day 0 (Randomization). Subjects on a stable 
dose of L-Dopa of at least 400 mg/day 
divided into 3 daily doses (TID) may be 
considered and authorized on a case-by-case 
basis if submitted as part of the screening 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 6
assessment to the sponsor and/or its designee 
for determination if the dosing regimen is 
considered optimized for that particular 
subject.
33. Section 4.2, new Exclusion Criteria #19, 
Section 5.8.1 and Appendix 3: Dopamine 
receptor agonist medications including 
pramipexole, ropinirole, rotigotine, and 
apomorphone are prohibited at least 28 days 
prior to Day 0 (Randomization) through the 
end of the double-blind treatment period.
Exclusion criteria following were renumbered 
sequentially.
34. Exclusion Criteria #20: Clarification added 
that herbal supplements must be discontinued 
at least 28 days prior to Day 0 
(Randomization).
35. Section 4.4.3: Text added regarding stable 
rehabilitation therapy (permitted if subject’s 
regimen remains stable over the course of the 
study). 
36.
37. Section 5.8.1 and Appendix 3: COMT 
inhibitor discontinuation removed.
38. Section 6: Added clarifying text to record 
missed doses or dosing errors to applicable 
visits:  Based on blister card review and/or 
tablet count, any subject who is noted not to 
have taken at least 80% or has taken more 
than 120% of required doses at any scheduled 
visit during the study will be considered out 
of compliance and this must be recorded on 
the CRF and documented as a Medication 
Error on the CRF and the source documents. 
39. Section 7.1.6: Clarification that MDS-UPDRS 
Part III should be assessed consistently and 
approximately 2 to 4 hours following L-Dopa 
dose (except at screening).
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 7
40. Section 7.1.7: Concordance testing may be 
performed by investigator or qualified site 
staff/rater (per the Rater Qualification Quide).
MDS-UPDRS Part III exam to be performed 
at least once while the subject is in the OFF 
state and at least once while the subject is in 
the ON state (Part III score from full 
screening MDS-UPDRS may be used, 
provided the concordance assessment is
continued/completed immediately after the 
exam).
41. Section 7.2.1, Footnote ‘f’: Clarification to 
central lab procedure. If ANCA test is 
positive or questionable, then quantitative 
Proteinase-3 Ab and Myeloperoxidase Ab 
tests will be performed by the central lab 
using existing specimen.
42. Section 7.3.9: Oral Symbol Digit Modality 
Test duration changed from 120 seconds to 
90 seconds for consistency with test materials.
43. Section 7.6: Blood Volume table updated to 
reflect change in visit schedule.
44.
45. Minor administrative updates throughout.
Amendment 1
19 July 2016
1. Protocol Summary, Sections 1.4.1 and 1.4.2:
Updated with completed Phase 1 study 
enrollment and safety data, with clarification 
that 104 healthy volunteer subjects have 
participated in the completed Phase 1 studies, 
with 88 having received PF-06649751.
2. Protocol Summary, Section 2.4.1 and 
Section 2.4.2: Primary and Secondary 
endpoints measured in ON and OFF “hours”.
3. Protocol Summary and Section 2.4.2: “Daily 
ON time with troublesome dyskinesia 
(hours)” added as a Secondary endpoint.
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 8
4. Protocol Summary and Section 2.4.2: 
Secondary endpoints measured as change 
from baseline.
5.
6.
7.
 
8. 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.
9.
10. Schedule of Activities, Section 6.2.11, and 
Section 6.2.12: OFF time diary dispensed to 
subject at Day 84.
11. Section 1.3.3: Results of Study 8001294 
included.
12. C-SSRS “Lifetime” replaced with 
“Lifetime/Past 12 months” throughout.
13. Clarification that Sinemet, Menesit, Madopar, 
Prolopa, and EC Doparl are provided 
throughout as examples of common L-Dopa 
medications.
14. Exclusion Criteria #2: History of intracranial
surgical intervention for indications other than 
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 9
Parkinson’s disease added.
15. Exclusion Criteria #6: Fever added.
16. Exclusion Criteria #7: “Epilepsy” definition 
clarified with Reference #27 added.
17. Exclusion Criteria #12: History of vasculitis 
added.
18. Exclusion Criteria #14: History of malignancy 
criteria clarified.
19. Section 5.8: Medications taken within 60 days 
before the first dose of study investigational 
product will be documented as a prior 
medication.  
20. Section 5.8.3: Specific risk of drug-drug-
interactions with PF-06649751 and primary 
substrates of CYP3A4 and BCRP added.
21. Section 6.1: At Screening only, urine drug 
screening test for drugs of abuse (including 
THC) are to be performed at the central lab.
22. Section 6.1 and Section 7.1.7: MDS-UPDRS 
Part III must be performed at 30 minute 
intervals during concordance testing at 
Screening.
23. Section 7: Prolactin test moved from 
Section 7.2 (Safety) to Section 7.8 (Other).
24. Section 7.2.1, Section 7.2.9 and Schedule of 
Activities Footnote #12: Additional safety 
laboratory tests added at Screening and 
Week 17/Day 119 visits (and/or during the 
treatment period if deemed necessary) for 
monitoring of vascular inflammation. 
25. Section 7.5: Prep B2 Banked Biospecimen
sample added at Day 0 (Randomization) and 
Week 17/Day 119.
26. Section 7.6: Blood Volume table updated.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 10
27. Section 7.7.2: PHQ-8 language clarified.
28. Section 9.5: Interim Analysis language 
clarified.
29. Section 13.2: End of Trial in a member state 
of the EU defined as LSLV.
30. Appendix 3: 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.
31. Minor administrative updates throughout. 
32. References updated.
Original protocol
15 December 2015
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).  
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 11
TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................16
LIST OF FIGURES .................................................................................................................16
APPENDICES .........................................................................................................................17
PROTOCOL SUMMARY.......................................................................................................18
SCHEDULE OF ACTIVITIES................................................................................................22
1. INTRODUCTION ...............................................................................................................26
1.1. Indication.................................................................................................................26
1.2. Purpose of Study .....................................................................................................26
1.3. Background and Rationale ......................................................................................26
1.3.1. Parkinson’s Disease....................................................................................26
1.3.2. PF-06649751 Mechanism of Action...........................................................27
1.3.3. Summary of Preclinical Toxicology...........................................................28
1.4. Previous Human Clinical Experience .....................................................................31
1.4.1. Clinical Studies...........................................................................................31
1.4.2. Safety..........................................................................................................32
1.4.3. Pharmacokinetics........................................................................................35
1.4.4. Additional Information ...............................................................................35
1.5. Rationale..................................................................................................................36
1.5.1. Study Rationale...........................................................................................36
1.5.2. Dose Rationale............................................................................................36
1.5.3. Summary of Benefit-Risk Assessment.......................................................37
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................38
2.1. Primary Objective ...................................................................................................38
2.2. Secondary Objectives..............................................................................................38
2.4. Endpoints.................................................................................................................38
2.4.1. Primary Endpoint (Efficacy).......................................................................38
2.4.2. Secondary Endpoints (Efficacy; Evaluated during the entire 
double-blind period).........................................................................................38
2.4.2.1. Secondary Endpoints (Safety and Tolerability) ........................39
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 12
3. STUDY DESIGN.................................................................................................................40
3.1. Study Overview.......................................................................................................40
3.1.1. Screening ....................................................................................................41
3.1.2. Double Blind Period ...................................................................................41
3.1.3. Follow-up Period ........................................................................................42
3.1.4. Open Label Extension Study ......................................................................42
4. SUBJECT SELECTION......................................................................................................42
4.1. Inclusion Criteria.....................................................................................................42
4.2. Exclusion Criteria....................................................................................................44
4.3. Randomization Criteria ...........................................................................................47
4.4. Lifestyle Guidelines ................................................................................................47
4.4.1. Meals and Dietary Restrictions...................................................................47
4.4.2. Alcohol, Caffeine, and Tobacco .................................................................47
4.4.3. Activity .......................................................................................................48
4.4.4. Contraception – Females ............................................................................48
4.4.5. Contraception – Males................................................................................48
4.5. Sponsor’s Qualified Medical Personnel..................................................................49
4.6. Rater Qualifications.................................................................................................50
5. STUDY TREATMENTS.....................................................................................................50
5.1. Allocation to Treatment ..........................................................................................51
5.2. Breaking the Blind ..................................................................................................51
5.3. Subject Compliance.................................................................................................51
5.4. Investigational Product Supplies.............................................................................52
5.4.1. Dosage Form(s) and Packaging..................................................................52
5.4.2. Preparation and Dispensing........................................................................52
5.5. Administration.........................................................................................................52
5.5.1. Titration of PF-06649751 ...........................................................................53
5.5.2. Period A: Primary Efficacy ........................................................................53
5.5.3. Period B: Maintenance ...............................................................................53
5.6. Investigational Product Storage ..............................................................................54
5.7. Investigational Product Accountability...................................................................54
5.7.1. Destruction of Investigational Product Supplies ........................................55
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 13
5.8. Concomitant Treatment(s).......................................................................................55
5.8.1. Medications for Parkinson’s disease ..........................................................55
5.8.2. Prohibited Other Concomitant Medications ...............................................56
5.8.3. Permitted Concomitant Medications ..........................................................56
5.9. Rescue Medication ..................................................................................................57
6. STUDY PROCEDURES .....................................................................................................57
6.1. Screening: Day -45 to Day -1..................................................................................57
6.2. Study Period ............................................................................................................59
6.2.1. Randomization: Day 0 ................................................................................60
6.2.2. Dosing: Day 1 through Day 105.................................................................61
6.2.3. Titration Period: Day 7 ...............................................................................61
6.2.4. Titration Period: Day 14 .............................................................................62
6.2.5. Titration Period: Day 21 .............................................................................64
6.2.6. Dose Adjustment: Day 28...........................................................................65
6.2.7. Dose Adjustment: Day 35...........................................................................66
6.2.8. Period A: Day 42 (Phone Visit)..................................................................67
6.2.9. Period A: Day 56 (Phone Visit)..................................................................68
6.2.10. Period A: Day 70 (Procedures may be used as screening for eligible 
and consenting subjects for the open label extension study)...........................68
6.2.11. Period B: Day 91 (Phone Visit)................................................................70
6.2.12. Period B: Day 105 (Procedures may be used as Visit 1 for eligible 
and consenting subjects for the open label extension study)...........................70
6.3. Follow-up Visit: Day 119........................................................................................71
6.4. Follow-up Visit: Day 133 (Phone Visit) .................................................................72
6.5. Unplanned Visits.....................................................................................................72
6.6. Subject Withdrawal.................................................................................................73
7. ASSESSMENTS..................................................................................................................75
7.1. Eligibility.................................................................................................................75
7.1.1. Review of Inclusion/Exclusion Criteria......................................................75
7.1.2. Medical History/Prior Medications/Procedures .........................................75
7.1.3. Diagnostic Criteria for Parkinson’s Disease (UK Parkinson’s Disease 
Society Brain Bank Clinical Diagnostic Criteria)............................................75
7.1.4. Mini Mental State Examination (MMSE) ..................................................75
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 14
7.1.5. Hoehn & Yahr (HY)...................................................................................76
7.1.6. Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).......................76
7.1.7. Concordance Testing and OFF Time Diary Training.................................76
7.1.8. Screening Verification Process...................................................................78
7.2. Safety.......................................................................................................................78
7.2.1. Laboratory Tests .........................................................................................78
7.2.2. Pregnancy Testing ......................................................................................80
7.2.3. Physical Examinations................................................................................80
7.2.4. Neurological Examinations ........................................................................80
7.2.5. Vital Signs (Blood Pressure, Pulse Rate, and Temperature) ......................81
7.2.6. Electrocardiogram.......................................................................................81
7.2.7. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease – Rating Scale (QUIP-RS)..................................................................82
7.2.8. Physician Withdrawal Checklist (PWC-20)...............................................83
7.2.9. Additional Laboratory Testing for Suspected Vascular Inflammation.......83
7.3. Efficacy Measures...................................................................................................83
7.3.1. OFF Time Diary (Hauser Diary) ................................................................83
7.6. Blood Volume .........................................................................................................88
7.7. Assessment of Suicidal Ideation and Behavior.......................................................90
7.7.1. Columbia Suicide Severity Rating Scale (C-SSRS)...................................90
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 15
7.7.2. Patient Health Questionnaire-8 (PHQ-8)....................................................91
7.8. Other........................................................................................................................91
7.8.1. Prolactin Test..............................................................................................91
8. ADVERSE EVENT REPORTING......................................................................................91
8.1. Adverse Events........................................................................................................91
8.2. Reporting Period .....................................................................................................92
8.3. Definition of an Adverse Event...............................................................................92
8.4. Medication Errors....................................................................................................93
8.5. Abnormal Test Findings..........................................................................................93
8.6. Serious Adverse Events...........................................................................................94
8.6.1. Protocol-Specified Serious Adverse Events ...............................................94
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................94
8.7. Hospitalization ........................................................................................................95
8.8. Severity Assessment................................................................................................97
8.9. Causality Assessment..............................................................................................97
8.10. Exposure During Pregnancy..................................................................................97
8.11. Occupational Exposure .........................................................................................99
8.12. Subject Withdrawal...............................................................................................99
8.13. Eliciting Adverse Event Information ....................................................................99
8.14. Reporting Requirements........................................................................................99
8.14.1. Serious Adverse Event Reporting Requirements .....................................99
8.14.2. Nonserious Adverse Event Reporting Requirements .............................100
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............100
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................100
9.1. Sample Size Determination...................................................................................100
9.2. Efficacy Analysis ..................................................................................................101
9.2.1. Analysis of the Primary Endpoint.............................................................101
9.2.2. Analysis of Secondary/
 Endpoints.........................................103
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 16
9.4. Safety Analysis......................................................................................................103
9.5. Interim Analysis ....................................................................................................104
9.6. Data Monitoring Committee .................................................................................104
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................104
11. DATA HANDLING AND RECORD KEEPING ...........................................................105
11.1. Case Report Forms/Electronic Data Record .......................................................105
11.2. Record Retention.................................................................................................106
12. ETHICS............................................................................................................................106
12.1. Institutional Review Board/Ethics Committee....................................................106
12.2. Ethical Conduct of the Study ..............................................................................106
12.3. Subject Information and Consent........................................................................107
12.4. Subject Recruitment ............................................................................................107
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................107
13. DEFINITION OF END OF TRIAL.................................................................................108
13.1. End of Trial in a Member State...........................................................................108
13.2. End of Trial in All Other Participating Countries...............................................108
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................108
15. PUBLICATION OF STUDY RESULTS........................................................................108
15.1. Communication of Results by Pfizer ..................................................................108
15.2. Publications by Investigators ..............................................................................109
16. REFERENCES ................................................................................................................111
LIST OF TABLES
Table 1.
Steady State Exposures of PF-06649751 after Multiple Dosing in 
Parkinson’s Disease Patients with Motor Fluctuations ........................................35
Table 2.
Proposed Titration Schemes for PF-06649751 and Placebo Doses......................53
LIST OF FIGURES
Figure 1.
Study Schematic ...................................................................................................40
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 17
APPENDICES
Appendix 1. Abbreviations....................................................................................................114
Appendix 2. Criteria for Safety Values of Potential Clinical Concern..................................118
Appendix 3. Permitted/Prohibited Concomitant Medications...............................................120
Appendix 4. Moderate or Strong CYP3A Inhibitors and Inducers........................................121
Appendix 5. Country-Specific Appendix – Applicable to France Only................................123
Appendix 6. UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria.......124
Appendix 7. Country-Specific Appendix - Japan..................................................................126
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 18
PROTOCOL SUMMARY
Background and Rationale
In Parkinson’s disease, motor function can be pharmacologically rescued with activation of 
either or both D1R-containing direct and D2R-containing indirect striatal output pathways.  
Levodopa (L-Dopa) therapy acts through both pathways and provides improvement of motor 
symptoms for a limited duration.1 As Parkinson’s disease progresses, L-Dopa becomes less 
well tolerated as a result of motor fluctuations and dyskinesias, whereby the initial consistent 
relief of symptoms is ultimately diminished by a relentlessly narrowing therapeutic window.  
D2/D3R agonists (such as pramipexole, ropinorole, rotigotine) are 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 
experiencing motor complications associated with L-Dopa use. 
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 (TMB; B7601007, n=9) Phase 1 
studies.  
Additionally, a total of 63 Parkinson’s disease subjects have participated in one open-label
multiple ascending dose Phase 1b study (B7601005; n=45) and one double-blind, 
placebo-controlled, single ascending dose Phase 1b study (B7601009; n=18).
In addition to the current study, another Phase 2 study in Parkinson’s disease subjects is
ongoing: B7601011 in early Parkinson’s disease subjects (88 subjects planned).
The results of study B7601001, B7601002, B7601007, B7601005, and B7601009 and the 
possible risks associated with the administration of PF-06649751 are summarized in the 
Investigator’s Brochure (IB). 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 19
Study Objectives
Primary Objective
x
To evaluate the effect on motor symptoms of PF-06649751 administered once daily 
as adjunctive treatment with stable doses of L-Dopa in Parkinson’s disease.
x
To determine the therapeutic window for motor symptom improvement of 
PF-06649751 administered once daily, ie, determining a dose, or a range of doses, for 
adequate control of motor symptoms.
Secondary Objectives
x
To evaluate the dose-response on motor symptoms of PF-06649751 administered 
once daily in patients with Parkinson’s disease.
x
To evaluate the safety and tolerability of PF-06649751 administered once daily in 
subjects with Parkinson’s disease.
x
To evaluate the effect of PF-06649751 administered once daily on dyskinesia in 
subjects with Parkinson’s disease.
Endpoints
Primary Endpoint (Efficacy)
x
Change from baseline in daily OFF time (hours OFF time; based on patient reported 
Hauser diary) at Week 10 (Day 70; end of Period A).
Secondary Endpoints (Efficacy; Evaluated during the entire double-blind period)
Change from baseline in:
x
Daily OFF time (hours).
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 20
x
Daily ON time with troublesome dyskinesia (hours).
x
Daily ON time without troublesome dyskinesia (hours).
x
Movement Disorder Society - Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) Part III.
x
MDS-UPDRS Parts I, II, IV, and total score.
Secondary Endpoints (Safety and Tolerability) 
x
Adverse events.
x
Clinical laboratory parameters.
x
Vital signs.
x
Electrocardiogram (ECG) parameters.
x
Columbia Suicidality Severity Rating Scale (C-SSRS).
x
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating 
Scale (QUIP-RS).
x
Physician Withdrawal Checklist (PWC-20).
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 21
Study Design
This study has a randomized, double-blind, placebo-controlled parallel group design.  
Approximately 198 subjects from approximately 60 centers in approximately 6 countries will 
be randomized to 5 treatment groups (15 mg once per day (QD), 7 mg QD, 3 mg QD, 
1 mg QD, or placebo), initially in a 2:0:0:0:1 ratio of approximately 54 subjects (Cohort 1) 
followed by a 1:2:2:2:1 ratio of approximately total 144 (Cohort 2), using a central 
randomization system with randomization blocks stratified by region. 
Each subject will participate in the study for approximately 25 weeks including up to a 
45 day screening period, 15 week double-blind treatment period (including up to 3 week 
titration, 2 week dose adjustment, 5 weeks of primary efficacy with adjunctive treatment to 
stable L-Dopa (Period A), and 5 weeks of maintenance with adjunctive treatment to stable 
L-Dopa (Period B)), and an approximately 28 day follow-up period.
Statistical Methods
The primary endpoint is the change from baseline in daily OFF time at Week 10 (end of 
Period A).  A four parameter Emax model will be primarily used to estimate the dose response 
for the change from baseline in daily OFF time at Week 10 (end of Period A). Bayesian 
estimation will be used to fit the model.  The details of the statistical model, the priors and 
the Bayesian analysis will be specified in the Statistical Analysis Plan (SAP).
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 22
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 based on Day 0 (Randomization), 
and not based on when the previous visit actually occurred.  The indicated visit windows are only intended to mitigate 
scheduling conflicts for study visits.
Double Blind Treatment Period
Visit Identifier
Protocol Activity
Screening
Titration Perioda,b
Dose 
adjustment
Period A: Primary Efficacy
Period B: 
Maintenance
Follow-up
Wk 1
Wk 2a,b
Wk 3a,b Wk 4 Wk 5
Wk 6
(Phone 
visit)
Wk 8
(Phone 
Visit)
Wk 10c
Wk 13
(Phone 
Visit) 
Wk 15c Wk 17
Wk 19 
(Phone 
visit)
D -45
to -1
D 0/
RAND
D 7 
+3
D 14 
+3
D 21
+3
D 28 
±3
D 35 
±3
D 42
±3
D 56
±3
D 70
±3
D 91 ±3
D 105 
±3/
Early 
Termi
nation
D 119
±3
D 133 
±3
Informed consent1
X
Demographics
X
Medical history 
X
X2
Contraception Check
X
Prior/concomitant medications assessment
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
Full physical and neurological examination
X
X
X
Brief physical and neurological examination3
X
X
X
Mini Mental State Examination (MMSE)
X
UK Parkinson’s Disease Society Brain Bank 
Clinical Diagnostic Criteria
X
Hoehn & Yahr Stage4
X
Height and weight, BMI
X
X5
X5
FSH Test6
X
Serological Testing7
X
Urine drug screening8
X
X
ECG9
X
X
X
(X)
(X)
X
X
X
X
X
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 23
Double Blind Treatment Period
Visit Identifier
Protocol Activity
Screening
Titration Perioda,b
Dose 
adjustment
Period A: Primary Efficacy
Period B: 
Maintenance
Follow-up
Wk 1
Wk 2a,b
Wk 3a,b Wk 4 Wk 5
Wk 6
(Phone 
visit)
Wk 8
(Phone 
Visit)
Wk 10c
Wk 13
(Phone 
Visit) 
Wk 15c Wk 17
Wk 19 
(Phone 
visit)
D -45
to -1
D 0/
RAND
D 7 
+3
D 14 
+3
D 21
+3
D 28 
r3
D 35 
r3
D 42
r3
D 56
r3
D 70
r3
D 91 r3
D 105 
±3/
Early 
Termi
nation
D 119
r3
D 133 
±3
Supine and standing blood pressure and pulse rate
X10
X10
X
(X)
(X)
X
X
X
X
X
Columbia Suicidality Severity Rating Scale 
(C-SSRS)11
X
X
X
(X)
(X)
X
X
X
X
X
Safety laboratory
X12
X
(X)
(X)
X
X

X
X12
Vasculitis laboratory panel
X

X
 
X


X13
Prolactin laboratory14
X
X
X

X
Patient Health Questionnaire-8 (PHQ-8)
X


Inclusion/exclusion criteria verification
X
X


Randomization
X


Dispensing of Investigational Product
X
X
X
X
X
X
X
Investigational Product accountability
X
X
X
X
X
X
X
Investigational Product and L-Dopa dosing 
documentation
X
X
(X)
(X)
X
X
X
X
Dosing compliance verification via phone15
X
X
X
X
X
PF-06649751 (or placebo) administration16
X17
o
o
o
o
o
o
o
o
o
X
Adjunct L-Dopa (open-label)
o
o
o
o
o
o
o
o
o
o
o
o
Blood sample for PF-06649751 concentration18



X
X
X
ON/OFF time concordance testing and OFF time 
diary training19
X
OFF time diary training video
X
X
Dispense OFF time diary
X
X
X
X
X
OFF time diary collection/review20
X
(X)
X
X
X
X
MDS-UPDRS III21
X
X
X

X
X

X
X
MDS-UPDRS I,II,IV
X
X



X

X

X
X
X
X
X
Questionnaire for Impulsive-Compulsive 
Disorders in Parkinson’s Disease - Rating Scale
(QUIP-RS)
X
X
X
X
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 24
Double Blind Treatment Period
Visit Identifier
Protocol Activity
Screening
Titration Perioda,b
Dose 
adjustment
Period A: Primary Efficacy
Period B: 
Maintenance
Follow-up
Wk 1
Wk 2a,b
Wk 3a,b Wk 4 Wk 5
Wk 6
(Phone 
visit)
Wk 8
(Phone 
Visit)
Wk 10c
Wk 13
(Phone 
Visit) 
Wk 15c Wk 17
Wk 19 
(Phone 
visit)
D -45
to -1
D 0/
RAND
D 7 
+3
D 14 
+3
D 21
+3
D 28 
r3
D 35 
r3
D 42
r3
D 56
r3
D 70
r3
D 91 r3
D 105 
±3/
Early 
Termi
nation
D 119
r3
D 133 
±3
 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physician Withdrawal Checklist (PWC-20)
X
X
X
X
X
X
 
 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: o = 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; 
; THC = tetrahydrocannabinol; UK = United Kingdom; (X) = procedure to be conducted only in the case of a clinic visit
a.
Refer to the Appendix 7 (Japan-specific Appendix) for additional observation visits to be conducted during the Titration Period. The Week 2 and Week 3
visits must be conducted as clinic visits in Japan. 
b.
At the discretion of the investigator and per local regulation, the Week 2 and Week 3 visits may be conducted as phone visits, in which case investigational 
product will be dispensed by the site to secure courier, and subsequently delivered to the subject following the phone visit. Investigational product will not 
be dispensed if the protocol specified phone visit has not been performed. Details of the courier process will be included in the study site reference guide. 
c.
The Week 10 visit may be used as the Screening visit for subjects eligible for the Open Label Extension study, B7601017 (subject to availability), and the 
Week 15 visit may subsequently be used as Visit 1 (Baseline) of the open label extension study. 
1.
Informed consent may be obtained up to 60 days prior to Day 0 (Randomization). All other screening procedures should take place within D -45 to D -1.
The Screening procedures may be split between multiple days/visits for feasibility and/or subject comfort, however individual procedures should not be split 
between multiple days/visits. 
2.
Medical history assessed at Day 0 (Randomization) to confirm no change in history post screening visit.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 25
3.
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 non-cerebellar tremors (eg, resting or 
positional), finger to nose, heel to shin, Romberg, gait and tandem walking, positional and gaze evoked nystagmus. Full physical and neurological 
examination may be performed at the investigator’s discretion.
4.
Assessed while subject is ON.
5.
Weight only assessed at Week 10 visit and Week 17 follow-up visit.
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 #3). 
7.
Hepatitis B antigen, Hepatitis C antibody, and HIV testing.
8.
Urine test for drugs of abuse (including THC).
9.
Triplicate ECG at all time points.
10. Triplicate vitals (HR and blood pressure) at Screening.  Vitals should be collected first while the subject is in the supine position and then in the standing 
position. Subject temperature must also be assessed at Screening and Day 0 (Randomization) to confirm no symptoms of fever (see Exclusion Criteria #6).
11. Columbia Suicidality Severity Rating Scale (C-SSRS) “Lifetime/Past 12 months” evaluation at Screening, and Columbia Suicidality Severity Rating Scale 
“Since last evaluation” at all other time points.
12. Refer to Section 7.2.1 for additional safety laboratory tests (blood and urine) to be completed at Screening and Week 17 follow-up visits, and/or as necessary 
throughout the study after consultation with the Medical Monitor/Sponsor per Section 7.2.9.
 
14. Prolactin results may be shared with the blinded study team after database release.
15. 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.
16. 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 PF-06649751 or placebo dose on study visit days.
17. First dose will be administered the morning of Day 1.
 
19. Diary training and concordance testing will be conducted during the screening visit, as detailed in Section 7.1.7.
20. Subjects will complete an OFF time diary (Hauser diary) for three consecutive days in the week prior to Day 0 (Randomization) Visit and each diary review 
visit (except the Day 28 visit, in which the OFF time diary will be completed between Day 14 and Day 21 and brought the next clinic visit).
21. UPDRS Part III should be assessed consistently and approximately 2 to 4 hours following L-Dopa dose (except at Screening).
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 26
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 up to 4 different doses of 
PF-06649751 in subjects with Parkinson’s disease as adjunctive therapy to L-Dopa.
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 or 6.3 million worldwide.  In people 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; MAO-B] or exogenous 
dopamine [catechol-O methyltransferase (COMT) inhibitors]), and C) are direct agonists of 
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 induces 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.
In Parkinson’s disease, motor function can be pharmacologically rescued with activation of 
either or both D1R-containing direct and D2R-containing indirect striatal output pathways.  
Although D2/D3R agonists (such as pramipexole, ropinorole, rotigotine) are approved for the 
symptomatic treatment of Parkinson’s disease,6 the maximal efficacy observed is considered 
inferior to L-Dopa. 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 27
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 
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 1-methyl-4-phenyl-1 2, 3, 6-tetrahydropyridine (MPTP) lesioned 
nonhuman primate model of Parkinson’s disease (see Investigators Brochure Section 5.1.3.2,
In Vivo Pharmacodynamics).  Severely lesioned MPTP-treated monkeys showed no response 
to D2 agonists and modest improvement with L-Dopa treatment, but showed marked 
improvement with D1 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 
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 moderate 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 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 has 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.  In MPTP treated 
monkeys, an animal model of Parkinson’s disease, PF-06649751 with or without L-Dopa
reversed parkinsonian disabilities with a reduced propensity to induce dyskinesia when 
compared to L-Dopa.  Finally, 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.  The predicted human 
plasma efficacious concentration (Ceff) of PF-06649751 is defined as a target threshold 
concentration above which efficacy is expected.  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, 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 28
corresponding to 32% receptor occupancy.  The Ceff value is derived from the exposure 
response relationship established through the 1 methyl 4 phenyl 1,2,3,6 tetrahydropyridine 
(MPTP) induced monkey model of Parkinson’s disease. 
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, enzymes, and ion 
channels evaluated except the primary pharmacologic target, D1R.  Therefore, the potential 
for secondary pharmacology is considered low at clinically relevant exposures. 
Detailed information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator Brochure.
1.3.3. Summary of Preclinical Toxicology
The primary target organs identified in the PF-06649751 safety pharmacology and toxicity 
studies up to 26 or 39 weeks in duration in rats or monkeys, respectively, were the central 
nervous system (monkeys and rats), vascular system (male rats), reproductive system (female 
rats), and cardiovascular system (monkeys). Other findings included nonadverse 
gastrointestinal, adrenal, thyroid, pituitary, and hepatic effects, minor effects on clinical 
pathology parameters (eg, decreased red cell mass, increased cholesterol, serum electrolytes, 
or urine volume), and nonadverse respiratory parameter changes. Exacerbation of artificial 
light-induced retinal atrophy present in albino female rats in a 26-week toxicity study was 
considered an adverse effect relevant only to nonpigmented animals and, because of the 
protection afforded by uveal pigment in the eye of nonalbino animals, not expected to be an 
adverse finding relevant to humans administered PF-06649751 in clinical studies.
Central Nervous System (CNS)
Adverse CNS observations have been limited to the 1-month monkey toxicity study.  At the 
high dose in this study, 1 female administered 7.5 mg/kg/day was euthanized on Day 1 due to 
self-injury (persistent biting and chewing at the tip of the tail, first noted ~ 5.5 hours 
post-dose (HPD)).  The plasma concentration in this animal was 1310 ng/mL (76.0 ng/mL 
unbound) at 7 HPD, which is 3.8x compared with the unbound human Cmax (19.8 ng/mL) at a 
dose of 15 mg.  Nonadverse CNS-related clinical observations were noted after single or 
repeated doses in monkeys and included chewing action, teeth grinding, cage 
manipulation/licking, locomotory stereotypy, excessive repetitive behavior/grooming, 
self-injurious behavior, auto-erotic behavior (≥0.15 mg/kg/day), cage biting, excessive 
scratching, jerky movements (≥0.75 mg/kg/day), head pressing, decreased activity, skin 
picking (≥2.5 mg/kg/day), yawning (7.5 mg/kg/day).  Persistent decreased activity associated 
with low to no food consumption in monkeys following a single dose of 15 mg/kg was 
considered dose limiting for repeat-dose studies.  In the 1-month toxicity study in monkeys, 
an isolated observation of clonic activity of short duration (~10 seconds of activity at 
~7.5 HPD) occurred in 1 male at 2.5 mg/kg/day.  However, in the 15-week monkey study, 
electroencephalography (EEG) evaluation results indicated no test article-related effects on 
EEG parameters, and this single episode of clonic activity was not reproducible across a wide 
exposure range in a large number of animals, including 15- or 39-week studies at doses up to 
6 mg/kg/day in monkeys.  
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 29
Vascular System 
In the 26-week rat toxicity study only, adverse degenerative vascular/perivascular 
inflammation was noted in the liver as well as in the stomach, pancreas, or urinary bladder of 
male rats.  There was minimal disruption of the vascular integrity and no associated 
degenerative effects in adjacent tissues or correlating functional effects in organ systems. 
Overall the microscopic features were consistent with test article-related exacerbation of 
spontaneous polyarteritis.  No vascular lesions were observed in the organs of any recovery 
phase animals, indicating complete recovery.  No similar vascular findings were observed in 
female rats in the 26-week study, or in male or female rats in the completed studies up to 
15 weeks, at doses up to 60 mg/kg/day.  In addition, there was no evidence of vascular or 
perivascular inflammation in any tissue in monkey studies following up to 39 weeks of 
dosing. These data suggest a later onset (ie, beyond 15 weeks of dosing) for the 
PF-06649751-induced vascular findings observed in male rats, and suggest a potential for
PF-06649751 to induce arterial lesions in rats with chronic dosing similar to rodent-specific 
findings reported for the D1 receptor (D1R) agonist fenoldopam.  Fenoldopam has a 
well-documented history of inducing vascular injury in rats with effects consisting largely of 
arteriolar hemorrhage as well as degeneration and necrosis in rats administered 24-hour 
continuous intravenous infusion.33  These lesions are morphologically identical to the lesions 
produced in rats following an infusion of dopamine, and mechanistic data suggest the injury 
involves activation of the D1R.34  Despite reproducibility of acute vascular injury in rats, 
arterial lesions have not been observed in mice or dogs, and there are no reports of similar 
lesions being observed in humans treated with fenoldopam, including safety data reported 
after long term dosing in clinical studies following oral administration.35  While potential for 
PF-06649751 to induce arterial lesions in humans cannot be ruled out with all certainty, the 
historical observations for fenoldopam and nonclinical data with PF-06649751 suggest that 
the rat is uniquely sensitive to this endpoint following administration of D1R agonists, and 
there is low likelihood for this finding to occur in human subjects administered 
PF-06649751.
At the NOAEL of 5 mg/kg/day for this finding in male rats in the 26 week study, the 
unbound margins were 5.7 and 2.1x, respectively, the unbound human exposures (Cmax
19.8 ng/mL, AUCtau366 ng•h/mL) at a dose of 15 mg.
Reproductive System 
In the 15- and 26-week rat studies, several PF-06649751-related microscopic findings in the 
ovary, and secondary changes in the ovary, mammary gland, or cervix, collectively indicated 
a recent reduction in ovarian function, and were considered adverse at doses ≥0.7 mg/kg/day.  
There were no necrotic or degenerative effects noted microscopically in the reproductive 
organs, and these findings are similar to those that begin to occur naturally with reproductive 
senescence in aging rats.  At the NOAEL of 0.2 mg/kg/day, the exposures in female rats were 
<1x the unbound human exposures at a dose of 15 mg.  In the 26-week study in rats, similar 
PF-06649751-related ovarian findings were present but not considered adverse given the 
nondegenerative nature and natural reproductive senescence occurring in all female groups.  
These findings were attributed to PF-06649751-related persistent estrus that was 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 30
characterized by daily vaginal cytology in a 15-week study, and in a 4-week investigative 
study in female rats that included recovery and an assessment of reproductive hormones.  In 
the 4-week study, persistent estrus was associated microscopically with estrous cycle 
asynchrony; both returned to normal during the recovery phase. Hormone concentrations for 
animals with persistent estrus induced by PF-06649751 were similar to other animals in the 
same stage of estrus.  
These findings in rats are not considered a risk for women of non-childbearing potential, 
based on the lack of necrotic or degenerative findings at the microscopic level, but are of 
potential concern for women of childbearing potential based on the anticipated adverse effect 
on reproductive function.  However, findings are specific to rat studies with PF-06649751 as 
there were no reproductive organ findings in monkeys in studies up to 39 weeks of dosing.  
In the 39-week toxicity study, sexually mature female monkeys with a stable menses baseline 
were used and menstrual cycle frequency was monitored.  There was no effect of 
PF-06649751 on menstrual cycles or in any reproductive organ at the end of 39 weeks of 
dosing at any dose (≤6 mg/kg/day).  At the dose of 6 mg/kg/day (NOAEL) in sexually 
mature female monkeys, the AUC24 was 14,100 ng•h/mL, which is 2.2x the unbound human 
AUCtau of 366 ng•h/mL at a dose of 15 mg.
Cardiovascular System
Cardiovascular findings in single dose safety pharmacology studies in monkeys included 
decreased blood pressure (within 0.75 to 8.5 HPD), followed by increased blood pressure 
during later time periods (within 9 to 20 HPD), and increased heart rate, QTc interval, and 
cardiac contractility.  Results of an in vitro hERG study and a monkey isolated heart 
(Langendorff Model) study suggested that the effects on heart rate, QTc, and contractility 
were indirect (ie, not mediated by direct PF-06649751 effects on the heart).  The IC50 for 
PF-06649751 in the hERG assay (64.9 μM, 25400 ng/mL) is ≥940x to 9700x the unbound 
Cmax range in monkeys at doses where QTc interval increases were observed. PF-06649751 
had no effects on heart rate, QT interval, or left ventricular pressure in the cynomolgus 
monkey isolated heart (Langendorff model) at concentrations up to 1 μM (391 ng/mL), or 
15x to 49x the unbound Cmax in monkeys at doses (0.6 to 2.5 mg/kg) where increased 
contractility was observed in vivo.  
Exposure margins from the NOAELs from the chronic toxicity studies in monkeys and male 
rats to the human exposure at 15 mg are similar. The NOAEL in the 39-week chronic 
monkey study was the highest administered dose of 6 mg/kg/day, and was associated with a 
combined sex mean total Cmax and AUC24 of 1370 ng/mL and 14,100 ng•h/mL (79.5 ng/mL 
and 818 ng•h/mL, unbound), respectively.   These values are 4x and 2.2x the unbound human 
Cmax (19.8 ng/mL) and AUCtau (366 ng•h/mL) at a dose of 15 mg.  In male rats, the NOAEL 
in the 26-week study was 5 mg/kg/day, based upon adverse vascular/perivascular 
inflammation noted in males at ≥20 mg/kg/day, and was associated with a Cmax and AUC24 of 
1610 ng/mL and 11,000 ng•h/mL (113 ng/mL and 770 ng•h/mL, unbound).  These values are 
5.7x and 2.1x the unbound human Cmax and AUCtau at a dose of 15 mg. In female rats, 
adverse test article-related microscopic findings in the eyes (exacerbation of light induced 
retinal atrophy) were present at all doses (≥1 mg/kg/day), therefore the NOAEL in female 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 31
rats was undetermined.  However, this eye finding was considered an adverse effect relevant 
only to nonpigmented animals and, as per expert consultation, not a likely finding or 
potential risk expected in humans. 
The nonclinical safety profile of PF-06649751 is considered to be adequately characterized to 
support progression into human clinical studies of 6 months or longer dosing duration for 
men and for women of non-childbearing potential. 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 (FIH), 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. 
•
Protocol B7601002 (n=77) was a Phase 1, placebo controlled, randomized, multiple 
ascending dose study 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. 
PF-0664975 has been evaluated in 2 completed clinical studies in 63 Parkinson’s disease 
patients which are described in the Investigator’s Brochure:
•
Protocol B7601005 (n=45) 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 Day 1 for the evaluation of L-Dopa responsiveness.  In the following
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 32
days, 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.  Within the study, pharmacokinetics of PF-06649751 in 
Parkinson’s disease patients was evaluated on Days 7, 13 and 22. Continued dosing 
of PF-06649751 up to 25 mg QD for up to 3 weeks were safe and well tolerated by 
subjects with Parkinson’s disease, with no new safety findings.
•
Protocol B7601009 (n=18) was a Phase 1b, double blind, placebo controlled, 
randomized, 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.
1.4.2. Safety
B7601001
One single ascending dose study in healthy subjects (B7601001) has been completed.  In this 
study, 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 PK 
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, 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 33
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.
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
B7601005 was a Phase 1b, 2-period, open label, multi-center, dose escalation study of 
PF-06649751 in subjects with Parkinson’s disease experiencing motor fluctuations and, in 
one of the cohorts, subjects with Parkinson’s disease experiencing levodopa induced 
dyskinesia (LID). In Period 1 of the study, L-Dopa and placebo were administered for the 
evaluation of L-Dopa responsiveness. During Period 2, PF-06649751 was administered for 
the evaluation of the safety, tolerability and pharmacokinetics of PF-06649751. The 
B7601005 study 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).
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 34
•
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.  Multiple ascending doses of PF-06649751 
up to 25 mg QD were safe and well tolerated by subjects with Parkinson’s disease, with no 
new safety findings.
There were no deaths reported in the study. There was 1 SAE, 6 severe AEs, and 
11 permanent discontinuations due to AEs. The majority of AEs occurred during the up 
titration period of PF-06649751 (Period 2, Days 3-24 and follow-up) but the timing and dose 
level at which AEs occurred were variable. The most common AE reported in all 
PF-06649751 treatment groups were headache, nausea, abnormal dreams, dizziness and 
vomiting. The gastrointestinal disorders appeared to be dose-driven as there were more 
nausea and vomiting in the 15 mg QD (including LID) and 25 mg QD doses compared with 
the 5 mg QD dose. Most AEs in all PF-06649751 treatment groups appeared related to pace 
and increment of up-titration rather than maximum exposure and were generally self-limited. 
Across cohorts there were no apparent trends or clinically significant changes in vital signs, 
ECG, physical findings, laboratory values and the Parkinson’s disease diary.
B7601009
B7601009 (n=18) was a Phase 1b, double-blind, placebo-controlled, randomized, study to 
evaluate the safety, tolerability and pharmacokinetics of single ascending doses of 
PF-06649751 in Parkinson’s disease subjects. Single doses of PF-06649751 0.75 mg, 
1.5 mg, 3 mg, 6 mg, 9 mg were evaluated in the study.
Two (2) sequential cohorts were planned and were to be conducted over 3 treatment periods. 
Study drug or placebo was administered once during each of 3 treatment periods, with an at 
least 7 day study drug wash out phase between treatment periods.
Single doses of PF-06649751 up to 9 mg were safe and well tolerated by subjects with 
Parkinson’s disease. There were no deaths, SAEs, severe AEs, discontinuations due to AEs, 
dose reductions or temporary discontinuation due to AEs. The most common mild to 
moderate AEs were headache, nausea, and vomiting. Nausea and vomiting appeared to be 
more common in the higher dose groups (PF-06649751 3 mg, PF-06649751 6 mg and 
PF-06649751 9 mg treatment groups).
There were no notable findings in clinical laboratory. There appeared to be a small 
dose-related increase in heart rate without consistent changes in blood pressure (BP), except 
for the observations of orthostatic hypotension.
There was an increase of mean QTcF values in the higher dose groups (PF-06649751 6 mg 
and PF-066449751 9 mg) between 2 and 8 hours post dose, but no subject had a QTcF 
≥500 msec or an increase of QTcF ≥60 msec.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 35
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 oral 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 modestly 
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.
Increases in steady state PF-06649751 exposures following multiple oral doses appeared to 
be approximately dose-proportional across the B7601002 and B7601005 studies. Consistent 
with the observed half-life, approximately 2-fold accumulation in exposures was observed 
following once daily dosing. Approximately 0.2% of the dose was excreted un-changed in 
urine at steady state. Evaluation of PF-06649751 pharmacokinetics in healthy Japanese 
subjects at 1.5 mg QD dose suggest no meaningful difference between Japanese and Western 
subjects.
Steady state PF-06649751 exposures in Parkinson’s disease patients at different doses from 
(studyB7601005) are presented in Table 1. Average steady state PF-06649751 exposures in 
healthy subjects (B7601002) were approximately 65% of the values observed in Parkinson’s 
disease patients (B7601005).  However, with limited number of subjects in B7601002 (N=5) 
and differences in the tolerability profile across populations, these differences are considered 
preliminary. 
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 once daily (n=9)
118.5 (33)
2.0 (1.0-4.0)
2105 (35)
15 mg once daily (n=7)
325.4 (46)
4.0(2.0-12.0)
5993 (61)
25 mg once daily (n=7)
401.6 (41)
4.03 (1.97-8.0)
7182 (52)
Values for Cmax,ss and AUC24,ss are presented as geometric means (%CV).  Median values (range) are 
presented for Tmax
1.4.4. Additional Information
Detailed information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator’s Brochure of PF-06649751, and 
the prescribing information for L-Dopa (for example, Sinemet, Menesit, Madopar, Prolopa, 
or EC Doparl).
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 36
1.5. Rationale
1.5.1. Study Rationale
This study will evaluate the efficacy, safety, and tolerability of PF-06649751 as a potential 
novel therapeutic agent in subjects with Parkinson’s disease. 
PF-06649751 is a novel D1 and D5 specific dopamine partial agonist and has the potential to 
reduce OFF time in subjects with moderate to advanced Parkinson’s disease who are 
experiencing significant OFF time despite their current dopaminergic therapy.  Following an 
initial titration phase, which is intended to mitigate potential dopaminergic adverse events 
such as nausea and vomiting, fixed doses of PF-06649751 will be evaluated as adjunctive 
treatment with L-Dopa.  The overall doses of PF-06649751 selected for this study were 
influenced by the aim to identify not only a minimally-effective dose but also characterize 
the maximum efficacious dose.
The study was initially limited to a maximum 15 week treatment period due to the available 
toxicological coverage.  Subsequently, the nonclinical safety profile of PF-06649751 is 
considered to be adequately characterized to support progression into human clinical studies 
of 6 months or longer dosing duration for men and for women of non-childbearing potential.
Subjects who complete through Week 15 of the B7601003 study will have the option to 
enroll in an open label extension study (B7601017). If the pre-specified Inclusion/Exclusion 
criteria are met at Week 10 (screening), the subject may exit the current B7601003 study at 
Week 15 for continued treatment and follow-up under the extension study (B7601017), 
provided they remain eligible. Subjects not directly entering study B7601017 at Week 15 
must complete the Week 17 and Week 19 Follow-up visits and must rescreen under the 
B7601017 protocol.
Based on reports of other dopaminergic drugs, the peak effect on OFF time has been 
observed after approximately 8 weeks of treatment.
The study population will include male subjects and female subjects of non-childbearing 
potential diagnosed with Parkinson’s disease who experience motor fluctuations.
1.5.2. Dose Rationale
PF-06649751 doses for this study are selected based on evidence of pharmacological activity 
from preclinical data and clinical studies in Parkinson’s disease subjects. Based on 
experiments in MPTP monkeys, the human Ceff was established at 27.6 ng/mL. Based on the 
human Phase 1 pharmacokinetic data, a dose of 3 mg QD is expected to produce total plasma 
concentrations of PF-06649751 of at least 27.6 ng/mL, across the entire dosing interval, in
Parkinson’s disease subjects.  Based on observed MDS-UPDRS Part III data from B7601009 
and B7601005, a dose of 1 mg QD is likely to be a no- or minimal effect dose to evaluate the 
lower part of the dose-response curve. The top dose of 15 mg is chosen to establish safety 
and efficacy at a dose that is at the top part of the dose-response curve. The 7 mg QD dose 
will provide safety, tolerability and efficacy data at a dose lower than 15 mg dose to establish 
maximum efficacious dose with adequate safety in case of safety/tolerability issues at 15 mg 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 37
PF-06649751 dose group. The overall doses of PF-06649751 selected for this study were 
influenced by the aim to identify not only a minimally-effective dose but also characterize 
the maximum efficacious dose with adequate safety using the limited tablet strengths 
available (ie, 1 mg and 5 mg) as efficiently as possible without exceeding more than three 
tablets per dose. The selected dose range of 1 mg – 15 mg PF-06649751 QD is wide enough 
to facilitate appropriate dose selection for Phase 3 studies.
Even though MDS-UPDRS Part III scores from Phase 1b studies are used to drive dose 
selection, it should be noted that the primary endpoint for the current study is OFF time and 
not MDS-UPDRS Part III. Moreover, due to the uncontrolled, open-label study design, data 
from B7601005 may be subject to bias. These shortcomings in dose selection are addressed 
in the study design in order to achieve the primary aim of the study (establish dose response 
with OFF time).
•
Confirm OFF time reduction at 15 mg dose (only) at the first interim analysis before 
initiating the dose ranging part of the study (see DATA ANALYSIS/STATISTICAL 
METHODS).
•
Uncertainty in Phase 1b data is addressed by including doses (1 mg and 7 mg) 
bracketing the current preclinical estimate (~3 mg).
Based on the observed exposures from the 15 mg cohort in study B7601005, the top dose of 
15 mg QD dose is expected to provide exposure ~2-3 fold lower than the stopping criteria 
from 15 week monkey toxicological study.  Given the CYP3A4 mediated metabolism of 
PF-06649751, this provides a margin to allow for a possible increase in exposure of 
PF-06649751 when used together with weak inhibitors of CYP3A4.  Patients receiving 
moderate to strong CYP3A4 inhibitors will be excluded from the study until further 
elucidation of the exact interaction magnitude in a drug-drug interaction study. 
Therefore, based on the objectives to identify a minimum efficacious dose, maximum 
efficacious dose and evaluate dose-response, the following four PF-06649751 doses are 
proposed for the study along with a placebo: 1 mg QD, 3 mg QD, 7 mg QD and 15 mg QD 
PF-06649751.  
1.5.3. Summary of Benefit-Risk Assessment
The study is designed to assess the efficacy, safety, tolerability, and pharmacokinetics of 
PF-06649751 in subjects with Parkinson’s disease. Based on the clinical safety data 
available to-date, PF-06649751 doses 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. Any potential risks will be further minimized 
by safety monitoring during the study and follow up for the subjects’ well-being.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 38
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Primary Objective
x
To evaluate the effect on motor symptoms of PF-06649751 administered once daily 
as adjunctive treatment with stable doses of L-Dopa in Parkinson’s disease.
x
To determine the therapeutic window for motor symptom improvement of 
PF-06649751 administered once daily, ie, determining a dose, or a range of doses, for 
adequate control of motor symptoms.
2.2. Secondary Objectives
x
To evaluate the dose-response on motor symptoms of PF-06649751 administered 
once daily in subjects with Parkinson’s disease.
x
To evaluate the safety and tolerability of PF-06649751 administered once daily in 
subjects with Parkinson’s disease.
x
To evaluate the effect of PF-06649751 administered once daily on dyskinesia in 
subjects with Parkinson’s disease.
2.4. Endpoints
2.4.1. Primary Endpoint (Efficacy)
x
Change from baseline in daily OFF time (hours OFF time; based on patient reported 
Hauser diary) at Week 10 (Day 70; end of Period A).
2.4.2. Secondary Endpoints (Efficacy; Evaluated during the entire double-blind period)
Change from baseline in:
x
Daily OFF time (hours).
x
Daily ON time with troublesome dyskinesia (hours).
x
Daily ON time without troublesome dyskinesia (hours).
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 39
x
MDS - Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III.
x
MDS-UPDRS Parts I, II, IV, and total score.
2.4.2.1. Secondary Endpoints (Safety and Tolerability)
x
Adverse events.
x
Clinical laboratory parameters.
x
Vital signs.
x
ECG parameters.
x
Columbia Suicide Severity Rating Scale (C-SSRS).
x
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating 
Scale (QUIP-RS).
x
Physician Withdrawal Checklist (PWC-20).
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 40
3. STUDY DESIGN
3.1. Study Overview
The study has a randomized, double-blind, placebo-controlled parallel group design.  
Approximately 198 subjects from approximately 60 centers in approximately 6 countries will 
be randomized to 5 treatment groups (15 mg QD, 7 mg QD, 3 mg QD, 1 mg QD, or placebo), 
initially in a 2:0:0:0:1 ratio of approximately 54 subjects (Cohort 1) followed by a 
1:2:2:2:1 ratio of approximately 144 subjects (Cohort 2), using a central randomization 
system with randomization blocks stratified by region.
Each subject will participate in the study for approximately 25 weeks including up to a 
45 day screening period, 15 week double-blind treatment period (comprising up to a 3 week 
titration, 2 week dose adjustment, 5 weeks of primary efficacy with adjunctive treatment to 
stable L-Dopa (Period A), and 5 weeks of maintenance with adjunctive treatment to stable 
L-Dopa (Period B)), and an approximately 28 day follow-up period.
The study design is illustrated in the figure below.  For details on the dosing during the
titration phase, see Section 5.5.1, Titration of PF-06649751.
Figure 1.
Study Schematic
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 41
3.1.1. Screening
Screening evaluation will occur within 45 days prior to Day 0 (Randomization).  Rescreening 
may be permitted after discussion with the study medical monitor. Screening procedures 
may split between multiple days/visits for feasibility and/or subject comfort; however 
individual procedures should not be split between multiple days/visits.
Subjects will document their symptoms (ON, OFF, ON with/without dyskinesia, ON with 
non-troublesome dyskinesia, ON with troublesome dyskinesia) in a patient diary (see
Section 7.3.1 OFF Time Diary (Hauser Diary)).  
•
For Screening ON/OFF time concordance testing (see Section 7.1.7, Concordance 
Testing and OFF Time Diary Training), the subject must have at least 
75% concordance with investigator (or qualified site staff/rater).
•
For the final Inclusion/Exclusion criteria verification on Day 0 (Randomization) by 
the investigator, subjects must have ≥2.5 hours OFF time each day, collected over 
3 consecutive days during the week prior to Day 0 (Randomization), with fewer than 
4 errors or missing entries in diary data per day.
3.1.2. Double Blind Period 
Eligible subjects will enter the 15 week double blind treatment phase, consisting of:
•
Up to 3 week titration of PF-06649751 or placebo administered once daily to the 
randomized target dose (Section 5.5.1).
•
2 week stabilization period for dose adjustment after reaching the target dose with 
possible return to previous dose level after completion of the titration period.  For 
subjects with intolerable adverse events, adjunct L-Dopa dose may subsequently be 
reduced after consultation with the Medical Monitor (see Section 5.5.1 Titration of 
PF-06649751). 
•
Period A (Primary Efficacy): a 5 week period of PF-06649751 or placebo 
administered once daily adjunctive to stable doses of L-Dopa (Section 5.5.2).
•
Period B (Maintenance): a 5 week maintenance period of PF-06649751 or placebo 
administered once daily adjunctive to stable doses of L-Dopa (Section 5.5.3).
Subjects will return to the clinic at the end of Weeks 1, 2, 3, 4, 5, 10, 15, and 17. Weeks 2 
and 3 may be conducted as phone visits, at the discretion of the investigator.
All other visits will be conducted as phone visits; as per Section 6.5 (Unplanned Visits), the 
investigator has the discretion to conduct an unplanned clinic visit if warranted for subject 
safety. For guidance on concomitant medications for Parkinson’s disease and other disorders 
please see Section 5.8, Concomitant Treatment(s).
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 42
3.1.3. Follow-up Period
A follow up visit two weeks after discontinuation of PF-06649751 or placebo will take place 
at Week 17 for subject safety. A follow up phone visit will occur approximately 28 days 
after discontinuation of PF-06649751 or placebo at Week 19 for subject safety assessment.
For all subjects who have received at least 1 dose of investigational product (except a subject 
who withdraws consent), follow-up contact will be completed at least 28 calendar days, and 
up to 35 calendar days after the last administration of the investigational product.
3.1.4. Open Label Extension Study
Subjects who complete through Week 15 of the B7601003 study will have the option to 
enroll in an open label extension study (B7601017). If all specified Inclusion/Exclusion 
criteria are met at Week 10/Screening Visit (B7601017), the subject may exit the current 
B7601003 study at Week 15/Baseline Visit (B7601017) for continued treatment and 
follow-up under the open label extension study (B7601017), provided they remain eligible.
Subjects not directly entering study B7601017 at Week 15 must complete the Week 17 and 
Week 19 Follow-up visits as required per protocol.
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.  Unless 
otherwise specified, the following Inclusion and Exclusion Criteria are referring to the 
Screening Visit.
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, including dosing and Parkinson’s disease 
diaries.
3. Females of non-childbearing potential and/or male subjects between the ages of 
40 and 85 years, inclusive. Male subjects able to father children must agree to use 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 43
one (1) highly effective method of contraception throughout the study and for at least 
28 days after the last dose of assigned treatment.
Female subjects who are not of childbearing potential (ie, who meet at least 1 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 female subjects (including females with tubal ligations) will be considered 
to be of childbearing potential and are not eligible for participation.
Diagnosis:
4. Clinical diagnosis of Parkinson’s disease consistent with the United Kingdom (UK)
Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria.12 (See 
Appendix 6 for detailed criteria).
5. Parkinson’s disease Hoehn & Yahr Stage less than or equal to III while the subject is 
ON.
6. Currently responding to L-Dopa therapy. 
7. Total duration of ≥2.5 hours OFF time each day, based on the OFF time diary 
(Hauser diary) collected over 3 consecutive days during the screening period (with 
fewer than 4 errors or missing entries in diary data per day) and at least 
75% concordance with investigator (or qualified site staff/rater) for Screening 
ON/OFF time concordance testing (see Concordance Testing and OFF Time Diary 
Training).
8. Subjects must be able to recognize their “wearing off” symptoms and confirm that 
they usually improve after their next dose of Parkinson’s disease medication. 
9. On a stable dose of L-Dopa of at least 400 mg total daily dose for at least 21 days 
prior to Day 0 (Randomization), in conjunction with a dopa-decarboxylase inhibitor 
(eg, L-Dopa/carbidopa or L-Dopa/benserazide) divided in at least 4 doses per day.
Subjects on a stable dose of L-Dopa of at least 400 mg/day divided into 3 daily doses 
(TID) may be considered and authorized on a case-by-case basis if submitted as part 
of the screening assessment to the sponsor and/or its designee for determination if the 
dosing regimen is considered optimized for that particular subject.  No subject on TID 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 44
dosing will be considered eligible for Randomization without this additional 
eligibility assessment.  Please refer to Section 7.1.8 for details.
10. Willing and able to refrain from any Parkinson’s disease medication not permitted by 
the protocol throughout participation in the study. 
Screening assessments:
11. Body Mass Index (BMI) of 17.5 to 35 kg/m2; and a total body weight ≥45 kg. 
12. A score of ≥26 on the Mini Mental State Examination (MMSE). 
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
Diagnosis:
1. History or clinical features consistent with an atypical Parkinsonian syndrome.
2. History of intracranial surgical intervention for Parkinson’s disease or other 
indications (pallidotomy, thalamotomy, deep brain stimulation, etc).
3. A score of 4 on item 4.2 Functional Impact of Dyskinesias of MDS-UPDRS 
Part IV (motor complications) at Screening.
4. Psychotic symptoms related to Parkinson’s disease requiring treatment with an 
antipsychotic medication within 6 months prior to Screening.
5. 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:
6. Severe acute or chronic medical, including fever, psychiatric condition, 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.
7. 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),27 or conditions that lower seizure threshold, seizures of any etiology 
(including substance or drug withdrawal), or known increased risk of seizures. 
8. A significant Axis I psychiatric disease as defined by the Diagnostic and Statistical 
Manual of Mental Disorders, 4th edition-Revised (DSM IV-TR, American Psychiatric 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 45
Association, 2000) that in the opinion of the investigator could interfere with study 
participation or poses a risk to the subject.  Presence of minor depression or treated, 
stable depressive disorder is acceptable.
9. History of clinically significant alcohol or substance dependency (other than caffeine 
or nicotine), as defined in the Diagnostic and Statistical Manual of Mental Disorders, 
Fourth Edition (DSM-IV), within 1 year before Screening.
10. 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.
11. Any condition possibly affecting drug absorption, past surgery of the gastrointestinal
tract (eg, gastrectomy, colectomy), except cholecystectomy.
12. History of vasculitis.
13. History of Human Immunodeficiency Virus (HIV) infection.
14. History of malignancy other than:
•
Non-metastatic basal or squamous cell carcinoma of the skin or carcinoma in situ 
that was surgically removed in total >1 year before screening and has not 
recurred.
•
Other type of malignancy which has been in remission 5 years or more before 
screening and has not recurred.
15. Subjects with first degree family history of unexplained sudden death, or of Long QT 
syndrome (LQTS). 
Concomitant Medications:
16. Currently receiving an antipsychotic, metoclopramide, reserpine, or amphetamine.
17. Currently receiving moderate or strong CYP3A4 inducers or CYP3A4 inhibitors 
(except for topical administration). 
18. Previous implantation of apomorphine pump, or surgery for intraduodenal use of 
Duodopa®.
19. Dopamine receptor agonist medications including pramipexole, ropinirole, rotigotine 
and apomorphine must be discontinued at least 28 days prior to Day 0 
(Randomization).
20. Herbal supplements must be discontinued at least 28 days prior to Day 0 
(Randomization).
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 46
21. Prohibited concomitant medications as outlined in Section 5.8, Concomitant 
Treatment(s), and Appendix 3. 
Screening assessments:
22. Females of childbearing potential (assessed at Screening); Pregnant female subjects; 
breastfeeding female subjects; male subjects with partners currently pregnant; male 
subjects able to father children who are unwilling or unable to use one (1) 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.
23. Suicidal ideation associated with actual intent and/or plan in the past year; (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 
10 years (a “YES” answer to any of the suicidal behavior items of the C-SSRS with 
the behavior occurring in the past 10 years).
24. Subjects with Clinically significant depression: PHQ-8 total score ≥15.
25. 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.
26. 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 
>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).
27. 12-lead ECG (average of triplicate measures) demonstrating QTcF >450 msec 
(>470 msec for females) or a QRS interval >120 msec at Screening. 
28. 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 aminotransferase (AST)/serum glutamic oxaloacetic transminase 
(SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transminase 
(SGPT) ≥2x 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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 47
29. A positive test for hepatitis B surface antigen or hepatitis C antibody.
30. A positive urine drug screen for drugs of abuse unless explained by medically 
indicated medication.
General and Administrative:
31. 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.
32. Participation in other studies involving investigational drug(s), or treatment with any 
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).
33. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 56 days prior to Day 0 (Randomization). 
34. Unwilling or unable to comply with the lifestyle requirements described in 
Section 4.4 of this protocol.
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 
5 treatment groups (15 mg QD, 7 mg QD, 3 mg QD, 1 mg QD, or placebo), initially in a 
2:0:0:0:1 ratio (Cohort 1) followed by a 1:2:2:2:1 ratio (Cohort 2).  Randomization blocks 
will be stratified by region. 
If following an interim analysis a decision is made to stop enrollment in one or more dose 
groups, the randomization schedule will be adjusted to reflect the number of treatment 
groups.
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 
Investigational Product until the end of double blind study medication.
4.4.2. Alcohol, Caffeine, and Tobacco
•
Subjects should abstain from alcohol for at least 12 hours prior to every study visit. 
•
Subjects may undergo an alcohol breath test at the discretion of the investigator.
•
Coffee and caffeine-containing products are permitted throughout the study.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 48
•
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. 
•
Stable rehabilitation therapy is permitted if regimen remains stable during the course 
of the study.
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 and at risk for 
causing a pregnancy 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/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 or 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 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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 49
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. For a female partner, 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.
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 contact list located in the team 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 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 50
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
For specific rating assessments, only qualified raters will be allowed to evaluate and/or rate 
subjects in this study.  The list of relevant study rating assessments and the minimum 
qualifications a rater must meet for each assessment will be outlined in the “Rater 
Qualification Guide” provided to each participating site.  The level of experience with the 
target population (or equivalent), and specific scale experience (or equivalent), certification 
required (if applicable) will be listed 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 Guide before he/she can participate in the administration of the 
assessments in the study.  For specifically defined assessments, rater training and 
standardization exercises may be conducted, and written & signed documentation will be 
provided by the site for each rater’s certification.  In return each site will be provided written 
documentation outlining each rater’s certification for specific study assessments.  
Recertification may be required at periodic intervals during the study.  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. 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. 
Raters performing certain assessments will require certification by a vendor designated by 
the Sponsor prior to rating in this study.  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. 
5. STUDY TREATMENTS
Investigational Product 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).
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 51
5.1. Allocation to Treatment
All subjects will be on L-Dopa treatment (for example, Sinemet, Menesit, Madopar, Prolopa, 
or EC Doparl).
For PF-06649751 or placebo, allocation of subjects to treatment groups will proceed through 
the use of an interactive web response (IWR) technology 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 IWR system.  The IWR 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 IWR helpdesk available for any questions or 
issues.  The study specific IWR reference manual (ie, B7601003 Impala Quick Reference 
Guide) will provide the contact information and further details on the use of the IWR system. 
Note: The IWR is the source of the subject number.  The IWR system will provide the 
subject number at the end of the first IWR subject transaction. 
5.2. Breaking the Blind
L-Dopa treatment is open-label and not blinded. 
For PF-06649751 or placebo, treatment assignment will be sponsor, subject, and investigator 
blinded.  At the initiation of the study, the study site will be instructed on the method for 
breaking the blind.  The method will be either through the IRT system or a call center.  
Blinding codes should be broken only in emergency situations for reasons of subject safety.  
Whenever possible, the investigator or subinvestigator consults 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.
5.3. Subject Compliance
L-Dopa will be administered daily by the subject or caregiver at dose and frequency 
prescribed or as instructed by the investigator.  A subject will be considered compliant with 
the protocol at a study treatment compliance range of 80%-120%.
PF-06649751 or placebo will be administered by the subject or caregiver in the outpatient 
setting (each morning, daily for the duration of the treatment period).  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 medication, that 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 52
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 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.  The 1 mg, 5 mg, and their matching placebos will be supplied in weekly 
blister cards.  At each dispensing visit, subjects will receive sufficient quantity of
investigational product (IP) 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 1 mg, 5 mg, and its matched placebo should 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 provided, in quantities appropriate for the 
study visit schedule.  The subject/caregiver should be instructed to maintain the product in 
the blister cards provided throughout the course of dosing and return the blister cards to the 
site at the next study visit.
5.5. Administration
For L-dopa, subjects should be instructed to take the L-dopa in accordance with instructions 
provided in the product labelling information, at a dose and frequency per the instructions of 
the investigator and in consideration of the administration instructions provided in the 
instructions in Section 5.5.1 (Titration of PF-06649751); Section 5.5.2 (Period A: Primary 
Efficacy) and Section 5.5.3 (Period B: Maintenance).
For PF-06649751 or placebo, subjects (and caregivers, as applicable) should be instructed as 
follows:
•
Take 3 tablets at approximately the same time each morning. 
•
Swallow each tablet whole, with water.
•
Do not manipulate or chew the tablet prior to swallowing.
•
All 3 tablets should be taken within approximately 5 minutes.
•
The tablets may be taken with or without food.
•
If L-Dopa is taken in the morning, the PF-06649751 or placebo tablets may be taken 
before or after the morning dose of L-Dopa.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 53
•
Subjects will document the timing of PF-06649751 or placebo dose on study visit 
days.
5.5.1. Titration of PF-06649751
Each subject is planned to be up-titrated in a double-blind fashion to the assigned target dose 
level of PF-06649751 or placebo according to the following titration scheme:
Table 2.
Proposed Titration Schemes for PF-06649751 and Placebo Doses
Treatment Group
Week/ Start 
Day of Dose 
Level
Placebo
1 mg
3 mg
7 mg
15 mg
Week 1 /
from Day 1
P
1 mg
1 mg
1 mg
1 mg
Week 2/ 
from Day 8
P
1 mg
3 mg
3 mg
3 mg
Week 3 / 
from Day 15
P
1 mg
3 mg
7 mg
7 mg
Weeks 4-15 / 
from Day 22
P
1 mg
3 mg
7 mg
15 mg
Titration (Week 1 to Week 3): No modifications to the upward titration of Study 
Medication can be made.  Subjects who experience intolerable adverse events during titration 
will need to be discontinued from the study. 
Post Week 3 (Week 4 to Week 5): For subjects who experience unacceptable new adverse 
events after having achieved the target dose (after Day 21) and deemed related to the dose 
increase, the dose of investigational product can be changed to the previous dose level 
(Week 3 dose level).  This results in a dose reduction from 15 mg/day to 7 mg/day for the 
highest dose group, and no change in dose for the other dose groups in a blinded fashion.  
Only one dose modification of investigational product is permitted. 
L-Dopa Adjustment for Unacceptable Dopaminergic Side Effects (Week 1 to Week 15): 
In the case of unacceptable dopaminergic side effects and following discussion with the 
Medical Monitor, the dose of L-Dopa may be reduced between Day 1 and Day 105 visit. 
5.5.2. Period A: Primary Efficacy
During Period A, subjects will be administered double blind study medication once daily (up 
to 4 different dose levels of investigational product) as adjunctive treatment to a stable dose 
of open-label L-Dopa. 
5.5.3. Period B: Maintenance
After the Week 10 Visit (primary endpoint collection), subjects will enter Period B.  During 
Period B, double-blind treatment with investigational product will continue as adjunctive 
treatment to a stable dose of open label L-Dopa.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 54
5.6. Investigational Product Storage 
The investigator, or an approved representative, 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 taking home 
investigational products, including how to report temperature excursions.  See the single 
reference safety document (SRSD) for this study, the Investigator’s Brochure for
PF-06649751.
Storage conditions stated in the Investigator’s Brochure 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.
Specific details regarding information the site should report for each excursion will be 
provided to the site.
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 55
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 3 and 
Appendix 4 except for:
•
The treatment of adverse events.
•
Rescue Medication, as described in Section 5.9.  
•
All concomitant medications 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 medication at each clinic and telephone 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:
•
Subjects must be on a stable dose of L-Dopa of at least 400 mg total daily dose for at 
least 21 days prior to Randomization, in conjunction with a dopa-decarboxylase 
inhibitor (eg, L-Dopa/carbidopa or L-Dopa/benserazide) divided into at least 4 doses 
per day. Subjects on a stable dose of L-Dopa of at least 400 mg/day divided into 
3 daily doses (TID) may be considered and authorized on a case-by-case basis if 
submitted as part of the screening assessment to the sponsor and/or its designee for 
determination if the dosing regimen is considered optimized for that particular 
subject. 
•
MAO-B inhibitors or COMT inhibitors, amantadine, and anticholinergics are 
permitted but should remain at stable dose from 42 days prior to Day 0 
(Randomization) through the end of the double blind treatment period.
Prohibited Parkinson’s disease medications:
•
Dopamine receptor agonist medications including pramipexole, ropinirole, rotigotine 
and apomorphine are prohibited for at least 28 days prior to Randomization and
through the end of the double blind treatment period.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 56
•
Istradefylline and zonisamide are prohibited 42 days prior to Randomization and 
through the end of the double blind treatment period.
•
The use of inhaled L-Dopa is prohibited from Screening through the end of the 
double blind treatment period.
•
Subjects with prior implantation of apomorphine pump, or surgery for intraduodenal 
use of Duodopa® are not eligible.
5.8.2. Prohibited Other Concomitant Medications
The following medications will not be permitted within 28 days prior to Randomization:
•
CYP3A4 inducers: the use of moderate and strong inducers of CYP3A4 is not 
permitted, since they may decrease the levels of PF-06649751.  A list of potential 
drug inducers is provided in Appendix 4. 
•
CYP3A4 inhibitors: the use of moderate or strong inhibitors of CYP3A4 is not 
permitted throughout the study since concomitant use these may lead to increased 
levels of PF-06649751.  A list of potential CYP3A4 inhibitors is provided in
Appendix 4.
•
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 Randomization:
•
The use of amphetamines, methylphenidate or other stimulants.
•
Antipsychotics (except stable low dose quetiapine), metoclopramide, or reserpine are 
not permitted.
•
Lithium, MAO-A/B inhibitor antidepressants (including moclobemide, 
tranylcypromine, and phenelzine); stable low dose opioids for chronic painful 
medical conditions may be permitted based on a consultation with the medical 
monitor.
•
Antiepileptics are not permitted except if used for chronic painful conditions at steady 
doses (for example, gabapentin or pregabalin).
5.8.3. Permitted Concomitant Medications
Subjects will use background L-Dopa (for example, Sinemet, Menesit, Madopar, Prolopa, or 
EC Doparl) provided in the local commercial packaging throughout the study. Subjects 
should remain on the same formulation of L-Dopa from Screening through the duration of 
the study. The daily L-dopa dose should not change from 21 days prior to Day 0 
(Randomization) through the end of the study. In the case of unacceptable dopaminergic side 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 57
effects, and only following discussion with the Medical Monitor, the dose of L-Dopa may be 
reduced between the Day 1 and Day 105 visit. 
Stable doses of concomitant medications for treatment of medical conditions are permitted 
during the course of the study, including antihypertensives, antidepressants (other than MAO 
inhibitors), anticoagulants, lipid lowering agents, oral antidiabetics, thyroid replacement 
hormones, and antacids.
The potential risk for drug-drug-interactions with PF-06649751 and primary substrates of 
CYP3A4 (especially those with a narrow therapeutic index; eg, vinca alkaloids), and BCRP 
is considered to be 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 substrates (eg, alfentanil, 
ergotamine, irinotecan, ticagrelor, simvastatin, etc.). Further information on potential 
drug-drug-interactions and data available to date can be found in Section 5.2.7 
Pharmacokinetic-Drug Interactions of the Investigator’s Brochure.
5.9. Rescue Medication
Rescue medication is permitted in the form of L-Dopa.  The dose and dose frequency can be 
defined using investigator discretion based on patients’ needs.  Rescue L-Dopa may be 
administered if needed in between study visits based on a phone consultation and the 
discretion of the investigator. 
6. STUDY PROCEDURES 
6.1. Screening: Day -45 to Day -1
Subjects will be screened within 45 days prior to Day 0 (Randomization) 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, Subject Information and Consent.  The informed 
consent may be obtained up to 60 days prior to Day 0 (Randomization).
The Screening procedures may be split between multiple days/visits for feasibility and/or
subject comfort, however individual procedures should not be split between multiple 
days/visits.
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 58
•
Collect Demographics.
•
Obtain prior medical history, medication history including current medications, and 
demography.
•
Contraception Check.
•
Assessment of prior/concomitant medications.
•
Collect height, weight, and BMI.
•
Perform full physical and neurological examination.
•
Perform Mini Mental State Examination (MMSE).
•
Confirm clinical diagnosis of Parkinson’s disease using the UK Parkinson’s Disease 
Society Brain Bank Clinical Diagnostic Criteria (Appendix 6).
•
Perform Hoehn & Yahr Stage assessment while subject is ON.
•
Collect blood and urine specimens for the following:
•
Safety laboratory tests (including specific tests for monitoring of vascular 
inflammation);
•
Serological testing (HIV testing, Hepatitis B antigen, and Hepatitis C antibody);
•
Urine drug screening test for drugs of abuse (including tetrahydrocannabinol
(THC) performed at the central lab;
•
FSH test for females who are amenorrheic for at least 12 consecutive months.
This 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 #3). 
•
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
•
Perform standard triplicate supine and standing vitals (heart rate (HR) and blood 
pressure) and assess subject temperature to confirm no symptoms of fever.
•
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) 
“Lifetime/Past 12 months” Evaluation.
•
Perform the Patient Health Questionnaire-8 (PHQ-8).
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 59
x
Perform Movement Disorder Society-sponsored revision of the Unified Parkinson’s 
Disease Rating Scale (MDS-UPDRS) Parts I, II, III, and IV (all parts to be completed 
on the same screening day).
x
Train subject on OFF time recognition and OFF time diary (Hauser diary) with use of 
training video, and test concordance. Concordance testing includes at least one 
MDS-UPDRS Part III in the OFF state and one MDS-UPDRS Part III in the ON state
(Part III score from full screening MDS-UPDRS may be used to fulfill one of these 
two exams, if the concordance assessment is continued/completed immediately after 
exam) which must be performed by the investigator (or qualified site staff/rater).  At 
least 75% concordance with investigator (or qualified site staff/rater) for Screening 
ON/OFF time is required for eligibility (see Section 7.1.7).
x
Dispense OFF time diary, review instructions including requirement to complete 
diary for 3 consecutive days in the week prior to Day 0 (Randomization).
x
Instruct subjects on adjunct stable L-Dopa (open-label) administration.
x
Review and assess adverse events (AEs).
x
Review Inclusion and Exclusion criteria.
To prepare for study participation, subjects will be instructed on the use Section 4.4 and 
Section 5.8, Lifestyle Guidelines and Concomitant Treatment(s).
6.2. Study Period
For the study period described below, there is a +3 day visit window for scheduling of visits 
during Weeks 1, 2, and 3.
For Weeks 4-19, the visit window for scheduling visits will be r3 days. 
Study visit times are relative to Day 0 (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, and efforts should be made to return the 
subject to the correct timelines.
For each visit, the following chronology of events should be adhered to, where possible:
x
Patient Reported Outcome scales (ie,
, 
QUIP-RS, 
): obtain prior to UPDRS.
x
UPDRS Assessment: obtain prior to ECGs.
x
ECGs: obtain prior to blood pressure and heart rate.
x
Blood pressure/pulse rate: obtain prior to safety laboratory tests.
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 60
x
Safety laboratory tests: obtain prior to pharmacokinetic (PK) blood.
x
Pharmacokinetic blood specimens.
x
Other procedures may be obtained before or after those listed above.
6.2.1. Randomization: Day 0
x
Assessment of prior/concomitant medications.
x
Review changes in medical history since screening visit.
x
Review Inclusion and Exclusion criteria.
x
Perform brief physical and neurological examination.
x
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 dosed
with PF-06649751 or placebo.
x
Urine drug screening in the form of a dipstick performed at the site.
x
x
Collect Prolactin laboratory sample.
x
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
x
Perform standard single supine and standing vitals (HR and blood pressure) and 
assess subject temperature to confirm no symptoms of fever.
x
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.
x
Collect and review OFF time diary while subject is present; confirm subject eligibility
for OFF time has been met.
x
Perform MDS-UPDRS I, II, III, and IV.
x
.
x
.
x
.
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 61
x
.
x
.
x
Perform Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease –
Rating Scale (QUIP-RS).
x
Perform Oral Symbol Digit Modality Test (SDMT).
x
Perform Modified Clinical Global Impression - Severity (MCGI-S).
x
.
x
Review and assess adverse events (AEs).
x
Register subject as Randomized in IWR system in order to obtain randomization 
number.
x
Dispense Investigational Product.  Subjects will begin PF-06649751 or placebo 
dosing the following morning (Day 1).
x
Instruct subjects on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751) and instruct subjects on proper dosing documentation.
x
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
6.2.2. Dosing: Day 1 through Day 105
x
Continued once daily dosing of PF-06649751 or placebo in accordance with 
randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration of 
PF-06649751).
x
Continued adjunct stable open-label L-Dopa administration (through Period B).
6.2.3. Titration Period: Day 7
x
Dosing compliance verification (Investigational product accountability and 
documentation) while subject is present to confirm reasons for missed/additional 
doses.  Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
x
Review and assess adverse events (AEs).
x
Assessment of concomitant medications.
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 62
•
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.
•
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
•
Perform standard single supine and standing vitals (HR and blood pressure).
•
Perform MDS-UPDRS Part III.
•
Dispense OFF time diary, review instructions including requirement to wait until the 
next phone visit before completion of the diary.
•
Dispense Investigational Product.  Next immediate dose level of PF-06649751 or 
placebo will be taken the next morning.
•
Instruct subjects on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751).
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
6.2.4. Titration Period: Day 14
In the case of a phone visit:
•
Dosing compliance verification via phone to confirm reasons for missed/additional 
doses. Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
•
Review and assess adverse events (AEs).
•
Assessment of concomitant medications.
•
Instruct subjects on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751). 
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
•
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, and remind subjects to bring used blister cards to the next 
clinic visit.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 63
•
Review OFF time diary instructions including requirement to complete diary for 3 
consecutive days during the following week.
•
Dispense Investigational Product.  Next immediate dose level of PF-06649751 or 
placebo will be taken the next morning following secure courier delivery.
In the case of a clinic visit:
•
Dosing compliance verification (Investigational product accountability and 
documentation) while subject is present to confirm reasons for missed/additional 
doses. Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
•
Review and assess adverse events (AEs).
•
Assessment of concomitant medications.
•
Collect blood and urine for safety lab tests.
•
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
•
Perform standard single supine and standing vitals (HR and blood pressure).
•
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.
•
Dispense Investigational Product.  Next immediate dose level of PF-06649751 or 
placebo will be taken on the next morning.
•
Instruct subjects on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751).
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
•
Review OFF time diary instructions including requirement to complete diary for 
3 consecutive days during the following week.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 64
6.2.5. Titration Period: Day 21
In the case of a phone visit:
•
Dosing compliance verification via phone to confirm reasons for missed/additional 
doses. Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
•
Review and assess adverse events (AEs).
•
Assessment of concomitant medications.
•
Instruct subjects on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751). 
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
•
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, and remind subjects to bring all used blister cards to the next 
clinic visit.
•
Confirm the completion of the OFF time diary for 3 consecutive days during the past 
week and remind the subject to bring the completed diary to the next clinic visit.
•
Dispense Investigational Product.  Next immediate dose level of PF-06649751 or 
placebo will be taken the next morning following secure courier delivery.
In the case of a clinic visit:
•
Dosing compliance verification (Investigational product accountability and 
documentation) while subject is present to confirm reasons for missed/additional 
doses.  Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
•
Collect and review OFF time diary while subject is present.
•
Review and assess adverse events (AEs).
•
Assessment of concomitant medications.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 65
•
Collect blood and urine for safety lab tests.
•
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
•
Perform standard single supine and standing vitals (HR and blood pressure).
•
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.
•
Dispense Investigational Product.  Next immediate dose level will be taken the next 
morning. 
•
Instruct subjects on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751).
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
6.2.6. Dose Adjustment: Day 28
•
Dosing compliance verification (Investigational product accountability and 
documentation) while subject is present to confirm reasons for missed/additional 
doses.  Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
•
Collect and review OFF time diary while subject is present (if first clinic visit since 
Day 7).
•
Review and assess adverse events (AEs).
•
Assessment of concomitant medications.
•
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
•
Perform standard single supine and standing vitals (HR and blood pressure).
•
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.
•
Perform MDS-UPDRS Part III.
•
Dispense Investigational Product.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 66
x
Instruct subjects on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751).
x
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
x
Dispense OFF time diary, review instructions including requirement to complete 
diary for 3 consecutive days during the following week.
6.2.7. Dose Adjustment: Day 35
x
Dosing compliance verification (Investigational product accountability and 
documentation) while subject is present to confirm reasons for missed/additional 
doses.  Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
x
Collect and review OFF time diary while subject is present.
x
Review and assess adverse events (AEs).
x
Assessment of concomitant medications.
x
Perform brief physical and neurological examination.
x
Collect blood and urine for safety lab tests.
x
Collect Prolactin laboratory sample.
x
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
x
Perform standard single supine and standing vitals (HR and blood pressure).
x
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.
x
x
Perform MDS-UPDRS Parts I, II, III, and IV.
x
.
x
.
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 67
x
x
x
x
Perform Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease –
Rating Scale (QUIP-RS).
x
x
x
x
x
).
x
Dispense Investigational Product.
x
Instruct subjects on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751).
x
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
x
Dispense OFF time diary, re-watch instructional training video and review
instructions including requirement to complete diary for 3 consecutive days during 
Week 10.
6.2.8. Period A: Day 42 (Phone Visit)
x
Dosing compliance verification via phone to confirm reasons for missed/additional 
doses.  Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
x
Review and assess adverse events (AEs).
x
Assessment of concomitant medications.
x
Instruct subjects on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751).
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 68
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
6.2.9. Period A: Day 56 (Phone Visit)
•
Dosing compliance verification via phone to confirm reasons for missed/additional 
doses.  Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
•
Review and assess adverse events (AEs).
•
Assessment of concomitant medications.
•
Instruct subjects on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751). 
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
•
Review OFF time diary instructions including requirement to complete OFF time 
diary for 3 consecutive days during Week 10.
6.2.10. Period A: Day 70 (Procedures may be used as screening for eligible and 
consenting subjects for the open label extension study)
•
Dosing compliance verification (Investigational product accountability and 
documentation) while subject is present to confirm reasons for missed/additional 
doses.  Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
•
Collect and review OFF time diary while subject is present.
•
Review and assess adverse events (AEs).
•
Assessment of concomitant medications.
•
Perform full physical and neurological examination.
•
Collect weight. 
•
Collect blood and urine for safety lab tests.
•
Collect Prolactin laboratory sample.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 69
x
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
x
Perform standard single supine and standing vitals (HR and blood pressure).
x
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.
x
PK blood sample collection for PF-06649751 concentration.  The time of sample 
collection and the date and time of the most recent dose of study medication prior to 
PK sampling should be recorded in the source documentation.
x
Perform MDS-UPDRS Parts I, II, III, and IV.
x
.
x
x
x
x
x
Perform Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease –
Rating Scale (QUIP-RS).
x
x
x
x
x
x
Dispense Investigational Product.
x
Dispense OFF time diary and review instructions including requirement to complete 
diary for 3 consecutive days during Week 15.
x
Instruct subject on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751).
x
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 70
•
Instruct subject to begin simultaneous adjunct down-titration of stable L-Dopa dose 
(refer to Section 5.5.3, Period B: ).
6.2.11. Period B: Day 91 (Phone Visit)
•
Dosing compliance verification via phone to confirm reasons for missed/additional 
doses. Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
•
Review and assess adverse events (AEs).
•
Assessment of concomitant medications.
•
Instruct subject on continued daily dosing of PF-06649751 or placebo in accordance 
with randomized dose arm up-titration scheme (see Table 2, Section 5.5.1, Titration 
of PF-06649751).
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
•
Review OFF time diary instructions including requirement to complete diary for 
3 consecutive days during Week 15.
6.2.12. Period B: Day 105 (Procedures may be used as Visit 1 for eligible and consenting 
subjects for the open label extension study)
•
Dosing compliance verification (Investigational product accountability and 
documentation) while subject is present to confirm reasons for missed/additional 
doses.  Based on blister card review and/or tablet count, any subject who is noted 
not to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
•
Collect and review OFF time diary while subject is present.
•
Review and assess adverse events (AEs).
•
Assessment of concomitant medications.
•
Perform full physical and neurological examination.
•
Collect blood and urine for safety lab tests.
•
Collect Prolactin laboratory sample.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 71
x
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
x
Perform standard single supine and standing vitals (HR and blood pressure).
x
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.
x
PK blood sample collection for PF-06649751 concentration.  The time of sample 
collection and the date and time of the most recent dose of study medication prior to 
PK sampling should be recorded in the source documentation.
x
Perform MDS-UPDRS Parts I, II, III, and IV.
x
x
x
x
x
x
Perform Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease –
Rating Scale (QUIP-RS).
x
 
x
x
x
x
x
Perform Physician Withdrawal Checklist (PWC-20).
6.3. Follow-up Visit: Day 119
x
Review and assess adverse events (AEs).
x
Assessment of concomitant medications.
x
Perform brief physical and neurological examination.
x
Collect weight.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 72
x
Collect blood and urine for safety lab tests (including specific tests for monitoring of 
vascular inflammation).
x
x
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
x
Perform standard single supine and standing vitals (HR and blood pressure).
x
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.
x
Perform Physician Withdrawal Checklist (PWC-20).
6.4. Follow-up Visit: Day 133 (Phone Visit)
x
Review and assess adverse events (AEs).
6.5. Unplanned Visits
During an unplanned site visit for adjustments of PF-06649751, placebo, L-dopa or other 
purposes, the following assessments should occur at a minimum:
x
Review and assess adverse events (AEs).
x
Assessment of concomitant medications.
x
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
x
Perform standard single supine and standing vitals (HR and blood pressure).
x
Dosing compliance verification (Investigational product accountability and 
documentation) while subject is present to confirm reasons for missed/additional 
doses.
x
Dispense Investigational Product, if appropriate.
x
If appropriate, instruct subject on continued daily dosing of PF-06649751 or placebo 
in accordance with randomized dose arm up-titration scheme (see Table 2, Section 
5.5.1, Titration of PF-06649751).
Additional procedures are at the discretion of the investigator to ensure subject safety.
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 73
6.6. Subject Withdrawal
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).
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 
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.
It may be appropriate for the subject to return to the clinic for final safety assessments and to 
be questioned regarding their reason for withdrawal.  At the early withdrawal visit, every 
effort must be made to complete the assessments as specified in the Early Termination Visit.
•
Full physical and neurological examination, if there is a new or open AE or clinically 
significant abnormal physical finding from the last visit;
•
Assessment of concomitant medications;
•
Single supine and standing blood pressure and pulse rate measurements;
•
Triplicate 12-lead ECG measurement;
•
Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last evaluation”;
•
Blood and urine specimens for safety laboratory;
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 74
x
Blood sample for pharmacokinetic analysis;
x
Review OFF time diary since dosing was stopped;
x
MDS-UPDRS Part I, II, III, and IV;
x
;
x
;
x
x
x
Perform Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease –
Rating Scale (QUIP-RS).
x
x
Physician Withdrawal Checklist (PWC-20);
x
x
x
x
x
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.
For all subjects (including Early Termination) who have received at least 1 dose of 
investigational product (except a subject who withdraws consent), follow-up contact will be 
completed at least 28 calendar days, and up to 35 calendar days after the last administration
of the investigational product to capture any potential adverse events (see the Time Period for 
Collecting AE/SAE Information section) and to confirm appropriate contraception usage (see 
the Contraception section).  Contact with the subject may be done via a phone call.
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.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 75
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 
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. If not otherwise specified, 
the baseline will be Day 0 (Randomization).
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 may be specifically monitored by the sponsor via a Screening 
Verification Process (Section 7.1.8).
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. Alcohol and tobacco use history will be documented at the screening visit and 
subjects will be asked about their lifetime consumption. 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 (UK Parkinson’s Disease Society 
Brain Bank Clinical Diagnostic Criteria)
Investigators should confirm and thoroughly document the diagnosis of Parkinson’s disease.  
Parkinson’s disease must be consistent with Brain Bank Criteria.12 Patients should be 
currently responding to L-Dopa.  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 with reference to Appendix 6.
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 76
7.1.5. Hoehn & Yahr (HY)
The HY is widely used to define broad categories of function in Parkinson’s disease.14 The 
HY is commonly used for describing, in broad terms, how Parkinson’s disease symptoms 
progress and the relative level of disability.  See Inclusion Criteria #5 for HY definition for 
this study.
7.1.6. Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)
The total MDS-UPDRS score is the most common method of evaluating the severity of 
Parkinson’s disease across behaviors, activities of daily living, motor abilities, and other 
complications of Parkinson’s disease.15 The MDS-UPDRS focuses primarily on measuring 
impairments associated with Parkinson’s disease, with subsections organized according to 
motor and non-motor aspects of the disease. 
The MDS-UPDRS includes components assessed by the study investigator as well as 
sections completed by the subject. 
Part I assesses non-motor experiences of daily living and is comprised of two components:
•
Part IA contains 6 questions that are assessed by the investigator and focuses on 
complex behaviors.
•
Part IB contains 7 questions that are part of the Patient Questionnaire completed by 
the subject.
Part II assesses motor experiences of daily living.  There are an additional 13 questions that 
are also part of the Patient Questionnaire completed by the subject.
Part III assesses the motor signs of Parkinson’s disease and is administered by the 
investigator.
Part IV assesses motor complications, dyskinesias, and motor fluctuations using historical 
and objective information.  The investigator will complete this assessment once a subject has 
started Parkinson’s disease medication.
Although not required, every effort should be made to have the same individual perform the 
ratings for an individual subject throughout the course of the study.  MDS-UPDRS Part III 
should be assessed consistently and approximately 2 to 4 hours following L-Dopa dose
(except at screening). At screening, a baseline MDS-UPDRS Part III should be performed 
prior to concordance testing. 
7.1.7. Concordance Testing and OFF Time Diary Training
At the Screening and Week 5 visits, subjects will be instructed to watch a training video on 
the completion of the OFF time diary (Hauser diary).
At the Screening visit, subjects and investigators (or qualified site staff/rater as per the Rater 
Qualification Guide) will then complete concordance testing over 2 hours consisting of 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 77
4 consecutive assessments at time-matched intervals (assessment at baseline followed by 
further assessments every 30 minutes). Subjects may complete other assessments 
(eg, questionnaires) during concordance testing, but should not engage in physical 
examinations (including ECGs, vitals, etc.) which could affect the outcome of the ON- and 
OFF-state assessment during concordance testing. The concordance testing should be started 
at a time point when it is expected that the subject’s status will switch from OFF to ON, or 
from ON to OFF within the assessment period.  The Part III score from full screening 
MDS-UPDRS may be utilized as the first concordance testing assessment, provided further 
concordance testing is initiated immediately following this exam.
During the concordance testing, the subject and the investigator (or qualified site staff/rater)
will complete the OFF time diary at the end of each 30 minute interval separately and 
independently. Over the course of the testing, the investigator (or qualified site staff/rater) 
will complete at least one MDS-UPDRS Part III while the subject is in the OFF state and at 
least one MDS-UPDRS Part III while the subject is in the ON state (Part III score from full 
screening MDS-UPDRS may be used to fulfill one of these two exams, if the concordance
assessment continued/completed immediately after exam). Investigators and qualified site 
staff/raters may also refer to vendor instructions for further details and examples. At a 
minimum, the rater must:
•
Withhold their ON/OFF determinations from the subject for the duration of the 
concordance testing. 
•
Conduct four exams of which a minimum of two must be MDS-UPDRS Part III 
exams (one in OFF state, and one in ON state; Part III score from full screening 
MDS-UPDRS acceptable, if the concordance assessment is continued/completed 
immediately after exam). For the intervals of concordance testing in which 
MDS-UPDRS Part III is not conducted, the investigator (or qualified site staff/rater) 
may assess ON/OFF status using an exam of their choosing. 
Subjects must experience ON- and OFF-state during the concordance testing; subjects may 
take their regular antiparkinsonian medication during the concordance testing. Dyskinesia 
(troublesome or non-troublesome) is not to be considered in concordance testing.
At the end of the 2 hour concordance testing, if the concordance criterion is not met or if the 
subject’s status does not switch between OFF and ON or ON and OFF, concordance testing 
may be extended to 4 hours. If after this first session the concordance criterion is still not 
met, the concordance testing may be repeated one more time within the screening period.
Successful completion of the concordance testing requires a) at least 75% concordance in 
ON/OFF status between subject and investigator (or qualified site staff/rater; ratings must be 
concordant at 3 or more out of 4 post-baseline assessments, or 6 out of 8, respectively) AND 
b) at least one concordant ON period AND one concordant OFF period.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 78
7.1.8. Screening Verification Process
The sponsor or designee may verify critical elements of the screening and enrollment process 
and, in cases where verification is required, will provide written authorization (eg, e-mail) 
concurring with the investigator assessment that the subject is eligible to return for Day 0 
(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 scores, concordance 
testing results, 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 study training.  It is critical that the sponsor 
be provided with all requested data in a timely fashion in advance of the planned Day 0 
(Randomization) visit, as will be instructed during study training. 
The sponsor may waive the requirement for screening verification at any given time if the 
site has demonstrated consistent compliance with the eligibility requirements.  In such cases, 
written notification will be provided indicating to the site that screening verification process 
has been waived.  However, such information will continue to be evaluated as part of the 
general study monitoring process.  The sponsor reserves the right to reinstate the screening 
verification process that had been previously waived, if deemed necessary, to ensure quality 
standards regarding subject eligibility.
For any potential subject on TID dosing of L-Dopa at Screening, the site must submit the 
rationale for this dosing and its optimized regimen during screening verification, and retain 
as part of the subject’s source documentation. The sponsor and/or its designated 
representative will review and validate eligibility or non-eligibility of this criterion.
7.2. Safety
7.2.1. Laboratory Tests
The following safety laboratory tests will be performed at times defined in the STUDY 
PROCEDURES section of this protocol.  Day 0 (Randomization) labs will be used as 
baseline. 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.  Please refer to Appendix 2 for criteria for safety laboratory values 
of potential clinical concern.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 79
Hematologyf
Chemistryf
Urinalysisf
Otherf
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
Anti-neutrophil 
cytoplasmic antibody
panel (C-ANCA and 
P-ANCA)e,f
Qualitative 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 0 only.
d At Screening only 
e At Screening and Week 17/Day 119 visits 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.  If anti-neutrophil cytoplasmic antibody 
(ANCA) is positive or questionable, then quantitative Proteinase-3 Ab and Myeloperoxidase Ab tests will 
be performed by the central lab using existing specimen. 
•
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 Investigational Product. 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 80
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 PF-06649751 or placebo dosing. 
Confirmation of non-childbearing potential is required before the subject may receive
PF-06649751 or placebo. 
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 or 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 0 will be 
captured as an AE.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 81
7.2.5. Vital Signs (Blood Pressure, Pulse Rate, and Temperature) 
Blood pressure and pulse rate will be measured at times specified in the STUDY 
PROCEDURES section of this protocol.  Subject temperature must also be assessed at 
Screening and Day 0 (Randomization) to confirm no symptoms of fever (see Exclusion 
Criteria #6). 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.
The same arm (preferably the dominant arm) will be used 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 pulse rate is 
acceptable, although, when done manually, pulse 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 pulse 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.  
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 pulse rate (≥30 beats per minute (BPM).
7.2.6. Electrocardiogram
Electrocardiograms (ECGs) should be collected at times specified in the STUDY 
PROCEDURES section of this protocol.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 82
Triplicate 12-lead ECGs will be obtained approximately 2-4 minutes apart; the average of the 
triplicate ECG measurements collected on Day 0 will serve as each subject’s baseline QTcF
value. 
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  If either of the QTcF values from these repeated 
ECGs remains 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 the average of QTcF values from the triplicate measurements remains 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.  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 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 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 brief, patient reported outcome measure designed to assess the severity 
of symptoms of ICDs and related behaviors reported to occur in Parkinson’s disease.
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 
subjects 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.20
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 83
7.2.8. Physician Withdrawal Checklist (PWC-20)
The PWC-20 is a physician-completed, 20-item reliable and sensitive instrument for the 
assessment of benzodiazepine 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. Efficacy Measures
7.3.1. OFF Time Diary (Hauser Diary)
In patient diaries, “OFF” time is defined as a period when medication has worn off and is no 
longer providing benefit with regard to mobility, slowness, and stiffness.  During this period, 
Parkinson’s disease patients experience relatively poor overall function with worsening of 
tremor, rigidity, balance, or bradykinesia.  “ON” time is defined as the time when medication 
is providing benefit with regard to mobility, slowness, and stiffness.  “ON” time can be 
classified as associated with or without troublesome dyskinesia that interfere with activities 
of daily living.  It has been demonstrated that “OFF” time and “ON” time with troublesome 
dyskinesia are generally considered by patients to be “bad time” with regard to motor 
function, whereas “ON” time without dyskinesia and on time with non-troublesome 
dyskinesia are generally considered to be “good time”.17
Currently, available diaries are designed to record patient motor state for half hour intervals.  
These diaries are a way for patients to assess their own health status without clinician bias or 
interpretation.  Diaries are especially useful in understanding symptoms’ temporal dynamics, 
including triggers that exacerbate symptoms.  They also help individuals to evaluate the 
impact of their treatment.18
For the purposes of this study, a paper Hauser diary will be utilized.  Entries are made on the 
days noted in the STUDY PROCEDURES section of the protocol.  Training on the diary will 
be provided to sites and subjects.  Subjects will complete the diary for three consecutive days 
in the week prior to each visit (except Day 28 visit) as indicated in the STUDY 
PROCEDURES section, including three consecutive days during the week prior to Day 0 
(Randomization).
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 84
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 85
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 86
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 87
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 88
7.6. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 
205 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 
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 89
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
7
1
6
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
Prolactin
1
4
4
HIV/Hepatitis 
Panel
4.
1
4
6
3
18
4
1
4
10
1
1
20
30
1
1
60
TOTAL
205.4
This total volume does not include discarded blood from pre-draws used to remove fluid from flushed 
catheters, if applicable.  
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 90
7.7. Assessment of Suicidal Ideation and Behavior
7.7.1. 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.25 Versions are available for 
“lifetime/Past 12 months” and “since last evaluation”.  The “lifetime/Past 12 months” 
evaluation is done at screening, and the “since last evaluation” is done at all other time 
points.
The C-SSRS should be collected at times specified in the STUDY PROCEDURES section 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 study.  Specific criteria that indicate a need for such an assessment are:
•
Suicidal ideation associated with actual intent and/or plan in the past year; (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 10 years (a “YES” answer to any of 
the suicidal behavior items of the C-SSRS with the behavior occurring in the past 
10 years).
•
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 visits (Screening, Day 0, or both), 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 study.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 91
Subjects who respond “YES” to items 4, 5 or to any behavioral question of the C-SSRS at 
any time after the baseline visit (Screening or Day 0 (Randomization)) will be assessed by 
clinician/MHP to determine whether it is safe for the subject to continue in the study.
Subjects who respond “YES” to items 4, 5 or to any behavioral question of the C-SSRS on 
more than one occasion during a study 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 
study.
7.7.2. Patient Health Questionnaire-8 (PHQ-8)
PHQ-8 is a self-report 8-item questionnaire used to assess depression and takes about
3-5 minutes to complete.  The PHQ-8 will be performed only at screening.  The following
criterion indicates a need for risk assessment by mental health professional (MHP):
•
PHQ-8 total score ≥15.
The risk assessment involves an evaluation by a clinician/MHP skilled in the evaluation of 
suicidality in the subjects by virtue of training or experience (eg, psychiatrist, licensed 
clinical psychologist).  A written copy of the risk assessment should be included in the 
subject's clinical record (source documentation) and include whether it was determined it was 
safe for the subject to be enrolled.
7.8. Other
7.8.1. Prolactin Test
A blood sample of approximately 1 mL for Prolactin will be collected at Day 0 
(Randomization), Week 5, Week 10, and Week 15 visits in a standard red top or SST tube.  
Detailed collection, processing, storage, and shipment instructions are provided in the central 
laboratory manual. Results will not be reported to investigators and will remain blinded until 
the end of the study.
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.  
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 92
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.
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;
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 93
•
Drug withdrawal;
•
Drug misuse; 
•
Drug interactions;
•
Extravasation;
•
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
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 94
•
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.
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 
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. 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 95
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:
•
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 liver function test (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 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 96
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.
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 97
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 
non-serious); 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).
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 98
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 99
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. Subject Withdrawal
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.
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 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 100
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. Nonserious 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 a pair-wise comparison of a dose of the PF-06649751 against 
placebo and is based on the primary endpoint, the change from Baseline to Week 10 (end of 
Period A) in the daily OFF time.  The decision criteria for efficacy are given as below, which 
will be based on a Bayesian interpretation of the results:
•
C1: Point estimate of PF-06649751 vs. placebo effect ≥1.5 hours, and
•
C2: 95% confident of PF-06649751 vs. placebo effect ≥0.
Better is defined as a reduction in the daily OFF time.
The sample size indicates that 32 evaluable subjects per arm will give sufficient precision for 
a comparison of an active dose versus placebo to meet criterion C2 with observed effects of 
≥1.5 hours (Criterion C1).  It’s estimated that the probability of passing both criteria for a 
true effect of 2.25 hours would be 85%, and the probability of passing the criteria for a true 
null effect (0 hour) would be 2%.
Accounting for a 10% rate of non-evaluable subjects as well as dropouts before the stable 
dose period (ie, by 5 weeks post dose), 36 subjects per arm and an approximate total of
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 101
198 subjects (54 in Cohort 1 and 144 in Cohort 2) are expected to be randomized for the 
study. Depending on actual enrollment, additional subjects may be randomized in the same 
treatment ratio, but there will be no more than 260 subjects in total.
The calculations were based on an estimate of the variability obtained from a meta-analysis 
of the historical Parkinson’s disease trials.  This provided an estimate of the between subject 
standard deviation of 2.9 hours in change from baseline in daily OFF time.  The 
meta-analysis also provided an informative prior for placebo effect, which will be included in 
the Bayesian data analysis.
9.2. Efficacy Analysis
The dataset used in the efficacy analyses will be the Full Analysis Set (FAS), consisting of 
all subjects who receive at least 1 post-dose efficacy measurement.  Analyses may be 
repeated using a Per Protocol Set (PPS) as appropriate, which will exclude subjects who are 
major protocol deviators and subjects whose dosing compliance is less than 80%.
9.2.1. Analysis of the Primary Endpoint
The primary endpoint is the change from baseline in daily OFF time at Week 10 (end of 
Period A).  A four parameter Emax model will be primarily used to estimate the dose response 
for the change from baseline in daily OFF time at Week 10 (end of Period A).  The model is 
as follows:
; where,
•
y is the change from baseline in daily OFF time;
•
D is the PF-06649751 dose in mg;
•
E0 is the placebo response;
•
Emax is the additive increase over placebo in the response of PF-06649751 at a 
theoretically infinite dose;
•
ED50 is the PF-06649751 dose in mg that provides an effect of E0 + Emax/2;
•
λ is the Hill parameter and measures the steepness of the dose response curve.
Bayesian estimation will be used to fit the model. An informative prior distribution will be 
used for the placebo response derived from the meta-analysis of historical Parkinson’s 
disease trials. Weak empirically-based prior distributions will be specified for the other 
model parameters, which were obtained from a meta-analysis of many dose response 
studies.26 The details of the priors and the Bayesian analysis will be specified in the SAP.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 102
The efficacy comparisons will be based on the treatment difference vs. placebo estimated at 
Week 10.  Their point estimates and two-sided 90% credible intervals from the fitted model 
will be reported.
An acceptable range of a true effect for an MED will be evaluated from the Emax model, and 
is defined as the lowest PF-06649751 efficacious dose that 
•
is within the range of tested doses in the study, 
•
has a lower dose that is not efficacious, and
•
has placebo-corrected effect between 1.5 and 2 hours.
If the Emax model is deemed to be inappropriate for the data, the pairwise comparison of the 
active doses vs. placebo based on an analysis of a restricted maximum likelihood 
(REML)-based mixed model for repeated measures (MMRM) will be primarily utilized for 
efficacy.  In such case, the response variable will be the change from baseline to each post
baseline visit, and the model will include the following fixed effects:
•
treatment (with 5 levels: PF-06649751 1 mg QD, 3 mg QD, 7 mg QD, 15 mg QD, 
and placebo), a categorical factor;
•
visit, a categorical factor;
•
treatment-by-visit interaction;
•
baseline daily OFF time, 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 10 using least-squares means for each PF-06649751 dose.  
Their point estimates, standard errors, and two-sided 90% CIs will be reported.  It will also 
be conducted within a Bayesian framework utilizing informative placebo prior.  The details 
of the prior and the Bayesian analysis will be specified in the SAP.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 103
All 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.
9.4. Safety Analysis
The safety analysis set will include all patients who received at least one dose of 
PF-06649751 or placebo.
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 104
Adverse events, ECGs, blood pressure, pulse 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 AEs, ECGs, blood pressure, pulse rate, C-SSRS,
QUIP-RS, PWC-20 and safety laboratory data 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 two interim analyses may be performed when approximately 27% and 80% subjects 
are randomized and have the opportunity to complete through Period A of the study. The 
first interim analysis will be conducted when Cohort 1 (approximately 54 subjects in a 
2:1 ratio of 15 mg QD and placebo groups respectively) is completed through Period A and 
efficacy data have been collected, databased and cleaned. A second interim analysis may be 
undertaken when approximately 104 subjects complete through Period A of Cohort 2 
(1:2:2:2:1 in 15 mg QD, 7 mg QD, 3 mg QD, 1 mg QD, and placebo respectively) and 
efficacy data have been collected, databased and cleaned. The purpose of these interim 
analyses 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 blinded 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 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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 105
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.
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 106
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 
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 107
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 
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 108
13. DEFINITION OF END OF TRIAL
13.1. 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.  For this study, the End of trial in EU Member States is defined as Last 
Subject Last Visit (LSLV) based on the total of randomized subjects in accordance with 
protocol Section 9.1. 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.
13.2. 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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 109
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 110
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 111
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 112
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.
Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 
1967; 17(5):427-42.
15.
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.
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.
Papapetropoulos, S. S. (2012). "Patient diaries as a clinical endpoint in Parkinson's 
disease clinical trials." CNS Neurosci Ther 18(5): 380-387.
18.
Zanni GR. Patient diaries: charting the course. Consult Pharm 2007; 22(6):472-6, 
479 82.
19.
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. 
20.
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.
21.
Brown RG1, Dittner A, Findley L, Wessely SC. The Parkinson fatigue scale. 
Parkinsonism Relat Disord. 2005;11(1):49-55.
22.
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness 
scale. Spee 1991; 50-55.
23.
Peto V, Jenkinson C, Fitzpatrick R. PDQ-39: a review of the development, validation 
and application of a Parkinson's disease quality of life questionnaire and its associated 
measures. J Neurol. 1998;245(Suppl 1):S10-4.
24.
Herdman M, et al. Development and preliminary testing of the new five-level version of 
EQ-5D (EQ-5D-5L). Qual Life Res. 2011; 20(10): 1727–1736.
25.
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.
26.
N. Thomas, K. Sweeney, and V. Somayaji. Meta-analysis of clinical dose-response in a 
large drug development portfolio. Statistics in Biopharmaceutical Research, 6(4): 302–
317, 2014.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 113
27.
Fisher RS, et al. ILAE official report: a practical clinical definition of epilepsy. 
Epilepsia, 55(4): 475-82, 2014.
28.
Food and Drug Administration (FDA). Guidance for Industry - Patient-Reported 
Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 
Silver Spring, MD: Food & Drug Administration; 2009.
29.
The Prescription Drug User Fee Act V (PDUFA-V) reauthorized in July 2012 by the 
Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012. 
Information accessed at: 
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm272170.htm.
30.
Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012.  
[PL 112-144].
Information accessed at: https://www.gpo.gov/fdsys/pkg/PLAW-
112publ144/pdf/PLAW-112publ144.pdf.
31.
Drutyte G, Forjaz MJ, Rodriguez-Blazquez C, Martinez-Martin P, Breen KC. What 
impacts on the stress symptoms of Parkinson's carers? Results from the Parkinson's UK 
Members' Survey. Disabil Rehabil 2014; 36:199-204.
32.
The Voice of the Patient - Parkinson’s Disease. From: A series of reports from the U.S. 
Food and Drug Administration’s (FDA’s) Patient-Focused Drug Development 
Initiative. Report Date: April 2016; updated May 2016. Accessed at, 
http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM4
98266.pdf.
33.
Yuhas EM, Morgan DG, Arena E et al.  Arterial medial necrosis and hemorrhage 
induced in rats by intravenous infusion of fenoldopam mesylate, a dopaminergic 
vasodilator.  Am J Pathol 1985;119(1)(Apr):83-91.
34.
Kerns WD, Arena E, Macia RA et al.  Pathogenesis of arterial lesions induced by 
dopaminergic compounds in the rat.  Toxicol Pathol 1989;17 (1 pt 2):203-13.
35.
Corlopam (fenoldopam mesylate), US NDA 019922 Review, Sept 1997, US FDA, 
Drugs@FDA.  Accessed 28 Jun 2016. 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/019922ap_corlopam_medrevp1.
pdf.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 114
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
ANCA
Anti-Neutrophil cytoplasmic 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
BID
“bis in die”, twice per day
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
predicted human plasma efficacious concentration
CI
confidence interval
CNS
central nervous system
COMT
catechol-O methyltransferase 
Cmax
maximum (peak) observed concentration
CRF
case report form
CRP
C-Reactive Protein
CSA
clinical study agreement
C-SSRS
Columbia Suicidality Severity Rating Scale
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
D1R
D1 receptor
DAI
dosage and administration instructions
DNA
deoxyribonucleic acid
DU
dispensable unit
EBR
eye blink rate
EC
ethics committee
ECG
electrocardiogram
EDMC
external data monitoring committee 
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 115
Abbreviation
Term
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EEG
electroencephalogram
EOT
End of Trial
ESR
Erythrocyte Sedimentation Rate
EU
European Union
EudraCT
European Clinical Trials Database
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
hERG
Human ether-a-go-go-related gene
HIV
human immunodeficiency virus
HPD
hours post-dose
HRQL
health-related quality of life
HR
heart rate
HY
Hoehn and 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
IWR
interactive web response
K2EDTA
dipotassium ethylene diamine tetraacetic acid
L-Dopa
levodopa
LFT
liver function test
LID
levodopa-induced dyskinesia
LMA
locomotor activity
LQTS
Long QT Syndrome
LSLV
last subject last visit 
MAD
Multiple ascending dose
MAO-B
monoamine oxidase B
MCH
Mean corpuscular hemoglobin
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 116
Abbreviation
Term
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MED
Minimal Efficacious Dose
MDS-UPDRS
Movement Disorder Society-Universal Parkinson’s Disease Rating 
Scale
MHP
Mental health professional
MMSE
Mini Mental State Examination
MPTP
1 methyl 4 phenyl 1,2,3,6 tetrahydropyridine
MTD
maximum tolerated dose
NDA
new drug application
NOAEL
No observed adverse effect level
NRS
numerical rating scale
P-ANCA
Perinuclear Anti-Neutrophil Cytoplasmic Antibody
PBMC
Peripheral Blood Mononuclear Cell
PBGT
Patient Best Guess at Treatment
PCD
primary completion date
PD
pharmacodynamics
PD AID
Parkinson’s Disease Activities, Interference, and Dependence
PET
positron emission tomography
 
PT
prothrombin time
PWC-20
Physician Withdrawal Checklist
QD
“quaque die”, once per day
QID
“quater in die”, four times per day
QTcF
corrected QT (Fridericia correction)
QUIP-RS
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease
RBC
red blood cell
REM
rapid eye movement
RNA
ribonucleic acid 
RO
receptor occupancy
SAD
Single Ascending Dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCL
Supply Chain Lead
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 117
Abbreviation
Term
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
TID
“ter in die”, three times per day
Tmax
time to reach maximum concentration
TMB
trimethobenzamide
UK
United Kingdom
ULN
upper limit of normal
US
United States
USPI
United States package insert
WBC
white blood cell
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 118
Appendix 2. Criteria for Safety Values of Potential Clinical Concern
Hematology
Hemoglobin
<0.8 times the lower limit of the reference range
Hematocrit
<0.8 times the lower limit of the reference range
RBC Count
<0.8 times the lower limit of the reference range
MCV
<0.9 or >1.1 times the limits of the reference range
MCH
<0.9 or >1.1 times the limits of the reference range
MCHC
<0.9 or >1.1 times the limits of the reference range
Platelets
<0.5 or >1.75 times the limits of the reference range
Total Neutrophils (Abs)
<0.8 or >1.2 times the limits of the reference range
Eosinophils (Abs)
>1.2 times the upper limit of the reference range
Basophils (Abs)
>1.2 times the upper limit of the reference range
Lymphocytes (Abs)
<0.8 or >1.2 times the limits of the reference range
Monocytes (Abs)
>1.2 times the upper limit of the reference range
Chemistry
Total bilirubin
>1.5 times the upper limit of the reference range
Direct bilirubin
>1.5 times the upper limit of the reference range
Indirect bilirubin
>1.5 times the upper limit of the reference range
AST
>3 times upper limit of the reference range
ALT
>3 times upper limit of the reference range
Alk Phosphatase
>3 times upper limit of the reference range
Creatinine
>1.3 times upper limit of the reference range
BUN
>1.3 times upper limit of the reference range
Glucose
<0.6 or >1.5 times the limits of the reference range
Uric acid
>1.2 times upper limit of the reference range
Sodium
<0.95 or >1.05 times the limits of the reference range
Potassium
<0.9 or >1.1 times the limits of the reference range
Chloride
<0.9 or >1.1 times the limits of the reference range
Bicarbonate
<0.9 or >1.1 times the limits of the reference range
Calcium
<0.9 or >1.1 times the limits of the reference range
Albumin
<0.8 or >1.2 times the limits of the reference range
Total protein
<0.8 or >1.2 times the limits of the reference range
Creatine Kinase
>2.0 times upper limit of the reference range
Urinalysis
Urine WBC
≥20/HPF
Urine RBC
≥20/HPF
Urobilinogen
≥1
Urine Bilirubin
≥1
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 119
Vital Signs
Pulse Rate
Supine/Sitting: <40 or >120 bpm     Standing: <40 or >140 bpm
Blood Pressure
Systolic ≥30 mm Hg change from baseline in same posture
Systolic <90 mm Hg
Diastolic ≥20 mm Hg change from baseline in same posture
Diastolic <50 mm Hg
Electrocardiogram
PR interval
≥300 msec; ≥25% increase when baseline >200 msec
Increase ≥50% when baseline ≤200 msec
QRS interval
≥140 msec; ≥50% increase from baseline
QTc interval
≥500 msec
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 120
Appendix 3. 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 needs1
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-benzodiazepine hypnotics are permitted. 
Monoaminooxidase B (MAO-B) 
inhibitors
Permitted if at a stable dose for at least 42 days prior to 
Randomization.  No dose changes should be anticipated for 
the duration of the study.
Catechol O methyltransferase 
(COMT) inhibitors
Permitted if at a stable dose for at least 42 days prior to 
Randomization.  
Antidepressants except
MAO-A/B inhibitor 
antidepressants
Permitted if subject is taking a stable dose at least 42 days
prior to Randomization. 
Anticholinergics
Permitted if at a stable dose for at least 42 days prior to 
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 
Randomization.  No dose changes should be anticipated for 
the duration of the study.
Prohibited
Dopamine receptor agonist 
medications including 
pramipexole, ropinirole, rotigotine 
and apomorphine
Prohibited for at least 28 days prior to Randomization and 
through the end of the double blind treatment period.
Istradefylline and zonisamide
Prohibited for at least 42 days prior to Randomization and 
through the end of the double blind treatment period.
Inhaled L-Dopa, intraduodenal 
use of Duodopa®
Not permitted.
Antipsychotics or neuroleptics
Antipsychotics (except stable low dose quetiapine), 
metoclopramide, or reserpine are not permitted.
Antiepileptics
Antiepileptics are prohibited except if used for chronic 
painful conditions at steady doses (for example, gabapentin 
or pregabalin).
Lithium, MAO-A/B inhibitor 
antidepressants (including 
moclobemide, tranylcypromine, 
and phenelzine)
Prohibited for at least 42 days prior to Randomization and 
throughout the study.  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
Drugs that induce or inhibit the hepatic metabolizing 
cytochrome 3A4 enzymes; CYP3A inducers or inhibitors are 
prohibited from at least 28 days prior to Randomization
Marijuana
Prohibited from Screening through the end of the double 
blind treatment period.
1. Investigator to discuss with sponsor as needed.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 121
Appendix 4. 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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 122
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
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 123
Appendix 5. Country-Specific Appendix – Applicable to France Only 
The following supplementary text should be read in conjunction with the B7601003 protocol:
•
Prior to enrollment of any subjects, the investigator and any sub-investigators will 
complete the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP 
Training”) or training deemed equivalent by Pfizer.  Any investigators who later join 
the Study will complete the Pfizer GCP Training or equivalent before performing 
Study-related duties.  For studies of applicable duration, the investigator and 
sub-investigators will complete Pfizer GCP Training or equivalent every three years 
during the term of the Study, or more often if there are significant changes to the ICH 
GCP guidelines or course materials.
•
No subjects or third-party payers will be charged for investigational product.
•
The investigator(s) will notify Pfizer or its service provider immediately of any 
regulatory inspection notification in relation to the study.  Furthermore, the 
investigator will cooperate with Pfizer or its service provider to prepare the study site 
for the inspection and will allow Pfizer or its service provider (if not prohibited by 
law) to be present during the inspection.  The study site and investigator will 
promptly resolve any discrepancies that are identified between the study data and the 
subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its service provider.  Before response submission to 
the regulatory authorities, the investigator will provide Pfizer or its service provider 
with an opportunity to review and comment on responses to any such findings. 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 124
Appendix 6. UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria 
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 
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 125
•
negative response to large doses of levodopa in absence of malabsorption 
•
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.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 126
Appendix 7. Country-Specific Appendix - Japan
Schedule of Activities and Study Procedures (Section 6)
For sites in Japan, the Week 2 (Day 14) and Week 3 (Day 21) visits during the Titration 
Period must be conducted as site (in-clinic) visits. Additionally, two phone visits are 
required a day after both the Day 0 (Randomization) Visit (Day 1) and Week 1 Visit (Day 7 
[+3 day window]) and two additional study site visits are required a day after both Week 2
Visit (Day 14 [+3 day window]) and Week 3 Visit (21 [+3 day window]). Phone visits can 
optionally be conducted as site visits (eg, for logistical reasons). Subjects should be offered 
an optional overnight stay at the study site prior to a site visit. Study drug administration on 
both site visits (day after Week 2 Visit and Week 3 Visit) should occur at the study site. For 
phone visits, the phone calls should take place approximately 4 hours post-dose. During site 
visits, the study procedures are to be performed approximately 4 hours post-dose.
Afterwards, subjects may be discharged at investigator’s discretion if no safety concerns are 
identified. These visits (Day 1, Day 8, Day 15, and Day 22) are to be conducted in addition 
to the protocol Schedule of Activities/Study Procedures (Section 6).
Japan Specific Visits (including additional observation visits)
Protocol Activity
Rand. Visit
Wk 1 
Observation 
Visit
Wk 2
Wk 2 
Observation
Visit
Wk 3
Wk 3 
Observation
Visit
Day 1
(phone visit or 
optional site 
visit)
Day 8 
(phone visit or 
optional site 
visit)
Day 14 
(site visit)
Day 15 
(site visit)
Day 21 
(site visit)
Day 22
(site visit)
Concomitant medications 
assessment
X
X
X
X
X
X
AE assessment
X
X
X
X
X
X
Triplicate ECG
X
X
X
X
Supine and standing blood 
pressure and pulse rate 
X
X
X
X
Columbia Suicidality Severity 
Rating Scale (C-SSRS)
X
X
Safety Laboratory
X
X
Dispensing of Investigational 
Product
X
X
Investigational Product 
accountability
X
X
Investigational Product and 
L-Dopa dosing documentation
X
X
PF-06649751 (or placebo) 
administration
X
→
→
→
→
→
Adjunct L-Dopa (open-label)
→
→
→
→
→
→
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 127
Day 1 and Day 8
•
Assessment of concomitant medications.
•
Review and assess adverse events (AEs).
•
PF-06649751 or placebo administration in accordance with randomized dose arm 
up-titration scheme (see Table 2, Section 5.5.1, Titration of PF-06649751).
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
Day 14
•
Dosing compliance verification to confirm reasons for missed/additional doses. 
Based on blister card review and/or capsule count, any subject who is noted not 
to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
•
Assessment of concomitant medications.
•
Review and assess adverse events (AEs).
•
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
•
Perform standard single supine and standing vitals (HR and blood pressure).
•
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.
•
Collect blood and urine for safety lab tests.
•
Dispense Investigational Product.  Next dose level of PF-06649751 or placebo will be 
taken on the morning of Day 15.
•
PF-06649751 or placebo administration in accordance with randomized dose arm 
up-titration scheme (see Table 2, Section 5.5.1, Titration of PF-06649751).
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
Day 15
•
Assessment of concomitant medications.
•
Review and assess adverse events (AEs).
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 128
•
Perform standard supine triplicate 12-lead electrocardiogram (ECG), approximately 
4 hours post-dose.
•
Perform standard single supine and standing vitals (HR and blood pressure), 
approximately 4 hours post-dose.
•
PF-06649751 or placebo administration in accordance with randomized dose arm 
up-titration scheme (see Table 2, Section 5.5.1, Titration of PF-06649751).
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
Day 21
•
Dosing compliance verification to confirm reasons for missed/additional doses. 
Based on blister card review and/or capsule count, any subject who is noted not 
to have taken at least 80% or has taken more than 120% of required doses at 
any scheduled visit during the study will be considered out of compliance and 
this must be recorded on the CRF and documented as a Medication Error on the 
CRF and the source documents.
•
Assessment of concomitant medications.
•
Review and assess adverse events (AEs).
•
Perform standard supine triplicate 12-lead electrocardiogram (ECG).
•
Perform standard single supine and standing vitals (HR and blood pressure), if clinic 
visit.
•
Perform the Columbia Suicidality Severity Rating Scale (C-SSRS) “Since last 
evaluation”.
•
Collect blood and urine for safety lab tests.
•
Dispense Investigational Product.  Next dose level of PF-06649751 or placebo will be 
taken on the morning of Day 22.
•
PF-06649751 or placebo administration in accordance with randomized dose arm 
up-titration scheme (see Table 2, Section 5.5.1, Titration of PF-06649751).
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
Day 22
•
Assessment of concomitant medications.
•
Review and assess adverse events (AEs).
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 129
•
Perform standard supine triplicate 12-lead electrocardiogram (ECG), approximately 4 
hours post-dose.
•
Perform standard single supine and standing vitals (HR and blood pressure), 
approximately 4 hours post-dose.
•
PF-06649751 or placebo administration in accordance with randomized dose arm 
up-titration scheme (see Table 2, Section 5.5.1, Titration of PF-06649751).
•
Instruct subjects on continued adjunct stable L-Dopa (open-label) administration.
Reason(s) for Additional Visits (Day 1, Day 8, Day 15, and Day 22) in Japan:
The titration scheme implemented in the study (Section 5.5.1) results in patients randomized 
into PF-06649751 7 mg QD and 15 mg QD dose groups to be administered with 7 mg and 
15 mg dose of PF-06649751 for the first time on Day 15 and Day 22. These doses have not 
been previously evaluated for safety and tolerability in Parkinson’s disease patients of 
Japanese origin, to-date. 
Based on all the available data, 5 mg QD and 15 mg QD PF-06649751 doses have been 
demonstrated to be safe and well tolerated in PD patients of non-Japanese origin (Study 
B7601005). PF-06649751 dose of 1.5 mg QD has been evaluated in healthy subjects of 
Japanese origin in Study B7601002. Safety, tolerability and exposures at this dose 
(1.5 mg QD) were similar to those in non-Japanese healthy subjects. Moreover, 
PF-06649751 doses up to 5 mg QD were found to be safe and tolerable in healthy 
non-Japanese subjects. Generally, tolerability at 5 mg QD in Parkinson’s disease patients was 
better than healthy subjects. More information on safety, tolerability of PF-06649751 across 
different doses/studies can be found in the Investigator’s Brochure.
During titration up to target doses, Parkinson’s disease patients progressively step through 
PF-06649751 1 mg QD and 3 mg QD before being dosed with 7 mg QD followed by 
15 mg QD. It is expected that the first two PF-06649751 dose levels (1 mg QD and 
3 mg QD) during the titration period will be well tolerated in Japanese PD patients based on 
acceptable safety and tolerability observed at 1.5 mg QD (in healthy subjects; Study 
B7601002) and also better tolerability in PD study patients (Study B7601005) compared to 
healthy subjects.
Thus, phone visits with safety assessments (approximately 4 hours post dose) the day patients 
are dosed with PF-06649751 1 mg QD/Placebo and 3 mg QD/Placebo will help ensure 
Japanese patient safety and tolerability during the study.
Additional study site visits with safety assessments (approximately 4 hours post dose) on the
day patients are dosed with PF-06649751 7 mg QD/Placebo and 15 mg QD/Placebo will help 
assure Japanese patient safety and well-being during the study.
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 130
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 131
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 132
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 133
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 134
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)


PF-06649751
B7601003
Final Protocol Amendment 2, 22 November 2016
Page 135
CCI
090177e18f6e8739\Approved\Approved On: 26-Sep-2018 05:11 (GMT)

SAP_000.pdf: 
Protocol B7601003 (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 B7601003
A 15-WEEK, PHASE 2, DOUBLE BLIND, RANDOMIZED,
PLACEBO-CONTROLLED, DOSE RANGING STUDY TO INVESTIGATE THE 
EFFICACY, SAFETY AND TOLERABILITY OF PF-06649751 IN SUBJECTS WITH 
MOTOR FLUCTUATIONS DUE TO PARKINSON’S DISEASE
Statistical Analysis Plan 
(SAP)
Version:
3 
Date:
13 September 2017
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (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.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................5
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................9
2.1. Study Objectives .....................................................................................................10
2.1.1. Primary Objective.......................................................................................10
2.1.2. Secondary Objectives .................................................................................10
2.2. Study Design ...........................................................................................................11
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................13
3.1. Primary Endpoint(s) ................................................................................................13
3.2. Secondary Endpoint(s) ............................................................................................17
3.2.1. MDS-UPDRS Part III.................................................................................18
3.2.2. MDS-UPDRS Parts I, II, IV, and Total Score............................................19
CCI
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 3
TMF Doc ID: 98.03
3.4. Baseline Variables...................................................................................................26
3.5. Safety Endpoints .....................................................................................................27
3.5.1. Adverse Events...........................................................................................27
3.5.2. Laboratory Data..........................................................................................27
3.5.3. Vital Signs (Blood Pressure and Pulse Rate)..............................................28
3.5.4. Electrocardiogram (ECG)...........................................................................28
3.5.5. Physical Examination .................................................................................29
3.5.6. Neurological Examination..........................................................................29
3.5.7. Assessment of Suicidal Ideation and Behavior ..........................................29
3.5.7.1. Columbia Suicide Severity Rating Scale (C-SSRS) .................29
3.5.7.2. Mental Health Risk Assessment (MHRA)................................32
3.5.8. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease – Rating Scale (QUIP-RS)..................................................................32
3.5.9. Physician Withdrawal Checklist (PWC-20)...............................................33
4. ANALYSIS SETS ...............................................................................................................33
4.1. Full Analysis Set .....................................................................................................34
4.2. Per Protocol Analysis Set........................................................................................34
4.3. Safety Analysis Set..................................................................................................34
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................35
5.1. Hypotheses and Decision Rules ..............................................................................35
5.1.1. Statistical Hypotheses.................................................................................35
5.1.2. Statistical Decision Rules ...........................................................................35
5.2. General Methods .....................................................................................................36
5.2.1. Analyses for Binary Data............................................................................37
5.2.2. Analyses for Continuous Data....................................................................37
5.2.2.1. Mixed Model for Repeated Measures Analysis (Non-
Bayesian Approach) ..........................................................................37
5.2.2.2. Dose Response Analysis (Non-Bayesian Approach)................38
CCI
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 4
TMF Doc ID: 98.03
5.2.2.3. Bayesian Analysis .....................................................................39
5.2.2.4. Dose Response Trend Test........................................................41
5.2.3. Analyses for Categorical Data....................................................................41
5.3. Methods to Manage Missing Data ..........................................................................41
6. ANALYSES AND SUMMARIES ......................................................................................42
6.1. Primary Endpoint(s) ................................................................................................42
6.1.1. Change from Baseline in Daily OFF time at Week 10 (end of 
Period A)..........................................................................................................42
6.1.1.1. Primary Analysis.......................................................................42
6.1.1.2. Sensitivity/Robustness Analyses...............................................43
6.2. Secondary Endpoint(s) ............................................................................................44
6.2.1. Hauser Home Diary....................................................................................44
6.2.2. MDS-UPDRS .............................................................................................44
6.4. Subset Analyses.......................................................................................................47
6.5. Baseline and Other Summaries and Analyses.........................................................47
6.5.1. Study Conduct and Subject Disposition .....................................................47
6.5.2. Baseline Summaries....................................................................................48
6.5.3. Study Treatment Exposure .........................................................................48
6.5.4. Concomitant Medications and Non-Drug Treatments................................49
6.6. Safety Summaries and Analyses .............................................................................49
6.6.1. Adverse Events...........................................................................................49
6.6.2. Laboratory Data..........................................................................................50
6.6.3. Vital Signs (Blood Pressure and Pulse Rate)..............................................50
6.6.4. Electrocardiogram.......................................................................................51
6.6.5. Physical Examination .................................................................................52
6.6.6. Neurological Examination..........................................................................52
6.6.7. Assessment of Suicidal Ideation and Behavior ..........................................52
6.6.7.1. Columbia Suicide Severity Rating Scale (C-SSRS) .................52
6.6.7.2. Mental Health Risk Assessment (MHRA)................................52
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 5
TMF Doc ID: 98.03
6.6.8. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease – Rating Scale (QUIP-RS)..................................................................53
6.6.9. Physician Withdrawal Checklist (PWC-20)...............................................53
7. INTERIM ANALYSES.......................................................................................................53
7.1. Introduction .............................................................................................................53
7.2. Interim Analyses and Summaries............................................................................54
8. REFERENCES ....................................................................................................................55
9. APPENDICES .....................................................................................................................56
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments................................................6
Table 2.
Proposed Titration Schemes for PF-06649751 and Placebo Doses ....................12
Table 4.
C-SSRS Mapped to C-CASA - Suicidality Events and Codes.............................30
Table 4.
C-SSRS Mapped to C-CASA – Examples of Worsening/New Onset .................31
Table 5.
Safety QTcF1 ........................................................................................................51
LIST OF FIGURES
Figure 1.
Study Schematic ...................................................................................................12
APPENDICES
Appendix 1. SUMMARY OF EFFICACY ANALYSES........................................................56
Appendix 2. DATA SET DESCRIPTIONS ............................................................................59
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 6
TMF Doc ID: 98.03
1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B7601003 Version 3 is based on the protocol 
amendment 2 (A2) dated 22NOV2016 (approval date 14Dec16).  
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1
Not Applicable
Initial version
2
Section 2


Toxicology data updated

Included text on the B7601017 extension 
study
2
2
2
2
2
Section 2.2 and 
Figure 1
Days 14 & 21 may be phone visits
2
Section 2.2
Added text in regards to Japan specific visits.
2
Sections 2.2 and 
7.1
Interim Analysis language clarified.
2
Section 3.1
Updated Hauser diary rules:
CCI
CCI
CCI
CCI
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 7
TMF Doc ID: 98.03

Accounted for Pre-A2 diaries collected 
anytime during screening period

Addressed impact if Week 3 (Day 21) is 
either an in-clinic or phone visit

Modified rescue medication methods to 
include Period B for subjects Post A2 

Noted Week 13 is only relevant Pre-A2

Removed rules for subjects with more than 
one observation for the same 30 minute time 
period.  Data will be considered invalid and 
set to missing.
2
Sections 3.2, 6.2.1
and Appendix 1
“Daily ON time with troublesome dyskinesia 
(hours)” added as a secondary endpoint
2
Section 3.4
Baseline is noted as Day 0 throughout, which is 
consistent with the terminology in the protocol. 
However, for purposes of reporting it will be 
referred to as Day -1 which is consistent with 
CDISC standards.
2
Section 3.2.1
Added lip/jaw to the MDS-UPDRS Part III 
tremor subscale and updated rule for missing 
items.
2
2
2
2
2
Sections 3.5.3 and 
6.5.2
Added temperature.
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 8
TMF Doc ID: 98.03
2
Section 3.5.7 and 
6.6.7

C-SSRS “Lifetime” replaced with 
“Lifetime/Past 12 months” throughout.

Moved C-SSRS as a subsection of 
Assessment of Suicidal ideation and 
Behavior, and added Mental Health Risk 
Assessment (MHRA) subsections.
2
Section 4.2
Updated Per Protocol Analysis Set (PPAS) 
criteria
2
Section 5.2
All available visit data will be reported, and for 
descriptive statistics by time point each visit will 
be represented.
2
Section 5.3
Added general clarification on missing data at 
Baseline to use Screening values as Baseline 
(Day 0).
2
Section 5.3
Added handling of the early termination visit for 
safety.
2
Section 6
Clarified that data after Week 10 Pre-A2 will be 
in listings only, otherwise all data will be 
presented in summaries and used in statistical 
modelling.
2
Section 6.6.5
Removed non-standard table, since clinically 
significant abnormalities which meet the definition 
of an adverse event will be recorded as such.
2
Section 6.6.6
Neurological examination data will be presented 
now as only listings, since all newly abnormal 
findings are required to be logged as AEs.
3
Sections 3.1 and 6
Clarify impact of Protocol Amendment 2. 
Administrative change to align with the IA #1 
SAP.
3
Section 3.1
Added a rule to address excluding home diaries 
that are not within 7 days of the clinic visit. If the 
excluded home diary nominal visit is equal to the 
closet planned visit it will now be included, 
otherwise it is still excluded.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 9
TMF Doc ID: 98.03
3
Section 3.5.1
Adapted the “Rule of 4” for Tier 2 events.
3
Section 3.5.8
QUIP-RS was updated as follows:

Now 8 scoring types

Updated missing responses rules
3
Section 6.4
Added subset analysis based on L-Dopa intake 
during baseline.  
Explicitly stated for all subset analyses, a 
minimum number of subjects required for a 
subgroup to be analyzed.
3
Section 6.6.8
Added additional details on summarizing the 
QUIP-RS.
3
Appendix 1
Added that subset analyses were optional, as 
they require ≥ 10% of total subjects to be 
analyzed.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B7601003.  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. In Parkinson’s disease, motor function can be 
pharmacologically rescued with activation of either or both D1R-containing direct and 
D2R-containing indirect striatal output pathways.  In contrast to available D2/D3R agonists, 
D1/D5R agonists have demonstrated efficacy similar to L-Dopa in the 1-methyl-4-phenyl-1 2, 
3, 6-tetrahydropyridine (MPTP) lesioned nonhuman primate model of Parkinson’s disease 
(see Investigators Brochure Section 5.1.3.2, In Vivo Pharmacodynamics).  Severely lesioned 
MPTP-treated monkeys showed no response to D2 agonists and modest improvement with 
L-Dopa treatment, but showed marked improvement with D1 agonist treatment. 
PF-06649751 is a novel D1 and D5 specific dopamine partial agonist and has the potential 
to reduce OFF time in subjects with moderate to advanced Parkinson’s disease who are 
experiencing significant OFF time despite their current dopaminergic therapy.  Following an 
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 10
TMF Doc ID: 98.03
initial titration phase, which is intended to mitigate potential dopaminergic adverse events 
such as nausea and vomiting, fixed doses of PF-06649751 will be evaluated as adjunctive 
treatment with L-Dopa.  The overall doses of PF-06649751 selected for this study were 
influenced by the aim to identify not only a minimally-effective dose but also characterize the 
maximum efficacious dose. PF-06649751 doses for this study are selected based on evidence 
of pharmacological activity from preclinical data and clinical studies in Parkinson’s disease 
subjects (See the Protocol for more detail).
The study was initially limited to a maximum 15 week treatment period due to the available 
toxicological coverage. Subsequently, the nonclinical safety profile of PF-06649751 is 
considered to be adequately characterized to support progression into human clinical studies 
of 6 months or longer dosing duration for men and for women of non-childbearing potential.
Subjects who complete through Week 15 of the B7601003 study will have the option to enroll 
in an open label extension study (B7601017). If the pre-specified Inclusion/Exclusion criteria 
are met at Week 10 (screening), the subject may exit the current B7601003 study at Week 15 
for continued treatment and follow-up under the extension study (B7601017), provided they 
remain eligible. Subjects not directly entering study B7601017 at Week 15 must complete the 
Week 17 and Week 19 Follow-up visits and must rescreen under the B7601017 protocol.
The study population will include male subjects and female subjects of non-childbearing
potential diagnosed with Parkinson’s disease who experience motor fluctuations.
This study will evaluate the efficacy, safety, and tolerability of up to 4 different doses of 
PF-06649751 in subjects with Parkinson’s disease as adjunctive therapy to L-Dopa.
2.1. Study Objectives
2.1.1. Primary Objective

To evaluate the effect on motor symptoms of PF-06649751 administered once daily as 
adjunctive treatment with stable doses of L-Dopa in Parkinson’s disease.

To determine the therapeutic window for motor symptom improvement of 
PF-06649751 administered once daily, ie, determining a dose, or a range of doses, 
for adequate control of motor symptoms.
2.1.2. Secondary Objectives

To evaluate the dose-response on motor symptoms of PF-06649751 administered 
once daily in subjects with Parkinson’s disease.

To evaluate the safety and tolerability of PF-06649751 administered once daily in 
subjects with Parkinson’s disease. 
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 11
TMF Doc ID: 98.03

To evaluate the effect of PF-06649751 administered once daily on dyskinesia in 
subjects with Parkinson’s disease.
2.2. Study Design
The study has a randomized, double-blind, placebo-controlled parallel group design.  
Approximately 198 subjects from approximately 60 centers in approximately 6 countries will 
be randomized to 5 treatment groups (15 mg QD, 7 mg QD, 3 mg QD, 1 mg QD, or placebo), 
initially in a 2:0:0:0:1 ratio of approximately 54 subjects (Cohort 1) followed by a 
1:2:2:2:1 ratio of approximately 144 subjects (Cohort 2), using a central randomization 
system with randomization blocks stratified by region. Geographic region will be defined as 
North America, Japan, and Europe. 
Each subject will participate in the study for approximately 25 weeks including up to a 
45 day screening period, 15 week double-blind treatment period (comprising up to a 3 week 
titration, 2 week dose adjustment, 5 weeks of primary efficacy with adjunctive treatment to 
stable L-Dopa (Period A), and 5 weeks of maintenance with adjunctive treatment to stable L-
Dopa (Period B)), and an approximately 28 day follow-up period.
Note that prior to B7601003 Protocol Amendment 2 Days 14 and 21 were required in-clinic 
visits, but now with the option to be phone visits, as applicable. The impact of this change 
will be noted in subsequent sections.
For sites in Japan, the Week 2 (Day 14) and Week 3 (Day 21) visits during the Titration 
Period must be conducted as site (in-clinic) visits. Additionally, two additional phone visits 
are required a day after both the Day 0 (Randomization) Visit (Day 1) and Week 1 Visit (Day 
7 [+3 day window]) and two additional study site visits are required a day after both Week 2 
Visit (Day 14 [+3 day window]) and Week 3 Visit (21 [+3 day window]), ie Day 15 and Day 
22 respectfully. Phone visits can optionally be conducted as site visits (eg, for logistical 
reasons). 
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 12
TMF Doc ID: 98.03
The study design is illustrated in the figure below.  
Figure 1.
Study Schematic
Each subject is planned to be up-titrated in a double-blind fashion to the assigned target 
dose level of PF-06649751 or placebo according to the following titration scheme:
Table 2.
Proposed Titration Schemes for PF-06649751 and Placebo Doses
Treatment Group
Week/ Start 
Day of Dose 
Level
Placebo
1 mg
3 mg
7 mg
15 mg
Week 1 /
from Day 1
P
1 mg
1 mg
1 mg
1 mg
Week 2/ 
from Day 8
P
1 mg
3 mg
3 mg
3 mg
Week 3 / 
from Day 15
P
1 mg
3 mg
7 mg
7 mg
Weeks 4-15 / 
from Day 22
P
1 mg
3 mg
7 mg
15 mg
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 13
TMF Doc ID: 98.03
Titration (Week 1 to Week 3): No modifications to the upward titration of Study Medication 
can be made.  Subjects who experience intolerable adverse events during titration will need 
to be discontinued from the study. 
Post Week 3 (Week 4 to Week 5): For subjects who experience unacceptable new adverse 
events after having achieved the target dose (after Day 21) and deemed related to the dose 
increase, the dose of investigational product can be changed to the previous dose level 
(Week 3 dose level).  This results in a dose reduction from 15 mg/day to 7 mg/day for the 
highest dose group, and no change in dose for the other dose groups in a blinded fashion.  
Only one dose modification of investigational product is permitted. 
L-Dopa Adjustment for Unacceptable Dopaminergic Side Effects (Week 1 to Week 15): In 
the case of unacceptable dopaminergic side effects and following discussion with the Medical 
Monitor, the dose of L-Dopa may be reduced between Day 1 and Day 105 visit. 
Period A: Primary Efficacy: During Period A, subjects will be administered double blind 
study medication once daily (up to 4 different dose levels of investigational product) as 
adjunctive treatment to a stable dose of open-label L-Dopa. 
Period B: Maintenance: After the Week 10 Visit (primary endpoint collection), subjects will 
enter Period B.  During Period B, double-blind treatment with investigational product will 
continue as adjunctive treatment to a stable dose of open label L-Dopa. Note that prior to 
B7601003 Protocol Amendment 2 Period B allowed the open label L-Dopa dose to be 
reduced following a recommended downward titration based on the L-Dopa dose at the end 
of Period A. The impact of this change will be noted in subsequent sections.
Up to two interim analyses may be performed when approximately 27% and 80% subjects 
are randomized and have the opportunity to complete through Period A of the study.  The 
first interim analysis will be conducted when Cohort 1 (approximately 54 subjects in a 
2:1 ratio of 15 mg QD and placebo groups respectively) is completed through Period A and 
efficacy data have been collected, databased and cleaned.  A second interim analysis may be 
undertaken when approximately 104 subjects complete through Period A of Cohort 2 
(1:2:2:2:1 in 15 mg QD, 7 mg QD, 3 mg QD, 1 mg QD, and placebo respectively) and 
efficacy data have been collected, databased and cleaned. The purpose of these interim 
analyses 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.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
The primary endpoint is the change from baseline in daily OFF time at Week 10 (end of 
Period A). The daily OFF time is calculated as the average of the three consecutive daily 
OFF hours from the symptom diary at each visit.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 14
TMF Doc ID: 98.03
A paper Hauser diary, otherwise referred to as the “Parkinson’s Disease Home Diary”, will 
be utilized to record patient motor state for half hour intervals.  Entries are made on the days 
noted in the STUDY PROCEDURES section of the protocol.  Training on the diary will be 
provided to sites and subjects.  Subjects will complete the diary for three consecutive days in 
the week prior to each visit (except Day 28 visit) as indicated in the STUDY PROCEDURES 
section, including three consecutive days during the week prior to Day 0 (Randomization).
Note that prior to B7601003 Protocol Amendment 2, the three consecutive days prior to Day 
0 could occur anytime during the 45 day screening period. Rules will be implemented in this 
section to ensure that data is retained for analysis.  
Subjects are asked to make an independent assessment of motor fluctuations; caregivers or 
site study staff cannot participate (caregivers are not to provide opinions or tell the subject 
what he/she has observed). The subject will be instructed to answer the PD home diary on 
whether the subject has been ON with no dyskinesias, ON with non-troublesome dyskinesia, 
ON with troublesome dyskinesia, OFF, or ASLEEP.  The home diary is completed for the 
full 24 hours reflecting both time awake and time asleep.  A home diary day starts with the 
interval 24:00-0:30 thru 23:30-24:00 on each chronological day for 3 consecutive days.  On 
the days recording the home diary, subjects will be instructed to make an entry every 30 
minutes during their normal waking time and upon awakening from time asleep.  Double 
entries and unclear entries (e.g. participant checks in the middle of 2 options) are considered 
invalid and entered as missing data, which is handled at the point of data entry via these 
established rules.
An average daily OFF time (using 3 days recording the Hauser diary prior to the visit) will be 
calculated at all time points for each subject, which includes Baseline (prior to Day 0), Week 
3, Week 5 and Week 10 (End of Period A), Week 13 (Period B; exists prior to Protocol 
Amendment 2 only) and also Week 15 (End of Period B). Change from baseline will then be 
calculated. Week 10 is the primary endpoint.

Week 3 Hauser home diary data will be collected at the Week 3 visit for subjects 
randomized prior to Protocol Amendment 2, and at the Week 3 visit for subjects 
randomized under Protocol Amendment 2, where sites choose to perform an in-clinic
visit (instead of a phone visit).

Week 3 Hauser home diary data will be collected at Week 4 for subjects randomized 
under Protocol Amendment 2, when sites perform a phone visit for Week 3. The 
Week 3 phone visit will be used as the nominal visit.
In calculating the average daily OFF time, the following algorithms and rules are applied.
(Rescue medication methods below are for all periods through Period A, and additionally 
Period B for subjects consented under Protocol Amendment 2 prior to entering Period B).
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 15
TMF Doc ID: 98.03
Valid Hauser Diary Days
1. Subjects who do not complete at least 12 awake hours of symptom diary data (not 
including ASLEEP time) will have that daily data set to missing (i.e. will not be 
considered as a valid symptom diary day).  There will be no imputation of data for 
these diary days.
2. Any Hauser diary day on which rescue medication was used will NOT be considered 
a valid symptom diary day.  The Hauser diary data reported on that day hereafter 
referred to as a rescue diary day, will not be used.  As described more completely in 
the instruction for daily OFF time below, baseline data will be used to impute the 
observed response on these days. (All periods through Period A, and additionally 
Period B for subjects consented under Protocol Amendment 2 prior to entering Period 
B).
Entries at 30-minute Intervals (Only for subjects who have ≥ 12 awake hours of Hauser 
home diary data)
3. If a single entry of 30 minutes is missing (ie, adjacent time points to that missing 
entry are not missing), an imputation algorithm will be employed using the adjacent 
available diary values carried forward and backward.  If the missing time period was 
the first half-hour of the diary, the value is carried back from the second time period. 
If the missing time period was the last half-hour of the diary, the value is carried 
forward from the second to last time period.  For missing time periods between the 
first and last half-hours, the first 15 minutes is imputed by carrying forward the 
value(s) from the previous half-hour and the second 15 minutes is imputed by 
carrying back the value(s) from the succeeding half-hour.  This imputation will be 
completed prior to proceeding to the next steps, and will include ASLEEP time. 
4. If data are missing for two or more consecutive 30-minute intervals between recorded 
ASLEEP times, fill in the missing 30-minute intervals with ASLEEP. Otherwise, 
record any missing between 10 PM and 6 AM as ASLEEP.
5. If data is missing for two or more consecutive 30-minute intervals, an imputation 
algorithm will be employed for each 30-minute interval using the available data at the 
other time intervals across the whole Hauser diary day.

Determine the % of awake proportions (no rounding), using available data for that 
home diary day, for ON with no dyskinesias, ON with non-troublesome 
dyskinesia, ON with troublesome dyskinesia, and OFF time. For example 
(rounding done for simplicity), 14 waking hours, 8 hours ON with no dyskinesias 
(57.14%), 4 hours ON with non-troublesome dyskinesia (28.57%), 1 hour ON 
with troublesome dyskinesia (7.14%), and 1 hour OFF time (7.14%). 
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 16
TMF Doc ID: 98.03

Multiply each of these proportions by 30 (round to integer) to have the imputation 
minutes for each of the missing 30-minutes diary intervals. For example, 17 
minutes (30*0.5714) ON with no dyskinesias, 9 minutes ON with non-
troublesome dyskinesia (28.57%), 2 minutes ON with troublesome dyskinesia 
(7.14%), and 2 minutes OFF time (7.14%). 

Each missing 30 minute interval under this imputation will be similarly imputed 
with the minutes in the above calculation. 
Daily OFF Time
6. All Hauser home diary data will be determined for a 24-hour period. All times are
expressed in decimal hours (two decimal places).
7. The daily OFF time for every rescue diary day will be replaced by the subject’s 
baseline OFF time, that is, the baseline 3-day average. (All periods through Period A, 
and additionally Period for subjects consented under Protocol Amendment 2 prior to 
entering Period B).
Daily Average (Rescue diary days are for all periods through Period A, and additionally 
Period B for subjects consented under Protocol Amendment 2 prior to entering Period B)
8. Valid home diary days (at least 12 awake hours, after all imputation) and/or rescue 
diary days will be used to compute the average daily OFF time.  The valid home or 
rescue diary day must be within 7 days of the clinic visit (or phone visit for Week 3 
only as noted below or assigned to the closest planned visit as noted below) but not 
on or after the day of the clinic visit.  If more than 3 valid home or rescue diary days 
are available, the 3 days closest to the clinic visit will be used.

Prior to Protocol Amendment 2, the three consecutive days before Day 0 could 
occur anytime during the screening period and was not restricted to within a week 
of the visit. Therefore, all home diaries before Day 0 will be considered for 
Baseline, with the 3 days closest to Day 0 being used for analysis.

Subjects, who have a phone visit for Week 3 and their home diary collected at 
Week 4, will use their Week 3 phone visit to determine within 7 days.

If a valid home or rescue diary is considered for exclusion based on the “within 7 
days” rule, it will still be included if its nominal visit is equal to the closest 
planned visit, otherwise it will be excluded. Planned visits: Baseline (Day -1), 
Week 3 (Day 21), Week 5 (Day 35) or Week 10 (Day 70).
i.
Example 1: A subject who completed Week 3 diaries on Days 8, 9, and 10 
with the actual Week 3 visit occurring on Day 21. All diaries excluded as 
all Week 3 diaries would all have been closer to Baseline (Day -1) then 
Week 3 (Day 21).
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 17
TMF Doc ID: 98.03
ii.
Example 2: A subject who completed Week 10 diaries on Days 61, 62 and 
63 with the actual Week 10 visit occurring on Day 70. All diaries 
included because the diaries are closest to Day 70 which matches the 
clinic visit (Week 10).
iii.
Example 3: A subject who completed their Week 3 diaries on Days 11, 12 
and 13 but the actual Day 21 visit occurred on Day 24. All diaries 
included because the diaries are closest to Day 21 which matches the 
clinic visit (Week 3).
9. If only 2 valid home or rescue diary days are available prior to a visit, data from the 2 
days will be used to calculate the average daily OFF time.
10. If only one valid home or rescue diary day is available the average daily from the last 
available week will be averaged with the daily OFF time from the one valid diary 
day.
11. Subjects that do not have any valid home diary days for a visit or who are completely 
missing a visit will have the average daily OFF time set to missing for that visit.
The extent of missing data will be evaluated as part of the Blind Data Review Meeting(s).  
Tabular displays will be developed to describe the extent of missing data.
3.2. Secondary Endpoint(s)
Secondary endpoints evaluated during the entire double-blind period include:

Daily OFF time (hours): change from baseline in average daily OFF time by Visit.

Daily ON time with troublesome dyskinesia (hours): change from baseline in average 
daily ON time with troublesome dyskinesia by Visit.

Daily ON time without troublesome dyskinesia (hours): the change from baseline in 
average daily ON time without troublesome dyskinesia (i.e. without dyskinesia or 
with non-troublesome dyskinesia, or alternatively “good time”) by Visit.
The same algorithm and rules employed for the calculation of OFF time will be used for the 
secondary variables. Baseline is defined using the 3 Hauser diary days prior to Day 0.

MDS – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III: Change 
from Baseline in MDS-UPDRS Part III Score by Visit.

MDS-UPDRS Parts I, II, IV, and total score: Change from Baseline in the MDS-
UPDRS Parts I, II, IV and Total Scores by visit.
The MDS-UPDRS will be collected at times specified in the STUDY PROCEDURES 
section of this protocol. Although not required, every effort should be made to have the same 
individual perform the ratings for an individual subject throughout the course of the study.  
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 18
TMF Doc ID: 98.03
MDS-UPDRS Part III should be assessed consistently and approximately 2 to 4 hours 
following L-Dopa dose (except at screening).  
3.2.1. MDS-UPDRS Part III
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.  There are four subscales:

The tremor subscale, which is the sum of scores for resting tremor amplitude in five 
body parts (5 items: right upper extremities, left upper extremities, right lower 
extremities, left lower extremities, and lip/jaw), postural tremor (2 items) and Kinetic 
tremor (2 items) in the hands (range 0–36).
If more than 1 item (>20%) is missing for a time point, the subscale score for that 
time point is missing; otherwise, the subscale score will be imputed as follows: sum 
of the non-missing items X (total number of items)/ (number of items non-missing).

The rigidity subscale is the sum of rigidity scores for limbs and neck (5 items, range 
0–20).
The subscale score will be missing if more than 1 item (>20%) is missing.

The bradykinesia subscale is the sum of scores for finger tapping (2 items), hand 
movements (2 items), pronation and supination movements (2 items), toe tapping (2 
items) and Global spontaneity of movement (body bradykinesia) (1 item) (range 0–
36).
If more than 1 item (>20%) is missing for a time point, the subscale score for that 
time point is missing; otherwise, the subscale score will be imputed as follows: sum 
of the non-missing items X (total number of items)/ (number of items non-missing).

The PIGD subscale is the sum of gait (1 item), freezing of gait (1 item) and postural 
stability (1 item) (range 0-12).
The subscale score will be missing if more than 1 item (>20%) is missing.
If more than 7 of the MDS-UPDRS Part III items are missing for a time point,5 the part score 
for that time point is missing; otherwise, the part score will be imputed as follows: sum of the 
non-missing items X (total number of items)/ (number of items non-missing).
Baseline will be the Day 0 measurement.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 19
TMF Doc ID: 98.03
3.2.2. MDS-UPDRS Parts I, II, IV, and Total Score
MDS-UPDRS Parts I, II, and IV will be done at times specified in the STUDY 
PROCEDURES section of the protocol. 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. Higher part and total scores indicate more severe signs of 
Parkinson’s disease.

Part I: Non-Motor Aspects of Experiences of daily Living (nM-EDL); this portion of 
the scale assesses the non-motor impact of Parkinson's disease on patients’ 
experiences of daily living. There are 13 questions. Part 1A is administered by the 
rater (six questions) and focuses on complex behaviors. Part 1B is a component of the 
self-administered Patient Questionnaire that covers seven questions on non-motor 
experiences of daily living. (range 0-52)
If more than 1 item is missing for a time point,5 the part score for that time point is 
missing; otherwise, the part score will be imputed as follows: sum of the non-missing 
items X (total number of items)/ (number of items non-missing).

Part II: Motor Aspects of Experiences of Daily Living (M-EDL); this portion of the 
scale assesses the motor impact of Parkinson's disease on patients’ experiences of 
daily living. There are 13 questions. (range 0-52)
If more than 2 items are missing for a time point,5 the part score for that time point is 
missing; otherwise, the part score will be imputed as follows: sum of the non-missing 
items X (total number of items)/ (number of items non-missing).

Part IV: Motor Complications; in this section, the rater uses historical and objective 
information to assess two motor complications, dyskinesias and motor fluctuations 
that include OFF-state dystonia. Use all information from patient, caregiver, and the 
examination to answer the six questions that summarize function over the past week 
including today. (range 0-24)
The part score will be missing if any underlying question is missing.5

MDS-UPDRS Total Score: The sum of Parts I, II, III, and IV.
The total scores will be missing if any underlying part score is missing.
Baseline will be the Day 0 measurement.
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 20
TMF Doc ID: 98.03
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 21
TMF Doc ID: 98.03
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 22
TMF Doc ID: 98.03
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 23
TMF Doc ID: 98.03
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 24
TMF Doc ID: 98.03
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 25
TMF Doc ID: 98.03
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 26
TMF Doc ID: 98.03
3.4. Baseline Variables
Baseline is defined as Day -1 (study derived day and equals to nominal visit Day 0 as noted 
in the protocol) measurement.
Baseline variables include 

Demographics;

Medical history;

Prior/current medication;

MMSE Total Score;

Hoehn & Yahr Stage while the subject is ON (if applicable);

Diary endpoints (OFF time + all other diary measures);

MDS-UPDRS (Part I, II, III, IV, and Total Score);


;

;


;

;

;

QUIP-RS;

Primary diagnosis and duration;

Prescribed L-Dopa dose;

Background concomitant Parkinson’s Disease medications (ATC level classification 
and a combination of the different classifications);

Region (stratification factor).
These data will be summarized as part of the baseline characteristics.
The sponsor or designee may verify critical elements of the screening and enrollment process 
and, in cases where verification is required, will provide written authorization (eg, e-mail) 
concurring with the investigator assessment that the subject is eligible to return for Day 0
(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 scores, concordance 
testing results, medical history, concomitant medications, and select screening safety 
assessments including labs, ECGs, and vital signs.  
Baseline daily OFF time will be a continuous covariate in the MMRM analysis of the 
primary analysis (See Section 5.2.2.1). Geographic region will also be a factor, and defined 
as North America, Japan, and Europe. The geographic regions are stratification factors for 
the randomization.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 27
TMF Doc ID: 98.03
Concomitant and prior medications will be coded using the WHO-drug coding dictionary. In 
addition, concomitant and prior non-drug treatments/procedures will also be coded using the 
MedDRA coding dictionary.
3.5. Safety Endpoints
Adverse events, ECGs, blood pressure, pulse 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.  
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 are 4 or more subjects with that PT in any treatment group, 
given the trial will have less than 400 or fewer subjects per treatment group (“Rule of 4”).
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).
Adverse Events will be determined Overall, and separately for Period A and Period B.
3.5.2. Laboratory Data
Laboratory data will be measured at times specified in the STUDY PROCEDURES section of 
the protocol. Prolactin data collection has the potential to unblind subjects and will be handled 
blindly by the study team.  The Data Blinding Plan will provide details.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 28
TMF Doc ID: 98.03
Baseline will be the Day 0 measurement.
Determine if there are any laboratory data abnormalities of potential clinical concern as 
defined in Pfizer Data Standards. This data will be determined Overall, and separately for 
Period A and Period B.
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. Subject temperature must also be assessed at
Screening and Day 0 (Randomization) to confirm no symptoms of fever (see Exclusion
Criteria #6). 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 0 measurement.
Determine if there is any blood pressure or pulse rate data abnormalities of potential clinical 
concern as defined in Pfizer Data Standards. This data will be determined Overall, and 
separately for Period A and Period B.
3.5.4. Electrocardiogram (ECG)
Electrocardiograms (ECGs) should be collected at times specified in the STUDY 
PROCEDURES section of this protocol. 
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.
Baseline will be the average of the triplicate ECG measurements collected on Day 0. Change 
and percent change from baseline will be calculated at each time point for each ECG 
parameter.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 29
TMF Doc ID: 98.03
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. This data will be determined Overall, and separately for Period A and 
Period B.
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. Assessment of Suicidal Ideation and Behavior 
3.5.7.1. 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. Versions are available for 
“lifetime/Past 12 months” and “since last evaluation”.  The “lifetime/Past 12 months” 
evaluation is done at screening, and the “since last evaluation” is done at all other time 
points.
The C-SSRS should be collected at times specified in the STUDY PROCEDURES section 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.
C-SSRS responses will be mapped to the Columbia Classification Algorithm of Suicide 
Assessment (C-CASA).
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 30
TMF Doc ID: 98.03
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”
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.   
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 31
TMF Doc ID: 98.03
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.
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 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 visit)
Baseline
Any post-baseline 
(or by visit)
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.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 32
TMF Doc ID: 98.03
3.5.7.2. Mental Health Risk Assessment (MHRA)
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 study. Specific criteria that indicate a need for such an assessment are:

Suicidal ideation associated with actual intent and/or plan in the past year; (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 10 years (a “YES” answer to any of 
the suicidal behavior items of the C-SSRS with the behavior occurring in the past 10 
years).

In the investigators judgment a risk assessment or exclusion is warranted.
When there is a positive response to any question on the C-SSRS, the investigator should 
determine whether an adverse event has occurred.
The PHQ-8 will be performed only at screening. Subjects that meet the Criterion PHQ-8 total 
score ≥15 indicate a need for risk assessment by MHP.
At the baseline visits (Screening, Day 0, or both), 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 study.
Subjects who respond “YES” to items 4, 5 or to any behavioral question of the C-SSRS at 
any time after the baseline visit (Screening or Day 0 (Randomization)) will be assessed by 
clinician/MHP to determine whether it is safe for the subject to continue in the study.
3.5.8. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease –
Rating Scale (QUIP-RS)
The Questionnaire for Impulsive-Compulsive Disorders (ICDs) in Parkinson’s Disease –
Rating Scale (QUIP-RS) is a brief, patient reported outcome measure designed to assess the 
severity of symptoms of ICDs and related behaviors reported to occur in Parkinson’s 
disease. 
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 
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 33
TMF Doc ID: 98.03
instructs subjects to answer questions based on behaviors that occurred in the preceding 
4 weeks (or any 4-week period in a designated time frame). 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. Scores will be computed for 
Gambling (0-16), Buying (0-16), Sex (0-16), Eating (0-16) and Total ICD score (0-64). The 
Total ICD score includes all 4 impulsive-compulsive disorders. Additionally, scores are 
computed for Hobbyism-punding (combined, 0-32), Compulsive medication use (0-16) and 
Total QUIP-RS score (0-112).  The Total QUIP-RS score includes all 7 disorders. The higher 
score indicates a greater level of the Impulsive-Compulsive Disorder.
The general principle of allowing up to 20% of missing responses is applied. Therefore, the 
following subscores are set as missing if any of the pertaining 4 primary questions has a 
missing response: Each of the four ICDs (compulsive gambling, buying, eating and sexual 
behavior) and compulsive medication use. For the hobbyism-punding subscore that has 8 
items, 1 missing response is allowed. For the Total ICD score that has 16 items, up to 3 
missing responses are allowed. For the Total QUIP-RS score that has 28 items, up to 5 
missing responses are allowed. This rule allows for the derivation of total scores even when 
some of the subscores are missing. With the presence of allowable missing responses, any 
sub or total will be calculated as follows:
3.5.9. Physician Withdrawal Checklist (PWC-20)
The PWC-20 is a physician-completed, 20-item reliable and sensitive instrument for the 
assessment of benzodiazepine discontinuation symptoms. The PWC-20 is collected after the 
completion of study treatment and also at the first visit of follow-up. 
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. 
If more than 5 items are missing, the total PWC-20 score is missing; otherwise, the total 
PWC-20 score will be imputed as follows: sum of the non-missing items 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.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 34
TMF Doc ID: 98.03
4.1. Full Analysis Set
The dataset used in the efficacy analyses will be the Full Analysis Set (FAS), consisting of all
subjects randomized who receive at least 1 post-dose efficacy measurement (Hauser home 
diary).  The FAS is the primary population for efficacy.
All subjects who receive at least 1 post-dose efficacy measurement will be classified 
according to their randomized treatment assignment. Randomized but took incorrect 
treatment subjects and randomized but not treated subjects will be reported under their 
randomized treatment group for all efficacy analyses. Treated but not randomized subjects 
will be excluded from the efficacy analyses since randomized treatment is missing.
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:

Treatment compliance is outside the 80%-120% compliance range, calculated based 
on pill count (See Section 6.5.3).

Subjects who did not have valid Baseline Hauser home diaries or fail to complete at 
least Week 5 Hauser diary measurements.

Subject with 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) that will impact data quality and/or the interpretation of 
the results.
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.  
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 35
TMF Doc ID: 98.03
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 Analysis Set (PPAS) has been determined, and the database has 
been locked.
5.1. Hypotheses and Decision Rules
5.1.1. Statistical Hypotheses
There are no formal statistical hypotheses in this study generally, and the study decision will 
be based on the two-part decision rule described in Section 5.1.2 on the primary endpoint 
daily OFF time in hours at Week 10. To control its overall study Type I error, a preliminary 
dose-response trend test of the hypothesis of H0: no effect for all doses will be performed at 
the one-sided 0.05 level.
5.1.2. Statistical Decision Rules
The decision criteria for efficacy are given as below, which will be based on a Bayesian 
interpretation of the results:
CCI
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 36
TMF Doc ID: 98.03

C1: Point estimate of PF-06649751 vs. placebo effect 1.5 hours, and

C2: 95% confident of PF-06649751 vs. placebo effect 0.
Better is defined as a reduction in the daily OFF time.
No adjustments for the interim analysis or multiple comparisons will be made.
5.2. General Methods 
Descriptive summaries for the efficacy, safety, baseline, and 
 will be 
displayed overall (combining both cohorts) and by cohort/treatment using the following 
combinations.  

Overall

Placebo;

PF-06649751 1 mg QD;

PF-06649751 3 mg QD;

PF-06649751 7 mg QD;

PF-06649751 15 mg QD; all 15 mg QD subjects;

PF-06649751 15-15 mg QD (safety only); subjects not requiring down titration;

PF-06649751 15-7 mg QD (safety only); subjects requiring down titration.

Cohort 1

Placebo

PF-06649751 15 mg QD;

PF-06649751 15-15 mg QD (safety only);

PF-06649751 15-7 mg QD (safety only).

Cohort 2

Placebo;

PF-06649751 1 mg QD;

PF-06649751 3 mg QD;

PF-06649751 7 mg QD;

PF-06649751 15 mg QD;

PF-06649751 15-15 mg QD (safety only);

PF-06649751 15-7 mg QD (safety only).
Note that several visits have been changed as a result of the B7601003 Protocol Amendment 
2.  Days 14 (Week 2) and 21 (Week 3) were required “in-clinic” visits and now may be 
handled as phone visits, so those with phone visits will have less data collected. Additionally, 
Day 91 (Week 13) is now exclusively a phone visit, so only subjects consented under 
Protocol Amendment 2 will have data available. All available visit data will be reported, and 
for descriptive statistics by time point each visit will be represented. Additionally, for 
subjects randomized in Japan, specific “in-clinic” visits (eg, Days 15 and 22) were not 
previously mentioned in the previous version of the SAP, but will be included in all 
reporting. Tables and listings will add footnotes as appropriate.
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 37
TMF Doc ID: 98.03
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 a normal 
approximation method. Also, the difference of the response rates (with 90% CIs) between 
each PF-06649751 treatment group and placebo group will be presented.
The analyses for binary data will utilize the logistic regression model (SAS code will be 
provide in the Programmer’s Analysis & Reporting documentation).  The response variable 
of the model will be the binary measurement (
).  The 
model will include the following terms as explanatory variables: geographic region and 
treatment. The odds ratio and its 90% confidence interval comparing each PF-06649751 dose 
versus placebo 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.
5.2.2.1. Mixed Model for Repeated Measures Analysis (Non-Bayesian Approach) 
The Mixed Model for Repeated Measures (MMRM) analysis will be based on an analysis of 
a restricted maximum likelihood (REML)-based mixed model. The response variable will be 
the change from baseline to each post baseline visit, and the model will include the following 
fixed effects:

randomized treatment (with 5 levels: PF-06649751 1 mg QD, 3 mg QD, 7 mg QD, 
15 mg QD, and placebo), a categorical factor;

visit, a categorical factor;

treatment-by-visit interaction;

baseline endpoint value, a continuous covariate;

baseline-by-visit interaction;

geographic region as appropriate (e.g. North America, Japan, and Europe).
In addition, cohort (Part A, Part B) may also be included as a fixed effect 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 
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 38
TMF Doc ID: 98.03
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 method7 will be used for calculating the 
denominator degrees of freedom for tests of fixed effects. OM option will be used to derive 
the least squares means similar to the observed margins.  Example SAS code for the MMRM 
model will be provided in the Programmer’s Analysis & Reporting documentation. 
The least-squares mean estimates, standard errors, and two-sided 90% CIs for each treatment 
groups will be reported. The efficacy comparisons based on the treatment difference vs. 
placebo estimated using least-squares means for each PF-06649751 dose will be conducted, 
and their point estimates, standard errors, and two-sided 90% CIs will be reported. 
The assumptions of normality will be verified graphically using residual plots. For each fitted 
model, studentized residual plots will be produced. The residual plots will not be included in 
the clinical study report, but will be sent to the statistician for inspection at the time the 
analysis is conducted.
5.2.2.2. Dose Response Analysis (Non-Bayesian Approach)
A four parameter Emax model will be used to estimate the dose response relationship.  The 
model is as follows:
; where,

y is the endpoint change from baseline;

D is the PF-06649751 dose in mg;

E0 is the placebo response;

Emax is the additive increase over placebo in the response of PF-06649751 at a 
theoretically infinite dose;

ED50 is the PF-06649751 dose in mg that provides an effect of E0 + Emax/2;

is the Hill parameter and measures the steepness of the dose response curve.
The non-linear dose response model will be fitted in two stages: a MMRM model described 
in Section 5.2.2.1 will firstly be modelled to the repeated measures data, and the response 
least squares estimates for the specified visit time as well as the estimated covariance matrix 
for the response estimates will be obtained. These MMRM estimates will then be fitted to the 
Emax model, based on the generalized least squares criterion using the inverse of the 
covariance matrix S as the weighting matrix: (f(dose,theta)-resp)'S-1(f(dose,theta)-resp). This 
fitting is based on the asymptotic normality assumption of the first stage MMRM estimates. 
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 39
TMF Doc ID: 98.03
Example R code for the dose response model utilizing DoseFinding package will be provided 
in the Programmer’s Analysis & Reporting documentation.
The efficacy comparisons will be based on the treatment difference vs. placebo estimated 
from this Emax model fit.  Their point estimates and two-sided 90% CIs from the fitted model 
will be reported.
An acceptable range of a true effect for an minimum effective dose (MED) will be evaluated 
from the Emax model, and is defined as the lowest PF-06649751 efficacious dose that 

is within the range of tested doses in the study, 

has a lower tested dose that is not efficacious, and

has a placebo-corrected point estimate between 1.5 and 2 hours.
5.2.2.3. Bayesian Analysis
In Bayesian analysis approach, Bayesian methods will be used to estimate the posterior 
distribution of the treatment effect. This will be done by combining the data from the study 
with prior belief about the placebo response.
Informative priors for the placebo response were derived from a Bayesian predictive meta-
analysis of a few recent and diverse Parkinson’s disease studies. It is possible that whilst the 
study is ongoing, data information from more sources may become available for 
incorporation into the informative prior for the placebo effect. The priors specified in this 
SAP may therefore be amended prior to final study reporting. Any change to the SAP-
specified priors will be documented in the CSR.
The informative priors for the placebo effect are defined as

Prior for the placebo effect for daily OFF time change from baseline ~ N(-1.0, 0.602)
A robust mixture prior approach (Bolstad 2007)2 will be used for all Bayesian analysis when 
incorporating informative prior for the placebo effect. The robust mixture informative prior 
takes into account that should the final data on the endpoint be sufficiently different to the 
prior perceived knowledge of placebo, then low-informative priors will be used rather than 
the informative priors. The informative prior is initially weighted with a 90% probability, 
with a 10% weight to the low-informative prior. The actual weighting of the informative and 
low-informative priors will be estimated from the data.
A low-informative prior is defined as a distribution with large variance, e.g. N(0, 106).
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 40
TMF Doc ID: 98.03
5.2.2.3.1. Bayesian ANOVA Model
In Bayesian ANOVA analysis, treatment will be modelled as a fixed effect, and the least 
squares estimates and their covariance from MMRM analysis described in Section 5.2.2.1 
will be input to the Bayesian analysis. Robust mixture informative prior will be used for the 
placebo effect, and low-informative prior will be used for all PF-06649751 dose effects. 
Example R and JAGS code for the Bayesian ANOVA model will be provided in the 
Programmer’s Analysis & Reporting documentation. 
The efficacy comparisons will be based on the treatment difference vs. placebo estimated 
from this Bayesian analysis.  Their posterior point estimates and two-sided 90% credible 
intervals from the fitted model will be reported.
5.2.2.3.2. Bayesian Dose Response Model
In Bayesian dose response analysis, the same four parameter Emax model as described in 
Section 5.2.2.2 will be used to model the dose response relationship. The least squares 
estimates and their covariance from MMRM analysis described in Section 5.2.2.1 will be 
inputted in the Bayesian analysis. Robust mixture informative prior will be used for the 
placebo effect, and weak empirically-based prior distributions,  based on meta-analysis of 
many dose response studies (Thomas et al 2014), will be used for the other model 
parameters. These weak priors are defined in this study as: 

Prior for Emax ~ N(0, 106);

Prior for ED50 = exp(ed50t) * projected ED50 (which is 3mg projected for 
PF-06649751 based on Ph1 studies), where ed50t ~ t distribution t(0.79,2.78,5);

Prior for = 6*lamt, where lamt ~ dbeta(3.03,18.15).
Example R and JAGS code for the Bayesian Emax model will be provided in the 
Programmer’s Analysis & Reporting documentation. The efficacy comparisons will be based 
on the treatment difference vs. placebo estimated from this Bayesian Emax model.  Their 
posterior point estimates and two-sided 90% credible intervals from the fitted model will be 
reported. MED will be similarly evaluated as described in Section 5.2.2.2.
A Bayes posterior predictive test for the monotonicity of the Emax fit will be conducted by 
computing the probability that the maximum response from lower doses (all 3 lower doses in 
this case) compared to the response from the highest dose is no better than predicted by the 
model (eg, Thomas et al 2014). Example R function code will be provided in the 
Programmer’s Analysis & Reporting documentation. A Bayes predictive probability of < 
0.05 will reject the monotonic Emax fit.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 41
TMF Doc ID: 98.03
5.2.2.4. Dose Response Trend Test
A test of the hypothesis of no effect for all doses will be performed at the one-sided 0.05 
level.  The MCP-MOD test (Bretz et al 2005)4 will be used, with contrasts constructed from 
the Emax model with candidate ED50 values of 0.5, 1, 3, 7, 15 and 30 mg. Example R 
function code will be provided in the Programmer’s Analysis & Reporting documentation.
5.2.3. Analyses for Categorical Data
Categorical data (eg, 
and 
) 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. Each PF-06649751 treatment dose will be separately compared to placebo 
controlling for the geographic region effect.  
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 the Hauser home diary data, an algorithm is used to handle missing 30-minute intervals 
(See Section 3.1). A summary of missing diary data will be presented by treatment group. 
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. 
Efficacy endpoint analyses in this study will be primarily based on observed cases (OC) and 
missing data will not be imputed, except for 
, in which case last observation carried forward (LOCF) will be utilized. 
Efficacy and safety analyses will be based on nominal visits as recorded on the CRFs.  The 
only exception will be the early termination (ET) visit if a subject terminates before 
completion of Week 15.  If the subject terminates before Week 15, the data collected at the 
early termination visit will be assigned to the closest planned visit (target day) for that 
efficacy or safety assessment.  If the early termination visit is equidistant to 2 visits, it will be 
assigned to the later visit.  If the early termination visit is associated with a visit that already 
exists, the non ET visit will be the representative visit.  However, for purposes of LOCF, if 
more than one value is in a visit window the latter value will be used to carry forward. For all 
safety categorical determinations, early termination and unplanned visits are considered even 
if they are not assigned to a visit.
If a subject is missing Baseline (eg, Day 0), the last measurement, taken prior to first 
exposure to the investigational product, will be used.
CCI
CCI
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 42
TMF Doc ID: 98.03
Concentrations below the limit of quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification).
Deviations, missing concentrations and anomalous values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
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.  
For all efficacy analyses and summaries (Sections 6.1, 6.2, 6.3{except 
} and 6.4): All data collected for 
subjects consented under Protocol Amendment 2 prior to entering Period B will be included 
for modelling and summaries. Otherwise, only data collected through Week 10 (Period A) 
will be included for subjects who do not meet the above condition, and their data collected 
after Week 10 will be in listings only.
6.1. Primary Endpoint(s)
6.1.1. Change from Baseline in Daily OFF time at Week 10 (end of Period A)
6.1.1.1. Primary Analysis
Endpoint: Daily OFF time

Analysis time points:  Week 10 (End of Period A)

Analysis population (method of imputation for missing data):  FAS (See Section 3.1)

Analysis methodology
Change from baseline will primarily be analyzed using the Bayesian Dose Response 
Analysis (See Section 5.2.2.3.2). If the Bayes posterior predictive test rejects the 
monotonic Emax fit (prob < 0.05), then the primary analysis will be based on the 
MMRM analysis (See Section 5.2.2.1). An overall dose-response trend test (See 
Section 5.2.2.4) will also be performed to control family-wise error rate.
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 43
TMF Doc ID: 98.03

Supporting objective and Decision rule: Primary Objective (See Section 2.1.1), 
Secondary Objective (See Section 2.1.2), and Decision rules C1, C2 (See Section 
5.1.2)
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 Bayesian point 
estimates, 90% credible interval, difference from placebo for each pair of treatment 
groups and the corresponding 90% credible interval will be presented. The MED 
estimate if applicable will be presented.  
Figures

Vertical bar chart of Change from Baseline Bayesian point estimates and 90% 
credible interval at Week 10. 

Bayesian Emax model graph with the MMRM estimates.

Change from baseline time profile per MMRM for each treatment group.
6.1.1.2. Sensitivity/Robustness Analyses
To support the interpretation of the primary analysis the following analyses will be 
performed:  
Endpoint: Daily OFF time

Analysis time points:  Week 10 (End of Period A);

Analysis populations (method of imputation for missing data):  FAS, PPAS, FAS-
Cohort 1 only, FAS-Cohort 2 only (See Section 3.1);

Analysis methodology:  Change from baseline will be analyzed using the MMRM 
analysis (See Section 5.2.2.1; FAS, FAS-Cohort 1 only), Bayesian ANOVA analysis 
(See Section 5.2.2.3.1; FAS, FAS-Cohort 1 only), Dose Response analysis (See 
Section 5.2.2.2; FAS, FAS-Cohort 2 only), and Bayesian Dose Response analysis 
(See Section 5.2.2.3.2; PPAS,FAS-Cohort 2 only).
Reporting results:

Raw data:  The missing data pattern will be shown by treatment group and overall, for 
the Hauser Diary up to Week 10.

Change from baseline:  The point estimate, 90% confidence or credible interval for 
the point estimate, difference from placebo for each pair of treatment groups and the 
corresponding 90% confidence or credible interval will be presented. The MED 
estimate if applicable will be presented.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 44
TMF Doc ID: 98.03
Figures

Empirical cumulative distribution function showing % of subjects with change from 
baseline <= cutoff value at Week 10 by treatment group; (any drop outs are assigned 
to the left side of x axis).
6.2. Secondary Endpoint(s)
6.2.1. Hauser Home Diary
Endpoints: Daily OFF time, Daily ON time with troublesome dyskinesia and Daily ON 
time without troublesome dyskinesia

Analysis time points:  All Visits;

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) and Dose Response Analysis (Daily ON time without 
troublesome dyskinesia at Week 10 only, See Section 5.2.2.2);  

Supporting objective and Decision rule: Primary Objective (See Section 2.1.1), 
Secondary Objective (See Section 2.1.2)
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 (Daily ON time with troublesome dyskinesia, without troublesome dyskinesia)

Line graphs of LS means and 90% confidence interval at all post-baseline visits.

Vertical bar chart of LS means and 90% confidence intervals at Week 10.

Empirical cumulative distribution function showing % of subjects with change from 
baseline <= cutoff value at Week 10 by treatment group; (any drop outs are assigned 
to the left side of x axis)

Dose response Emax model graph with the MMRM estimates at Week 10.
6.2.2. MDS-UPDRS
Endpoints: MDS-UPDRS Parts I, II, III, IV, and total score

Analysis time points:  All Visits 

Analysis population (method of imputation for missing data):  FAS (See Sections
3.2.1 and 3.2.2).

Analysis methodology:  Change from baseline will be analyzed using the MMRM 
Analysis (See Section 5.2.2.1) and Dose Response Analysis (MDS-UPDRS Part III 
@ Week 10 only, See Section 5.2.2.2).
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 45
TMF Doc ID: 98.03

Supporting objective and Decision rule: Secondary Objective (See Section 2.1.2).
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 10. 

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 10 by treatment group; (any drop outs are assigned 
to the left side of x axis).

Dose response Emax model graph with the MMRM estimates (MDS-UPDRS Part III
at Week 10 only).
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 46
TMF Doc ID: 98.03
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 47
TMF Doc ID: 98.03
6.4. Subset Analyses 
The primary endpoint will also be analyzed respectively for subset of subjects

in different geographic regions;

that have or do not have background PD medication changes during Period A; and

subjects that have <1000 mg/day or ≥1000 mg/day of L-Dopa intake during baseline. 
Only subgroup that has ≥ 10% of total subjects will be analyzed. If conducted, 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. Study Conduct and Subject Disposition
Data will be reported in accordance with Pfizer Data Standards.  Disposition will be further 
categorized by the treatment phase Titration, Dose Adjustment, Period A, Period B (may be 
separated by preA2 and A2), and Follow-up.
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 48
TMF Doc ID: 98.03
Overall subject disposition will include data through Double-Blind treatment period (study 
treatment period) and separately through Follow-up (overall study).
The number of subjects by region and country will be displayed.
6.5.2. Baseline Summaries
A breakdown of demographic data will be provided for age, race, weight, body mass index, 
height, and temperature.  Each parameter will be summarized 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). Physical measurements at Baseline 
will include weight, height, BMI, and temperature.
Also, medical history and primary diagnosis will be tabulated and listed in in accordance 
with the Pfizer Data Standards.
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 PF-06649751 or placebo dosing. Information will 
be captured in the listings only.
The following baseline characteristics will be summarized:

Hauser home diary endpoints (OFF time + all other diary measures) (continuous 
data);








QUIP-RS;

MMSE Total Score (continuous data);

Hoehn & Yahr Stage while the subject is ON (categorical data);

MDS-UPDRS Part I, II, III, IV, and Total Score at Baseline (continuous data);

Prescribed L-Dopa dose (continuous data);

Number of Background concomitant Parkinson’s Disease medications @ 
Randomization (categorical);

Region (categorical).
6.5.3. Study Treatment Exposure
Duration of exposure will be presented in tables and listings in accordance with the Pfizer 
Data Standards.  
CCI
CCI
CCI
CCI
CCI
CCI
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 49
TMF Doc ID: 98.03
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 = 100 x (Actual # of Capsules Taken) / (Total # Capsules Prescribed)
Subjects who fail to return blister information will be considered missing for that visit.
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. Concomitant Parkinson’s 
Disease medication(s) use will also be summarized by treatment group.
Frequency and type of medication will be summarized categorically by treatment group. 
Descriptive statistics of doses of background antipsychotic medication will also be 
summarized.
The number of rescue medication doses used for subjects will be presented by treatment 
group overall and by visit (summarized as continuous data). 
The number and percentage of subjects with a change in their background PD medications 
(excluding L-Dopa) for Period A and Period B (summarized as categorical data). 
6.6. Safety Summaries and Analyses
The safety analysis set is the primary population for the safety summaries and analyses.
Safety will be summarized Overall, and separately for Period A and Period B for data that is 
not presented by time point (eg, AEs, concomitant medications, Lab/VS/ECG categorical 
determinations).
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.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 50
TMF Doc ID: 98.03
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 1 mg versus 
Placebo, PF-06649751 3 mg versus Placebo, PF-06649751 7 mg versus Placebo, and PF-
06649751 15 mg versus Placebo.”
Tier-1 events for risk difference and relative risk will use unconditional exact methods (an 
approach proposed by Chan and Zhang, 19996) 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 exploratory analysis and its purpose is to generate hypotheses for 
further investigation. The 3-tier approach facilitates this exploratory 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.
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.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 51
TMF Doc ID: 98.03
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, absolute 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 QTcF1
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.
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.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 52
TMF Doc ID: 98.03
6.6.5. Physical Examination
Physical examination data will be listed and summarized within treatment group in 
accordance with the Pfizer Data Standards.
6.6.6. Neurological Examination
Neurological examination data will be presented in the listings.
6.6.7. Assessment of Suicidal Ideation and Behavior 
6.6.7.1. 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.
6.6.7.2. Mental Health Risk Assessment (MHRA)
A summary table by visit will indicate the number and percent of subjects that met the 
criteria for MHRA evaluation, whether the MHRA module was performed, and if the subject 
was either eligible to enter the study (Screening) or eligible to continue in the study (All 
visits after Screening).  The category of subjects that met the criteria for MHRA evaluation 
will include additional details on the criteria met:

Screening: 

PHQ-8 total score ≥15, 

Subject answered “YES” on C-SSRS item 4, 5, or any suicidal behavior question 
on the C-SSRS, 

Active suicidal ideation (with method and/or plan and/or intent) in the past year, 

Previous history of suicidal behavior in the past 10 years, and 

Principal Investigator’s Discretion.

All Visits after Screening: 

Subject answered "YES" on C-SSRS item 4, 5, or on any suicidal behavior 
question on the C-SSRS, 

Principal Investigator’s Discretion.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 53
TMF Doc ID: 98.03
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, absolute values and 
change from baseline values within each treatment will be summarized with descriptive 
statistics for the 8 different scoring types. Additionally, the number and percentage of 
subjects with each of the 8 different scoring types will be presented.
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.
7. INTERIM ANALYSES
7.1. Introduction
Up to two interim analyses may be performed when approximately 27% and 80% subjects 
are randomized and have the opportunity to complete through Period A of the study.  The 
first interim analysis will be conducted when Cohort 1 (approximately 54 subjects in a 
2:1 ratio of 15 mg QD and placebo groups respectively) is completed through Period A and 
efficacy data have been collected, databased and cleaned.  A second interim analysis may be 
undertaken when approximately 104 subjects complete through Period A of Cohort 2 
(1:2:2:2:1 in 15 mg QD, 7 mg QD, 3 mg QD, 1 mg QD, and placebo respectively) and 
efficacy data have been collected, databased and cleaned.  The purpose of these interim 
analyses 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. 
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.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 54
TMF Doc ID: 98.03
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 blinded 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 interim analysis SAP.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 55
TMF Doc ID: 98.03
8. REFERENCES 
1.
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs.  CHMP/ICH/2/04.
2.
W. Bolstad (2007) Introduction to Bayesian Statistics: Second Edition London: John 
Wiley & Sons.
3.
N. Thomas, K. Sweeney, and V. Somayaji. Meta-analysis of clinical dose-response in a 
large drug development portfolio. Statistics in Biopharmaceutical Research, 6(4): 302-
317, 2014.
4.
F. Bretz, J. Pinheiro, and M. Branson (2005). Combining multiple comparisons and 
modeling techniques in dose-response studies. Biometrics 61, 738-748.
5.
Goetz, et al. Handling Missing Values in the MDS-UPDRS. Movement Disorders 
(2015).
6.
Chan ISF, Zhang Z. (1999). Test-based exact confidence intervals for the difference of 
two binomial proportions. Biometrics, 55:1201–1209.
7.
Kenward, M. G., and Roger, J. H. (1997). “Small Sample Inference for Fixed Effects 
from Restricted Maximum Likelihood.” Biometrics 53:983–997.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 56
TMF Doc ID: 98.03
9. APPENDICES 
Appendix 1. SUMMARY OF EFFICACY ANALYSES
Endpoint 
Analysis Set
Statistical Method 
Missing 
Data
Interpretation
Daily OFF time, 
Week 10
FAS
Bayesian Dose Response 
Analysis. If the Bayes 
posterior predictive test 
rejects the monotonic Emax 
fit (prob < 0.05), then the 
primary analysis will be 
based on the MMRM 
analysis. 
OC
Primary 
Analysis
Daily OFF time, 
Week 10
FAS
MMRM
OC
Sensitivity 
Analysis
Daily OFF time, 
Week 10
FAS
Bayesian ANOVA
OC
Sensitivity 
Analysis
Daily OFF time, 
Week 10
FAS
Dose Response
OC
Sensitivity 
Analysis
Daily OFF time, 
Week 10
PPAS
Bayesian Dose Response
OC
Sensitivity 
Analysis
Daily OFF time, 
Week 10
FAS-Cohort 1 
MMRM
OC
Sensitivity 
Analysis
Daily OFF time, 
Week 10
FAS-Cohort 1 
Bayesian ANOVA
OC
Sensitivity 
Analysis
Daily OFF time, 
Week 10
FAS-Cohort 2 
Dose Response
OC
Sensitivity 
Analysis
Daily OFF time, 
Week 10
FAS-Cohort 2 
Bayesian Dose Response
OC
Sensitivity 
Analysis
Daily OFF time, 
All Visits
FAS
MMRM
OC
Secondary 
Analysis
Daily ON time 
with troublesome 
FAS
MMRM
OC
Secondary 
Analysis
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 57
TMF Doc ID: 98.03
dyskinesia, All 
Visits
Daily ON time 
with troublesome 
dyskinesia, Week 
10
FAS
Dose Response
OC
Secondary 
Analysis
Daily ON time 
without 
troublesome 
dyskinesia, All 
Visits
FAS
MMRM
OC
Secondary 
Analysis
Daily ON time 
without
troublesome 
dyskinesia, Week 
10
FAS
Dose Response
OC
Secondary 
Analysis
MDS-UPDRS 
Parts III, All Visits
FAS
MMRM
OC
Secondary 
Analysis
MDS-UPDRS 
Parts III, Week 10
FAS
Dose Response
OC
Secondary 
Analysis
MDS-UPDRS 
Parts I, II, IV, and 
total score, All 
Visits
FAS
MMRM
OC
Secondary 
Analysis
Daily OFF time, 
Week 10
FAS-North 
America
(Optional*)
MMRM
OC
Subset
Analysis
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 58
TMF Doc ID: 98.03
Daily OFF time, 
Week 10
FAS-EU
(Optional*)
MMRM
OC
Subset 
Analysis
Daily OFF time, 
Week 10
FAS-Japan
(Optional*)
MMRM
OC
Subset 
Analysis
Daily OFF time, 
Week 10
FAS-no 
background PD 
medication 
change
(Optional*)
MMRM
OC
Subset 
Analysis
Daily OFF time, 
Week 10
FAS-background 
PD medication 
change
(Optional*)
MMRM
OC
Subset 
Analysis
Daily OFF time, 
Week 10
FAS-<1000 mg 
/day and ≥1000 
mg/day L-dopa 
intake 
(Optional*)
MMRM
OC
Subset 
Analysis
* Only subgroups that have ≥ 10% of total subjects will be analyzed.
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)


Protocol B7601003 (PF-06649751) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 59
TMF Doc ID: 98.03
CCI
090177e18f6e873a\Approved\Approved On: 26-Sep-2018 05:14 (GMT)