Efficacy, Safety and Tolerability of PF-06649751 in Parkinson's Disease Patients at Early Stage of the Disease

• Sponsor: Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02847650
• Collaborator: (none)
• Enrollment: 57
• Locations: 37
• Arms: 2
• Actual Duration (Months): 15.4
• Patients Per Site: 1.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Parkinson Disease	Drug: Placebo; Drug: PF-06649751	Phase 2

Detailed Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 57 participants
• Allocation: Randomized
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A 15-WEEK, PHASE 2, DOUBLE BLIND, RANDOMIZED, PLACEBO-CONTROLLED, FLEXIBLE DOSE STUDY TO INVESTIGATE THE EFFICACY, SAFETY AND TOLERABILITY OF PF-06649751 IN SUBJECTS WITH EARLY STAGE PARKINSON'S DISEASE
• Actual Study Start Date: Oct 17, 2016
• Actual Primary Completion Date: Jan 29, 2018
• Actual Study Completion Date: Jan 29, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo	Drug: Placebo; Other Names: oral tablet once daily
Experimental: PF-06649751	Drug: PF-06649751; Other Names: flexible dose oral tablet once daily

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III Total Score at Week 15 [Baseline (Day -1/randomization), Week 15]

   MDS-UPDRS Part III was used to assess the motor signs of Parkinson's disease. It was comprised of 33 sub-scores based on 18 items, several with right, left or other body distribution scores. Each question was anchored with 5 responses that were linked to commonly accepted clinical terms: 0=normal, 1=slight, 2=mild, 3=moderate, and 4=severe. The MDS-UPDRS Part III total score range is 0-132. Higher score indicates more severe motor signs of Parkinson's disease. A negative change from baseline represents an improvement in motor function.

Secondary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [From first dose of study treatment up to 28 days after last dose (up to Day 133)]

   An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment.

2. Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) [Baseline (Day -1/randomization) up to Day 119 follow-up visit]

   Following safety laboratory parameters were assessed against pre-defined abnormality criteria: hematology (hemoglobin, hematocrit, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, white blood cell count, absolute total neutrophils, absolute eosinophils, absolute basophils, absolute monocytes, and absolute lymphocytes); chemistry (blood urea nitrogen/urea and creatinine, glucose , calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, alkaline phosphatase, uric acid, albumin, total protein); urinalysis (pH, qualitative glucose, qualitative protein, qualitative blood, ketones, nitrites, leukocyte esterase, urine bilirubin, urobilinogen, urine creatinine, microscopy, and specific gravity).

3. Number of Participants With Vital Signs Data Meeting Categorical Summarization and Orthostatic Hypotension Criteria [Baseline (Day -1/randomization) up to Day 119 follow-up visit]

   Vital signs categorical summarization criteria: 1) supine and standing systolic blood pressure (SBP) <90 millimeters of mercury (mmHg); 2) supine and standing diastolic blood pressure (DBP) <50 mmHg; 3) supine pulse rate <40 or >120 beats per minute (bpm); 4) standing pulse rate <40 or >140 bpm; 5) maximum change from baseline (increase or decrease) in supine and standing DBP greater than or equal to (>=) 20 mmHg; 6) maximum change from baseline (increase or decrease) in supine and standing SBP >=30 mmHg. Orthostatic hypotension criterion was defined as a decrease of >=20 mmHg for SBP or >=10 mmHg for DBP 2 minutes after standing from a supine position.

4. Number of Participants Meeting the Categorical Summarization Criteria for Electrocardiogram (ECG) Parameters [Baseline (Day -1/randomization) up to Day 119 follow-up visit]

   ECG categorical summarization criteria: 1) QRS duration (time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization): >=140 milliseconds (msec), >=50% increase from baseline; 2) PR interval (the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization): >=300 msec, >=25% increase when baseline is > 200 msec or >=50% increase when baseline is less than or equal to (<=) 200 msec; 3) QT interval (time from ECG Q wave to the end of the T wave corresponding to electrical systole): absolute value of >=500 msec; 4) QTcF interval (QT corrected for heart rate using Fridericia's formula): absolute value of 450 to <480 msec, 480 to <500 msec, >=500 msec; an increase from baseline of 30 to <60 msec or >=60 msec.

5. Number of Participants With Worsening and New Onset Suicidality as Assessed by Columbia Suicide Severity Rating Scale (C-SSRS) [Baseline (Day -1/randomization) up to Day 119 follow-up visit]

   The C-SSRS is an interview based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS responses were mapped to the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Participants with new onset suicidality were those without suicidal ideation and behavior at baseline and reported any suicidal behavior or ideation post-baseline as assessed by C-CASA code mapped from C-SSRS data. Participants with worsening suicidality were those who moved to a lower numbered C-CASA category than was reported at baseline.

6. Change From Baseline in Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease - Rating Scale (QUIP-RS) Total Score at Days 35, 63, and 105 [Baseline (Day -1 or randomization); Days 35, 63, 105]

   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). Each question is anchored with the following 5 responses: Never (0), Rarely (1), Sometimes (2), Often (3), and Very Often (4). The scoring range for each item (ie, disorder) is 0-16. The QUIP-RS total score range is 0-64. Higher score indicates a greater level of the impulsive compulsive disorder.

7. Total Physician Withdrawal Checklist (PWC-20) Score [Day 119]

   The PWC-20 is a 20-item reliable and sensitive instrument for the assessment of benzodiazepine-like discontinuation symptoms. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Females of non-childbearing potential and/or male subjects

• Clinical diagnosis of Parkinson's disease.

• Parkinson's Disease Hoehn & Yahr Stage I-III inclusive

• Treatment naïve or history of prior incidental treatment with dopaminergic agents for no more than 28 days

• Able to refrain from any Parkinson's disease medication not permitted by the protocol.

Exclusion Criteria:

• History or presence of atypical Parkinsonian syndrome.

• Severe acute or chronic medical or psychiatric condition or cognitive impairment or laboratory abnormality.

• Any condition possibly affecting drug absorption.

• Participation in other studies involving investigational drug(s), or treatment with any investigational drug within 30 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St Joseph's Hospital and Medical Center, Barrow Neurology Clinics	Phoenix	Arizona	United States	85013
2	St. Joseph's Hospital and Medical Center	Phoenix	Arizona	United States	85013
3	Parkinson's Disease and Movement Disorders Center of Boca Raton	Boca Raton	Florida	United States	33486
4	University of Miami	Miami	Florida	United States	33136
5	University of South Florida Carol and Frank Morsani Center for Advanced Health Care	Tampa	Florida	United States	33612
6	University of South Florida Faculty Office Building	Tampa	Florida	United States	33612
7	University of South Florida	Tampa	Florida	United States	33612
8	University of South Florida Parkinson's Disease and Movement Disorders Center	Tampa	Florida	United States	33613
9	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30331
10	Rush University Medical Center	Chicago	Illinois	United States	60612
11	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
12	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
13	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
14	Asheville Neurology Specialists PA	Asheville	North Carolina	United States	28806
15	Cleveland Clinic	Cleveland	Ohio	United States	44195
16	University of Toledo, Gardner-McMaster Parkinson Center	Toledo	Ohio	United States	43614
17	University of Toledo	Toledo	Ohio	United States	43614
18	AS Clinical Research Consultants of North Texas, PLLC	Greenville	Texas	United States	75401
19	Baylor College of Medicine	Houston	Texas	United States	77030
20	Sentara Neurology Specialists	Virginia Beach	Virginia	United States	23456
21	Hôpital Henri Mondor	CRÉTEIL Cedex		France	94010
22	Hopital Henri Mondor	Créteil		France	94010
23	CHU de Grenoble Alpes	Grenoble		France	38043
24	CHU Grenoble Alpes	La Tronche		France	38700
25	Hospital de La Timone	Marseille		France	13385 Cedex 05
26	Hospital La Timone	Marseille		France	13385 cedex 05
27	Hopital Pitie Salpetriere	Paris		France	75013
28	Hopital Pitie-Salpetriere	Paris		France	75651 cedex 13
29	St. Josef Hospital GmbH	Bochum	Nordrhein-westfalen	Germany	44791
30	Praxis Oehlwein Outpatient clinic for PD, DBS, Movement Disorders	Gera		Germany	07551
31	Klinik Haag i. OB	Haag I. OB		Germany	83527
32	Paracelsus-Elena-Klinik Kassel	Kassel		Germany	34128
33	Universitätsklinikum Gießen und Marburg GmbH	Marburg		Germany	35043
34	University hospital Tuebingen	Tuebingen		Germany	72076
35	Universitaetsklinik Ulm	Ulm		Germany	89081
36	Edith Wolfson Medical Center	Holon		Israel	58100
37	Pharmacy, Edith Wolfson Medical Center	Holon		Israel	58100

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

• Study Protocol - Jul 20, 2016
• Statistical Analysis Plan - Aug 4, 2016

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02847650
• Other Study ID Numbers: B7601011; 2016-001575-71
• First Posted: Jul 28, 2016
• Last Update Posted: Nov 23, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Pfizer: Early Parkinson Disease; Phase 2
• Additional relevant MeSH terms: Parkinson Disease

Study Results

Participant Flow

Arm/Group Title	PF-06649751	Placebo
Arm/Group Description	Eligible participants were up-titrated in a double-blind fashion to an optimal dose level of PF-06649751 according to a flexible dose titration scheme (from 0.25 mg to 15 mg once daily [QD]). The 15-week treatment period included 9 weeks of dose optimization and 6 weeks of stable dosing. Blinded PF-06649751 was provided as tablets for oral administration in the outpatient setting (each morning, daily for the duration of the treatment period). Reaching of the maximum allowed dose level (15 mg) was not mandatory; participants might achieve a satisfactory clinical response at a lower dose level. There was an additional follow-up period of 28 days following discontinuation of PF-06649751.	Matching placebo tablet for QD dosing in the 15-week double-blind treatment period. There was an additional follow-up period of 28 days following discontinuation of placebo.
Period Title: Overall Study
STARTED	29	28
COMPLETED	25	22
NOT COMPLETED	4	6

Baseline Characteristics

Arm/Group Title	PF-06649751	Placebo	Total
Arm/Group Description	Eligible participants were up-titrated in a double-blind fashion to an optimal dose level of PF-06649751 according to a flexible dose titration scheme (from 0.25 mg to 15 mg once daily [QD]). The 15-week treatment period included 9 weeks of dose optimization and 6 weeks of stable dosing. Blinded PF-06649751 was provided as tablets for oral administration in the outpatient setting (each morning, daily for the duration of the treatment period). Reaching of the maximum allowed dose level (15 mg) was not mandatory; participants might achieve a satisfactory clinical response at a lower dose level. There was an additional follow-up period of 28 days following discontinuation of PF-06649751.	Matching placebo tablet for QD dosing in the 15-week double-blind treatment period. There was an additional follow-up period of 28 days following discontinuation of placebo.	Total of all reporting groups
Overall Participants	29	28	57
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.76 (8.34)	63.36 (9.16)	64.07 (8.71)
Sex: Female, Male (Count of Participants)
Female	9 31%	14 50%	23 40.4%
Male	20 69%	14 50%	34 59.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 6.9%	1 3.6%	3 5.3%
Not Hispanic or Latino	27 93.1%	27 96.4%	54 94.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 3.4%	3 10.7%	4 7%
White	28 96.6%	25 89.3%	53 93%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III Total Score at Week 15
Description	MDS-UPDRS Part III was used to assess the motor signs of Parkinson's disease. It was comprised of 33 sub-scores based on 18 items, several with right, left or other body distribution scores. Each question was anchored with 5 responses that were linked to commonly accepted clinical terms: 0=normal, 1=slight, 2=mild, 3=moderate, and 4=severe. The MDS-UPDRS Part III total score range is 0-132. Higher score indicates more severe motor signs of Parkinson's disease. A negative change from baseline represents an improvement in motor function.
Time Frame	Baseline (Day -1/randomization), Week 15

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study treatment (PF-06649751 or placebo) and had a baseline and Week 15 MDS-UPDRS score Part III.

Arm/Group Title	PF-06649751	Placebo
Arm/Group Description	Eligible participants were up-titrated in a double-blind fashion to an optimal dose level of PF-06649751 according to a flexible dose titration scheme (from 0.25 mg to 15 mg once daily [QD]). The 15-week treatment period included 9 weeks of dose optimization and 6 weeks of stable dosing. Blinded PF-06649751 was provided as tablets for oral administration in the outpatient setting (each morning, daily for the duration of the treatment period). Reaching of the maximum allowed dose level (15 mg) was not mandatory; participants might achieve a satisfactory clinical response at a lower dose level. There was an additional follow-up period of 28 days following discontinuation of PF-06649751.	Matching placebo tablet for QD dosing in the 15-week double-blind treatment period. There was an additional follow-up period of 28 days following discontinuation of placebo.
Measure Participants	25	22
Least Squares Mean (Standard Error) [units on a scale]	-9.0 (1.54)	-4.3 (1.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PF-06649751, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0407
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.8
	Confidence Interval	(2-Sided) 90%; -8.6 to -1.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.26
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment.
Time Frame	From first dose of study treatment up to 28 days after last dose (up to Day 133)

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study treatment (PF-06649751 or placebo).

Arm/Group Title	PF-06649751	Placebo
Arm/Group Description	Eligible participants were up-titrated in a double-blind fashion to an optimal dose level of PF-06649751 according to a flexible dose titration scheme (from 0.25 mg to 15 mg once daily [QD]). The 15-week treatment period included 9 weeks of dose optimization and 6 weeks of stable dosing. Blinded PF-06649751 was provided as tablets for oral administration in the outpatient setting (each morning, daily for the duration of the treatment period). Reaching of the maximum allowed dose level (15 mg) was not mandatory; participants might achieve a satisfactory clinical response at a lower dose level. There was an additional follow-up period of 28 days following discontinuation of PF-06649751.	Matching placebo tablet for QD dosing in the 15-week double-blind treatment period. There was an additional follow-up period of 28 days following discontinuation of placebo.
Measure Participants	29	28
AEs	25 86.2%	18 64.3%
SAEs	1 3.4%	0 0%

3. Secondary Outcome

Title	Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)
Description	Following safety laboratory parameters were assessed against pre-defined abnormality criteria: hematology (hemoglobin, hematocrit, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, white blood cell count, absolute total neutrophils, absolute eosinophils, absolute basophils, absolute monocytes, and absolute lymphocytes); chemistry (blood urea nitrogen/urea and creatinine, glucose , calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, alkaline phosphatase, uric acid, albumin, total protein); urinalysis (pH, qualitative glucose, qualitative protein, qualitative blood, ketones, nitrites, leukocyte esterase, urine bilirubin, urobilinogen, urine creatinine, microscopy, and specific gravity).
Time Frame	Baseline (Day -1/randomization) up to Day 119 follow-up visit

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study treatment (PF-06649751 or placebo) and had at least 1 observation of the given laboratory test.

Arm/Group Title	PF-06649751	Placebo
Arm/Group Description	Eligible participants were up-titrated in a double-blind fashion to an optimal dose level of PF-06649751 according to a flexible dose titration scheme (from 0.25 mg to 15 mg once daily [QD]). The 15-week treatment period included 9 weeks of dose optimization and 6 weeks of stable dosing. Blinded PF-06649751 was provided as tablets for oral administration in the outpatient setting (each morning, daily for the duration of the treatment period). Reaching of the maximum allowed dose level (15 mg) was not mandatory; participants might achieve a satisfactory clinical response at a lower dose level. There was an additional follow-up period of 28 days following discontinuation of PF-06649751.	Matching placebo tablet for QD dosing in the 15-week double-blind treatment period. There was an additional follow-up period of 28 days following discontinuation of placebo.
Measure Participants	28	28
Count of Participants [Participants]	19 65.5%	19 67.9%

4. Secondary Outcome

Title	Number of Participants With Vital Signs Data Meeting Categorical Summarization and Orthostatic Hypotension Criteria
Description	Vital signs categorical summarization criteria: 1) supine and standing systolic blood pressure (SBP) <90 millimeters of mercury (mmHg); 2) supine and standing diastolic blood pressure (DBP) <50 mmHg; 3) supine pulse rate <40 or >120 beats per minute (bpm); 4) standing pulse rate <40 or >140 bpm; 5) maximum change from baseline (increase or decrease) in supine and standing DBP greater than or equal to (>=) 20 mmHg; 6) maximum change from baseline (increase or decrease) in supine and standing SBP >=30 mmHg. Orthostatic hypotension criterion was defined as a decrease of >=20 mmHg for SBP or >=10 mmHg for DBP 2 minutes after standing from a supine position.
Time Frame	Baseline (Day -1/randomization) up to Day 119 follow-up visit

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study treatment (PF-06649751 or placebo).

Arm/Group Title	PF-06649751	Placebo
Arm/Group Description	Eligible participants were up-titrated in a double-blind fashion to an optimal dose level of PF-06649751 according to a flexible dose titration scheme (from 0.25 mg to 15 mg once daily [QD]). The 15-week treatment period included 9 weeks of dose optimization and 6 weeks of stable dosing. Blinded PF-06649751 was provided as tablets for oral administration in the outpatient setting (each morning, daily for the duration of the treatment period). Reaching of the maximum allowed dose level (15 mg) was not mandatory; participants might achieve a satisfactory clinical response at a lower dose level. There was an additional follow-up period of 28 days following discontinuation of PF-06649751.	Matching placebo tablet for QD dosing in the 15-week double-blind treatment period. There was an additional follow-up period of 28 days following discontinuation of placebo.
Measure Participants	29	28
Supine SBP <90 mmHg	0 0%	0 0%
Standing SBP <90 mmHg	0 0%	0 0%
Supine DBP <50 mmHg	0 0%	0 0%
Standing DBP <50 mmHg	0 0%	0 0%
Supine pulse rate <40 bpm	0 0%	0 0%
Supine pulse rate >120 bpm	0 0%	0 0%
Standing pulse rate <40 bpm	0 0%	0 0%
Standing pulse rate >140 bpm	0 0%	0 0%
Maximum increase in standing DBP >=20 mmHg	0 0%	0 0%
Maximum increase in standing SBP >=30 mmHg	0 0%	0 0%
Maximum increase in supine DBP >=20 mmHg	0 0%	1 3.6%
Maximum increase in supine SBP >=30 mmHg	0 0%	3 10.7%
Maximum decrease in standing DBP >=20 mmHg	8 27.6%	2 7.1%
Maximum decrease in standing SBP >=30 mmHg	4 13.8%	1 3.6%
Maximum decrease in supine DBP >=20 mmHg	9 31%	1 3.6%
Maximum decrease in supine SBP >=30 mmHg	5 17.2%	0 0%
SBP postural difference(supine-standing) >=20mmHg	1 3.4%	2 7.1%
DBP postural difference(supine-standing) >=10mmHg	3 10.3%	1 3.6%

5. Secondary Outcome

Title	Number of Participants Meeting the Categorical Summarization Criteria for Electrocardiogram (ECG) Parameters
Description	ECG categorical summarization criteria: 1) QRS duration (time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization): >=140 milliseconds (msec), >=50% increase from baseline; 2) PR interval (the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization): >=300 msec, >=25% increase when baseline is > 200 msec or >=50% increase when baseline is less than or equal to (<=) 200 msec; 3) QT interval (time from ECG Q wave to the end of the T wave corresponding to electrical systole): absolute value of >=500 msec; 4) QTcF interval (QT corrected for heart rate using Fridericia's formula): absolute value of 450 to <480 msec, 480 to <500 msec, >=500 msec; an increase from baseline of 30 to <60 msec or >=60 msec.
Time Frame	Baseline (Day -1/randomization) up to Day 119 follow-up visit

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study treatment (PF-06649751 or placebo). "Number Analyzed" represents the number of participants evaluable for each specified category.

Arm/Group Title	PF-06649751	Placebo
Arm/Group Description	Eligible participants were up-titrated in a double-blind fashion to an optimal dose level of PF-06649751 according to a flexible dose titration scheme (from 0.25 mg to 15 mg once daily [QD]). The 15-week treatment period included 9 weeks of dose optimization and 6 weeks of stable dosing. Blinded PF-06649751 was provided as tablets for oral administration in the outpatient setting (each morning, daily for the duration of the treatment period). Reaching of the maximum allowed dose level (15 mg) was not mandatory; participants might achieve a satisfactory clinical response at a lower dose level. There was an additional follow-up period of 28 days following discontinuation of PF-06649751.	Matching placebo tablet for QD dosing in the 15-week double-blind treatment period. There was an additional follow-up period of 28 days following discontinuation of placebo.
Measure Participants	29	28
PR interval >=300 msec	0 0%	0 0%
QRS duration >=140 msec	0 0%	0 0%
QT interval >=500 msec	0 0%	0 0%
QTcF interval >=450 msec to <480 msec	0 0%	0 0%
QTcF interval >=480 msec to <500 msec	0 0%	0 0%
QTcF interval >=500 msec	0 0%	0 0%
Percent increase in PR interval >=25/50%	0 0%	0 0%
Percent increase in QRS duration >=50%	0 0%	0 0%
Increase in QTcF interval >=30 msec to <60 msec	1 3.4%	2 7.1%
Increase in QTcF interval >=60 msec	0 0%	0 0%

6. Secondary Outcome

Title	Number of Participants With Worsening and New Onset Suicidality as Assessed by Columbia Suicide Severity Rating Scale (C-SSRS)
Description	The C-SSRS is an interview based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS responses were mapped to the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Participants with new onset suicidality were those without suicidal ideation and behavior at baseline and reported any suicidal behavior or ideation post-baseline as assessed by C-CASA code mapped from C-SSRS data. Participants with worsening suicidality were those who moved to a lower numbered C-CASA category than was reported at baseline.
Time Frame	Baseline (Day -1/randomization) up to Day 119 follow-up visit

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study treatment (PF-06649751 or placebo).

Arm/Group Title	PF-06649751	Placebo
Arm/Group Description	Eligible participants were up-titrated in a double-blind fashion to an optimal dose level of PF-06649751 according to a flexible dose titration scheme (from 0.25 mg to 15 mg once daily [QD]). The 15-week treatment period included 9 weeks of dose optimization and 6 weeks of stable dosing. Blinded PF-06649751 was provided as tablets for oral administration in the outpatient setting (each morning, daily for the duration of the treatment period). Reaching of the maximum allowed dose level (15 mg) was not mandatory; participants might achieve a satisfactory clinical response at a lower dose level. There was an additional follow-up period of 28 days following discontinuation of PF-06649751.	Matching placebo tablet for QD dosing in the 15-week double-blind treatment period. There was an additional follow-up period of 28 days following discontinuation of placebo.
Measure Participants	29	28
Worsening suicidality	0 0%	0 0%
New onset suicidality	1 3.4%	0 0%

7. Secondary Outcome

Title	Change From Baseline in Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease - Rating Scale (QUIP-RS) Total Score at Days 35, 63, and 105
Description	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). Each question is anchored with the following 5 responses: Never (0), Rarely (1), Sometimes (2), Often (3), and Very Often (4). The scoring range for each item (ie, disorder) is 0-16. The QUIP-RS total score range is 0-64. Higher score indicates a greater level of the impulsive compulsive disorder.
Time Frame	Baseline (Day -1 or randomization); Days 35, 63, 105

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study treatment (PF-06649751 or placebo). "Number Analyzed" = Participants evaluable for this outcome measure at specified time points.

Arm/Group Title	PF-06649751	Placebo
Arm/Group Description	Eligible participants were up-titrated in a double-blind fashion to an optimal dose level of PF-06649751 according to a flexible dose titration scheme (from 0.25 mg to 15 mg once daily [QD]). The 15-week treatment period included 9 weeks of dose optimization and 6 weeks of stable dosing. Blinded PF-06649751 was provided as tablets for oral administration in the outpatient setting (each morning, daily for the duration of the treatment period). Reaching of the maximum allowed dose level (15 mg) was not mandatory; participants might achieve a satisfactory clinical response at a lower dose level. There was an additional follow-up period of 28 days following discontinuation of PF-06649751.	Matching placebo tablet for QD dosing in the 15-week double-blind treatment period. There was an additional follow-up period of 28 days following discontinuation of placebo.
Measure Participants	29	28
Change from baseline at Day 35	0.2 (5.23)	1.9 (9.49)
Change from baseline at Day 63	-1.1 (5.99)	1.1 (9.02)
Change from baseline at Day 105	-1.6 (4.54)	-0.2 (5.38)

8. Secondary Outcome

Title	Total Physician Withdrawal Checklist (PWC-20) Score
Description	The PWC-20 is a 20-item reliable and sensitive instrument for the assessment of benzodiazepine-like discontinuation symptoms. 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.
Time Frame	Day 119

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study treatment (PF-06649751 or placebo) and had PWC-20 evaluation.

Arm/Group Title	PF-06649751	Placebo
Arm/Group Description	Eligible participants were up-titrated in a double-blind fashion to an optimal dose level of PF-06649751 according to a flexible dose titration scheme (from 0.25 mg to 15 mg once daily [QD]). The 15-week treatment period included 9 weeks of dose optimization and 6 weeks of stable dosing. Blinded PF-06649751 was provided as tablets for oral administration in the outpatient setting (each morning, daily for the duration of the treatment period). Reaching of the maximum allowed dose level (15 mg) was not mandatory; participants might achieve a satisfactory clinical response at a lower dose level. There was an additional follow-up period of 28 days following discontinuation of PF-06649751.	Matching placebo tablet for QD dosing in the 15-week double-blind treatment period. There was an additional follow-up period of 28 days following discontinuation of placebo.
Measure Participants	28	26
Median (Full Range) [units on a scale]	1.50	1.00

Adverse Events

Time Frame	From first dose of study treatment up to 28 days after last dose (up to Day 133)
Adverse Event Reporting Description	The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Arm/Group Title	PF-06649751		Placebo
Arm/Group Description	Eligible participants were up-titrated in a double-blind fashion to an optimal dose level of PF-06649751 according to a flexible dose titration scheme (from 0.25 mg to 15 mg once daily [QD]). The 15-week treatment period included 9 weeks of dose optimization and 6 weeks of stable dosing. Blinded PF-06649751 was provided as tablets for oral administration in the outpatient setting (each morning, daily for the duration of the treatment period). Reaching of the maximum allowed dose level (15 mg) was not mandatory; participants might achieve a satisfactory clinical response at a lower dose level. There was an additional follow-up period of 28 days following discontinuation of PF-06649751.		Matching placebo tablet for QD dosing in the 15-week double-blind treatment period. There was an additional follow-up period of 28 days following discontinuation of placebo.
All Cause Mortality
	PF-06649751		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/28 (0%)
Serious Adverse Events
	PF-06649751		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/29 (3.4%)		0/28 (0%)
Psychiatric disorders
Suicidal ideation	1/29 (3.4%)	1	0/28 (0%)	0
Other (Not Including Serious) Adverse Events
	PF-06649751		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/29 (75.9%)		12/28 (42.9%)
Gastrointestinal disorders
Dry mouth	5/29 (17.2%)	6	0/28 (0%)	0
Nausea	9/29 (31%)	15	2/28 (7.1%)	2
Diarrhoea	1/29 (3.4%)	1	3/28 (10.7%)	3
Dyspepsia	1/29 (3.4%)	1	2/28 (7.1%)	2
General disorders
Fatigue	3/29 (10.3%)	4	3/28 (10.7%)	3
Infections and infestations
Nasopharyngitis	2/29 (6.9%)	2	1/28 (3.6%)	1
Urinary tract infection	3/29 (10.3%)	3	0/28 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	3/29 (10.3%)	4	0/28 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	3/29 (10.3%)	3	0/28 (0%)	0
Back pain	3/29 (10.3%)	4	1/28 (3.6%)	1
Nervous system disorders
Dizziness	2/29 (6.9%)	2	1/28 (3.6%)	1
Dysgeusia	2/29 (6.9%)	2	0/28 (0%)	0
Dystonia	2/29 (6.9%)	2	0/28 (0%)	0
Headache	7/29 (24.1%)	10	2/28 (7.1%)	2
Paraesthesia	2/29 (6.9%)	2	0/28 (0%)	0
Somnolence	4/29 (13.8%)	4	1/28 (3.6%)	1
Tremor	4/29 (13.8%)	5	2/28 (7.1%)	5
Hypoaesthesia	2/29 (6.9%)	2	0/28 (0%)	0
Psychiatric disorders
Abnormal dreams	2/29 (6.9%)	3	0/28 (0%)	0
Anxiety	2/29 (6.9%)	2	1/28 (3.6%)	1
Depression	2/29 (6.9%)	2	0/28 (0%)	0
Insomnia	2/29 (6.9%)	2	2/28 (7.1%)	2
Irritability	2/29 (6.9%)	2	0/28 (0%)	0
Restlessness	2/29 (6.9%)	3	0/28 (0%)	0
Vascular disorders
Hot flush	3/29 (10.3%)	3	0/28 (0%)	0
Hypotension	2/29 (6.9%)	2	0/28 (0%)	0

Limitations/Caveats

This study was terminated early by the sponsor due to a companion study, B7601003 (NCT02687542; a dose ranging, Phase 2b study in motor fluctuators) meeting futility criteria at Interim Analysis.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.