Efficacy, Safety and Tolerability of PF-06649751 in Parkinson's Disease Patients With Motor Fluctuations

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Placebo
* Drug: PF-06649751 low dose (1 mg QD)
* Drug: PF-06649751 middle dose 1 (3 mg QD)
* Drug: PF-06649751 middle dose 2 (7 mg QD)
* Drug: PF-06649751 high dose (15 mg QD)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females of non-childbearing potential and/or male subjects between the ages of 40 and 85 years, inclusive. Clinical diagnosis of Parkinson's disease. Able to refrain from any Parkinson's disease medication not permitted by the protocol. Exclusion Criteria: Female of childbearing potential History or presence of atypical Parkinsonian syndrome. History of surgical intervention for Parkinson's disease. Severe acute or chronic medical or psychiatric condition 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|
| Experimental: PF-06649751 low dose (1 mg QD)<br>PF-06649751 low dose level (1 mg QD) | Drug: PF-06649751 low dose (1 mg QD)<br>* PF-06649751 low dose (1 mg QD)<br>|
| Experimental: PF-06649751 middle dose 1 (3 mg QD)<br>PF-06649751 lower middle dose 1 (3 mg QD) | Drug: PF-06649751 middle dose 1 (3 mg QD)<br>* PF-06649751 lower middle dose 1 (3 mg QD)<br>|
| Experimental: PF-06649751 middle dose 2 (7 mg QD)<br>PF-06649751 higher middle dose 2 (7 mg QD) | Drug: PF-06649751 middle dose 2 (7 mg QD)<br>* PF-06649751higher middle dose 2 (7 mg QD)<br>|
| Experimental: PF-06649751 high dose (15 mg QD)<br>PF-06649751 high dose (15 mg QD) | Drug: PF-06649751 high dose (15 mg QD)<br>* PF-06649751 high dose (15 mg QD)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Daily OFF Time at Week 10 | A paper Hauser diary was utilized to record motor state for half-hour intervals. Participants completed the diary by answering whether they had been OFF for 3 consecutive days in the week prior to each visit (except Day 28 visit), including 3 consecutive days during the week prior to Day 0 (Randomization). The daily OFF time was calculated as the average of the 3 consecutive daily OFF hours from the Hauser diary at each visit. | Week 10; Baseline was defined as the average daily OFF time (using 3 Hauser patient diary days) prior to Day -1 (study derived day and equalled to nominal visit day 0). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Daily OFF Time | A paper Hauser diary was utilized to record motor state for half hour intervals. Participants completed the diary by answering whether they had been OFF for 3 consecutive days in the week prior to each visit (except Day 28 visit), including 3 consecutive days during the week prior to Day 0 (Randomization). The daily OFF time was calculated as the average of the 3 consecutive daily OFF hours from the Hauser diary at each visit. Results at Week 15 should be interpreted with caution given almost half the participants were not available for this analysis at Week 15 as compared to Week 10 and the complicated nature of protocol changes that impacted the study design after Week 10. | Weeks 3, 5, 10 and 15; Baseline was defined as the average daily OFF time (using 3 Hauser patient diary days) prior to Day -1 (study derived day and equalled to nominal visit day 0). | 
| Change From Baseline in Daily ON Time With Troublesome Dyskinesia | A paper Hauser diary was utilized to record motor state for half hour intervals. The participants answered the Hauser diary on whether they had been ON with troublesome dyskinesia. A diary day started with the interval 24:00-0:30 through 23:30-24:00 on each chronological day for 3 consecutive days. On the days recording the home diary, participants made an entry every 30 minutes during their normal waking time and upon awakening from time asleep. The daily ON hours was calculated as the average of the 3 consecutive daily ON hours from the Hauser diary at each visit. Results at Week 15 should be interpreted with caution given almost half the participants were not available for this analysis at Week 15 as compared to Week 10 and the complicated nature of protocol changes that impacted the study design after Week 10. | Weeks 3, 5, 10 and 15; Baseline was defined as the average daily ON time with Troublesome Dyskinesia (using 3 Hauser patient diary Days) prior to Day -1 (study derived day and equalled to nominal visit Day 0). | 
| Change From Baseline in Daily ON Time Without Troublesome Dyskinesia | A paper Hauser diary was utilized to record motor state for half hour intervals. The participants answered the Hauser diary on whether they had been ON without troublesome dyskinesia. A diary day started with the interval 24:00-0:30 through 23:30-24:00 on each chronological day for 3 consecutive days. On the days recording the home diary, participants made an entry every 30 minutes during their normal waking time and upon awakening from time asleep. The daily ON hours was calculated as the average of the 3 consecutive daily ON hours from the Hauser diary at each visit. Results at Week 15 should be interpreted with caution given almost half the participants were not available for this analysis at Week 15 as compared to Week 10 and the complicated nature of protocol changes that impacted the study design after Week 10. | Weeks 3, 5, 10 and 15; Baseline was defined as the average daily ON time without Troublesome Dyskinesia (using 3 Hauser patient diary days) prior to Day -1 (study derived day and equalled to nominal visit Day 0) | 
| Change From Baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III | MDS-UPDRS Part III assessed the motor signs of Parkinson's disease and was administered by the investigator. 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. If more than 7 of the Part III items were missing, the score for that time point was missing, otherwise MDS-UPDRS Part III score was imputed as sum of the non-missing items*(total number of items)/ (number of items non-missing). The MDS-UPDRS Part III total score range is 0-132. Higher score indicated more severe motor signs of Parkinson's disease. Results at Week 15 should be interpreted with caution given almost half the participants were not available for this analysis at Week 15 as compared to Week 10 and the complicated nature of protocol changes that impacted the study design after Week 10. | Weeks 1, 2, 3, 4, 5, 10 and 15; Baseline was defined as the Day -1 (study derived day and equalled to nominal visit Day 0) measurement | 
| Change From Baseline in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I, II, IV, and Total Score | Each question of Part I,II or IV with 5 responses was linked to the same clinical terms as Part III.The score was missing if more than 7 items were missing for a time point; otherwise Part I,II or IV score was imputed as sum of non-missing items*(total number of items)/(number of items non-missing).•PartI (Non-Motor Aspects of Experiences of Daily Living) assessed non-motor experiences of daily living using 13questions(Range:0-52).•PartII(Motor Aspects of Experiences of Daily Living) assessed motor experiences of daily living using 13questions(Range:0-52).•PartIV(Motor Complications) assessed motor complications,dyskinesias, and motor fluctuations using historical and objective information with 6questions(Range:0-24).•MDS-UPDRS Total Score:the sum of Parts I,II,III,and IV(Range:0-260).Higher score indicated more severe motor signs of Parkinson's disease.Week15's results were interpreted cautiously given almost half participants were not available for the analysis as compared to Week10 | Weeks 5, 10 and 15; Baseline was defined as the Day -1 (study derived day and equalled to nominal visit Day 0) measurement | 
| Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality | The safety laboratory tests including Hematology, Clinical Chemistry and Urinalysis were performed. Determination if there were any laboratory data abnormalities of potential clinical concern was based on Pfizer Data Standards. Incidence of laboratory test abnormalities (without regard to baseline abnormality) was summarized within each treatment group. | Baseline (Day 0) to Week 17 | 
| Number of Participants With Vital Sign Results Meeting the Criteria for Categorical Summarization | Vital Signs including blood pressure and pulse rate were measured. Vital signs were collected first while the participant was in the supine position and then in the standing position. | Baseline (Day 0) to Week 17 | 
| Number of Participants With Electrocardiogram (ECG) Results Meeting the Criteria for Categorical Summarization | The average of the triplicate readings of ECG data was collected at each assessment time. Number of participants with ECG results meeting the criteria for categorical summarization for time from the beginning of the P wave until the beginning of the QRS complex (PR Interval), time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS Duration), time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QT Interval) and corrected QT (Fridericia correction) (QTcF Interval) were presented. | Baseline (Day 0) to Week 17 | 
| Number of Participants With Suicidal Ideation Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS) at Post-baseline Visits | The Columbia Suicide Severity Rating Scale (C-SSRS) was an interview based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS responses were mapped to the C-CASA. There were 3 key endpoints for suicidality data analysis and evaluation: Suicidal Behavior: A participant was said to have suicidal behavior if the participant had experienced completed suicide / suicide attempt / reparatory acts toward imminent suicidal behavior. Suicidal Ideation: Any observed suicidal ideation mapped to a single C-CASA category. Suicidal Behavior or Ideation (participants with new onset suicidality): A participant was considered to have a new onset of suicidality if the participant reported no ideation and no behavior at the baseline assessment and reported any behavior or ideation post-baseline. Data observed at screening was not considered in the definition of worsening. | Days 0 (Baseline), 7, 14, 21, 28, 35, 70, 77, 84, 91, 105 and 119 | 
| Change From Baseline in Total Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease - Rating Scale (QUIP-RS) | The QUIP-RS was a brief, patient reported outcome measure designed to assess the severity of symptoms of Impulsive-Compulsive Disorders (ICDs) and related behaviors reported to occur in Parkinson's disease. The QUIP-RS assessed 7 disorders (Gambling, Sex, Buying, Eating, Hobbyism-punding [performing tasks and repeating activities] and Taking medications). If more than 5 items were missing, the total QUIP-RS score was set as missing; otherwise, the total QUIP-RS score was imputed as follows: sum of the non-missing item scores * (total number of items) / (number of items non-missing). The higher score indicated a greater level of the ICD. The total QUIP-RS score for all ICDs and related disorders combined ranges from 0 to 112. | Baseline (Day 0) and Weeks 5, 10 and 15 | 
| Total Physician Withdrawal Checklist (PWC-20) on Days 105 and 119, and Change From Day 105 to Day 119 | The PWC-20 is a physician completed, 20 item reliable and sensitive instrument for the assessment of discontinuation symptoms. The PWC-20 was collected after the completion of study treatment and also at the first visit of follow-up. The total PWC-20 score was the sum of 20 item scores and ranged from 0 to 60. If more than 5 items were missing, the total PWC-20 score was missing; otherwise, the total PWC-20 score was imputed as follows: sum of the non-missing items * (total number of items) / (number of items non-missing). The higher score indicated more frequent/severe symptoms. | Days 105 and 119 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Discontinuation Due to AEs and Deaths | An AE was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event did not need necessarily to have a causal relationship with the treatment or usage. An SAE was any untoward medical occurrence at any dose that: Resulted in death; Was life threatening (immediate risk of death); Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); Resulted in congenital anomaly/birth defect. | Day 1 to follow-up (Week 19 visit) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson Disease, Motor Fluctuation