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 long term safety and tolerability of PF-06649751 in Parkinson's disease patients who experience motor-fluctuations.

Detailed Description
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This is an open label study evaluating the long term safety and tolerability of PF-06649751 in Parkinson's disease patients who experience motor-fluctuations. Subjects who completed Ph2 study B7601003 will be randomized to one of 4 treatment groups (15 mg QD, 7 mg QD, 3 mg QD, or 1 mg QD group) depending on the treatment received in B7601003 and titrated up to 15 mg QD over a 3 week period, as appropriate. All subjects who were blindly down-titrated during the B7601003 study will remain at/or be titrated to 7 mg QD only and remain at that dose for the rest of the B7601017 study in order to protect the blind for the prior study. Subjects who successfully titrate to 15 mg QD will enter the Adjustment Period at that dose. Subjects who cannot tolerate 15 mg QD at any time during the study will be allowed to down-titrate to 7 mg QD (but not lower) and will stay at that dose for the rest of the study. Subjects who cannot remain at a stable dose (7 mg or 15 mg QD) will be discontinued.

Official Title
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A PHASE 2, OPEN LABEL EXTENSION STUDY TO INVESTIGATE THE LONG TERM SAFETY AND TOLERABILITY OF PF-06649751 IN SUBJECTS WITH MOTOR FLUCTUATIONS DUE TO PARKINSON'S DISEASE

Conditions
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Parkinson's Disease With Motor Fluctuations

Intervention / Treatment
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* Drug: 1 mg QD to 15 mg QD PF-06649751
* Drug: 3 mg QD to 15 mg QD PF-06649751
* Drug: 7 mg QD to 15 mg QD PF-06649751
* Drug: 15 mg QD PF-06649751
* Drug: 1 mg QD to 7 mg QD PF-06649751 (if de-escalated in parent study)
* Drug: 3 mg QD to 7 mg QD PF-06649751 (de-escalated in parent study)
* Drug: 7 mg QD to 7 mg QD PF-06649751 (de-escalated in parent study)
* Drug: 15 mg QD de-escalated to 7 mg QD PF-06649751 in parent study remain at 7 mg QD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Having successfully completed parent study B7601003. 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. Severe acute or chronic medical or psychiatric condition or laboratory abnormality. 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: 87 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
Intervention Model: Parallel Assignment
Interventional Model Description: Depending on the actual treatment the subject received in B7601003, subjects will be randomized to one of 4 treatment groups (15 mg QD, 7 mg QD, 3 mg QD, or 1 mg QD group) and titrated up to 15 mg QD over a 3 week period, as appropriate. All subjects who were blindly down-titrated during the parent study (B7601003) will remain at/or be titrated to 7 mg QD only and remain at that dose for the rest of the B7601017 study in order to protect the blind for the parent study. Subjects who successfully titrate to 15 mg QD will enter the Adjustment Period at that dose. Subjects who cannot tolerate 15 mg QD at any time during the study will be allowed to down-titrate to 7 mg QD (but not lower) and will stay at that dose for the rest of the study. Subjects who cannot remain at a stable dose (7 mg or 15 mg QD) will be discontinued.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 mg QD to 15 mg QD PF-06649751<br>Up titration from 1 mg QD to 15 mg QD PF-06649751 | Drug: 1 mg QD to 15 mg QD PF-06649751<br>* Up titration from 1 mg QD to 15 mg QD PF-06649751<br>|
| Experimental: 3 mg QD to 15 mg QD PF-06649751<br>Up titration from 3 mg QD to 15 mg QD PF-06649751 | Drug: 3 mg QD to 15 mg QD PF-06649751<br>* Up titration from 3 mg QD to 15 mg QD PF-06649751<br>|
| Experimental: 7 mg QD to 15 mg QD PF-06649751<br>Up titration from 7 mg QD to 15 mg QD PF-06649751 | Drug: 7 mg QD to 15 mg QD PF-06649751<br>* Up titration from 7 mg QD to 15 mg QD PF-06649751<br>|
| Experimental: 15 mg QD PF-06649751<br>15 mg QD PF-06649751 remains at 15 mg QD PF-06649751 | Drug: 15 mg QD PF-06649751<br>* 15 mg QD PF-06649751 remaining at 15 mg QD PF-06649751<br>|
| Experimental: 1 mg to 7 mg QD PF-06649751<br>Up titration from 1 to 7 mg QD PF-06649751 if de-escalated in parent study | Drug: 1 mg QD to 7 mg QD PF-06649751 (if de-escalated in parent study)<br>* Up titration from 1 mg QD to 7 mg QD PF-06649751 for subject at 1 mg QD who were blindly de-escalated in the parent study<br>|
| Experimental: 3 mg QD to 7 mg QD PF-06649751<br>Up titration from 3 to 7 mg QD PF-06649751 if de-escalated in parent study | Drug: 3 mg QD to 7 mg QD PF-06649751 (de-escalated in parent study)<br>* Up titration from 3 mg QD to 7 mg QD PF-06649751 for 3 mg QD subjects who were blindly de-escalated in parent study<br>|
| Experimental: 7 mg QD to 7 mg QD PF-06649751<br>7 mg QD remains at 7 mg QD PF-06649751 if de-escalated in parent study | Drug: 7 mg QD to 7 mg QD PF-06649751 (de-escalated in parent study)<br>* 7 mg QD to remain at 7 mg QD PF-06649751 for subjects who were blindly de-escalated in parent study<br>|
| Experimental: 15 mg to 7 mg QD PF-06649751<br>15 mg QD de-escalated to 7 mg QD in parent study B7601003 remain at 15 mg QD PF-06649751 | Drug: 15 mg QD de-escalated to 7 mg QD PF-06649751 in parent study remain at 7 mg QD<br>* 7mg QD PF-06649751 for subjects assigned to 15 mg QD who were blindly de-escalated to 7 mg QD PF-06649751 in parent study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (All Causalities) | An adverse event (AE) is any untoward medical occurrence in a study participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. Any AE occurring following the start of treatment or occurring before treatment but increasing in severity afterward were counted as treatment-emergent AE (TEAE). | Baseline to last visit after termination (up to approximately 3 months) | 
| Number of Participants With Treatment-Emergent Adverse Events (Treatment Related) | An adverse event (AE) is any untoward medical occurrence in a study participant administered a product or medical device. Any AE occurring following the start of treatment or occurring before treatment but increasing in severity afterward were counted as treatment-emergent AE (TEAE). | Baseline to last visit after termination (up to approximately 3 months) | 
| Number of Participants With Clinically Significant Findings in Physical Examination | A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal and musculoskeletal systems. The clinical significance was determined by the investigator. | Baseline to last visit after termination (up to approximately 3 months) | 
| Number of Participants With Clinically Significant Findings in Neurological Examination | The full neurological examination included assessment of the visual fields and of the right and left optic fundus; cranial nerves; mental state; muscle strength and tone, abnormal movements; deep tendon reflexes; sensory exam, coordination, gait and station. Higher cortical and motor function was considered part of the complete neurological exam. The brief neurological exam included 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. The clinical significance was determined by the investigator. | Baseline to last visit after termination (up to approximately 3 months) | 
| Number of Participants With Abnormalities in Laboratory Test (Without Regard to Baseline Abnormality) | Laboratory tests included hematology(hemoglobin,hematocrit,red and white blood cell count,mean corpuscular volume,mean corpuscular hemoglobin,mean corpuscular hemoglobin concentration,platelet count,neutrophils,eosinophils,monocytes, basophils,lymphocytes), chemistry(blood urea nitrogen/urea and creatinine,fasting glucose, calcium,sodium,potassium, chloride,total carbon dioxide,aspartate and alanine aminotransferase,total bilirubin,alkaline phosphatase,uric acid,albumin,total protein),urinalysis(pH,qualitative glucose protein,blood,ketones,nitrites,leukocyte esterase,urobilinogen,urine bilirubin,microscopy,specific gravity,urine creatinine),other tests(urine drug screen,follicle stimulating hormone,anti neutrophil cytoplasmic antibody panel,qualitative antinuclear antibody,fibrinogen,C reactive protein,erythrocyte sedimentation rate,C3, C4, CH50/CH100,rheumatoid factor,immunoglobulin panel,if anti- neutrophil cytoplasmic antibody positive:proteinase 3 Ab,myeloperoxidase Ab tests). | Baseline to last visit after termination(up to approximately 3 months) | 
| Number of Participants With Vital Signs Data Meeting Pre-defined Criteria | Number of participants with vital signs findings meeting the following criteria is presented:(1) standing DBP increase from baseline>= 20 mm Hg; (2) standing SBP increase from baseline>= 30 mm Hg; (3) supine DBP increase from baseline >=20 mm Hg; (4) supine SBP increase from baseline >=30 mm Hg; (5)standing DBP decrease from baseline>= 20 mm Hg; (6) standing SBP decrease from baseline>= 30 mm Hg; (7) supine DBP decrease from baseline >=20 mm Hg; (8) supine SBP decrease from baseline >=30 mm Hg. | Baseline to last visit after termination (up to approximately 3 months) | 
| Number of Participants With Vital Signs Data of Orthostatic Hypotension Meeting Pre-defined Criteria | Orthostatic hypotension was defined as a decrease of >=20 mmHg for systolic blood pressure (SBP) or >=10 mmHg for diastolic blood pressure (DBP) 2 minutes after standing from a supine position. | Baseline to last visit after termination (up to approximately 3 months) | 
| Number of Participants With Electrocardiogram Data Meeting Pre-defined Criteria | PR interval (time from the beginning of P wave to the start of QRS complex, corresponding to the end of atrial depolarization and onset of ventricular depolarization), QRS duration (time from Q wave to the end of S wave, corresponding to ventricle depolarization), QT interval (time from the beginning of Q wave to the end of T wave) and QTcF interval ( QT interval corresponding to electrical systole corrected for heart rate using Fridericia's formula) are summarized. Number of participants with ECG findings meeting the following criteria is presented: (1) PR interval >=300 msec; (2) QRS duration >=140 msec; (3) QT interval >= 500; (4) QTcF interval: 450 to <480 msec; (5) QTcF interval: 480 to <500 msec; (6) QTcF interval >=500 msec. | Baseline to last visit after termination (up to approximately 3 months) | 
| Number of Participants With Worsening Suicidality and New Onset Suicidality | The Columbia Suicide Severity Rating Scale (C-SSRS) is an interview based rating scale to systematically assess suicidal ideation and suicidal behavior. At each suicidality assessment, participants 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 participants by virtue of training or experience who determined if it is safe for the participants to participate/continue in the trial. The denominator used in the percentages was the number of participants assessed for suicidality or worsening, the denominator included the subset of participants who had any level of suicidality reported at baseline. For new onset, the denominator included the subset of participants with no suicidality reported at baseline. | Baseline to last visit after termination (up to approximately 3 months) | 
| Number of Participants With Benzodiazepine Discontinuation Symptoms Based on 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, including anxiety and nervous, depersonalization and derealization, diarrhea, diaphoresis, difficulty concentrating and remembering, dizziness-lightheadedness, depression, fatigue, lethargy and lack of energy, headaches, increased acuity for sound, smell, touch, or pain, insomnia, irritability, loss of appetite, muscle aches or stiffness, nausea-vomiting paresthesias, poor coordination, restlessness and agitation, tremor-tremulousness, and weakness. Summaries of the count of participants experiencing symptoms and severity listed in the PWC-20 were provided. | At last visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline for Hauser Participant Diary Data in Daily OFF Time | Available diaries are designed to record participant motor state for half hour intervals. These diaries are a way for participant to assess their own health status without clinician bias or interpretation. In participant 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 (PD) participants experience relatively poor overall function with worsening of tremor, rigidity, balance, or bradykinesia. | Baseline, Day 21 and Day 35 | 
| Change From Baseline for Hauser Participant Diary Data in Daily ON Time With Troublesome Dyskinesia | Available diaries are designed to record participant motor state for half hour intervals. These diaries are a way for participants to assess their own health status without clinician bias or interpretation. 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 ON time with troublesome dyskinesia are generally considered by participants to be bad time with regard to motor function. | Baseline, Day 21 and Day 35 | 
| Change From Baseline for Hauser Participant Diary Data in Daily ON Time Without Troublesome Dyskinesia | Available diaries are designed to record participant motor state for half hour intervals. These diaries are a way for participants to assess their own health status without clinician bias or interpretation. 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. ON time without dyskinesia and on time with non troublesome dyskinesia are generally considered to be good time. | Baseline, Day 21 and Day 35 | 
| Change From Baseline in Movement Disorder Society Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I, II, III, IV, and Total Score | The total MDS-UPDRS score developed by the Movement Disorder Society is the most common method of evaluating the severity of Parkinson's Disease (PD). Part I assesses non motor experiences of daily living(range 0-52).Part II assesses motor experiences of daily living(0-52). Part III assesses the motor signs of PD.Part IV assesses motor complications, dyskinesias, and motor fluctuations(0-24).Total Score:The sum of Parts I, II, III, and IV.Each question is anchored with five responses:0=normal, 1=slight, 2=mild, 3= moderate, 4=severe.Higher part and total scores indicate more severe signs of PD.There are four subscales in Part III:the tremor subscale(range 0-36),the rigidity subscale(0-20),the bradykinesia subscale(0-36),the postural instability and gait disorder (PIGD) subscale(0-12). | Baseline to last visit after termination (up to approximately 3 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease, Motor Fluctuations, D1 partial agonist