PF 06412562 in Subjects With Advanced Stage Parkinson's Disease

Study Overview
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Brief Summary
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The purpose of this study is to test the safety and tolerability of the investigational drug PF-06412562 compared to the current medical standard of care medication for Parkinson's disease, carbidopa/levodopa. This research also is being done to find out if the investigational drug PF-06412562 can help improve the motor (movement) function, alertness, and cognitive (thinking) skills of people who are considered to be in the advanced-stage of Parkinson's disease. In this study, PF06412562 is 'investigational,' which means that it is experimental and has not been approved by the US Food and Drug Administration (FDA), but can be used in clinical research studies such as this one.

Detailed Description
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The investigators are conducting a randomized, double-blind, carbidopa/levodopa-controlled crossover safety, tolerability, and efficacy study of the investigational compound, PF-06412562, in advanced Parkinson's patients. The primary purpose of this study is to test the safety and tolerability of the investigational drug PF-06412562 compared to the current medical standard of care medication for Parkinson's disease, carbidopa/levodopa, in these patients. This secondary purpose of this research is to find out if the investigational drug PF-06412562 can help improve the motor (movement) function, alertness, and cognitive (thinking) skills of people who are considered to be in the advanced-stage of Parkinson's disease. This study will inform the field as to whether PF-06412562 is safe and well-tolerated in advanced Parkinson's patients, and also may provide preliminary data on its efficacy in several domains.

Official Title
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A Phase Ib Safety, Tolerability, and Efficacy Study of Two Days of Oral Split Dose (25/20 mg) Administration of PF 06412562 in Subjects With Advanced Stage Parkinson's Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: PF-06412562
* Drug: Standard of Care Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of classic PD with history of clinically meaningful response to levodopa Disease duration >15 years since diagnosis Hoehn & Yahr stage >IV on or off levodopa Consent signed by subject, if possible If subject is cognitively impaired, consent signed by power of attorney or legally authorized subject representative Assent from the study subject, if possible Stable dose of all medications for 60 days prior to Day 1 of first week of study Exclusion Criteria: Atypical parkinsonian syndrome (e.g., never responded to levodopa, and/or atypical signs) Acute or unstable medical condition such as heart disease, kidney and liver failure History of HIV, hepatitis B and C Use of moderate to strong CYP 3A4 modulators (see both inhibitors and inducers in Appendix BB)
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: Crossover Assignment
Interventional Model Description: Subjects will participate in study for 2 consecutive weeks. Days 2-3 of Week 1, they will be blindly and randomly assigned to one of two treatment arms (study drug PF-06412562 or standard of care carbidopa/levodopa). Whichever treatment arm they did not receive during Week 1, they will receive during Days 2-3 of Week 2.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06412562<br>Subjects will receive 25 mg of PF-06412562 twice daily on study Days 2 and 3, along with placebo carbidopa/levodopa dosed at these times. Additional carbidopa/levodopa placebo capsules also will be administered according to the subject's home regimen. | Drug: PF-06412562<br>* PF-06412562 is a dopamine agonist developed by Pfizer Inc. into a tablet form for oral usage. It will be provided as 5 mg tablets. Thus, to administer the 25 mg dose, 5 x 5 mg tablets will be given; and to administer the 20 mg dose, 4 x 5 mg tablets will be administered.<br>|
| Active Comparator: Standard of Care carbidopa/levodopa<br>Subjects will take placebo tablets for the PF-06412562 twice daily on study Days 2 and 3, along with active carbidopa/levodopa (25/100 mg) administered at these times. Additional active carbidopa/levodopa capsules also will be administered according to the subject's home regimen. | Drug: Standard of Care Placebo<br>* 25/100 mg tablet(s) of carbidopa/levodopa will be encapsulated and administered according to the subject's home regimen.<br>* Other names: Sinemet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of PF-06412562 assessed by blood sample results | NA (mmol/L), K(mmol/L), HCO3(mmol/L) | Day 1 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | Ca (mg/dL), Mg (mg/dL), BUN( mg/dL), Creatinine (mg/dL), Bilirubin (mg/dL) | Day 1 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | AST (U/L), ALT (U/L) | Day 1 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | white blood cell count (K/uL), platelets (K/uL) | Day 1 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | Hematocrit (%) | Day 1 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | hemoglobin (g/dL) | Day 1 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | NA (mmol/L), K(mmol/L), HCO3(mmol/L) | Day 4 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | Ca (mg/dL), Mg (mg/dL), BUN (mg/dL), creatinine (mg/dL), bilirubin (mg/dL) | Day 4 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | AST (U/L), ALT (U/L) | Day 4 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | white blood cell count (K/uL), platelets (K/uL) | Day 4 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | hematocrit (%) | Day 4 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | hemoglobin (g/dL) | Day 4 | 
| Safety and tolerability of PF-06412562 assessed by blood sample results | Red blood cell count (M/uL) | Day 4 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | height (inches) | Time Frame: Vital signs: X2 on Day 1 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | weight (lbs) | X2 on Day 1 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | blood pressure (mmHg) | X2 on Day 1 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | heart rate (bpm) | X2 on Day 1 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | respiratory rate (breathes/min) | X2 on Day 1 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | temperature (F) | X2 on Day 1 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | height (inches) | X3 on Days 2 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | blood pressure (mmHg) | X3 on Days 2 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | heart rate (bpm) | X3 on Days 2 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | respiratory rate (breathes/min) | X3 on Days 2 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | temperature (F) | X3 on Days 2 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | height (inches) | X3 on Days 3 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | weight (lbs) | X3 on Days 3 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | blood pressure (mmHg) | X3 on Days 3 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | heart rate (bpm) | X3 on Days 3 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | respiratory rate (breathes/min) | X3 on Days 3 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | temperature (F) | X3 on Days 3 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | height (inches) | X2 on Day 4 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | weight (lbs) | X2 on Day 4 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | blood pressure (mmHg) | X2 on Day 4 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | heart rate (bpm) | X2 on Day 4 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | respiratory rate (breathes/min) | X2 on Day 4 | 
| Safety and tolerability of PF-06412562 assessed by vital signs | temperature (F) | X2 on Day 4 | 
| Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function | Blood pressure (mmHg), cold pressor test measuring blood pressure (mmHg) | X1 on Day 1 over 15 min | 
| Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function | heart rate (beats/min), sinus arrhythmia (beats/min) | X1 on Day 1 over 15 min | 
| Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function | Blood pressure (mmHg), cold pressor test measuring blood pressure (mmHg) | X3 on Days 2 over 15 min each time | 
| Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function | heart rate (beats/min), sinus arrhythmia (beats/min) | X3 on Days 2 over 15 min each time | 
| Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function | Blood pressure (mmHg), cold pressor test measuring blood pressure (mmHg) | X3 on Days 3 over 15 min each time | 
| Safety and tolerability of PF-06412562 assessed by cardiology testing/cardiac autonomic function | heart rate (beats/min), sinus arrhythmia (beats/min) | X3 on Days 3 over 15 min each time | 
| Safety and tolerability of PF-06412562 assessed by UPDRS-IV | UPDRS-IV (United Parkinson's Disease Rating Scale): each questions scored on scale of 0 to 4, where 0= not present, 4= severe; subscales are summed to yield a total score, min total score:0, max total score:81; higher score corresponds to increased disease severity | X3 on Days 2 | 
| Safety and tolerability of PF-06412562 assessed by UPDRS-IV | UPDRS-IV (United Parkinson's Disease Rating Scale): each questions scored on scale of 0 to 4, where 0= not present, 4= severe; subscales are summed to yield a total score, min total score:0, max total score:81; higher score corresponds to increased disease severity | X3 on Days 3 | 
| Safety and tolerability of PF-06412562 assessed by Columbia Suicide Rating | C-SSRS measures suicidal ideation and/or behavior. Rated from Category 1-10 with Category 1 being the least severe, and Category 10 representing the most severe, i.e. completing suicide. | X1 on Day 1 | 
| Safety and tolerability of PF-06412562 assessed by Columbia Suicide Rating | C-SSRS measures suicidal ideation and/or behavior. Rated from Category 1-10 with Category 1 being the least severe, and Category 10 representing the most severe, i.e. completing suicide. | X1 on Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pilot data on potential efficacy of PF-06412562 compared to the standard of care treatment (i.e., carbidopa/levodopa) on overall signs and quality of life in subjects with advanced PD | • Clinician Global Impression of Change score: measures change in disease symptoms per clinician's judgement. Each item rated 1-7, 1=marked improvement, 7= marked worsening; min Caregiver perception of change interview: interviews with participants' caregiver(s). Open-ended questions elicit open-ended answers about subject's behavior, appearance, cognition, etc. over the study | Global Impression of Change: X3 on Days 2 and 3; Caregiver Perception of Change: X1 on Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease, Parkinson Disease, End-Stage, Progressed, Advanced Parkinson's Disease, End-Stage Parkinson's Disease, Clinical intervention, Double-blind, randomized