Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PF-06649751 in Parkinson's Disease

Study Overview
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Brief Summary
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This study will be an open label, dose escalation study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated daily quaque die (QD) doses given over 21 days (Day 3 to Day 23) to sequential cohorts of subjects with Parkinson's disease. Each cohort will have 2 study periods. For each cohort, subjects will enter Period 1 and if they meet criteria, approximately 12 subjects will be enrolled into Period 2 and dosed with PF 06649751. Based on results observed in a previous study, Cohorts 1 and 2 will not be conducted. Cohorts 3 - 6 will test doses uptitrated to 5 mg, 15 mg and 25 mg QD. Doses may be modified based on emerging safety, tolerability and PK data, but the maximum daily dose that will be given in any cohort will have PK predictions at steady state that are anticipated to be below toxicokinetic limits. An option for down titration to the previous dose level is available should the investigator consider that an AE is intolerable. Following down titration, a single up titration to the next dose level may be attempted if the subject remains symptom free for at least 48 hrs. Safety, tolerability and PK data of Cohort 3 will be reviewed prior to initiating the dosing in Cohorts 4 and 5. Available safety, tolerability and PK data up to Day 24 of at least 5 subjects from Cohorts 4 will be reviewed prior to initiating the dosing in Cohort 6.

Official Title
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A Phase 1b, 2-period, Open Label, Multicenter, Dose Escalation Study To Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Pf-06649751 In Subjects With Parkinson's Disease And Motor Fluctuations

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: PF-06649751
* Drug: PF-06649751
* Drug: PF-06649751
* Drug: PF-06649751


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of idiopathic Parkinson's Disease with at least 2 out of 3 cardinal characteristics (tremor, rigidity, bradykinesia) Mini-Mental State Examination (MMSE) ≥ 25 Hoehn & Yahr Stage I-III inclusive Documented history of end of L-Dopa wearing OFF Cohort 5 only: History of dyskinesia following L-Dopa dosing and Score of at least 2 on Part IV, item 4.2 (functional impact of dyskinesia) of the MDS-UPDRS Exclusion Criteria: Atypical/secondary parkinsonism History of surgical intervention for Parkinson's Disease Dementia/cognitive impairment that can interfere with study assessments

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 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: Basic Science
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 3<br>Titration of PF-06649751 up to 5 mg QD | Drug: PF-06649751<br>* Oral daily doses titrated up to 5mg QD<br>|
| Experimental: Cohort 4<br>Titration of PF-06649751 up to 15 mg QD | Drug: PF-06649751<br>* Oral daily doses titrated up to 15 mg QD<br>|
| Experimental: Cohort 5<br>Titration of PF-06649751 up to 15 mg QDi n subjects with Levodopa-induced dyskinesias (LID) | Drug: PF-06649751<br>* Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)<br>|
| Experimental: Cohort 6<br>Titration of PF-0649751 up to 25 mg QD | Drug: PF-06649751<br>* Oral daily doses titrated up to 25 mg QD<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 (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; Initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug to the end of study (up to Day 30) that were absent before treatment or that worsened relative to pre-treatment state. AEs included both serious and non-serious adverse events. | Baseline (Day 1) up to Day 30 | 
| Number of Participants With Laboratory Test Abnormalities | Criteria for laboratory abnormalities: Hemoglobin (Hgb),hematocrit, red blood cell(RBC) count: less than(<)0.8*lower limit of normal(LLN),mean corpuscular Hgb, mean corpuscular volume, mean corpuscular Hgb concentration:<0.9*LLN, greater than (>)1.1*upper limit of normal(ULN),platelet:<0.5*LLN,>1.75*ULN,lymphocyte,neutrophil:<0.8*LLN, >1.2*ULN, basophil, eosinophil, monocyte:>1.2*ULN, WBC:<0.6*LLN, >1.5*ULN;total bilirubin>1.5*ULN, aspartate aminotransferase,alanine aminotransferase,alkaline phosphatase:>3.0*ULN,total protein,albumin:<0.8*LLN,>1.2*ULN;blood urea nitrogen,creatinine:>1.3*ULN, uric acid>1.2*ULN;sodium<0.95*LLN,>1.05*ULN,potassium,chloride,calcium,bicarbonate:<0.9*LLN,>1.1*ULN;glucose<0.6*LLN,>1.5*ULN,urine pH:<4.5, >8; urine: WBC, RBC greater than or equal to (>=)20/high performance field, bacteria: >20; urobilinogen, urine: glucose, ketone, protein, Hgb, nitrite, leukocyte esterase, bilirubin: >=1. | Baseline up to Day 30 | 
| Number of Participants With Vital Sign Abnormalities | Criteria for vital sign abnormality included supine pulse rate of <40 beats per minute (bpm) or >120 bpm, standing pulse rate of <40 bpm or >140 bpm, supine and standing systolic blood pressure (SBP) <90 millimeter of mercury (mmHg), supine and standing diastolic blood pressure (DBP) <50 mmHg, supine and standing SBP of >=30 mmHg maximum (max.) increase from baseline (IFB) and and decrease from baseline (DFB) in same posture, supine and Standing DBP of >=20 mmHg max. increase and decrease from baseline in same posture. Categories in which there was atleast 1 abnormality are reported in this outcome measure. | Baseline up to Day 30 | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities | Criteria for ECG abnormalities: maximum PR interval >=300 milliseconds (msec) and maximum increase PR interval increase from baseline (IFB): percent change (Pctchg) >=25 percent (%) for baseline value of >200 msec and Pctchg>=50% for baseline value of <=200 msec for PR interval, maximum QRS interval >=140 msec and a maximum IFB: Pctchg>=50%, maximum QTCF interval (Fridericia's Correction) of 450 msec to <480 msec, 480 msec to <500 msec or >=500 msec and a maximum change of <=30change<60 or >=60 msec from baseline. | Baseline up to Day 30 | 
| Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings | Physical examination included examination of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision. | Baseline up to Day 30 | 
| Number of Participants With Clinically Significant Neurological Examination Abnormality | The complete or full neurological examination included assessment of the cranial nerves; muscle strength, tone, cortical drift, abnormal movements; deep tendon reflexes; sensory exam, coordination, gait and station. Higher cortical and motor function was considered part of the complete neurological exam. Findings were considered abnormal as confirmed by a certified neurologist. | Baseline up to Day 30 | 
| Number of Participants With Categorical Scores on The Columbia Suicide Severity Rating Scale (C-SSRS) | The C-SSRS was an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced any of the following 1: completed suicide, 2: suicide attempt (response of yes on actual attempt), 3: preparatory acts toward imminent suicidal behavior (yes on aborted attempt, interrupted attempt, preparatory acts or behavior), 4: any suicidal behavior or ideation, suicidal ideation (yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), 7: self-injurious behavior, no suicidal intent (yes on has participant engaged in non-suicidal self-injurious behavior). | Baseline up to Day 30 | 
| Change From Baseline in Parkinson's Disease Diary For Participants With Motor Fluctuations at Day 13 | According to Parkinson's disease diaries of participants OFF time was a time period when the medication no longer providing benefit with regard to mobility, slowness, and stiffness and participants experienced relatively poor overall function with worsening of tremor, rigidity, balance, or bradykinesia. ON time was a time period when medication was providing benefit with regard to mobility, slowness, and stiffness. ON time was classified as associated with or without troublesome dyskinesia (TD) that interfere with activities of daily living and with or without dyskinesia. OFF time and ON time with TD were generally considered to be bad time with regard to motor function, whereas ON time without dyskinesia (WD) and with non- troublesome dyskinesia (NTD) were generally considered to be good time. | Baseline, Day 13 | 
| Change From Baseline in Parkinson's Disease Diary For Participants With Motor Fluctuations at Day 20 | According to Parkinson's disease diaries of participants OFF time was a time period when the medication no longer providing benefit with regard to mobility, slowness, and stiffness and participants experienced relatively poor overall function with worsening of tremor, rigidity, balance, or bradykinesia. ON time was a time period when medication was providing benefit with regard to mobility, slowness, and stiffness. ON time was classified as associated with or without troublesome dyskinesia (TD) that interfere with activities of daily living and with or without dyskinesia. OFF time and ON time with TD were generally considered to be bad time with regard to motor function, whereas ON time without dyskinesia (WD) and with non- troublesome dyskinesia (NTD) were generally considered to be good time. | Baseline, Day 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of L-Dopa |  | Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of L-Dopa |  | Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 | 
| Apparent Clearance (CL/F) of L-Dopa | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 | 
| Terminal Half-Life (t1/2) of L-Dopa | Terminal half-life is the time measured for the plasma concentration of drug to decrease by one half. It was calculated as dividing the natural logarithm to the base e (Log e)*2/k el, where k el is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. | Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 | 
| Area Under the Curve From Time Zero Extrapolated to Infinite Time of L-Dopa | AUC (0 - inf)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). | Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration of L-Dopa | Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (C last). | Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 | 
| Apparent Volume of Distribution (Vz/F) of L-Dopa | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 | 
| Maximum Observed Plasma Concentration (Cmax) of PF-06649751 |  | Pre-dose on Day 3, 4, 8, 11, 14, 17, 20, Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 7, 13, 22 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06649751 |  | Pre-dose on Day 3, 4, 8, 11, 14, 17, 20, Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 7, 13, 22 | 
| Apparent Clearance (CL/F) of PF-06649751 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 22 | 
| Area Under the Curve From Time Zero to End of Dosing Interval of PF-06649751 | Area under the concentration curve from time zero to end of dosing interval (AUCtau), where dosing interval was 12 hours. | Pre-dose on Day 3, 4, 8, 11, 14, 17, 20, Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 7, 13, 22 | 
| Minimum Observed Plasma Trough Concentration (Cmin) of PF-06649751 |  | Pre-dose on Day 3, 4, 8, 11, 14, 17, 20, Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 7, 13, 22 | 
| Ratio of Accumulation for Area Under the Curve From Time Zero to End of Dosing Interval of PF-06649751 | Rac was obtained from AUCtau after last dose divided by AUCtau after first dose, where AUC(tau) = Area under the concentration curve from time zero to end of dosing interval (AUCtau), where dosing interval was 12 hours. | Pre-dose on Day 3, 4, 8, 11, 14, 17, 20, Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 7, 13, 22 |