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
Overview
- Phase
- Phase 1
- Intervention
- PF-06649751
- Conditions
- Parkinson's Disease
- Sponsor
- Pfizer
- Enrollment
- 50
- Locations
- 17
- Primary Endpoint
- Number of Participants With Vital Sign Abnormalities
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
Cohort 3
Titration of PF-06649751 up to 5 mg QD
Intervention: PF-06649751
Cohort 4
Titration of PF-06649751 up to 15 mg QD
Intervention: PF-06649751
Cohort 5
Titration of PF-06649751 up to 15 mg QDi n subjects with Levodopa-induced dyskinesias (LID)
Intervention: PF-06649751
Cohort 6
Titration of PF-0649751 up to 25 mg QD
Intervention: PF-06649751
Outcomes
Primary Outcomes
Number of Participants With Vital Sign Abnormalities
Time Frame: Baseline up to Day 30
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.
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: Baseline (Day 1) up to Day 30
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.
Number of Participants With Laboratory Test Abnormalities
Time Frame: Baseline up to Day 30
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.
Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings
Time Frame: Baseline up to Day 30
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.
Change From Baseline in Parkinson's Disease Diary For Participants With Motor Fluctuations at Day 13
Time Frame: Baseline, 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".
Number of Participants With Categorical Scores on The Columbia Suicide Severity Rating Scale (C-SSRS)
Time Frame: Baseline up to Day 30
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").
Number of Participants With Electrocardiogram (ECG) Abnormalities
Time Frame: Baseline up to Day 30
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.
Number of Participants With Clinically Significant Neurological Examination Abnormality
Time Frame: Baseline up to Day 30
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.
Change From Baseline in Parkinson's Disease Diary For Participants With Motor Fluctuations at Day 20
Time Frame: Baseline, 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".
Secondary Outcomes
- Apparent Clearance (CL/F) of L-Dopa(Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1)
- Terminal Half-Life (t1/2) 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)
- Area Under the Curve From Time Zero Extrapolated to Infinite Time of L-Dopa(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(Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1)
- Maximum Observed Plasma Concentration (Cmax) of L-Dopa(Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1)
- Apparent Clearance (CL/F) of PF-06649751(Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 22)
- Ratio of Accumulation for Area Under the Curve From Time Zero to End of Dosing Interval 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 Volume of Distribution (Vz/F) 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 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)
- 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)
- 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)
- Area Under the Curve From Time Zero to End of Dosing Interval 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)