Clinical trial NCT02224664: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PF-06649751 in Parkinson's Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Parkinson's Disease
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2014-08-25
Enrollment: 50
Sex: ALL
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Primary purpose: BASIC_SCIENCE

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.


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

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline (Day 1) up to Day 30
measure: Number of Participants With Laboratory Test Abnormalities
timeFrame: Baseline up to Day 30
measure: Number of Participants With Vital Sign Abnormalities
timeFrame: Baseline up to Day 30
measure: Number of Participants With Electrocardiogram (ECG) Abnormalities
timeFrame: Baseline up to Day 30
measure: Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings
timeFrame: Baseline up to Day 30
measure: Number of Participants With Clinically Significant Neurological Examination Abnormality
timeFrame: Baseline up to Day 30
measure: Number of Participants With Categorical Scores on The Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: Baseline up to Day 30
measure: Change From Baseline in Parkinson's Disease Diary For Participants With Motor Fluctuations at Day 13
timeFrame: Baseline, Day 13
measure: Change From Baseline in Parkinson's Disease Diary For Participants With Motor Fluctuations at Day 20
timeFrame: Baseline, Day 20
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of L-Dopa
timeFrame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of L-Dopa
timeFrame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
measure: Apparent Clearance (CL/F) of L-Dopa
timeFrame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
measure: Terminal Half-Life (t1/2) of L-Dopa
timeFrame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
measure: Area Under the Curve From Time Zero Extrapolated to Infinite Time of L-Dopa
timeFrame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration of L-Dopa
timeFrame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
measure: Apparent Volume of Distribution (Vz/F) of L-Dopa
timeFrame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
measure: Maximum Observed Plasma Concentration (Cmax) of PF-06649751
timeFrame: 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
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06649751
timeFrame: 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
measure: Apparent Clearance (CL/F) of PF-06649751
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 22
measure: Area Under the Curve From Time Zero to End of Dosing Interval of PF-06649751
timeFrame: 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
measure: Minimum Observed Plasma Trough Concentration (Cmin) of PF-06649751
timeFrame: 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
measure: Ratio of Accumulation for Area Under the Curve From Time Zero to End of Dosing Interval of PF-06649751
timeFrame: 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
Other outcomes:
Locations:
city: Fountain Valley
country: United States
facility: Orange Coast Memorial Medical Center
state: California
city: Fountain Valley
country: United States
facility: The Parkinson's and Movement Disorder Institute
state: California
city: Long Beach
country: United States
facility: Collaborative Neuroscience Network, LLC
state: California
city: Englewood
country: United States
facility: Rocky Mountain Movement Disorders Center
state: Colorado
city: Lakewood
country: United States
facility: Davita Clinical Research Center
state: Colorado
city: Hallandale Beach
country: United States
facility: MD Clinical
state: Florida
city: Orlando
country: United States
facility: Compass Research, LLC
state: Florida
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital -- FOR DRUG SHIPMENT ONLY
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Farmington Hills
country: United States
facility: Quest Research Institute
state: Michigan
city: Marlton
country: United States
facility: PRA International
state: New Jersey
city: Raleigh
country: United States
facility: Carolina Phase I Research, LLC
state: North Carolina
city: Oklahoma City
country: United States
facility: Lynn Health Science Institute
state: Oklahoma
city: Dallas
country: United States
facility: Neurology Consultants of Dallas, PA
state: Texas
city: Dallas
country: United States
facility: Walnut Hill Medical Center
state: Texas
city: Brussels
country: Belgium
facility: Pfizer Clinical Research Unit
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Sohur US, Gray DL, Duvvuri S, Zhang Y, Thayer K, Feng G. Phase 1 Parkinson's Disease Studies Show the Dopamine D1/D5 Agonist PF-06649751 is Safe and Well Tolerated. Neurol Ther. 2018 Dec;7(2):307-319. doi: 10.1007/s40120-018-0114-z. Epub 2018 Oct 25.