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

NCT02224664 | Completed Phase 1 Results

• 2 other identifiers: B76010052014-003472-22
• Study Type: interventional
• Target: 50
• Locations: 2 countries
• Sites: 17

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.

Conditions

Parkinson's Disease

Outcome Measures

Primary Outcomes (9)

• 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 Outcomes (13)

• 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

  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

• 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

Study Arms (4)

Cohort 3

EXPERIMENTAL

Titration of PF-06649751 up to 5 mg QD

Drug: PF-06649751

Cohort 4

EXPERIMENTAL

Titration of PF-06649751 up to 15 mg QD

Drug: PF-06649751

Cohort 5

EXPERIMENTAL

Titration of PF-06649751 up to 15 mg QDi n subjects with Levodopa-induced dyskinesias (LID)

Drug: PF-06649751

Cohort 6

EXPERIMENTAL

Titration of PF-0649751 up to 25 mg QD

Drug: PF-06649751

Interventions

PF-06649751 DRUG

Oral daily doses titrated up to 5mg QD

Cohort 3

Eligibility Criteria

• Age: 30 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Atypical/secondary parkinsonism
• History of surgical intervention for Parkinson's Disease
• Dementia/cognitive impairment that can interfere with study assessments

Sponsors & Collaborators

• Pfizer: lead

Study Sites (17)

Orange Coast Memorial Medical Center

Fountain Valley, California, 92708, United States

Location

The Parkinson's and Movement Disorder Institute

Fountain Valley, California, 92708, United States

Location

Collaborative Neuroscience Network, LLC

Long Beach, California, 90806, United States

Location

Rocky Mountain Movement Disorders Center

Englewood, Colorado, 80113, United States

Location

Davita Clinical Research Center

Lakewood, Colorado, 80228, United States

Location

MD Clinical

Hallandale, Florida, 33009, United States

Location

Compass Research, LLC

Orlando, Florida, 32806, United States

Location

Atlanta Center for Medical Research

Atlanta, Georgia, 30331, United States

Location

Massachusetts General Hospital -- FOR DRUG SHIPMENT ONLY

Boston, Massachusetts, 02114, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Quest Research Institute

Farmington Hills, Michigan, 48334, United States

Location

PRA International

Marlton, New Jersey, 08053, United States

Location

Carolina Phase I Research, LLC

Raleigh, North Carolina, 27612, United States

Location

Lynn Health Science Institute

Oklahoma City, Oklahoma, 73112, United States

Location

Neurology Consultants of Dallas, PA

Dallas, Texas, 75231, United States

Location

Walnut Hill Medical Center

Dallas, Texas, 75231, United States

Location

Pfizer Clinical Research Unit

Brussels, B-1070, Belgium

Location

Related Publications (1)

• 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.

  PMID: 30361858 DERIVED

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Parkinson Disease

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 15, 2014
• First Posted: August 25, 2014
• Study Start: October 1, 2014
• Primary Completion: March 1, 2016
• Study Completion: March 1, 2016
• Last Updated: March 27, 2017
• Results First Posted: March 27, 2017

Record last verified: 2016-12

Locations

US (16); BE (1)