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

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ClinicalTrials.gov Identifier: NCT02224664
Recruitment Status : Completed
First Posted : August 25, 2014
Results First Posted : March 27, 2017
Last Update Posted : March 27, 2017
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Description
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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.

Condition or disease Intervention/treatment Phase
Parkinson's Disease Drug: PF-06649751 Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Non-Randomized
Masking: None (Open Label)
Primary Purpose: Basic Science
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 Start Date : October 2014
Actual Primary Completion Date : March 2016
Actual Study Completion Date : March 2016

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 3
Titration of PF-06649751 up to 5 mg QD
 Drug: PF-06649751
Oral daily doses titrated up to 5mg QD
Experimental: Cohort 4
Titration of PF-06649751 up to 15 mg QD
 Drug: PF-06649751
Oral daily doses titrated up to 15 mg QD
Experimental: Cohort 5
Titration of PF-06649751 up to 15 mg QDi n subjects with Levodopa-induced dyskinesias (LID)
 Drug: PF-06649751
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
Experimental: Cohort 6
Titration of PF-0649751 up to 25 mg QD
 Drug: PF-06649751
Oral daily doses titrated up to 25 mg QD


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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").

  8. 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".

  9. 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 Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) of L-Dopa [ Time Frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 ]
  2. Time to Reach Maximum Observed Plasma Concentration (Tmax) of L-Dopa [ Time Frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 ]
  3. Apparent Clearance (CL/F) of L-Dopa [ Time Frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 ]
    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.

  4. Terminal Half-Life (t1/2) of L-Dopa [ Time Frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 ]
    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.

  5. Area Under the Curve From Time Zero Extrapolated to Infinite Time of L-Dopa [ Time Frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 ]
    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).

  6. Area Under the Curve From Time Zero to Last Quantifiable Concentration of L-Dopa [ Time Frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 ]
    Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (C last).

  7. Apparent Volume of Distribution (Vz/F) of L-Dopa [ Time Frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1 ]
    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.

  8. Maximum Observed Plasma Concentration (Cmax) of PF-06649751 [ Time Frame: 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 ]
  9. Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06649751 [ Time Frame: 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 ]
  10. Apparent Clearance (CL/F) of PF-06649751 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 22 ]
    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.

  11. Area Under the Curve From Time Zero to End of Dosing Interval of PF-06649751 [ Time Frame: 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 concentration curve from time zero to end of dosing interval (AUCtau), where dosing interval was 12 hours.

  12. Minimum Observed Plasma Trough Concentration (Cmin) of PF-06649751 [ Time Frame: 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 ]
  13. Ratio of Accumulation for Area Under the Curve From Time Zero to End of Dosing Interval of PF-06649751 [ Time Frame: 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 ]
    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.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02224664


Locations
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Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02224664    
Other Study ID Numbers: B7601005
2014-003472-22 ( EudraCT Number )
First Posted: August 25, 2014    Key Record Dates
Results First Posted: March 27, 2017
Last Update Posted: March 27, 2017
Last Verified: December 2016
Additional relevant MeSH terms:
Layout table for MeSH terms
Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
 Nervous System Diseases
Movement Disorders
Synucleinopathies
Neurodegenerative Diseases