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

2017年2月3日 更新者：Pfizer

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

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.

研究概览

地位

完全的

条件

干预/治疗

研究类型

介入性

注册 (实际的)

50

阶段

  • 阶段1

联系人和位置

本节提供了进行研究的人员的详细联系信息，以及有关进行该研究的地点的信息。

学习地点

  • 比利时
      • Brussels、比利时、B-1070
        • Pfizer Clinical Research Unit
  • 美国
    • California
      • Fountain Valley、California、美国、92708
        • The Parkinson's and Movement Disorder Institute
      • Fountain Valley、California、美国、92708
        • Orange Coast Memorial Medical Center
      • Long Beach、California、美国、90806
        • Collaborative Neuroscience Network, LLC
    • Colorado
      • Englewood、Colorado、美国、80113
        • Rocky Mountain Movement Disorders Center
      • Lakewood、Colorado、美国、80228
        • Davita Clinical Research Center
    • Florida
      • Hallandale Beach、Florida、美国、33009
        • MD Clinical
      • Orlando、Florida、美国、32806
        • Compass Research, LLC
    • Georgia
      • Atlanta、Georgia、美国、30331
        • Atlanta Center for Medical Research
    • Massachusetts
      • Boston、Massachusetts、美国、02114
        • Massachusetts General Hospital
      • Boston、Massachusetts、美国、02114
        • Massachusetts General Hospital -- FOR DRUG SHIPMENT ONLY
    • Michigan
      • Farmington Hills、Michigan、美国、48334
        • Quest Research Institute
    • New Jersey
      • Marlton、New Jersey、美国、08053
        • PRA International
    • North Carolina
      • Raleigh、North Carolina、美国、27612
        • Carolina Phase I Research, LLC
    • Oklahoma
      • Oklahoma City、Oklahoma、美国、73112
        • Lynn Health Science Institute
    • Texas
      • Dallas、Texas、美国、75231
        • Neurology Consultants of Dallas, PA
      • Dallas、Texas、美国、75231
        • Walnut Hill Medical Center

参与标准

研究人员寻找符合特定描述的人，称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

30年 至 80年 (成人、年长者)

接受健康志愿者

不

有资格学习的性别

全部

描述

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

学习计划

本节提供研究计划的详细信息，包括研究的设计方式和研究的衡量标准。

研究是如何设计的？

设计细节

  • 主要用途：基础科学
  • 分配：非随机化
  • 屏蔽：无（打开标签）

武器和干预

参与者组/臂
干预/治疗
实验性的：Cohort 3
Titration of PF-06649751 up to 5 mg QD
药品：PF-06649751
Oral daily doses titrated up to 5mg QD
药品：PF-06649751
Oral daily doses titrated up to 15 mg QD
药品：PF-06649751
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
药品：PF-06649751
Oral daily doses titrated up to 25 mg QD
实验性的：Cohort 4
Titration of PF-06649751 up to 15 mg QD
药品：PF-06649751
Oral daily doses titrated up to 5mg QD
药品：PF-06649751
Oral daily doses titrated up to 15 mg QD
药品：PF-06649751
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
药品：PF-06649751
Oral daily doses titrated up to 25 mg QD
实验性的：Cohort 5
Titration of PF-06649751 up to 15 mg QDi n subjects with Levodopa-induced dyskinesias (LID)
药品：PF-06649751
Oral daily doses titrated up to 5mg QD
药品：PF-06649751
Oral daily doses titrated up to 15 mg QD
药品：PF-06649751
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
药品：PF-06649751
Oral daily doses titrated up to 25 mg QD
实验性的：Cohort 6
Titration of PF-0649751 up to 25 mg QD
药品：PF-06649751
Oral daily doses titrated up to 5mg QD
药品：PF-06649751
Oral daily doses titrated up to 15 mg QD
药品：PF-06649751
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
药品：PF-06649751
Oral daily doses titrated up to 25 mg QD

研究衡量的是什么？

主要结果指标

结果测量
措施说明
大体时间
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
大体时间：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.
Baseline (Day 1) up to Day 30
Number of Participants With Laboratory Test Abnormalities
大体时间：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.
Baseline up to Day 30
Number of Participants With Vital Sign Abnormalities
大体时间：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.
Baseline up to Day 30
Number of Participants With Electrocardiogram (ECG) Abnormalities
大体时间：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.
Baseline up to Day 30
Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings
大体时间：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.
Baseline up to Day 30
Number of Participants With Clinically Significant Neurological Examination Abnormality
大体时间：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.
Baseline up to Day 30
Number of Participants With Categorical Scores on The Columbia Suicide Severity Rating Scale (C-SSRS)
大体时间：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").
Baseline up to Day 30
Change From Baseline in Parkinson's Disease Diary For Participants With Motor Fluctuations at Day 13
大体时间：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".
Baseline, Day 13
Change From Baseline in Parkinson's Disease Diary For Participants With Motor Fluctuations at Day 20
大体时间：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".
Baseline, Day 20

次要结果测量

结果测量
措施说明
大体时间
Maximum Observed Plasma Concentration (Cmax) of L-Dopa
大体时间：Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
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
大体时间：Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
Apparent Clearance (CL/F) of L-Dopa
大体时间：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.
Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
Terminal Half-Life (t1/2) of L-Dopa
大体时间：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.
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
大体时间：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).
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
大体时间：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).
Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
Apparent Volume of Distribution (Vz/F) of L-Dopa
大体时间：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.
Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
Maximum Observed Plasma Concentration (Cmax) of PF-06649751
大体时间：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
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
大体时间：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
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
大体时间：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.
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
大体时间：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.
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
大体时间：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
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
大体时间：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.
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

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

赞助

Pfizer

出版物和有用的链接

负责输入研究信息的人员自愿提供这些出版物。这些可能与研究有关。

一般刊物

有用的网址

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查，以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始

2014年10月1日

初级完成 (实际的)

2016年3月1日

研究完成 (实际的)

2016年3月1日

研究注册日期

首次提交

2014年8月15日

首先提交符合 QC 标准的

2014年8月21日

首次发布 (估计)

2014年8月25日

研究记录更新

最后更新发布 (实际的)

2017年3月27日

上次提交的符合 QC 标准的更新

2017年2月3日

最后验证

2016年12月1日

更多信息

与本研究相关的术语

其他相关的 MeSH 术语

其他研究编号

  • B7601005
  • 2014-003472-22 (EudraCT编号)

此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.

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