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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.

調査の概要

状態

完了

条件

介入・治療

研究の種類

介入

入学 (実際)

50

段階

  • フェーズ 1

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究場所

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

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

30年～80年 (大人、高齢者)

健康ボランティアの受け入れ

いいえ

受講資格のある性別

全て

説明

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

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

  • 主な目的：基礎科学
  • 割り当て：非ランダム化
  • マスキング：なし（オープンラベル）

武器と介入

参加者グループ / アーム
介入・治療
実験的：Cohort 3
Titration of PF-06649751 up to 5 mg QD
薬：PF-06649751
Oral daily doses titrated up to 5mg QD
薬：PF-06649751
Oral daily doses titrated up to 15 mg QD
薬：PF-06649751
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
薬：PF-06649751
Oral daily doses titrated up to 25 mg QD
実験的：Cohort 4
Titration of PF-06649751 up to 15 mg QD
薬：PF-06649751
Oral daily doses titrated up to 5mg QD
薬：PF-06649751
Oral daily doses titrated up to 15 mg QD
薬：PF-06649751
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
薬：PF-06649751
Oral daily doses titrated up to 25 mg QD
実験的：Cohort 5
Titration of PF-06649751 up to 15 mg QDi n subjects with Levodopa-induced dyskinesias (LID)
薬：PF-06649751
Oral daily doses titrated up to 5mg QD
薬：PF-06649751
Oral daily doses titrated up to 15 mg QD
薬：PF-06649751
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
薬：PF-06649751
Oral daily doses titrated up to 25 mg QD
実験的：Cohort 6
Titration of PF-0649751 up to 25 mg QD
薬：PF-06649751
Oral daily doses titrated up to 5mg QD
薬：PF-06649751
Oral daily doses titrated up to 15 mg QD
薬：PF-06649751
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
薬：PF-06649751
Oral daily doses titrated up to 25 mg QD

この研究は何を測定していますか？

主要な結果の測定

結果測定
メジャーの説明
時間枠
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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)
時間枠：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
時間枠：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
時間枠：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

二次結果の測定

結果測定
メジャーの説明
時間枠
Maximum Observed Plasma Concentration (Cmax) of L-Dopa
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

Pfizer

出版物と役立つリンク

研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。

一般刊行物

便利なリンク

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始

2014年10月1日

一次修了 (実際)

2016年3月1日

研究の完了 (実際)

2016年3月1日

試験登録日

最初に提出

2014年8月15日

QC基準を満たした最初の提出物

2014年8月21日

最初の投稿 (見積もり)

2014年8月25日

学習記録の更新

投稿された最後の更新 (実際)

2017年3月27日

QC基準を満たした最後の更新が送信されました

2017年2月3日

最終確認日

2016年12月1日

詳しくは

本研究に関する用語

追加の関連 MeSH 用語

その他の研究ID番号

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

この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。

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