Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PF-06649751 in Parkinson's Disease
3 lutego 2017 zaktualizowane przez: 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.
Przegląd badań
Status
Status
Zakończony
Warunki
Warunki
Interwencja / Leczenie
Interwencja / Leczenie
Typ studiów
Typ studiów
Interwencyjne
Zapisy (Rzeczywisty)
Zapisy
50
Faza
Faza
- Faza 1
Kontakty i lokalizacje
Ta sekcja zawiera dane kontaktowe osób prowadzących badanie oraz informacje o tym, gdzie badanie jest przeprowadzane.
Lokalizacje studiów
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Brussels, Belgia, B-1070
- Pfizer Clinical Research Unit
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California
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Fountain Valley, California, Stany Zjednoczone, 92708
- The Parkinson's and Movement Disorder Institute
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Fountain Valley, California, Stany Zjednoczone, 92708
- Orange Coast Memorial Medical Center
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Long Beach, California, Stany Zjednoczone, 90806
- Collaborative Neuroscience Network, LLC
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Colorado
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Englewood, Colorado, Stany Zjednoczone, 80113
- Rocky Mountain Movement Disorders Center
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Lakewood, Colorado, Stany Zjednoczone, 80228
- Davita Clinical Research Center
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Florida
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Hallandale Beach, Florida, Stany Zjednoczone, 33009
- MD Clinical
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Orlando, Florida, Stany Zjednoczone, 32806
- Compass Research, LLC
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Georgia
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Atlanta, Georgia, Stany Zjednoczone, 30331
- Atlanta Center for Medical Research
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Massachusetts
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Boston, Massachusetts, Stany Zjednoczone, 02114
- Massachusetts General Hospital
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Boston, Massachusetts, Stany Zjednoczone, 02114
- Massachusetts General Hospital -- FOR DRUG SHIPMENT ONLY
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Michigan
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Farmington Hills, Michigan, Stany Zjednoczone, 48334
- Quest Research Institute
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New Jersey
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Marlton, New Jersey, Stany Zjednoczone, 08053
- PRA International
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North Carolina
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Raleigh, North Carolina, Stany Zjednoczone, 27612
- Carolina Phase I Research, LLC
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Oklahoma
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Oklahoma City, Oklahoma, Stany Zjednoczone, 73112
- Lynn Health Science Institute
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Texas
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Dallas, Texas, Stany Zjednoczone, 75231
- Neurology Consultants of Dallas, PA
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Dallas, Texas, Stany Zjednoczone, 75231
- Walnut Hill Medical Center
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Kryteria uczestnictwa
Badacze szukają osób, które pasują do określonego opisu, zwanego kryteriami kwalifikacyjnymi. Niektóre przykłady tych kryteriów to ogólny stan zdrowia danej osoby lub wcześniejsze leczenie.
Kryteria kwalifikacji
Kryteria kwalifikacji
Wiek uprawniający do nauki
30 lat do 80 lat (Dorosły, Starszy dorosły)
Akceptuje zdrowych ochotników
Nie
Płeć kwalifikująca się do nauki
Wszystko
Opis
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
Plan studiów
Ta sekcja zawiera szczegółowe informacje na temat planu badania, w tym sposób zaprojektowania badania i jego pomiary.
Jak projektuje się badanie?
Szczegóły projektu
- Główny cel: Podstawowa nauka
- Przydział: Nielosowe
- Maskowanie: Brak (otwarta etykieta)
Liczba ramion
4
Broń i interwencje
Grupa uczestników / ArmGrupa uczestników / Arm |
Interwencja / LeczenieInterwencja / Leczenie |
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Eksperymentalny: Cohort 3
Titration of PF-06649751 up to 5 mg QD
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Oral daily doses titrated up to 5mg QD
Oral daily doses titrated up to 15 mg QD
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
Oral daily doses titrated up to 25 mg QD
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Eksperymentalny: Cohort 4
Titration of PF-06649751 up to 15 mg QD
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Oral daily doses titrated up to 5mg QD
Oral daily doses titrated up to 15 mg QD
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
Oral daily doses titrated up to 25 mg QD
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Eksperymentalny: Cohort 5
Titration of PF-06649751 up to 15 mg QDi n subjects with Levodopa-induced dyskinesias (LID)
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Oral daily doses titrated up to 5mg QD
Oral daily doses titrated up to 15 mg QD
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
Oral daily doses titrated up to 25 mg QD
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Eksperymentalny: Cohort 6
Titration of PF-0649751 up to 25 mg QD
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Oral daily doses titrated up to 5mg QD
Oral daily doses titrated up to 15 mg QD
Oral daily doses titrated up to 15 mg QD (slow titration with option to down titrate)
Oral daily doses titrated up to 25 mg QD
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Co mierzy badanie?
Podstawowe miary wyniku
Podstawowe miary wyniku
Miara wyniku |
Opis środka |
Ramy czasowe |
|---|---|---|
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Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Ramy czasowe: 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.
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Baseline (Day 1) up to Day 30
|
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Number of Participants With Laboratory Test Abnormalities
Ramy czasowe: 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.
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Baseline up to Day 30
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Number of Participants With Vital Sign Abnormalities
Ramy czasowe: 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.
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Baseline up to Day 30
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Number of Participants With Electrocardiogram (ECG) Abnormalities
Ramy czasowe: 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.
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Baseline up to Day 30
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Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings
Ramy czasowe: Baseline up to Day 30
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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.
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Baseline up to Day 30
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Number of Participants With Clinically Significant Neurological Examination Abnormality
Ramy czasowe: Baseline up to Day 30
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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.
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Baseline up to Day 30
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Number of Participants With Categorical Scores on The Columbia Suicide Severity Rating Scale (C-SSRS)
Ramy czasowe: Baseline up to Day 30
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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").
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Baseline up to Day 30
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Change From Baseline in Parkinson's Disease Diary For Participants With Motor Fluctuations at Day 13
Ramy czasowe: Baseline, Day 13
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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".
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Baseline, Day 13
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Change From Baseline in Parkinson's Disease Diary For Participants With Motor Fluctuations at Day 20
Ramy czasowe: Baseline, Day 20
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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".
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Baseline, Day 20
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Miary wyników drugorzędnych
Miary wyników drugorzędnych
Miara wyniku |
Opis środka |
Ramy czasowe |
|---|---|---|
|
Maximum Observed Plasma Concentration (Cmax) of L-Dopa
Ramy czasowe: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
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Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
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Time to Reach Maximum Observed Plasma Concentration (Tmax) of L-Dopa
Ramy czasowe: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
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Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
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Apparent Clearance (CL/F) of L-Dopa
Ramy czasowe: 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.
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Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
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Terminal Half-Life (t1/2) of L-Dopa
Ramy czasowe: 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.
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Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
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Area Under the Curve From Time Zero Extrapolated to Infinite Time of L-Dopa
Ramy czasowe: 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).
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Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
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Area Under the Curve From Time Zero to Last Quantifiable Concentration of L-Dopa
Ramy czasowe: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
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Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (C last).
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Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
|
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Apparent Volume of Distribution (Vz/F) of L-Dopa
Ramy czasowe: 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.
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Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1
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Maximum Observed Plasma Concentration (Cmax) of PF-06649751
Ramy czasowe: 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
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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
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Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06649751
Ramy czasowe: 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
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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
|
|
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Apparent Clearance (CL/F) of PF-06649751
Ramy czasowe: 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
|
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Area Under the Curve From Time Zero to End of Dosing Interval of PF-06649751
Ramy czasowe: 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
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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
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Minimum Observed Plasma Trough Concentration (Cmin) of PF-06649751
Ramy czasowe: 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
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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
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Ratio of Accumulation for Area Under the Curve From Time Zero to End of Dosing Interval of PF-06649751
Ramy czasowe: 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
|
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Publikacje i pomocne linki
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Daty zapisu na studia
Daty te śledzą postęp w przesyłaniu rekordów badań i podsumowań wyników do ClinicalTrials.gov. Zapisy badań i zgłoszone wyniki są przeglądane przez National Library of Medicine (NLM), aby upewnić się, że spełniają określone standardy kontroli jakości, zanim zostaną opublikowane na publicznej stronie internetowej.
Główne daty studiów
Rozpoczęcie studiów
Rozpoczęcie studiów
1 października 2014
Zakończenie podstawowe (Rzeczywisty)
Zakończenie podstawowe
1 marca 2016
Ukończenie studiów (Rzeczywisty)
Ukończenie studiów
1 marca 2016
Daty rejestracji na studia
Pierwszy przesłany
Pierwszy przesłany
15 sierpnia 2014
Pierwszy przesłany, który spełnia kryteria kontroli jakości
Pierwszy przesłany, który spełnia kryteria kontroli jakości
21 sierpnia 2014
Pierwszy wysłany (Oszacować)
Pierwszy wysłany
25 sierpnia 2014
Aktualizacje rekordów badań
Ostatnia wysłana aktualizacja (Rzeczywisty)
Ostatnia wysłana aktualizacja
27 marca 2017
Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości
Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości
3 lutego 2017
Ostatnia weryfikacja
Ostatnia weryfikacja
1 grudnia 2016
Więcej informacji
Terminy związane z tym badaniem
Dodatkowe istotne warunki MeSH
Inne numery identyfikacyjne badania
Inne numery identyfikacyjne badania
- B7601005
- 2014-003472-22 (Numer EudraCT)
Te informacje zostały pobrane bezpośrednio ze strony internetowej clinicaltrials.gov bez żadnych zmian. Jeśli chcesz zmienić, usunąć lub zaktualizować dane swojego badania, skontaktuj się z register@clinicaltrials.gov. Gdy tylko zmiana zostanie wprowadzona na stronie clinicaltrials.gov, zostanie ona automatycznie zaktualizowana również na naszej stronie internetowej .