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A Study To Observe Safety And Blood Concentrations Of PF-06649751 During And Following The Oral Administration Of Multiple Doses Of PF-06649751 In Healthy Adult Western and Japanese Volunteers

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ClinicalTrials.gov Identifier: NCT02066909
Recruitment Status : Completed
First Posted : February 20, 2014
Last Update Posted : June 24, 2015
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE February 7, 2014
First Posted Date  ICMJE February 20, 2014
Last Update Posted Date June 24, 2015
Study Start Date  ICMJE February 2014
Actual Primary Completion Date April 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 23, 2015)
  • Supine and standing vital sign measurements [ Time Frame: Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up ]
    Measurement of blood pressure and pulse rate
  • Amount of unchanged drug excreted in urine relative to dose (Ae%) [ Time Frame: Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8) ]
  • Renal Clearance (CLR) [ Time Frame: Day 14 (Cohort 1 - 4, 9), Day 21 (Cohort 5) and Day 28 (Cohorts 6 - 8) ]
  • Area Under the Curve from Time Zero to end of dosing interval (AUCtau) [ Time Frame: Day 1, Day 14 (Cohorts 1 - 4, 9), Day 1 and Day 21 (Cohort 5), Day 1 and Day 28 (Cohorts 6 - 8) ]
  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Day 1, Day 7, Day 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8) ]
    Maximum plasma concentration
  • Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Day 1, Day 7, Day 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8) ]
    Time for Cmax
  • Plasma Decay Half-Life (t1/2) [ Time Frame: Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8) ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
  • Apparent Oral Clearance (CL/F) [ Time Frame: Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8) ]
    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.
  • Apparent Volume of Distribution (Vz/F) [ Time Frame: Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8) ]
    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.
  • Trough Concentration (Ctrough) [ Time Frame: Day 1 to 14 (Cohorts 1 - 4, 9), Day 1 to 21 (Cohort 5), Day 1 to 28 (Cohorts 6 - 8) ]
    Minimum concentration pre-dose
  • Ratio of accumulation for AUCtau (Rac AUCtau) [ Time Frame: Day 1 and 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8) ]
    Ratio of accumulation for AUCtau. Corrected for titrated doses.
  • Ratio of accumulation for Cmax (Rac Cmax) [ Time Frame: Day 1, Day 7 and Day 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8) ]
    Ratio of accumulation for Cmax. Corrected for titrated doses.
  • Peak-to-trough ratio (PTR) [ Time Frame: Day 7 and Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8) ]
    Peak-to-trough ratio at steady state
  • Number of Participants with categorical scores on the Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Day 0 and 14 (Cohorts 1 - 4, 9), Day 0 and 21 (Cohort 5), Day 0 and 28 (Cohort 6 - 8) and follow-up ]
    C-SSRS assessed whether participant experienced following: completed suicide (1), suicide attempt (2) (response of "Yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior (3)("Yes" on "preparatory acts or behavior"), suicidal ideation (4) ("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), any suicidal behavior or ideation, self-injurious behavior (7)("Yes" on "Has subject engaged in non-suicidal self-injurious behavior").
  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up ]
    Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to [study drug] was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.
  • Electrocardiogram (ECG) [ Time Frame: Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up ]
    Measurement of standard 12-lead ECG, single or triplicate
  • Number of Participants With Laboratory Test Values of Potential Clinical Importance [ Time Frame: Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up ]
    Pre-defined criteria were established for each laboratory test to define the values that would be identified as of potential clinical importance.
  • Changes from baseline in total cholesterol, High Density Lipoprotein (HDL) cholesterol, Low Density Lipoprotein (LDL) cholesterol, triglycerides [ Time Frame: Day 1 and Day 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8) ]
  • Amount of unchanged drug excreted in urine relative to dose (Ae) [ Time Frame: Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8) ]
    Calculated from urinary volumes and concentration
Original Primary Outcome Measures  ICMJE
 (submitted: February 18, 2014)
  • Supine and standing vital sign measurements [ Time Frame: 0-18 days ]
    Measurement of blood pressure and pulse rate
  • Amount of unchanged drug excreted in urine relative to dose (Ae%) [ Time Frame: Day 14 ]
  • Renal Clearance (CLR) [ Time Frame: Day 14 ]
  • Area Under the Curve from Time Zero to end of dosing interval (AUCtau) [ Time Frame: Day 1, 7 and 14 ]
  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Day 1, 7 and 14 ]
    Maximum plasma concentration
  • Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Day 1, 7 and 14 ]
    Time for Cmax
  • Plasma Decay Half-Life (t1/2) [ Time Frame: 14 - 18 days ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
  • Apparent Oral Clearance (CL/F) [ Time Frame: 0 - 18 days ]
    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. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
  • Apparent Volume of Distribution (Vz/F) [ Time Frame: 0 - 18 days ]
    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.
  • Trough Concentration (Ctrough) [ Time Frame: 0 - 14 days ]
    Minimum concentration pre-dose
  • Ratio of accumulation for AUCtau (Rac AUCtau) [ Time Frame: Day 1, 7 and 14 ]
    Ratio of accumulation for AUCtau
  • Ratio of accumulation for Cmax (Rac Cmax) [ Time Frame: Day 1, 7 and 14 ]
    Ratio of accumulation for Cmax
  • Peak-to-trough ratio (PTR) [ Time Frame: Day 7 and 14 ]
    Peak-to-trough ratio at steady state
  • Number of Participants with categorical scores on the Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Day 0 and 14 ]
    C-SSRS assessed whether participant experienced following: completed suicide (1), suicide attempt (2) (response of "Yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior (3)("Yes" on "preparatory acts or behavior"), suicidal ideation (4) ("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), any suicidal behavior or ideation, self-injurious behavior (7)("Yes" on "Has subject engaged in non-suicidal self-injurious behavior").
  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 0 - 18 days ]
    Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to [study drug] was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.
  • Electrocardiogram (ECG) [ Time Frame: 0 - 18 days ]
    Measurement of standard 12-lead ECG, single or triplicate
  • Number of Participants With Laboratory Test Values of Potential Clinical Importance [ Time Frame: 0 - 18 days ]
    Pre-defined criteria were established for each laboratory test to define the values that would be identified as of potential clinical importance.
  • Cogstate [ Time Frame: Day 0, 1, 7 and 14 ]
    Cognitive impairment as measured by various tests in the Cogstate battery
  • Changes from baseline in total cholesterol, High Density Lipoprotein (HDL) cholesterol, Low Density Lipoprotein (LDL) cholesterol, triglycerides [ Time Frame: Day 1 and 14 ]
Change History Complete list of historical versions of study NCT02066909 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2015)
Metabolite Scouting [ Time Frame: Day 1 (Cohorts 1 - 9) , Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8) ]
Identification of metabolites from blood and urine samples.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study To Observe Safety And Blood Concentrations Of PF-06649751 During And Following The Oral Administration Of Multiple Doses Of PF-06649751 In Healthy Adult Western and Japanese Volunteers
Official Title  ICMJE A Phase 1, Double Blind, Sponsor Open, Randomized, Placebo Controlled, Dose Escalation, Parallel Group Study To Investigate The Safety, Tolerability And Pharmacokinetics Of Repeat Doses Of Pf-06649751 In Healthy Western And Japanese Subjects
Brief Summary This study is designed to evaluate the safety and plasma concentrations of PF-06649751 in healthy volunteers following one or two times daily oral dosing of PF-06649751 for 14 days (Cohorts 1 - 4), 21 days (Cohort 5), or 28 days (Cohorts 6 - 8). Cohort 9 will dose Japanese healthy volunteers in a manner identical to Cohort 4 and is intended to bridge the safety/tolerability and PK data from the Western and Japanese populations.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Condition  ICMJE Healthy
Intervention  ICMJE
  • Drug: 0.15 mg PF-06649751
    Oral dosing of 0.15 mg PF-06649751 extemporaneously-prepared solution given once-daily for 14 days.
  • Drug: 0.5 mg PF-06649751
    Oral dosing of 0.5 mg PF-06649751 extemporaneously-prepared solution given once-daily for 14 days.
  • Drug: 0.5 mg PF-06649751
    Oral dosing of tablets up to 0.5 mg PF-06649751 given once-daily for 14 days.
  • Drug: 1.5 mg PF-06649751
    Oral dosing of tablets up to 1.5 mg PF-06649751 given once-daily for 14 days.
  • Drug: 1.5 mg PF-06649751 21 Days
    Oral dosing of tablets up to 1.5 mg PF-06649751 given once-daily for 21 days.
  • Drug: 3.0 mg PF-06649751
    Oral dosing of tablets up to 3.0 mg PF-06649751 given once-daily for 28 days.
  • Drug: 5.0 mg PF-06649751
    Oral dosing of tablets up to 5.0 mg PF-06649751 given once-daily for 28 days.
  • Drug: 8.0 mg PF-06649751
    Oral dosing of tablets up to 8.0 mg PF-06649751 given once-daily for 28 days.
  • Drug: 1.5 mg PF-06649751 in healthy Japanese subjects
    Oral dosing of tablets up to 1.5 mg PF-06649751 given once-daily for 14 days given in healthy Japanese subjects.
Study Arms  ICMJE
  • Experimental: Cohort 1
    Dosing in healthy Western subjects.
    Intervention: Drug: 0.15 mg PF-06649751
  • Experimental: Cohort 2
    Dosing in healthy Western subjects.
    Intervention: Drug: 0.5 mg PF-06649751
  • Experimental: Cohort 3
    Dosing in healthy Western subjects.
    Intervention: Drug: 0.5 mg PF-06649751
  • Experimental: Cohort 4
    Dosing in healthy Western subjects.
    Intervention: Drug: 1.5 mg PF-06649751
  • Experimental: Cohort 5
    Dosing in healthy Western subjects.
    Intervention: Drug: 1.5 mg PF-06649751 21 Days
  • Experimental: Cohort 6
    Dosing in healthy Western subjects.
    Intervention: Drug: 3.0 mg PF-06649751
  • Experimental: Cohort 7
    Dosing in healthy Western subjects.
    Intervention: Drug: 5.0 mg PF-06649751
  • Experimental: Optional Cohort 8
    Dosing in healthy Western subjects. Cohort may not be conducted.
    Intervention: Drug: 8.0 mg PF-06649751
  • Experimental: Cohort 9
    Dosing in healthy Japanese subjects.
    Intervention: Drug: 1.5 mg PF-06649751 in healthy Japanese subjects
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 23, 2015)
77
Original Estimated Enrollment  ICMJE
 (submitted: February 18, 2014)
50
Actual Study Completion Date  ICMJE April 2015
Actual Primary Completion Date April 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Healthy males and/or female subjects of non childbearing potential between the ages of 18 and 55 years, inclusive (healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12 lead ECG and clinical laboratory tests).
  • Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs).
  • Cohort 9 only: Japanese subjects must have four biologic Japanese grandparents who were born in Japan.

Exclusion Criteria:

  • Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02066909
Other Study ID Numbers  ICMJE B7601002
2014-003776-23 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date June 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP