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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Healthy

Intervention / Treatment
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* Drug: 0.15 mg PF-06649751
* Drug: 0.5 mg PF-06649751
* Drug: 0.5 mg PF-06649751
* Drug: 1.5 mg PF-06649751
* Drug: 1.5 mg PF-06649751 21 Days
* Drug: 3.0 mg PF-06649751
* Drug: 5.0 mg PF-06649751
* Drug: 8.0 mg PF-06649751
* Drug: 1.5 mg PF-06649751 in healthy Japanese subjects


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Dosing in healthy Western subjects. | Drug: 0.15 mg PF-06649751<br>* Oral dosing of 0.15 mg PF-06649751 extemporaneously-prepared solution given once-daily for 14 days.<br>|
| Experimental: Cohort 2<br>Dosing in healthy Western subjects. | Drug: 0.5 mg PF-06649751<br>* Oral dosing of 0.5 mg PF-06649751 extemporaneously-prepared solution given once-daily for 14 days.<br>|
| Experimental: Cohort 3<br>Dosing in healthy Western subjects. | Drug: 0.5 mg PF-06649751<br>* Oral dosing of tablets up to 0.5 mg PF-06649751 given once-daily for 14 days.<br>|
| Experimental: Cohort 4<br>Dosing in healthy Western subjects. | Drug: 1.5 mg PF-06649751<br>* Oral dosing of tablets up to 1.5 mg PF-06649751 given once-daily for 14 days.<br>|
| Experimental: Cohort 5<br>Dosing in healthy Western subjects. | Drug: 1.5 mg PF-06649751 21 Days<br>* Oral dosing of tablets up to 1.5 mg PF-06649751 given once-daily for 21 days.<br>|
| Experimental: Cohort 6<br>Dosing in healthy Western subjects. | Drug: 3.0 mg PF-06649751<br>* Oral dosing of tablets up to 3.0 mg PF-06649751 given once-daily for 28 days.<br>|
| Experimental: Cohort 7<br>Dosing in healthy Western subjects. | Drug: 5.0 mg PF-06649751<br>* Oral dosing of tablets up to 5.0 mg PF-06649751 given once-daily for 28 days.<br>|
| Experimental: Optional Cohort 8<br>Dosing in healthy Western subjects. Cohort may not be conducted. | Drug: 8.0 mg PF-06649751<br>* Oral dosing of tablets up to 8.0 mg PF-06649751 given once-daily for 28 days.<br>|
| Experimental: Cohort 9<br>Dosing in healthy Japanese subjects. | Drug: 1.5 mg PF-06649751 in healthy Japanese subjects<br>* Oral dosing of tablets up to 1.5 mg PF-06649751 given once-daily for 14 days given in healthy Japanese subjects.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Supine and standing vital sign measurements | Measurement of blood pressure and pulse rate | Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up | 
| Amount of unchanged drug excreted in urine relative to dose (Ae%) |  | Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8) | 
| Renal Clearance (CLR) |  | 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) |  | 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) | Maximum plasma concentration | Day 1, Day 7, Day 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Time for Cmax | Day 1, Day 7, Day 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8) | 
| Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8) | 
| Apparent Oral Clearance (CL/F) | 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. | Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8) | 
| Apparent Volume of Distribution (Vz/F) | 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. | Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8) | 
| Trough Concentration (Ctrough) | Minimum concentration pre-dose | Day 1 to 14 (Cohorts 1 - 4, 9), Day 1 to 21 (Cohort 5), Day 1 to 28 (Cohorts 6 - 8) | 
| Ratio of accumulation for AUCtau (Rac AUCtau) | Ratio of accumulation for AUCtau. Corrected for titrated doses. | 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 Cmax (Rac Cmax) | Ratio of accumulation for Cmax. Corrected for titrated doses. | Day 1, Day 7 and Day 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8) | 
| Peak-to-trough ratio (PTR) | Peak-to-trough ratio at steady state | Day 7 and Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8) | 
| Number of Participants with categorical scores on the Columbia Suicide Severity Rating Scale (C-SSRS) | 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). | Day 0 and 14 (Cohorts 1 - 4, 9), Day 0 and 21 (Cohort 5), Day 0 and 28 (Cohort 6 - 8) and follow-up | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up | 
| Electrocardiogram (ECG) | Measurement of standard 12-lead ECG, single or triplicate | Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up | 
| Number of Participants With Laboratory Test Values of Potential Clinical Importance | Pre-defined criteria were established for each laboratory test to define the values that would be identified as of potential clinical importance. | Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up | 
| Changes from baseline in total cholesterol, High Density Lipoprotein (HDL) cholesterol, Low Density Lipoprotein (LDL) cholesterol, triglycerides |  | 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) | Calculated from urinary volumes and concentration | Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolite Scouting | Identification of metabolites from blood and urine samples. | Day 1 (Cohorts 1 - 9) , Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, safety, tolerability, healthy volunteers, steady state, multiple doses, Japanese subjects