A Study In Healthy People Of Multiple Doses Of UK-396,082 Given By Mouth, To Investigate The Safety, Toleration And Time Course Of Blood Concentration Of UK-396,082 And Its Effects.

Study Overview
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Brief Summary
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The purpose of this study in healthy people is to investigate the safety, toleration and time course of UK-396,082 concentration in the blood and any changes in relevant markers of drug effects, following multiple doses given twice daily by mouth for 14 days.

Official Title
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A Double Blind, Randomized 3rd Party Open, Placebo Controlled, Parallel Group Multiple Oral Escalating Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of UK-396,082 In Healthy Subjects

Conditions
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Phase 1, Multiple Dose, Safety, Toleration, Pharmacokinetic

Intervention / Treatment
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* Drug: UK-396,082
* Drug: placebo
* Drug: UK-396,082
* Drug: placebo
* Drug: UK-396,082
* Drug: placebo
* Drug: UK-396,082
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subjects. (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). 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 time of dosing). A positive urine drug screen. Treatment with an investigational drug within 30 days (or as determined by the local requirement, whichever is longer) or 5 half-lives preceding the first dose of study medication.

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>Subjects will be assigned to receive either UK-396,082 or placebo | Drug: UK-396,082<br>* 100mg given orally twice daily for 14 days The decision to proceed to the next higher dose will be made jointly by the Pfizer Study Team and the Investigator after careful review of available safety, tolerability and PK information from previous cohorts and dosing periods. The doses will be selected such that the predicted Cmax will not exceed 2.95 mcg/mL and/or the predicted increase in exposure will not exceed 3.5-fold that of the previously studied dose.<br>Drug: placebo<br>* given orally twice daily for 14 days<br>|
| Experimental: Cohort 2<br>Subjects will be assigned to receive either UK-396,082 or placebo | Drug: UK-396,082<br>* 300mg given orally twice daily for 14 days The decision to proceed to the next higher dose will be made jointly by the Pfizer Study Team and the Investigator after careful review of available safety, tolerability and PK information from previous cohorts and dosing periods. The doses will be selected such that the predicted Cmax will not exceed 2.95 mcg/mL and/or the predicted increase in exposure will not exceed 3.5-fold that of the previously studied dose.<br>Drug: placebo<br>* given orally twice daily for 14 days<br>|
| Experimental: Cohort 3<br>Subjects will be assigned to receive either UK-396,082 or placebo | Drug: UK-396,082<br>* 1000mg given orally twice daily for 14 days The decision to proceed to the next higher dose will be made jointly by the Pfizer Study Team and the Investigator after careful review of available safety, tolerability and PK information from previous cohorts and dosing periods. The doses will be selected such that the predicted Cmax will not exceed 2.95 mcg/mL and/or the predicted increase in exposure will not exceed 3.5-fold that of the previously studied dose.<br>Drug: placebo<br>* given orally twice daily for 14 days<br>|
| Experimental: Cohort 4<br>Subjects will be assigned to receive either UK-396,082 or placebo | Drug: UK-396,082<br>* UK-396,082 given orally, once on Days 1 & 14, and twice daily on Days 3-13. The decision to proceed to the next higher dose will be made jointly by the Study Team and the Investigator after careful review of available safety, tolerability and PK information from previous cohorts. Dependent on the emerging safety, tolerability and PK data, Cohort 4 may be recruited to study a higher (or lower) dose of UK-396,082 in order to characterize further the safety, toleration and PK and/or to define the maximum tolerated dose. The dose in Cohort 4 will be selected such that the predicted Cmax will not exceed 46 mcg/mL and/or the predicted increase in exposure will not exceed 3.5-fold that of the previously studied dose.<br>Drug: placebo<br>* given orally, once on Days 1 & 14, and twice daily on Days 3-13.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety & toleration: Adverse events, vital signs, 12 lead ECG, blood and urine safety tests and physical examination. |  | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma pharmacokinetics: Cmax, Tmax, AUCtau, t½, Rac (=AUCtau (Day 14)/AUCtau (Day 1)), CL/F, Vz/f, Cmin, Cav Urine pharmacokinetics: Aetau & Aetau%, CLR on Day 14 |  | 14 days | 
| Time course of changes in prothrombin time, activated partial thromboplastin time, TAFi inhibition, fibrinogen and D-dimer concentrations. |  | 14 days |