Study of Evacetrapib (LY2484595) and Warfarin in Healthy Participants

Study Overview
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Brief Summary
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All study participants will receive both warfarin and a study drug called evacetrapib. The main purpose of this study is to look at how much warfarin gets into the blood stream and how long it takes the body to get rid of warfarin when given both with and without evacetrapib. Another purpose is to evaluate the effectiveness of warfarin therapy to prevent blood clots when given with evacetrapib by measuring the time it takes for blood to clot and comparing it to an average of the international normalized ratio (INR). INR measures the time it takes for blood to clot and compares it to an average. The study will last approximately 5 weeks, not including screening.

Official Title
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Effect of Evacetrapib on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Evacetrapib
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants have given written informed consent approved by Lilly and the ethical review board (ERB) governing the site A medical history and physical examination consistent with a being a healthy individual Male participants will use a reliable method of birth control (as deemed by the investigator) and not donate sperm during the study and for 3 months following the last dose of the investigational product Female participants are not of child-bearing potential due to surgical sterilization (at least 6 weeks after surgical hysterectomy, bilateral oophorectomy, or tubal ligation) confirmed by medical history, or post-menopausal Have a body mass index of 18 to 32 kilograms per square meter (kg/m^2) Participants are predicted to be cytochrome P450 2C9 (CYP2C9) extensive metabolizers as determined by genotyping assessment Exclusion Criteria: Have an abnormality in the 12-lead electrocardiogram (ECG) that increases the risks associated with participating in the study Have an abnormal supine blood pressure Have a history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a risk when taking the study medication; or of interfering with the interpretation of data Show evidence of human immunodeficiency virus (HIV) infection and/or positive human HIV antibodies Show evidence of hepatitis C and/or positive hepatitis C antibody or evidence of hepatitis B and/or positive hepatitis B surface antigen Women who are pregnant or are lactating Have used or intend to use over-the-counter or prescription medications (including vitamins/mineral supplements, herbal medicine) 14 days prior to enrollment and during the study Have consumed grapefruit, cranberries, or grapefruit- or cranberry-containing products within 7 days prior to the first dose of warfarin Have a history or presence of significant bleeding disorders that is, hematemesis, melena, severe or recurrent epistaxis, hemoptysis, clinically overt hematuria or intracranial hemorrhage, gastrointestinal ulcers with hemorrhage Have a personal or family history of coagulation or bleeding disorders or reasonable suspicion of vascular malformations, for example, cerebral hemorrhage, aneurysm or premature stroke (cerebrovascular accident less than 65 years of age) Have a history of major head trauma (with loss of consciousness) within the past year or minor head trauma (without loss of consciousness) within the last 3 months prior to screening or history of major surgery within 3 months of screening Have planned surgery within 14 days after the last day of dosing Have an international normalized ratio/prothrombin time (INR/PT), or activated partial thromboplastin time (aPTT) above the normal reference range or abnormal Protein S antigen and/or Protein C activity at screening

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Warfarin<br>15 milligram (mg) warfarin administered as a single oral dose on Day 1 | Drug: Warfarin<br>* Oral administration<br>|
| Experimental: Evacetrapib + Warfarin<br>Evacetrapib administered once daily (QD), orally, for 16 days with 15 mg warfarin co-administered once orally on Day 17 | Drug: Evacetrapib<br>* Oral administration<br>* Other names: LY2484595;Drug: Warfarin<br>* Oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC[0-∞]) of S-Warfarin |  | Days 1 and 17: 0, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose | 
| PK: Maximum Observed Concentration (Cmax) of S-warfarin |  | Days 1 and 17: 0, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK: AUC[0-∞] of R-warfarin |  | Days 1 and 17: 0, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose | 
| PK: Cmax of R-warfarin |  | Days 1 and 17: 0, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose | 
| Pharmacodynamics (PD): Area Under the International Normalized Ratio Curve (AUC[INR]) of Warfarin | The INR is a standardized ratio of the prothrombin time (PT), time it takes for blood to clot. AUC[INR] is the time curve used to measure change in INR over time. | Days 1 and 17: 0, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose | 
| PD: Maximum Observed International Normalized Ratio Response (INRmax) of Warfarin |  | Days 1 and 17: 0, 6, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose |