Healthy Volunteers
Conditions
Brief summary
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.
Interventions
DRUGEvacetrapib
Oral administration
DRUGWarfarin
Oral administration
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | Days 1 and 17: 0, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose | 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. |
| 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 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Warfarin Then Evacetrapib + Warfarin 15 mg warfarin administered as a single oral dose on Day 1. Evacetrapib administered QD, orally, for 16 days, Days 7- 22 with 15 mg warfarin co-administered once orally on Day 17. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2 (Day 7 Dosing to Day 23) | Adverse Event | 0 | 1 |
| Period 2 (Day 7 Dosing to Day 23) | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Warfarin Then Evacetrapib + Warfarin |
|---|---|
| Age, Continuous | 36.0 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 24 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 24 | 2 / 24 | 0 / 23 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 | 0 / 23 |
Outcome results
Primary
Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC[0-∞]) of S-Warfarin
Time frame: Days 1 and 17: 0, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose
Population: All participants who received a dose of study drug and had evaluable data for AUC \[0-∞\].
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC[0-∞]) of S-Warfarin | 128 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 23 |
| Evacetrapib + Warfarin | Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC[0-∞]) of S-Warfarin | 114 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 19 |
Primary
PK: Maximum Observed Concentration (Cmax) of S-warfarin
Time frame: Days 1 and 17: 0, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose
Population: All participants who received a dose of study drug and had evaluable data for Cmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | PK: Maximum Observed Concentration (Cmax) of S-warfarin | 4.20 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 21 |
| Evacetrapib + Warfarin | PK: Maximum Observed Concentration (Cmax) of S-warfarin | 4.34 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 29 |
Secondary
PD: Maximum Observed International Normalized Ratio Response (INRmax) of Warfarin
Time frame: Days 1 and 17: 0, 6, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose
Population: All participants who received a dose of study drug and had evaluable date for INRmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | PD: Maximum Observed International Normalized Ratio Response (INRmax) of Warfarin | 1.47 ratio | Geometric Coefficient of Variation 18 |
| Evacetrapib + Warfarin | PD: Maximum Observed International Normalized Ratio Response (INRmax) of Warfarin | 1.34 ratio | Geometric Coefficient of Variation 11 |
Secondary
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.
Time frame: Days 1 and 17: 0, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose
Population: All participants who received a dose of study drug and had evaluable data for AUC\[INR\].
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | Pharmacodynamics (PD): Area Under the International Normalized Ratio Curve (AUC[INR]) of Warfarin | 174 ratio times hour (ratio*h) | Geometric Coefficient of Variation 7 |
| Evacetrapib + Warfarin | Pharmacodynamics (PD): Area Under the International Normalized Ratio Curve (AUC[INR]) of Warfarin | 165 ratio times hour (ratio*h) | Geometric Coefficient of Variation 5 |
Secondary
PK: AUC[0-∞] of R-warfarin
Time frame: Days 1 and 17: 0, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose
Population: All participants who received a dose of study drug and had evaluable data for AUC\[0-∞\].
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | PK: AUC[0-∞] of R-warfarin | 287 ng*h/mL | Geometric Coefficient of Variation 16 |
| Evacetrapib + Warfarin | PK: AUC[0-∞] of R-warfarin | 271 ng*h/mL | Geometric Coefficient of Variation 17 |
Secondary
PK: Cmax of R-warfarin
Time frame: Days 1 and 17: 0, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose
Population: All participants who received a dose of study drug and had evaluable data for Cmax of R- enantiomers of Warfarin.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | PK: Cmax of R-warfarin | 5.03 ng/mL | Geometric Coefficient of Variation 21 |
| Evacetrapib + Warfarin | PK: Cmax of R-warfarin | 5.27 ng/mL | Geometric Coefficient of Variation 27 |