A Study of Evacetrapib (LY2484595) and Warfarin in Healthy Participants

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT01825876
Collaborator
(none)
17
1
2
2
8.5

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
17 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
Effect of Evacetrapib on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects
Study Start Date :
Apr 1, 2013
Actual Primary Completion Date :
Jun 1, 2013
Actual Study Completion Date :
Jun 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Warfarin

15 milligrams (mg) warfarin administered as a single oral dose

Drug: Warfarin
Oral administration

Experimental: Evacetrapib + Warfarin

130 mg evacetrapib administered once daily (QD), orally, for 16 days with 15 mg warfarin co-administered once orally on Day 10

Drug: Evacetrapib
Oral administration
Other Names:
  • LY2484595
  • Drug: Warfarin
    Oral administration

    Outcome Measures

    Primary Outcome Measures

    1. Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-∞) 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]

    2. 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

    1. PK: AUC0-∞ 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]

    2. 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]

    3. Pharmacodynamics (PD): Area Under the International Normalized Ratio Curve (AUCINR) of Warfarin [Days 1 and 17: 0, 6, 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. AUCINR is the time curve used to measure change in INR over time.

    4. PD: Maximum Observed INR Response (INRmax) of Warfarin [0, 6, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose on Days 1 and 17]

      The INR is a standardized ratio of the PT, time it takes for blood to clot.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 55 Years
    Sexes Eligible for Study:
    All
    Accepts 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 (BMI) 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, melanena, 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 at <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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Madison Wisconsin United States 53704

    Sponsors and Collaborators

    • Eli Lilly and Company

    Investigators

    • Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT01825876
    Other Study ID Numbers:
    • 14616
    • I1V-MC-EIAO
    First Posted:
    Apr 8, 2013
    Last Update Posted:
    Oct 9, 2018
    Last Verified:
    Feb 1, 2018
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title 15 mg Warfarin 130 mg Evacetrapib + 15 mg Warfarin
    Arm/Group Description 15 milligram (mg) warfarin administered as a single oral dose on Day 1 130 mg evacetrapib alone administered once daily (QD), orally, on Days 7 to 22 and with 15 mg warfarin co-administered once orally on Day 17
    Period Title: Period 1
    STARTED 17 0
    Received 1 Dose of Study Drug 17 0
    COMPLETED 17 0
    NOT COMPLETED 0 0
    Period Title: Period 1
    STARTED 0 17
    Received 1 Dose of Study Drug 0 17
    COMPLETED 0 16
    NOT COMPLETED 0 1

    Baseline Characteristics

    Arm/Group Title Overall Study
    Arm/Group Description Participants were administered 15 mg warfarin as a single oral dose on Days 1 and 17; 130 mg evacetrapib was administered QD, orally, on Days 7 to 22.
    Overall Participants 17
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    38.2
    (9.4)
    Sex: Female, Male (Count of Participants)
    Female
    1
    5.9%
    Male
    16
    94.1%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    4
    23.5%
    Not Hispanic or Latino
    13
    76.5%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    4
    23.5%
    White
    13
    76.5%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    17
    100%

    Outcome Measures

    1. Primary Outcome
    Title Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-∞) of S-Warfarin
    Description
    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

    Outcome Measure Data

    Analysis Population Description
    All participants who received a dose of study drug and had evaluable data for AUC(0-∞).
    Arm/Group Title Warfarin Evacetrapib + Warfarin
    Arm/Group Description 15 mg warfarin administered as a single oral dose 130 mg evacetrapib alone administered QD, orally, on Days 7 to 22 and with 15 mg warfarin co-administered once orally on Day 17
    Measure Participants 17 16
    Geometric Mean (Geometric Coefficient of Variation) [nanograms*hour/milliliter (ng*h/mL)]
    132
    (35)
    126
    (39)
    2. Primary Outcome
    Title PK: Maximum Observed Concentration (Cmax) of S-Warfarin
    Description
    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

    Outcome Measure Data

    Analysis Population Description
    All participants who received a dose of study drug and had evaluable data for Cmax.
    Arm/Group Title 15 mg Warfarin 130 mg Evacetrapib + 15 mg Warfarin
    Arm/Group Description 15 mg warfarin administered as a single oral dose on Day 1 130 mg evacetrapib alone administered QD, orally, on Days 7 to 22 and with 15 mg warfarin co-administered once orally on Day 17
    Measure Participants 17 16
    Geometric Mean (Geometric Coefficient of Variation) [nanograms/milliliter (ng/mL)]
    4.69
    (20)
    4.72
    (15)
    3. Secondary Outcome
    Title PK: AUC0-∞ of R-Warfarin
    Description
    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

    Outcome Measure Data

    Analysis Population Description
    All participants who received a dose of study drug and had evaluable data for AUC(0-∞).
    Arm/Group Title 15 mg Warfarin 130 mg Evacetrapib + 15 mg Warfarin
    Arm/Group Description 15 mg warfarin administered as a single oral dose on Day 1 130 mg evacetrapib alone administered QD, orally, on Days 7 to 22 and with 15 mg warfarin co-administered once orally on Day 17
    Measure Participants 17 16
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    321
    (25)
    314
    (25)
    4. Secondary Outcome
    Title PK: Cmax of R-Warfarin
    Description
    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

    Outcome Measure Data

    Analysis Population Description
    All participants who received a dose of study drug and had evaluable data for Cmax.
    Arm/Group Title 15 mg Warfarin 130 mg Evacetrapib + 15 mg Warfarin
    Arm/Group Description 15 mg warfarin administered as a single oral dose on Day 1 130 mg evacetrapib alone administered QD, orally, on Days 7 to 22 and with 15 mg warfarin co-administered once orally on Day 17
    Measure Participants 17 16
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    6.02
    (19)
    6.22
    (15)
    5. Secondary Outcome
    Title Pharmacodynamics (PD): Area Under the International Normalized Ratio Curve (AUCINR) of Warfarin
    Description The INR is a standardized ratio of the prothrombin time (PT), time it takes for blood to clot. AUCINR is the time curve used to measure change in INR over time.
    Time Frame Days 1 and 17: 0, 6, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose

    Outcome Measure Data

    Analysis Population Description
    All participants who received a dose of study drug and had evaluable data for AUCINR.
    Arm/Group Title 15 mg Warfarin 130 mg Evacetrapib + 15 mg Warfarin
    Arm/Group Description 15 mg warfarin administered as a single oral dose on Day 1 130 mg evacetrapib alone administered QD, orally, on Days 7 to 22 and with 15 mg warfarin co-administered once orally on Day 17
    Measure Participants 16 14
    Geometric Mean (Geometric Coefficient of Variation) [ratio*h]
    167
    (7.9)
    162
    (5.2)
    6. Secondary Outcome
    Title PD: Maximum Observed INR Response (INRmax) of Warfarin
    Description The INR is a standardized ratio of the PT, time it takes for blood to clot.
    Time Frame 0, 6, 12, 24, 36, 48, 72, 96, 120, and 144 hours following warfarin dose on Days 1 and 17

    Outcome Measure Data

    Analysis Population Description
    All participants who received a dose of study drug and had evaluable data for INRmax.
    Arm/Group Title 15 mg Warfarin 130 mg Evacetrapib + 15 mg Warfarin
    Arm/Group Description 15 mg warfarin administered as a single oral dose on Day 1 130 mg evacetrapib alone administered QD, orally, on Days 7 to 22 and with 15 mg warfarin co-administered once orally on Day 17
    Measure Participants 17 16
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    1.36
    (17.4)
    1.25
    (12.9)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title 15 mg Warfarin 130 mg Evacetrapib 130 mg Evacetrapib + 15 mg Warfarin
    Arm/Group Description 15 mg warfarin administered as a single oral dose on Day 1 130 mg evacetrapib alone administered QD, orally, on Days 7 to 22 130 mg evacetrapib alone administered QD, orally, on Days 7 to 22 and with 15 mg warfarin co-administered once orally on Day 17
    All Cause Mortality
    15 mg Warfarin 130 mg Evacetrapib 130 mg Evacetrapib + 15 mg Warfarin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    15 mg Warfarin 130 mg Evacetrapib 130 mg Evacetrapib + 15 mg Warfarin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/17 (0%) 0/17 (0%) 0/16 (0%)
    Other (Not Including Serious) Adverse Events
    15 mg Warfarin 130 mg Evacetrapib 130 mg Evacetrapib + 15 mg Warfarin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/17 (29.4%) 2/17 (11.8%) 4/16 (25%)
    Blood and lymphatic system disorders
    Lymphadenopathy 0/17 (0%) 0 0/17 (0%) 0 1/16 (6.3%) 1
    Gastrointestinal disorders
    Constipation 0/17 (0%) 0 1/17 (5.9%) 1 0/16 (0%) 0
    General disorders
    Vessel puncture site haemorrhage 2/17 (11.8%) 3 0/17 (0%) 0 2/16 (12.5%) 2
    Infections and infestations
    Tooth abscess 0/17 (0%) 0 0/17 (0%) 0 1/16 (6.3%) 1
    Injury, poisoning and procedural complications
    Contusion 1/17 (5.9%) 1 0/17 (0%) 0 0/16 (0%) 0
    Nail injury 0/17 (0%) 0 1/17 (5.9%) 1 0/16 (0%) 0
    Nervous system disorders
    Headache 0/17 (0%) 0 0/17 (0%) 0 1/16 (6.3%) 2
    Skin and subcutaneous tissue disorders
    Acne 0/17 (0%) 0 1/17 (5.9%) 1 0/16 (0%) 0
    Ecchymosis 1/17 (5.9%) 1 0/17 (0%) 0 0/16 (0%) 0
    Erythema 1/17 (5.9%) 1 0/17 (0%) 0 0/16 (0%) 0
    Papule 1/17 (5.9%) 1 0/17 (0%) 0 0/16 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Chief Medical Officer
    Organization Eli Lilly and Company
    Phone 800-545-5979
    Email
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT01825876
    Other Study ID Numbers:
    • 14616
    • I1V-MC-EIAO
    First Posted:
    Apr 8, 2013
    Last Update Posted:
    Oct 9, 2018
    Last Verified:
    Feb 1, 2018