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A Study of LY2216684 and Warfarin in Healthy Subjects

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ClinicalTrials.gov Identifier: NCT01263119
Recruitment Status : Completed
First Posted : December 20, 2010
Results First Posted : October 19, 2018
Last Update Posted : January 21, 2019
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Tracking Information
First Submitted Date  ICMJE December 16, 2010
First Posted Date  ICMJE December 20, 2010
Results First Submitted Date  ICMJE February 17, 2018
Results First Posted Date  ICMJE October 19, 2018
Last Update Posted Date January 21, 2019
Study Start Date  ICMJE December 2010
Actual Primary Completion Date February 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 26, 2018)
  • Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of S-Warfarin [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 ]
    Least Squares (LS) geometric mean was based on AUC0-∞ of S-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
  • Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 ]
    Least Squares (LS) geometric mean was based on Cmax of S-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
  • Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of S-Warfarin [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 ]
    This outcome was measured based on Tmax of S-warfarin on Day 1 of Period 1 when warfarin was administered alone (reference) and on Day 3 of Period 2 when coadministered with LY2216684 (test).
Original Primary Outcome Measures  ICMJE
 (submitted: December 16, 2010)
  • Pharmacokinetics (PK) of S-warfarin, area under the concentration curve (AUC,0-∞) [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post warfarin administration ]
  • Pharmacokinetics (PK) of S-warfarin, maximum concentration (Cmax) [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post warfarin administration ]
  • Pharmacokinetics (PK) of S-warfarin, time to concentration maximum (tmax) [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post warfarin administration ]
Change History Complete list of historical versions of study NCT01263119 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 26, 2018)
  • Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of R-Warfarin [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 ]
    Least Squares (LS) geometric mean was based on AUC0-∞ of R-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
  • Pharmacokinetics: Maximum Plasma Concentration (Cmax) of R-Warfarin [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 ]
    Least Squares (LS) geometric mean was based on Cmax of R-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
  • Pharmacokinetics: Time to Maximum Concentration (Tmax) of R-Warfarin [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 ]
    This outcome was measured based on Tmax of R-warfarin on Day 1 of Period 1 when warfarin was administered alone (reference) and on Day 3 of Period 2 when coadministered with LY2216684 (test).
  • Pharmacodynamics: Area Under the Curve of the International Normalized Ratio (AUCINR) of Warfarin [ Time Frame: Predose, 6, 12, 24, 48, 72, 96, 120, 144 hours post-warfarin administration on Days 1 and 3 ]
    The INR is the ratio of a participant's prothrombin time to a normal (control) sample. AUCINR was calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
  • Pharmacodynamics: Maximum Observed International Normalized Ratio (INRmax) [ Time Frame: Predose, 6, 12, 24, 48, 72, 96, 120, 144 hours post-warfarin administration on Days 1 and 3 ]
    INR is the ratio of a participant's prothrombin time to a normal (control) sample. INRmax was calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 16, 2010)
  • Pharmacokinetics (PK) of R-warfarin, area under the concentration curve (AUC,0-∞) [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post warfarin administration ]
  • Pharmacokinetics (PK) of R-warfarin, concentration maximum (Cmax) [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post warfarin administration ]
  • Pharmacokinetics (PK) of R-warfarin, time to concentration maximum (tmax) [ Time Frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post warfarin administration ]
  • Area under the INR (international normalized ratio) curve [ Time Frame: Predose, 6, 12, 24, 48, 72, 96, 120, 144 hours after warfarin administration ]
  • Maximum observed INR response [ Time Frame: Predose, 6, 12, 24, 48, 72, 96, 120, 144 hours after warfarin administration ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of LY2216684 and Warfarin in Healthy Subjects
Official Title  ICMJE Effect of LY2216684 on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects
Brief Summary The purpose of this study is to determine how warfarin might affect LY2216684 and how giving LY2216684 might affect warfarin in the body. Information about any side effects that may occur will also be collected.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Major Depressive Disorder
Intervention  ICMJE
  • Drug: Warfarin
    10-mg warfarin oral dose
  • Drug: LY2216684
    18-mg LY2216684 oral dose
Study Arms  ICMJE Experimental: Warfarin, LY2216684 + Warfarin
Period 1: Single 10-milligram (mg) warfarin oral dose on Day 1; Washout Period of at least 14 days; Period 2: 18-mg LY2216684 oral dose, once daily on Days 1 to 12, with single 10-mg warfarin oral dose coadministered on Day 3.
Interventions:
  • Drug: Warfarin
  • Drug: LY2216684
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 16, 2010)
18
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE February 2011
Actual Primary Completion Date February 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Are overtly healthy, as determined by medical history and physical examination
  • Male participants - Agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug
  • Female participants - Are women of child-bearing potential who test negative for pregnancy at the time of enrollment, have used a reliable method of birth control for 6 weeks prior to administration of study drug, and agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug; or women not of child-bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause (at least 1 year without menses or 6 months without menses and a follicle stimulating hormone [FSH] >40 mass International Units per milliliter [mIU/mL])
  • Have body weight >50 kilogram (kg)
  • Have clinical laboratory test results within normal reference range for the population or investigator site, or results with acceptable deviations that are judged to be not clinically significant by the investigator
  • Have venous access sufficient to allow blood sampling as per the protocol
  • Have normal blood pressure and pulse rate (sitting position) as determined by the investigator
  • Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures
  • Have given written informed consent approved by Lilly and the ethical review board (ERB) governing the site
  • Are cytochrome P450 2C9 (CYP2C9) extensive metabolizers, as determined by genotyping assessment

Exclusion Criteria:

  • Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device other than the study drug, or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
  • Have known allergies to LY2216684, warfarin, or related compounds
  • Are persons who have previously completed or withdrawn from this study or any other study investigating LY2216684 within 6 months prior to screening
  • Have an abnormality in the 12-lead electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study
  • Have a history of or current 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
  • Have a history or show evidence of significant active neuropsychiatric disease, or have a history of suicide attempt or ideation
  • Regularly use known drugs of abuse and/or show positive findings on urinary drug screening
  • Show evidence of human immunodeficiency virus (HIV) and/or positive human HIV antibodies
  • Show evidence of hepatitis C and/or positive hepatitis C antibody
  • Show evidence of hepatitis B and/or positive hepatitis B surface antigen
  • Are women with a positive pregnancy test or women who are lactating
  • Intend to use over-the-counter or prescription medication (including hormonal contraceptives) within 14 days prior to dosing unless deemed acceptable by the investigator and sponsor's medical monitor
  • Use of any drugs or substances that are known to be substrates, inducers, or inhibitors of cytochrome P450 2C19 (CYP2C19) or CYP2C9 within 30 days prior to dosing
  • Have donated blood of more than 500 mL within the last month
  • Have an average weekly alcohol intake that exceeds 14 units per week, or are unwilling to stop alcohol consumption 48 hours prior to dosing in each period and while resident at the CRU (1 unit = 12 ounces [oz] or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits)
  • Consume 5 or more cups of coffee (or other beverages of comparable caffeine content) per day, on a habitual basis, or any subjects unwilling to adhere to study caffeine restrictions
  • Have used any tobacco-containing or nicotine-containing products (including, but not limited to, cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months prior to enrollment
  • Have consumed grapefruit or grapefruit-containing products 7 days prior to enrollment and during the study.
  • Have a documented or suspected history of glaucoma
  • History or presence of significant bleeding disorders; that is, hematemesis, melanena, severe or recurrent epistaxis, hemoptysis, clinically overt hematuria or intracranial hemorrhage
  • Subjects with a history of gastrointestinal ulcers or hemorrhage
  • 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 <65 years of age)
  • Self-reported history of increased bleeding from trauma (for example, prolonged bleeding after tooth extraction)
  • History of major surgery within 3 months of screening
  • Planned surgery within 14 days after the last day of dosing
  • International normalized ratio/prothrombin time (INR/PT), or activated partial thromboplastin time (APTT) above the normal reference range at screening
  • Positive fecal occult blood examination at screening
  • Female subjects with a history of menorrhagia
  • Subjects determined to be unsuitable by the investigator for any reason
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01263119
Other Study ID Numbers  ICMJE 12595
H9P-EW-LNCF ( Other Identifier: Eli Lilly and Company )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Eli Lilly and Company
Study Sponsor  ICMJE Eli Lilly and Company
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account Eli Lilly and Company
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP