A Study of LY2216684 and Warfarin in Healthy Subjects

• ClinicalTrials.gov Identifier: NCT01263119
• Recruitment Status: Completed
• First Posted: December 20, 2010
• Results First Posted: October 19, 2018
• Last Update Posted: January 22, 2019
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Major Depressive Disorder	Drug: Warfarin; Drug: LY2216684	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effect of LY2216684 on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects
• Study Start Date: December 2010
• Actual Primary Completion Date: February 2011
• Actual Study Completion Date: February 2011

Arms and Interventions

Arm	Intervention/treatment
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.	Drug: Warfarin; 10-mg warfarin oral dose; Drug: LY2216684; 18-mg LY2216684 oral dose

Outcome Measures

Primary Outcome Measures :

1. 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.
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.
3. 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).

Secondary Outcome Measures :

1. 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.
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.
3. 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).
4. 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.
5. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, Texas

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.

Dallas, Texas, United States

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

More Information

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01263119
• Other Study ID Numbers: 12595; H9P-EW-LNCF ( Other Identifier: Eli Lilly and Company )
• First Posted: December 20, 2010
• Results First Posted: October 19, 2018
• Last Update Posted: January 22, 2019
• Last Verified: January 2019

Additional relevant MeSH terms:

Depressive Disorder; Depressive Disorder, Major; Mood Disorders; Mental Disorders; Warfarin; Anticoagulants