Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Help guide our efforts to modernize ClinicalTrials.gov.
Send us your comments by March 14, 2020.
Trial record 21 of 157 for:    warfarin AND Vitamin K

Genetic Response to Warfarin in Healthy Subjects

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01520402
Recruitment Status : Completed
First Posted : January 30, 2012
Results First Posted : February 7, 2013
Last Update Posted : February 12, 2013
Sponsor:
Information provided by (Responsible Party):
Jonathan L. Halperin, Icahn School of Medicine at Mount Sinai

Tracking Information
First Submitted Date  ICMJE January 18, 2012
First Posted Date  ICMJE January 30, 2012
Results First Submitted Date  ICMJE October 24, 2012
Results First Posted Date  ICMJE February 7, 2013
Last Update Posted Date February 12, 2013
Study Start Date  ICMJE June 2009
Actual Primary Completion Date May 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 7, 2013)
  • Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype [ Time Frame: average of 2 - 13 days ]
    To assess the effect of genotype variants (CYP2C9 and VKORC1 -1639 G>A) on the anticoagulant response to warfarin, the primary outcome was the cumulative dose required to achieve an INR value in the usual clinical therapeutic range (>2.0) for two consecutive days.
  • Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) [ Time Frame: 2-30 days ]
    Subjects were also grouped into four categories based on CYP2C9 and VKORC1 genotype profile: Group 1 (CYP2C9 wild-type and VKORC1 wild-type), Group 2 (CYP2C9 wild-type and VKORC1 variant), Group 3 (CYP2C9 variant and VKORC1 wild-type), and Group 4 (CYP2C9 variant and VKORC1 variant). Median cumulative warfarin dose requirement was determined for each genotype category.
Original Primary Outcome Measures  ICMJE
 (submitted: January 24, 2012)
Cumulative therapeutic warfarin dose (milligrams) [ Time Frame: average of 2 - 13 days ]
To assess the effect of genotype variants (CYP2C9 and VKORC1 -1639 G>A) on the anticoagulant response to warfarin, the primary outcome was the cumulative dose required to achieve an INR value in the usual clinical therapeutic range (>2.0) for two consecutive days.
Change History Complete list of historical versions of study NCT01520402 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 7, 2013)
  • Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status [ Time Frame: average of 2 - 30 days ]
    To assess the effect of CYP4F2 genotype variants on the anticoagulant response to warfarin.
  • Explained Variation in Combined Therapeutic Warfarin Dose Models [ Time Frame: average of 2 - 30 days ]
    The proportion of variance (R^2) explained by each predictor was calculated using multivariate regression analysis and adjusted for age, gender and reported race, with outcome values logarithmically transformed. The study was powered to detect R^2 > 20%, and significance was accepted at p<0.05.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2012)
  • CYP4F2 genotype status [ Time Frame: average of 2 - 30 days ]
    To assess the effect of CYP4F2 genotype variants on the anticoagulant response to warfarin.
  • Recovery time of INR to baseline [ Time Frame: average of 2 - 30 days ]
    To assess the effect of genotype variants on the rate of INR recovery to baseline after warfarin cessation. Subjects underwent daily fingerstick INR measurements until INR < 1.2.
  • VKORC1 gene analysis [ Time Frame: average of 2 - 30 days ]
  • plasma vitamin K and S-warfarin levels at INR > 2 and study exit (recovered INR < 1.2) [ Time Frame: average of 2 - 13 days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Genetic Response to Warfarin in Healthy Subjects
Official Title  ICMJE Quantitative Pharmacogenomics of the Anticoagulant Response to Warfarin in Healthy Subjects
Brief Summary The purpose of this study is to determine the importance of genetic differences on individuals' response to warfarin in a group of healthy subjects. Warfarin is also known by the "trade name" Coumadin and is in a class of medications called anticoagulants or "blood thinners." Warfarin works by reducing the blood's ability to make clots. It is used to stop blood clots from forming or growing larger in your blood and blood vessels. Warfarin is prescribed for many conditions, including for people with certain types of irregular heartbeat, people with replacement or mechanical heart valves, people who have suffered a heart attack, people who have had orthopedic surgery, or who have a history of having blood clots. Warfarin is used to prevent or treat deep vein thrombosis (swelling and blood clot in a vein), pulmonary embolism (a blood clot in the lung), and strokes (a blood clot in the brain). Researchers have found that certain genes may affect how a person's body will break down or react to warfarin. If genetic information can help doctors better determine the best dose of warfarin before it is first given, this may help the doctors get patients to the correct levels of blood thinning and thereby reduce the risk of bleeding or the risk of developing a blood clot. The expectation of this study is that this information will ultimately improve warfarin therapy while lessening the risks associated with dosing errors. This study is considered investigational because the subjects are healthy and not being prescribed warfarin for clinical care.
Detailed Description Warfarin is a highly effective oral anticoagulant that is increasingly prescribed in the United States. It has a narrow therapeutic window, however, that represents an inherent limitation, such that insufficient and excessive levels of anticoagulation are associated with elevated risks of thrombosis and bleeding particularly frequent early in the initial dose-finding phase of therapy. Typically, anticoagulation is achieved through empiric dosing and titration with consideration of certain variables and frequent assessment of the international normalized ratio (INR). Despite these precautions, conventional dosing strategies are associated with therapeutic levels of anticoagulation only about half the time on treatment. Recently, genetic variants, specifically variations in the CYP2C9 and VKORC1 genes, have been identified that affect warfarin dose requirements, prompting the expectation that gene-based dosing strategies may maximize therapeutic efficacy while minimizing the risks associated with dosing errors. While the association between variation in these genes and differences in warfarin dose requirements has been identified, the specific contribution of allelic variation to the response to warfarin administration has not been thoroughly identified. The investigators therefore seek to assess the impact of allelic variation on warfarin dose-response relationships in a group of healthy subjects. The investigators hypothesize that genetic variation in the CYP2C9 and VKORC1 enzymes will result in differences in the warfarin dose-response relationships when accounting for non-genetic factors that can affect the pharmacokinetics of warfarin and its effect on coagulation.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Healthy
Intervention  ICMJE Drug: Warfarin
Enrolled subjects on a fixed vitamin K diet followed a standard warfarin dosing algorithm with daily point-of-care INR checks to goal INR ≥ 2 for two consecutive days, then to baseline INR≤1.2 off warfarin. Genotyping for common and rare polymorphisms in CYP2C9, VKORC1, and CYP4F2 performed at study entry and unblinded at completion. Plasma Vitamin K and S-warfarin levels are obtained at goal INR ≥ 2 and study exit (INR ≤1.2 off warfarin).
Other Names:
  • anticoagulant
  • Coumadin
Study Arms  ICMJE Experimental: Warfarin
Healthy subjects age 18-74 with no medical indication for warfarin therapy, who are free of medications and co-morbid medical conditions with the potential to interfere with warfarin metabolism, and who are willing to follow a fixed vitamin K diet (men 120 micrograms/day, women 90 micrograms/day) are included.
Intervention: Drug: Warfarin
Publications *

*   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: January 24, 2012)
35
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2011
Actual Primary Completion Date May 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Healthy adult (> 18 years old.) subjects not taking warfarin
  • Willing and able to grant written informed consent
  • Available in proximity to the Medical Center for the anticipated duration of data collection (approximately 3 weeks).
  • Pre-menopausal women required negative pregnancy test at study onset and willingness to abstain from sexual activity or use barrier contraception; oral contraceptives interfere with coumadin.

Exclusion Criteria:

  • Daily prescribed medications including (1) a medication known to interact with warfarin, based on interactions listed in Micromedex as moderate or severe, and probable or definite (as of study start date, Appendix A) (2) aspirin or clopidogrel, which may increase bleeding risk in combination with warfarin.
  • Recent therapy (within two weeks) with a medication known to interact with warfarin based on medication interactions listed in Micromedex
  • History of thrombotic disorder requiring anticoagulant therapy
  • Thrombophilia or coagulopathy, by history or screening coagulation profile with INR or PTT level > 2x the upper limit of normal
  • Family history of thrombophilia or coagulopathy; prisoners or wards of the state; scheduled elective surgery within one month
  • Active liver disease based on clinical history or serum transaminase levels > 2x the upper limit of normal
  • Protein C or S Deficiency assessed on screening protein C and S activity profile
  • Age ≥ 75
  • Pre-menopausal women on oral contraception
  • Non-English speaking individuals
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 74 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 NCT01520402
Other Study ID Numbers  ICMJE GCO 08-1442
HSM # 11-00577
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jonathan L. Halperin, Icahn School of Medicine at Mount Sinai
Study Sponsor  ICMJE Icahn School of Medicine at Mount Sinai
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jonathan L Halperin, MD Icahn School of Medicine at Mount Sinai
PRS Account Icahn School of Medicine at Mount Sinai
Verification Date February 2013

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