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Genetic Response to Warfarin in Healthy Subjects

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Jonathan L. Halperin, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier:
NCT01520402
First received: January 18, 2012
Last updated: February 6, 2013
Last verified: February 2013
History of Changes
Results First Received: October 24, 2012  
Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Basic Science
Condition: Healthy
Intervention: Drug: Warfarin

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Thirty-five subjects responded to email and printed solicitations advertised at Mount Sinai Medical Center for the study, and five were excluded due to medication conflicts, unwillingness to take warfarin, and medical conditions precluding participation. Dates of recruitment spanned 04/2009 - 05/2012.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Subjects were educated regarding vitamin K restricted diet. Each maintained a food intake log and refrained from medications or alcohol for one week. Only subjects adhering to the prescribed diet and avoiding medications that could potentially interfere with warfarin metabolism qualified for the dose-response testing phase.

Reporting Groups
  Description
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.

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).

Participant Flow:   Overall Study
    Warfarin  
STARTED     35  
COMPLETED     30  
NOT COMPLETED     5  
Withdrawal by Subject                 2  
Physician Decision                 3  



  Baseline Characteristics
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Reporting Groups
  Description
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.

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).

Baseline Measures
    Warfarin  
Number of Participants  
[units: participants]
 		  30  
Age  
[units: participants]
 		 
<=18 years     0  
Between 18 and 65 years     30  
>=65 years     0  
Age  
[units: years]
Mean ± Standard Deviation 		  32  ± 8  
Gender  
[units: participants]
 		 
Female     12  
Male     18  
Region of Enrollment  
[units: participants]
 		 
United States     30  



  Outcome Measures
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1.  Primary:   Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype   [ Time Frame: average of 2 - 13 days ]
  Show Outcome Measure 1

2.  Primary:   Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination)   [ Time Frame: 2-30 days ]
  Show Outcome Measure 2

3.  Secondary:   Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status   [ Time Frame: average of 2 - 30 days ]
  Show Outcome Measure 3

4.  Secondary:   Explained Variation in Combined Therapeutic Warfarin Dose Models   [ Time Frame: average of 2 - 30 days ]
  Show Outcome Measure 4


  Serious Adverse Events
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  Other Adverse Events
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  More Information
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Certain Agreements:  
All Principal Investigators ARE employed by the organization sponsoring the study.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Small number of subjects, which prevented detection of modest effects; relied on self-reported race and self-reported adherance to vitamin K restricted diet without objective markers such as ancestry informative markers and serum vitamin k levels.  


Results Point of Contact:  
Name/Title: Dr. Daniella Kadian-Dodov
Organization: Mount Sinai School of Medicine
phone: (212) 241-9454
e-mail: daniella.kadian-dodov@mssm.edu


Publications:


Responsible Party: Jonathan L. Halperin, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier: NCT01520402     History of Changes
Other Study ID Numbers: GCO 08-1442, HSM # 11-00577
Study First Received: January 18, 2012
Results First Received: October 24, 2012
Last Updated: February 6, 2013
Health Authority: United States: Institutional Review Board