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Genetic Response to Warfarin in Healthy Subjects

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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

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Condition Healthy
Intervention Drug: Warfarin
Enrollment 35
Recruitment Details 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 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.
Arm/Group Title Warfarin
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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).

Period Title: Overall Study
Started 35
Completed 30
Not Completed 5
Reason Not Completed
Withdrawal by Subject             2
Physician Decision             3
Arm/Group Title Warfarin
Hide Arm/Group Description

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).

Overall Number of Baseline Participants 30
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
<=18 years
0
   0.0%
Between 18 and 65 years
30
 100.0%
>=65 years
0
   0.0%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 30 participants
32  (8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
Female
12
  40.0%
Male
18
  60.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 30 participants
30
1.Primary Outcome
Title Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype
Hide Description 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.
Time Frame average of 2 - 13 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Of the 35 subjects enrolled, 30 were included in the study as listed above.
Arm/Group Title CYP2C9 VKORC1 -1639 G>A
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The wild-type CYP2C9 allele (*1) was assigned in the absence of other detectable variant alleles. Extensive metabolizers (EMs) were defined as *1/*1 "wild-type", intermediate metabolizers (IMs) as *1/variant "single variant"; and poor metabolizers (PMs) as variant/variant "double variant".
VKORC1 GG was defined as "wild-type"; VKORC1 G/A was defined as "single variant"; and VKORC1 A/A was defined as "double variant".
Overall Number of Participants Analyzed 30 30
Median (Inter-Quartile Range)
Unit of Measure: milligrams
Wild -Type
52
(35 to 72)
52
(35 to 72)
Single Variant
17
(15 to 42)
35
(35 to 53)
Double Variant
27
(15 to 35)
15
(10 to 20)
2.Primary Outcome
Title Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination)
Hide Description 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.
Time Frame 2-30 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Of the 35 subjects enrolled, 30 were included in the study as above.
Arm/Group Title CYP2C9/VKORC1 Genotype Group
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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).
Overall Number of Participants Analyzed 30
Median (Inter-Quartile Range)
Unit of Measure: milligrams
Group 1
52
(44 to 72)
Group 2
42
(35 to 72)
Group 3
35
(27 to 42)
Group 4
15
(15 to 35)
3.Secondary Outcome
Title Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status
Hide Description To assess the effect of CYP4F2 genotype variants on the anticoagulant response to warfarin.
Time Frame average of 2 - 30 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Of 35 subjects were enrolled, 30 were included as listed above.
Arm/Group Title CYP4F2 (p.V433M; c.1297G>A)
Hide Arm/Group Description:
CYP4F2 G/G was defined as "wild-type", CYP4F2 G/A was defined as "single-variant", and CYP4F2 A/A was defined as "double-variant"
Overall Number of Participants Analyzed 30
Median (Inter-Quartile Range)
Unit of Measure: milligrams
Wild-Type
31
(15 to 42)
Single-Variant
52
(35 to 72)
Double-Variant
54
(35 to 72)
4.Secondary Outcome
Title Explained Variation in Combined Therapeutic Warfarin Dose Models
Hide Description 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.
Time Frame average of 2 - 30 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Of the 35 subjects enrolled, 30 completed the study as described above.
Arm/Group Title Demographic Only Demographic Plus CYP2C9 Demographic Plus CYP2C9 and VKORC1 Demographic Plus CYP2C9 and VKORC1 and CYP4F2
Hide Arm/Group Description:
Demographic variables were gender, age, and race.
[Not Specified]
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 30 30 30 30
Measure Type: Number
Unit of Measure: proportion of variance
0.03 0.57 0.64 0.65
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Warfarin
Hide Arm/Group Description 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).
All-Cause Mortality
Warfarin
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Warfarin
Affected / at Risk (%)
Total   0/30 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Warfarin
Affected / at Risk (%)
Total   0/30 (0.00%) 
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.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Dr. Daniella Kadian-Dodov
Organization: Mount Sinai School of Medicine
Phone: (212) 241-9454
Publications:
FDA approves updated warfarin (Coumadin) prescribing information. Press release of the Food and Drug Administration, August 16, 2007. (Accessed December 22, 2011 at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108967.htm).
FDA clears genetic lab test for warfarin sensitivity. Press release of the Food and Drug Administration, September 17, 2007. (Accessed December 22, 2011 at http://www.fda.gov/newsevents/newsroom/pressannouncements/2007/ucm108984.htm).
Responsible Party: Jonathan L. Halperin, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT01520402     History of Changes
Other Study ID Numbers: GCO 08-1442
HSM # 11-00577
First Submitted: January 18, 2012
First Posted: January 30, 2012
Results First Submitted: October 24, 2012
Results First Posted: February 7, 2013
Last Update Posted: February 12, 2013