Trial Outcomes & Findings for Genetic Response to Warfarin in Healthy Subjects (NCT NCT01520402)

NCT ID: NCT01520402

Last Updated: 2013-02-12

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 35 participants
• Primary outcome timeframe: average of 2 - 13 days
• Results posted on: 2013-02-12

Participant Flow

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.

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.

Participant milestones

Measure	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).
Overall Study STARTED	35
Overall Study COMPLETED	30
Overall Study NOT COMPLETED	5

Reasons for withdrawal

Measure	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).
Overall Study Withdrawal by Subject	2
Overall Study Physician Decision	3

Baseline Characteristics

Genetic Response to Warfarin in Healthy Subjects

Baseline characteristics by cohort

Measure	Warfarin n=30 Participants 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).
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	30 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age Continuous	32 years STANDARD_DEVIATION 8 • n=5 Participants
Sex: Female, Male Female	12 Participants n=5 Participants
Sex: Female, Male Male	18 Participants n=5 Participants
Region of Enrollment United States	30 participants n=5 Participants

PRIMARY outcome

Timeframe: average of 2 - 13 days

Population: Of the 35 subjects enrolled, 30 were included in the study as listed above.

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.

Outcome measures

Measure	CYP2C9 n=30 Participants 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 -1639 G>A n=30 Participants VKORC1 GG was defined as "wild-type"; VKORC1 G/A was defined as "single variant"; and VKORC1 A/A was defined as "double variant".	Demographic Plus CYP2C9 and VKORC1	Demographic Plus CYP2C9 and VKORC1 and CYP4F2
Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype Wild -Type	52 milligrams Interval 35.0 to 72.0	52 milligrams Interval 35.0 to 72.0	—	—
Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype Single Variant	17 milligrams Interval 15.0 to 42.0	35 milligrams Interval 35.0 to 53.0	—	—
Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype Double Variant	27 milligrams Interval 15.0 to 35.0	15 milligrams Interval 10.0 to 20.0	—	—

PRIMARY outcome

Timeframe: 2-30 days

Population: Of the 35 subjects enrolled, 30 were included in the study as above.

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.

Outcome measures

Measure	CYP2C9 n=30 Participants 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 -1639 G>A VKORC1 GG was defined as "wild-type"; VKORC1 G/A was defined as "single variant"; and VKORC1 A/A was defined as "double variant".	Demographic Plus CYP2C9 and VKORC1	Demographic Plus CYP2C9 and VKORC1 and CYP4F2
Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) Group 1	52 milligrams Interval 44.0 to 72.0	—	—	—
Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) Group 2	42 milligrams Interval 35.0 to 72.0	—	—	—
Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) Group 3	35 milligrams Interval 27.0 to 42.0	—	—	—
Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) Group 4	15 milligrams Interval 15.0 to 35.0	—	—	—

SECONDARY outcome

Timeframe: average of 2 - 30 days

Population: Of 35 subjects were enrolled, 30 were included as listed above.

To assess the effect of CYP4F2 genotype variants on the anticoagulant response to warfarin.

Outcome measures

Measure	CYP2C9 n=30 Participants 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 -1639 G>A VKORC1 GG was defined as "wild-type"; VKORC1 G/A was defined as "single variant"; and VKORC1 A/A was defined as "double variant".	Demographic Plus CYP2C9 and VKORC1	Demographic Plus CYP2C9 and VKORC1 and CYP4F2
Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status Wild-Type	31 milligrams Interval 15.0 to 42.0	—	—	—
Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status Single-Variant	52 milligrams Interval 35.0 to 72.0	—	—	—
Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status Double-Variant	54 milligrams Interval 35.0 to 72.0	—	—	—

SECONDARY outcome

Timeframe: average of 2 - 30 days

Population: Of the 35 subjects enrolled, 30 completed the study as described above.

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.

Outcome measures

Measure	CYP2C9 n=30 Participants 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 -1639 G>A n=30 Participants VKORC1 GG was defined as "wild-type"; VKORC1 G/A was defined as "single variant"; and VKORC1 A/A was defined as "double variant".	Demographic Plus CYP2C9 and VKORC1 n=30 Participants	Demographic Plus CYP2C9 and VKORC1 and CYP4F2 n=30 Participants
Explained Variation in Combined Therapeutic Warfarin Dose Models	0.03 proportion of variance	0.57 proportion of variance	0.64 proportion of variance	0.65 proportion of variance

Adverse Events

Warfarin

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Dr. Daniella Kadian-Dodov

Mount Sinai School of Medicine

Phone: (212) 241-9454

Email: daniella.kadian-dodov@mssm.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place