Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Pharmacogenetics of Warfarin Induction and Inhibition

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: NCT01447511
Recruitment Status : Completed
First Posted : October 6, 2011
Results First Posted : August 18, 2014
Last Update Posted : November 14, 2018
Sponsor:
Collaborator:
National Institute of General Medical Sciences (NIGMS)
Information provided by (Responsible Party):
University of Minnesota

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Condition Healthy
Interventions Drug: Control - Warfarin only
Drug: Fluconazole - Warfarin
Drug: Rifampin - Warfarin
Enrollment 39
Recruitment Details  
Pre-assignment Details Thirty-nine participants were enrolled in the study; however, only twenty-nine of the enrolled participants participated in the study. Per study protocol, participants with the CYP2C9*1B/*1B haplotype did not complete the Fluconazole Period. Individuals with the CYP2C9*1B/*1B haplotype only completed the Control Period and Rifampin Period.
Arm/Group Title CYP2C9*1/*1 Genotype CYP2C9*1B/*1B Haplotype CYP2C9*1/*3 Genotype CYP2C9*2/*3 Genotype CYP2C9*3/*3 Genotype
Hide Arm/Group Description This genotype is considered the wild type genotype. Individuals with the CYP2C9*1/*1 genotype have two *1 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. Individuals with the CYP2C9*1B/*1B haplotype have two *1B alleles and participated in the following periods: Control Period and Rifampin Period. Individuals with the CYP2C9*1/*3 genotype have one *1 allele and one *3 allele and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. Individuals with the CYP2C9*2/*3 genotype have one *2 allele and one *3 allele and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. Individuals with the CYP2C9*3/*3 genotype have two *3 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period.
Period Title: Control Period
Started 8 5 9 3 4
Completed 8 5 9 3 4
Not Completed 0 0 0 0 0
Period Title: Fluconazole Period
Started 8 0 9 3 4
Completed 8 0 8 3 4
Not Completed 0 0 1 0 0
Period Title: Rifampin Period
Started 8 5 8 3 4
Completed 8 5 8 2 4
Not Completed 0 0 0 1 0
Arm/Group Title CYP2C9*1/*1 Genotype CYP2C9*1B/*1B Haplotype CYP2C9*1/*3 Genotype CYP2C9*2/*3 Genotype CYP2C9*3/*3 Genotype Total
Hide Arm/Group Description This genotype is considered the wild type genotype. Individuals with the CYP2C9*1/*1 genotype have two *1 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. Individuals with the CYP2C9*1B/*1B haplotype have two *1B alleles and participated in the following periods: Control Period and Rifampin Period. Individuals with the CYP2C9*1/*3 genotype have one *1 allele and one *3 allele and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. Individuals with the CYP2C9*2/*3 genotype have one *2 allele and one *3 allele and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. Individuals with the CYP2C9*3/*3 genotype have two *3 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. Total of all reporting groups
Overall Number of Baseline Participants 8 5 9 3 4 29
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 8 participants 5 participants 9 participants 3 participants 4 participants 29 participants
22
(19 to 54)
23
(22 to 31)
26
(18 to 52)
28
(21 to 51)
29
(19 to 33)
25
(18 to 54)
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 5 participants 9 participants 3 participants 4 participants 29 participants
<=18 years
0
   0.0%
0
   0.0%
1
  11.1%
0
   0.0%
0
   0.0%
1
   3.4%
Between 18 and 65 years
8
 100.0%
5
 100.0%
8
  88.9%
3
 100.0%
4
 100.0%
28
  96.6%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 5 participants 9 participants 3 participants 4 participants 29 participants
Female
4
  50.0%
2
  40.0%
5
  55.6%
3
 100.0%
0
   0.0%
14
  48.3%
Male
4
  50.0%
3
  60.0%
4
  44.4%
0
   0.0%
4
 100.0%
15
  51.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 8 participants 5 participants 9 participants 3 participants 4 participants 29 participants
8 5 9 3 4 29
1.Primary Outcome
Title Warfarin Clearance.
Hide Description Warfarin enantiomer (S-warfarin and R-warfarin) clearance was measured in healthy volunteers genotyped for CYP2C9*1/*1, CYP2C9*1B/*1B, CYP2C9*1/*3, CYP2C9*2/*3 and CYP2C9*3/*3 to determine the magnitude of the warfarin-fluconazole (inhibition) and warfarin-rifampin (induction) drug interactions.
Time Frame Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with the CYP2C9*1B/*1B haplotype did not participate in the fluconazole period (inhibition). One CYP2C9*1/*3 participant only completed the control period. One CYP2C9*2/*3 participant only completed the control and fluconazole (inhibition) study periods.
Arm/Group Title CYP2C9*1/*1 Genotype CYP2C9*1B/*1B Haplotype CYP2C9*1/*3 Genotype CYP2C9*2/*3 Genotype CYP2C9*3/*3 Genotype
Hide Arm/Group Description:
This genotype is considered the wild type genotype. Individuals with the CYP2C9*1/*1 genotype have two *1 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period.
Individuals with the CYP2C9*1B/*1B haplotype have two *1B alleles and participated in the following periods: Control Period and Rifampin Period.
Individuals with the CYP2C9*1/*3 genotype have one *1 allele and one *3 allele and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period.
Individuals with the CYP2C9*2/*3 genotype have one *2 allele and one *3 allele and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period.
Individuals with the CYP2C9*3/*3 genotype have two *3 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period.
Overall Number of Participants Analyzed 8 5 9 3 4
Mean (Standard Deviation)
Unit of Measure: mL/h
S warfarin - Control Period 282  (62) 246  (69) 180  (49) 84  (7) 71  (5)
R warfarin - Control Period 136  (37) 124  (54) 122  (27) 95  (10) 153  (38)
S warfarin - Fluconazole Period 89  (17) NA [1]   (NA) 68  (22) 35  (7) 36  (6)
R warfarin - Fluconazole Period 66  (13) NA [1]   (NA) 68  (10) 55  (13) 72  (7)
S warfarin - Rifampin Period 520  (69) 486  (151) 347  (140) 195  (20) 157  (8)
R warfarin - Rifampin Period 342  (64) 307  (151) 339  (64) 368  (74) 406  (108)
[1]
Participants with the CYP2C9*1B/*1B haplotype did not participate in the fluconazole period per study protocol.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection CYP2C9*1/*1 Genotype, CYP2C9*1B/*1B Haplotype, CYP2C9*1/*3 Genotype, CYP2C9*2/*3 Genotype, CYP2C9*3/*3 Genotype
Comments The null hypothesis is that the mean S-warfarin clearance among the five CYP2C9 genotypes under control conditions is the same.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection CYP2C9*1/*1 Genotype, CYP2C9*1B/*1B Haplotype, CYP2C9*1/*3 Genotype, CYP2C9*2/*3 Genotype, CYP2C9*3/*3 Genotype
Comments The null hypothesis is that the mean S-warfarin clearance among the five CYP2C9 genotypes under fluconazole conditions is the same.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection CYP2C9*1/*1 Genotype, CYP2C9*1B/*1B Haplotype, CYP2C9*1/*3 Genotype, CYP2C9*2/*3 Genotype, CYP2C9*3/*3 Genotype
Comments The null hypothesis is that the mean S-warfarin clearance among the five CYP2C9 genotypes under rifampin conditions is the same.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection CYP2C9*1/*1 Genotype, CYP2C9*1B/*1B Haplotype, CYP2C9*1/*3 Genotype, CYP2C9*2/*3 Genotype, CYP2C9*3/*3 Genotype
Comments The null hypothesis is that the mean R-warfarin clearance among the five CYP2C9 genotypes under control conditions is the same.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.3058
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection CYP2C9*1/*1 Genotype, CYP2C9*1B/*1B Haplotype, CYP2C9*1/*3 Genotype, CYP2C9*2/*3 Genotype, CYP2C9*3/*3 Genotype
Comments The null hypothesis is that the mean R-warfarin clearance among the five CYP2C9 genotypes under fluconazole conditions is the same.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.3278
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection CYP2C9*1/*1 Genotype, CYP2C9*1B/*1B Haplotype, CYP2C9*1/*3 Genotype, CYP2C9*2/*3 Genotype, CYP2C9*3/*3 Genotype
Comments The null hypothesis is that the mean R-warfarin clearance among the five CYP2C9 genotypes under rifampin conditions is the same.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.6155
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title CYP2C9*1/*1 Genotype CYP2C9*1B/*1B Haplotype CYP2C9*1/*3 Genotype CYP2C9*2/*3 Genotype CYP2C9*3/*3 Genotype
Hide Arm/Group Description This genotype is considered the wild type genotype. Individuals with the CYP2C9*1/*1 genotype have two *1 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. Individuals with the CYP2C9*1B/*1B haplotype have two *1B alleles and participated in the following periods: Control Period and Rifampin Period. Individuals with the CYP2C9*1/*3 genotype have one *1 allele and one *3 allele and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. Individuals with the CYP2C9*2/*3 genotype have one *2 allele and one *3 allele and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. Individuals with the CYP2C9*3/*3 genotype have two *3 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period.
All-Cause Mortality
CYP2C9*1/*1 Genotype CYP2C9*1B/*1B Haplotype CYP2C9*1/*3 Genotype CYP2C9*2/*3 Genotype CYP2C9*3/*3 Genotype
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
CYP2C9*1/*1 Genotype CYP2C9*1B/*1B Haplotype CYP2C9*1/*3 Genotype CYP2C9*2/*3 Genotype CYP2C9*3/*3 Genotype
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/8 (0.00%)      0/5 (0.00%)      0/9 (0.00%)      0/3 (0.00%)      0/4 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
CYP2C9*1/*1 Genotype CYP2C9*1B/*1B Haplotype CYP2C9*1/*3 Genotype CYP2C9*2/*3 Genotype CYP2C9*3/*3 Genotype
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/8 (50.00%)      4/5 (80.00%)      6/9 (66.67%)      0/3 (0.00%)      2/4 (50.00%)    
Gastrointestinal disorders           
Blood in Bowel *  1/8 (12.50%)  1 0/5 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0
Diarrhea *  1/8 (12.50%)  1 1/5 (20.00%)  1 1/9 (11.11%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0
Nausea *  1/8 (12.50%)  1 0/5 (0.00%)  0 2/9 (22.22%)  4 0/3 (0.00%)  0 0/4 (0.00%)  0
Stomach Pain *  1/8 (12.50%)  1 2/5 (40.00%)  2 0/9 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0
Vomiting *  2/8 (25.00%)  2 0/5 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0
General disorders           
Body Ache *  1/8 (12.50%)  1 0/5 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0
Chills *  1/8 (12.50%)  1 0/5 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0
Common Cold Symptoms *  0/8 (0.00%)  0 0/5 (0.00%)  0 4/9 (44.44%)  7 0/3 (0.00%)  0 1/4 (25.00%)  1
Fatigue *  0/8 (0.00%)  0 3/5 (60.00%)  4 2/9 (22.22%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0
Fever *  1/8 (12.50%)  1 0/5 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0
Injury, poisoning and procedural complications           
Bruising *  0/8 (0.00%)  0 1/5 (20.00%)  1 1/9 (11.11%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0
Nervous system disorders           
Dizziness *  2/8 (25.00%)  3 0/5 (0.00%)  0 2/9 (22.22%)  2 0/3 (0.00%)  0 1/4 (25.00%)  1
Headache *  0/8 (0.00%)  0 2/5 (40.00%)  5 4/9 (44.44%)  4 0/3 (0.00%)  0 1/4 (25.00%)  1
Skin and subcutaneous tissue disorders           
Dry Lips *  1/8 (12.50%)  1 0/5 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0
Rash *  0/8 (0.00%)  0 0/5 (0.00%)  0 2/9 (22.22%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0
Skin Abrasion *  0/8 (0.00%)  0 0/5 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1
*
Indicates events were collected by non-systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Richard Brundage
Organization: University of Minnesota
Phone: 612-624-3115
EMail: brund001@umn.edu
Layout table for additonal information
Responsible Party: University of Minnesota
ClinicalTrials.gov Identifier: NCT01447511     History of Changes
Other Study ID Numbers: 0807M38361
P01GM032165-26 ( U.S. NIH Grant/Contract )
First Submitted: January 29, 2010
First Posted: October 6, 2011
Results First Submitted: July 30, 2014
Results First Posted: August 18, 2014
Last Update Posted: November 14, 2018