Trial Outcomes & Findings for Pharmacogenetics of Warfarin Induction and Inhibition (NCT NCT01447511)
NCT ID: NCT01447511
Last Updated: 2018-11-14
Results Overview
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.
Recruitment status
COMPLETED
Study phase
NA
Target enrollment
39 participants
Primary outcome timeframe
Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods.
Results posted on
2018-11-14
Participant Flow
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.
Participant milestones
| Measure |
CYP2C9*1/*1 Genotype
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.
|
CYP2C9*1B/*1B Haplotype
Individuals with the CYP2C9\*1B/\*1B haplotype have two \*1B alleles and participated in the following periods: Control Period and Rifampin Period.
|
CYP2C9*1/*3 Genotype
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.
|
CYP2C9*2/*3 Genotype
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.
|
CYP2C9*3/*3 Genotype
Individuals with the CYP2C9\*3/\*3 genotype have two \*3 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period.
|
|---|---|---|---|---|---|
|
Control Period
STARTED
|
8
|
5
|
9
|
3
|
4
|
|
Control Period
COMPLETED
|
8
|
5
|
9
|
3
|
4
|
|
Control Period
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
|
Fluconazole Period
STARTED
|
8
|
0
|
9
|
3
|
4
|
|
Fluconazole Period
COMPLETED
|
8
|
0
|
8
|
3
|
4
|
|
Fluconazole Period
NOT COMPLETED
|
0
|
0
|
1
|
0
|
0
|
|
Rifampin Period
STARTED
|
8
|
5
|
8
|
3
|
4
|
|
Rifampin Period
COMPLETED
|
8
|
5
|
8
|
2
|
4
|
|
Rifampin Period
NOT COMPLETED
|
0
|
0
|
0
|
1
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Pharmacogenetics of Warfarin Induction and Inhibition
Baseline characteristics by cohort
| Measure |
CYP2C9*1/*1 Genotype
n=8 Participants
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.
|
CYP2C9*1B/*1B Haplotype
n=5 Participants
Individuals with the CYP2C9\*1B/\*1B haplotype have two \*1B alleles and participated in the following periods: Control Period and Rifampin Period.
|
CYP2C9*1/*3 Genotype
n=9 Participants
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.
|
CYP2C9*2/*3 Genotype
n=3 Participants
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.
|
CYP2C9*3/*3 Genotype
n=4 Participants
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
n=29 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|---|
|
Age, Continuous
|
22 years
n=5 Participants
|
23 years
n=7 Participants
|
26 years
n=5 Participants
|
28 years
n=4 Participants
|
29 years
n=21 Participants
|
25 years
n=10 Participants
|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=21 Participants
|
1 Participants
n=10 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
8 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
8 Participants
n=5 Participants
|
3 Participants
n=4 Participants
|
4 Participants
n=21 Participants
|
28 Participants
n=10 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=21 Participants
|
0 Participants
n=10 Participants
|
|
Sex: Female, Male
Female
|
4 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
5 Participants
n=5 Participants
|
3 Participants
n=4 Participants
|
0 Participants
n=21 Participants
|
14 Participants
n=10 Participants
|
|
Sex: Female, Male
Male
|
4 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
4 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
4 Participants
n=21 Participants
|
15 Participants
n=10 Participants
|
|
Region of Enrollment
United States
|
8 participants
n=5 Participants
|
5 participants
n=7 Participants
|
9 participants
n=5 Participants
|
3 participants
n=4 Participants
|
4 participants
n=21 Participants
|
29 participants
n=10 Participants
|
PRIMARY outcome
Timeframe: Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods.Population: 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.
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.
Outcome measures
| Measure |
CYP2C9*1/*1 Genotype
n=8 Participants
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.
|
CYP2C9*1B/*1B Haplotype
n=5 Participants
Individuals with the CYP2C9\*1B/\*1B haplotype have two \*1B alleles and participated in the following periods: Control Period and Rifampin Period.
|
CYP2C9*1/*3 Genotype
n=9 Participants
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.
|
CYP2C9*2/*3 Genotype
n=3 Participants
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.
|
CYP2C9*3/*3 Genotype
n=4 Participants
Individuals with the CYP2C9\*3/\*3 genotype have two \*3 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period.
|
|---|---|---|---|---|---|
|
Warfarin Clearance.
R warfarin - Fluconazole Period
|
66 mL/h
Standard Deviation 13
|
NA mL/h
Standard Deviation NA
Participants with the CYP2C9\*1B/\*1B haplotype did not participate in the fluconazole period per study protocol.
|
68 mL/h
Standard Deviation 10
|
55 mL/h
Standard Deviation 13
|
72 mL/h
Standard Deviation 7
|
|
Warfarin Clearance.
S warfarin - Control Period
|
282 mL/h
Standard Deviation 62
|
246 mL/h
Standard Deviation 69
|
180 mL/h
Standard Deviation 49
|
84 mL/h
Standard Deviation 7
|
71 mL/h
Standard Deviation 5
|
|
Warfarin Clearance.
R warfarin - Control Period
|
136 mL/h
Standard Deviation 37
|
124 mL/h
Standard Deviation 54
|
122 mL/h
Standard Deviation 27
|
95 mL/h
Standard Deviation 10
|
153 mL/h
Standard Deviation 38
|
|
Warfarin Clearance.
S warfarin - Fluconazole Period
|
89 mL/h
Standard Deviation 17
|
NA mL/h
Standard Deviation NA
Participants with the CYP2C9\*1B/\*1B haplotype did not participate in the fluconazole period per study protocol.
|
68 mL/h
Standard Deviation 22
|
35 mL/h
Standard Deviation 7
|
36 mL/h
Standard Deviation 6
|
|
Warfarin Clearance.
S warfarin - Rifampin Period
|
520 mL/h
Standard Deviation 69
|
486 mL/h
Standard Deviation 151
|
347 mL/h
Standard Deviation 140
|
195 mL/h
Standard Deviation 20
|
157 mL/h
Standard Deviation 8
|
|
Warfarin Clearance.
R warfarin - Rifampin Period
|
342 mL/h
Standard Deviation 64
|
307 mL/h
Standard Deviation 151
|
339 mL/h
Standard Deviation 64
|
368 mL/h
Standard Deviation 74
|
406 mL/h
Standard Deviation 108
|
Adverse Events
CYP2C9*1/*1 Genotype
Serious events: 0 serious events
Other events: 4 other events
Deaths: 0 deaths
CYP2C9*1B/*1B Haplotype
Serious events: 0 serious events
Other events: 4 other events
Deaths: 0 deaths
CYP2C9*1/*3 Genotype
Serious events: 0 serious events
Other events: 6 other events
Deaths: 0 deaths
CYP2C9*2/*3 Genotype
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
CYP2C9*3/*3 Genotype
Serious events: 0 serious events
Other events: 2 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
CYP2C9*1/*1 Genotype
n=8 participants at risk
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.
|
CYP2C9*1B/*1B Haplotype
n=5 participants at risk
Individuals with the CYP2C9\*1B/\*1B haplotype have two \*1B alleles and participated in the following periods: Control Period and Rifampin Period.
|
CYP2C9*1/*3 Genotype
n=9 participants at risk
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.
|
CYP2C9*2/*3 Genotype
n=3 participants at risk
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.
|
CYP2C9*3/*3 Genotype
n=4 participants at risk
Individuals with the CYP2C9\*3/\*3 genotype have two \*3 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period.
|
|---|---|---|---|---|---|
|
Gastrointestinal disorders
Blood in Bowel
|
12.5%
1/8 • Number of events 1
|
0.00%
0/5
|
0.00%
0/9
|
0.00%
0/3
|
0.00%
0/4
|
|
General disorders
Body Ache
|
12.5%
1/8 • Number of events 1
|
0.00%
0/5
|
11.1%
1/9 • Number of events 1
|
0.00%
0/3
|
0.00%
0/4
|
|
Injury, poisoning and procedural complications
Bruising
|
0.00%
0/8
|
20.0%
1/5 • Number of events 1
|
11.1%
1/9 • Number of events 2
|
0.00%
0/3
|
0.00%
0/4
|
|
General disorders
Chills
|
12.5%
1/8 • Number of events 1
|
0.00%
0/5
|
0.00%
0/9
|
0.00%
0/3
|
0.00%
0/4
|
|
General disorders
Common Cold Symptoms
|
0.00%
0/8
|
0.00%
0/5
|
44.4%
4/9 • Number of events 7
|
0.00%
0/3
|
25.0%
1/4 • Number of events 1
|
|
Gastrointestinal disorders
Diarrhea
|
12.5%
1/8 • Number of events 1
|
20.0%
1/5 • Number of events 1
|
11.1%
1/9 • Number of events 1
|
0.00%
0/3
|
0.00%
0/4
|
|
Nervous system disorders
Dizziness
|
25.0%
2/8 • Number of events 3
|
0.00%
0/5
|
22.2%
2/9 • Number of events 2
|
0.00%
0/3
|
25.0%
1/4 • Number of events 1
|
|
Skin and subcutaneous tissue disorders
Dry Lips
|
12.5%
1/8 • Number of events 1
|
0.00%
0/5
|
0.00%
0/9
|
0.00%
0/3
|
0.00%
0/4
|
|
General disorders
Fatigue
|
0.00%
0/8
|
60.0%
3/5 • Number of events 4
|
22.2%
2/9 • Number of events 2
|
0.00%
0/3
|
0.00%
0/4
|
|
General disorders
Fever
|
12.5%
1/8 • Number of events 1
|
0.00%
0/5
|
0.00%
0/9
|
0.00%
0/3
|
0.00%
0/4
|
|
Nervous system disorders
Headache
|
0.00%
0/8
|
40.0%
2/5 • Number of events 5
|
44.4%
4/9 • Number of events 4
|
0.00%
0/3
|
25.0%
1/4 • Number of events 1
|
|
Gastrointestinal disorders
Nausea
|
12.5%
1/8 • Number of events 1
|
0.00%
0/5
|
22.2%
2/9 • Number of events 4
|
0.00%
0/3
|
0.00%
0/4
|
|
Skin and subcutaneous tissue disorders
Rash
|
0.00%
0/8
|
0.00%
0/5
|
22.2%
2/9 • Number of events 2
|
0.00%
0/3
|
0.00%
0/4
|
|
Skin and subcutaneous tissue disorders
Skin Abrasion
|
0.00%
0/8
|
0.00%
0/5
|
0.00%
0/9
|
0.00%
0/3
|
25.0%
1/4 • Number of events 1
|
|
Gastrointestinal disorders
Stomach Pain
|
12.5%
1/8 • Number of events 1
|
40.0%
2/5 • Number of events 2
|
0.00%
0/9
|
0.00%
0/3
|
0.00%
0/4
|
|
Gastrointestinal disorders
Vomiting
|
25.0%
2/8 • Number of events 2
|
0.00%
0/5
|
0.00%
0/9
|
0.00%
0/3
|
0.00%
0/4
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place