To determine whether a dosing algorithm containing genetic information increases the time within therapeutic INR range during anticoagulation therapy with phenprocoumon compared to a dosing regimen that does not contain this genetic information.…
ID
Source
Brief title
Condition
- Cardiac arrhythmias
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The % time within therapeutic INR range in the first 3 months of
anticoagulation therapy.
Secondary outcome
1. Time to and the number of patients with INR above 4.0, which indicates
over-anticoagulation.
2. Percent time spent above INR 4.0.
3. Percent time spent below INR 1.5, which indicates under-anticoagulation.
4. Time to reach therapeutic INR defined as the time to the first INR within
target range, providing that a subsequent INR more than 1 week later is also
within target range.
5. Time to reach stable dose defined as INR within target range for a period of
at least 3 weeks with <10% change in dose.
6. Time to and number of minor and major bleeding events.
7. Time to and number of thromboembolic events (therapeutic failure).
8. The incidence of sensitivity defined as less than 1.5 mg phenprocoumon/day
at stable dose within the therapeutic range. Patients who are on enzyme
inhibitors will be excluded from the sensitive group.
9. The incidence of resistance defined as more than 6 phenprocoumon mg/day at
stable dose within the therapeutic range. Patients who are on enzyme inducers
will be excluded from the resistant group.
10. Number of coumarin dose adjustments.
11. The clinical utility of the rapid genotyping test developed by LGC.
12. Quality of life as reported by the patient tested by the EuroQol (EQ)-5D
questionnaire.
13. The cost-effectiveness of genotype-guided dosing for each coumarin compared
with non-genotype-guided dosing.
Background summary
The narrow therapeutic range and wide inter-patient variability in dose
requirement make anticoagulation response to coumarin derivatives difficult to
predict. As a result, patients require frequent monitoring to avert adverse
effects and maintain therapeutic efficacy. Polymorphisms in cytochrome P450 2C9
(CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) jointly account for
about 40% of the inter-individual variability in dose requirements. To date,
several pharmacogenetic-guided dosing algorithms for coumarin derivatives,
predominately for warfarin, have been developed. However, the potential benefit
of these dosing algorithms in terms of their safety and clinical utility has
not been adequately investigated in randomized settings.
Study objective
To determine whether a dosing algorithm containing genetic information
increases the time within therapeutic INR range during anticoagulation therapy
with phenprocoumon compared to a dosing regimen that does not contain this
genetic information. Secondary research-questions of the study include the cost
effectiveness, number of thromboembolic and bleeding events, time to reach
stable dose and number of supratherapeutic INR peaks.
Study design
This is consist of a two-armed, single-blinded, randomised controlled trial. In
the intervention arm patients commencing anticoagulation therapy with
phenprocoumon will be dosed according to a drug-specific genotype-guided dosing
algorithm, which is based on genetic information, clinical data and (in the
monitoring phase) previous INR. In the control arm patients will be dosed
according to a non-genotype-guided dosing regimen which does not include
genetic information. The follow-up period per patient is 3 months.
Intervention
Patients will be dosed according to a newly developed dosing algorithm.
Study burden and risks
Burden: 7 extra blood samples (33mL) are taken from each participant at the
start of the study, and 3 (15mL) at visit 8. Patients also have to attend 8
scheduled visits within the 3 months study period and are asked to fill in
questionnaires before 6 visits (total time: 90 minutes).
Risks: As well the newly developed genotype-guided dosing algorithm as the
newly developed nongenotype-guided dosing algorithm are anticipated to improve
the accuracy of coumarin dosing and thus improve the safety (less bleedings)
and efficacy (more time spent in INR range) of anticoagulation therapy.
Sorbonnelaan 16, PO box 80082
3508 TB Utrecht
NL
Sorbonnelaan 16, PO box 80082
3508 TB Utrecht
NL
Listed location countries
Age
Inclusion criteria
1. Patients with either venous thromboembolism (VTE) or atrial fibrillation (AF) requiring treatment with phenprocoumon for at least 12 weeks and a target INR in the low intensity range (INR range 2-3 in the United Kingdom, Sweden, Germany, Austria, Greece and Spain and INR 2.5-3.5 in the Netherlands)
2. Age >= 18 years
3. Ability to attend scheduled visits
4. Signed informed consent
Exclusion criteria
1. Abnormal clotting function at baseline (at least one of):
a. INR >1.5
b. platelet count <100 x 10^9 per Liter blood
c. prolonged APTT >1.3 times the upper reference value that is not explained by presence of lupus anticoagulants
2. Presence of a mechanical heart valve
3. Severe cognitive impairment
4. Known genotype CYP2C9 or VKORC1 at start of the study
5. Previous or current treatment with any coumarin
6. Pregnancy or lactation
7. Non-eligible subject, e.g. fysical or mental health problems.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-016994-13-NL |
| CCMO | NL29816.058.09 |