EUropean Pharmacogenetics of AntiCoagulant Therapy - Phenprocoumon

Study Overview
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Brief Summary
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Rationale: The narrow therapeutic range and wide inter-patient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. 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 randomised settings. Objective: To determine whether a dosing algorithm containing genetic information increases the time within therapeutic INR range during anticoagulation therapy with each of warfarin, acenocoumarol and phenprocoumon compared to a dosing regimen that does not contain this information. Secondary outcomes of the study include cost effectiveness, number of thromboembolic and bleeding events, time to reach stable dose and number of supratherapeutic INR peaks. Study design: This is a two-armed, single-blinded, randomised controlled trial. In one arm (intervention) patients commencing anticoagulation therapy with either warfarin, acenocoumarol or 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. For the other arm (control) 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. Study population: Newly diagnosed patients of both genders and at least 18 years old who need anticoagulant treatment with either acenocoumarol, phenprocoumon or warfarin within the low intensity INR range will be included in the trial. Main study parameters/endpoints: The % time within therapeutic INR range in the first 3 months of anticoagulation therapy. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Six extra blood samples are taken from each participant at the start of the study. Patients also have to attend 8 scheduled visits within the 3 months study period and are asked to fill in questionnaires. The genotype-guided dosing algorithm is anticipated to improve the accuracy of coumarin dosing and thus improve the safety and efficacy of anticoagulation therapy.

Official Title
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EUropean Pharmacogenetics of AntiCoagulant Therapy - Phenprocoumon

Conditions
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Venous Thromboembolism (VTE), Atrial Fibrillation (AF)

Intervention / Treatment
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* Other: Genotype-guided dosing algorithm
* Other: Non-genotype-guided dosing algorithm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with either venous thromboembolism (VTE) or atrial fibrillation (AF) requiring coumarin therapy 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 and Greece and INR 2.5-3.5 in the Netherlands) Age ≥ 18 years Ability to attend scheduled visits Signed informed consent Exclusion Criteria: Presence of a mechanical heart valve Severe cognitive impairment Known genotype CYP2C9 or VKORC1 at start of the study Previous or current treatment with any coumarin Pregnancy or lactation Non-eligible subject

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Non-genotype-guided dosing algorithm<br> | Other: Non-genotype-guided dosing algorithm<br>* Loading and monitoring dose according to non-genotype-guided dosing algorithm<br>|
| Experimental: Genotype-guided dosing algorithm<br> | Other: Genotype-guided dosing algorithm<br>* Loading and monitoring dose according to genotype-guided dosing algorithm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent time within therapeutic INR range 2-3 during 12 weeks following the initiation of coumarin therapy |  | 12 weeks | 
| Number of patients with INR > or = 4.0, which indicates overanticoagulation |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time INR > or = 4.0, which indicates overanticoagulation |  | 12 weeks | 
| Percent time spent > or = INR 4.0 |  | 12 weeks | 
| Percent time spent < or = INR 2, which indicates under-anticoagulation |  | 12 weeks | 
| Time to reach therapeutic INR defined as the time to the first INR within target range, providing that a subsequent INR > or =1 week later is also within target range |  | 12 weeks | 
| Time to reach stable dose defined as INR within target range for a period of at least 3 weeks with <10% change in dose |  | 12 weeks | 
| Time to and number of minor and major bleeding events |  | 12 weeks | 
| Time to and number of thromboembolic events (therapeutic failure) |  | 12 weeks | 
| The incidence of coumarin sensitivity |  | 12 weeks | 
| The incidence of coumarin resistance |  | 12 weeks | 
| Number of coumarin dose adjustments |  | 12 weeks | 
| The clinical utility of the rapid genotyping test developed by LGC |  | 2 years | 
| Quality of life as reported by the patient tested by the EuroQol (EQ)-5D questionnaire |  | 12 weeks | 
| The cost-effectiveness of genotype-guided dosing for each coumarin compared with non-genotype-guided dosing |  | Will be assessed after inclusion of all patients |