EUropean Pharmacogenetics of AntiCoagulant Therapy - Phenprocoumon

Summary

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.

Conditions

• Venous Thromboembolism (VTE)
• Atrial Fibrillation (AF)

Interventions

OTHER

Genotype-guided dosing algorithm

Loading and monitoring dose according to genotype-guided dosing algorithm

OTHER

Non-genotype-guided dosing algorithm

Loading and monitoring dose according to non-genotype-guided dosing algorithm

Sponsors & Collaborators

• Utrecht University

  collaborator OTHER

• Leiden University Medical Center

  collaborator OTHER

• Erasmus Medical Center

  collaborator OTHER

• University of Ulm

  collaborator OTHER

• Newcastle University

  collaborator OTHER

• University of Liverpool

  collaborator OTHER

• LGC Limited

  collaborator INDUSTRY

• Uppsala University

  collaborator OTHER

• Democritus University of Thrace

  collaborator OTHER

• Elisabethinen Hospital

  collaborator OTHER

• Utrecht Institute for Pharmaceutical Sciences

  lead OTHER

Study Design

Allocation

RANDOMIZED

Masking

SINGLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2010-11-30

Primary Completion

2013-01-31

Completion

2013-04-30

Countries

• Austria
• Germany
• Netherlands

Study Locations