EUropean Pharmacogenetics of AntiCoagulant Therapy - Acenocoumarol (EU-PACT)

June 17, 2013 updated by: Anke-Hilse Maitland-van der Zee, Utrecht Institute for Pharmaceutical Sciences

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

970

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Greece
      • Alexandropoulis, Greece
        • Democritus University of Thrace Medical School
  • Netherlands
      • Utrecht, Netherlands
        • Utrecht University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Percent time within therapeutic INR range 2-3 during 12 weeks following the initiation of coumarin therapy
Time Frame: 12 weeks
12 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
Number of patients with INR > or = 4.0, which indicates overanticoagulation
Time Frame: 12 weeks
12 weeks
Percent time spent > or = INR 4.0
Time Frame: 12 weeks
12 weeks
Percent time spent < or = INR 2, which indicates under-anticoagulation
Time Frame: 12 weeks
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
Time Frame: 12 weeks
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
Time Frame: 12 weeks
12 weeks
Time to and number of minor and major bleeding events
Time Frame: 12 weeks
12 weeks
Time to and number of thromboembolic events (therapeutic failure)
Time Frame: 12 weeks
12 weeks
The incidence of coumarin sensitivity
Time Frame: 12 weeks
12 weeks
The incidence of coumarin resistance
Time Frame: 12 weeks
12 weeks
Number of coumarin dose adjustments
Time Frame: 12 weeks
12 weeks
The clinical utility of the rapid genotyping test developed by LGC
Time Frame: 2 years
2 years
Quality of life as reported by the patient tested by the EuroQol (EQ)-5D questionnaire
Time Frame: 12 weeks
12 weeks
Time to INR > or = 4.0, which indicates overanticoagulation.
Time Frame: 12 weeks
12 weeks
The cost-effectiveness of genotype-guided dosing for each coumarin compared with non-genotype-guided dosing
Time Frame: 2 years
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Utrecht Institute for Pharmaceutical Sciences

Collaborators

Uppsala University
Erasmus Medical Center
Newcastle University
University of Liverpool
University of Ulm
Leiden University Medical Center
Democritus University of Thrace
Utrecht University
LGC Limited
Elisabethinen Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2010

Primary Completion (Actual)

June 1, 2013

Study Completion (Actual)

June 1, 2013

Study Registration Dates

First Submitted

May 4, 2010

First Submitted That Met QC Criteria

May 6, 2010

First Posted (Estimate)

May 7, 2010

Study Record Updates

Last Update Posted (Estimate)

June 18, 2013

Last Update Submitted That Met QC Criteria

June 17, 2013

Last Verified

June 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • COU-001A
  • 223062 (Other Grant/Funding Number: European Union - Seventh Framework Programme)
  • 2009-016992-31 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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