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

This study has been completed.
Sponsor:
Collaborators:
Utrecht University
Leiden University Medical Center
Erasmus Medical Center
University of Ulm
Newcastle University
University of Liverpool
LGC Ltd.
Uppsala University
Democritus University of Thrace
Elisabethinen Hospital
Information provided by (Responsible Party):
Anke-Hilse Maitland-van der Zee, Utrecht Institute for Pharmaceutical Sciences
ClinicalTrials.gov Identifier:
NCT01119261
First received: May 4, 2010
Last updated: June 17, 2013
Last verified: June 2013

May 4, 2010
June 17, 2013
November 2010
June 2013   (final data collection date for primary outcome measure)
Percent time within therapeutic INR range 2-3 during 12 weeks following the initiation of coumarin therapy [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT01119261 on ClinicalTrials.gov Archive Site
  • Time to INR > or = 4.0, which indicates overanticoagulation. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Percent time spent > or = INR 4.0 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Percent time spent < or = INR 2, which indicates under-anticoagulation [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Time to and number of minor and major bleeding events [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • Time to and number of thromboembolic events (therapeutic failure) [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • The incidence of coumarin sensitivity [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • The incidence of coumarin resistance [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Number of coumarin dose adjustments [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • The clinical utility of the rapid genotyping test developed by LGC [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Quality of life as reported by the patient tested by the EuroQol (EQ)-5D questionnaire [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • The cost-effectiveness of genotype-guided dosing for each coumarin compared with non-genotype-guided dosing [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Number of patients with INR > or = 4.0, which indicates overanticoagulation [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Time to INR > or = 4.0, which indicates overanticoagulation. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Percent time spent > or = INR 4.0 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Percent time spent < or = INR 2, which indicates under-anticoagulation [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Time to and number of minor and major bleeding events [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • Time to and number of thromboembolic events (therapeutic failure) [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • The incidence of coumarin sensitivity [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • The incidence of coumarin resistance [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Number of coumarin dose adjustments [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • The clinical utility of the rapid genotyping test developed by LGC [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Quality of life as reported by the patient tested by the EuroQol (EQ)-5D questionnaire [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • The cost-effectiveness of genotype-guided dosing for each coumarin compared with non-genotype-guided dosing [ Time Frame: will be assessed after inclusion of all patients ] [ Designated as safety issue: No ]
  • Number of patients with INR > or = 4.0, which indicates overanticoagulation [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
EUropean Pharmacogenetics of AntiCoagulant Therapy - Acenocoumarol
EUropean Pharmacogenetics of AntiCoagulant Therapy - Acenocoumarol

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.

Not Provided
Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
  • Venous Thromboembolism
  • Atrial Fibrillation
  • 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
  • Active Comparator: Non-genotype-guided dosing algorithm
    Intervention: Other: Non-genotype-guided dosing algorithm
  • Experimental: Genotype-guided dosing algorithm
    Intervention: Other: Genotype-guided dosing algorithm

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
970
June 2013
June 2013   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Greece,   Netherlands
 
NCT01119261
COU-001A, 223062, 2009-016992-31
Yes
Anke-Hilse Maitland-van der Zee, Utrecht Institute for Pharmaceutical Sciences
Utrecht Institute for Pharmaceutical Sciences
  • Utrecht University
  • Leiden University Medical Center
  • Erasmus Medical Center
  • University of Ulm
  • Newcastle University
  • University of Liverpool
  • LGC Ltd.
  • Uppsala University
  • Democritus University of Thrace
  • Elisabethinen Hospital
Not Provided
Utrecht Institute for Pharmaceutical Sciences
June 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP