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 Limited
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
  Purpose

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.


Condition Intervention Phase
Venous Thromboembolism
Atrial Fibrillation
Other: Genotype-guided dosing algorithm
Other: Non-genotype-guided dosing algorithm
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Official Title: EUropean Pharmacogenetics of AntiCoagulant Therapy - Acenocoumarol

Resource links provided by NLM:


Further study details as provided by Utrecht Institute for Pharmaceutical Sciences:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 970
Study Start Date: November 2010
Study Completion Date: June 2013
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01119261

Locations
Greece
Democritus University of Thrace Medical School
Alexandropoulis, Greece
Netherlands
Utrecht University
Utrecht, Netherlands
Sponsors and Collaborators
Utrecht Institute for Pharmaceutical Sciences
Utrecht University
Leiden University Medical Center
Erasmus Medical Center
University of Ulm
Newcastle University
University of Liverpool
LGC Limited
Uppsala University
Democritus University of Thrace
Elisabethinen Hospital
  More Information

Additional Information:
Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Anke-Hilse Maitland-van der Zee, PharmD, PhD, Utrecht Institute for Pharmaceutical Sciences
ClinicalTrials.gov Identifier: NCT01119261     History of Changes
Other Study ID Numbers: COU-001A, 223062, 2009-016992-31
Study First Received: May 4, 2010
Last Updated: June 17, 2013
Health Authority: The Netherlands: Central Committee on Research inv. Human Subjects
Greece: National Drug Organisation

Keywords provided by Utrecht Institute for Pharmaceutical Sciences:
Venous thromboembolism (VTE)
Atrial fibrillation (AF)

Additional relevant MeSH terms:
Atrial Fibrillation
Thromboembolism
Venous Thromboembolism
Venous Thrombosis
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Thrombosis
Acenocoumarol
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 21, 2014