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

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ClinicalTrials.gov Identifier: NCT01119300
Recruitment Status : Completed
First Posted : May 7, 2010
Last Update Posted : December 3, 2014
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

Tracking Information
First Submitted Date  ICMJE May 4, 2010
First Posted Date  ICMJE May 7, 2010
Last Update Posted Date December 3, 2014
Study Start Date  ICMJE January 2011
Actual Primary Completion Date October 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 6, 2010)
Percent time within therapeutic INR range 2-3 during 12 weeks following the initiation of coumarin therapy [ Time Frame: 12 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01119300 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 6, 2010)
  • Time INR > or = 4.0, which indicates overanticoagulation [ Time Frame: 12 weeks ]
  • Percent time spent > or = INR 4.0 [ Time Frame: 12 weeks ]
  • Percent time spent < or = INR 2, which indicates under-anticoagulation [ Time Frame: 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 ]
  • 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 ]
  • Time to and number of minor and major bleeding events [ Time Frame: 12 weeks ]
  • Time to and number of thromboembolic events (therapeutic failure) [ Time Frame: 12 weeks ]
  • The incidence of coumarin sensitivity [ Time Frame: 12 weeks ]
  • The incidence of coumarin resistance [ Time Frame: 12 weeks ]
  • Number of coumarin dose adjustments [ Time Frame: 12 weeks ]
  • The clinical utility of the rapid genotyping test developed by LGC [ Time Frame: 2 years ]
  • Quality of life as reported by the patient tested by the EuroQol (EQ)-5D questionnaire [ Time Frame: 12 weeks ]
  • 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 ]
  • Number of patients with INR > or = 4.0, which indicates overanticoagulation [ Time Frame: 12 weeks ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE EUropean Pharmacogenetics of AntiCoagulant Therapy - Warfarin
Official Title  ICMJE EUropean Pharmacogenetics of AntiCoagulant Therapy - Warfarin
Brief 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.

Detailed Description 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Condition  ICMJE
  • Venous Thromboembolism
  • Atrial Fibrillation
Intervention  ICMJE
  • Other: Genotype-guided dosing algorithm
    Loading and monitoring dose according to genotype-guided dosing algorithm
  • Other: Standard care
    Standard care
Study Arms  ICMJE
  • Active Comparator: Standard care
    Standard care
    Intervention: Other: Standard care
  • Experimental: Genotype-guided dosing algorithm
    Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days.
    Intervention: Other: Genotype-guided dosing algorithm
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 2, 2014)
455
Original Estimated Enrollment  ICMJE
 (submitted: May 6, 2010)
970
Actual Study Completion Date  ICMJE October 2013
Actual Primary Completion Date October 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Sweden,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01119300
Other Study ID Numbers  ICMJE COU-001W
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Anke-Hilse Maitland-van der Zee, Utrecht Institute for Pharmaceutical Sciences
Study Sponsor  ICMJE Utrecht Institute for Pharmaceutical Sciences
Collaborators  ICMJE
  • 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
Investigators  ICMJE
Principal Investigator: Munir Pirmohamed, MD PhD University of Liverpool
PRS Account Utrecht Institute for Pharmaceutical Sciences
Verification Date December 2014

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