EUropean Pharmacogenetics of AntiCoagulant Therapy - Acenocoumarol

NCT01119261 | Completed Phase 4 DMC

• 3 other identifiers: COU-001A2230622009-016992-31
• Study Type: interventional
• Target: 970
• Locations: 2 countries
• Sites: 2

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. 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; Atrial Fibrillation

Keywords

Venous thromboembolism (VTE); Atrial fibrillation (AF)

Outcome Measures

Primary Outcomes (1)

• Percent time within therapeutic INR range 2-3 during 12 weeks following the initiation of coumarin therapy

  12 weeks

Secondary Outcomes (14)

• Time to INR > or = 4.0, which indicates overanticoagulation.

  12 weeks

• Percent time spent > or = INR 4.0

  12 weeks

• Percent time spent < or = INR 2, which indicates under-anticoagulation

  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

  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

  12 weeks

Study Arms (2)

Non-genotype-guided dosing algorithm

ACTIVE COMPARATOR

Other: Non-genotype-guided dosing algorithm

Genotype-guided dosing algorithm

EXPERIMENTAL

Other: Genotype-guided dosing algorithm

Interventions

Genotype-guided dosing algorithm OTHER

Loading and monitoring dose according to genotype-guided dosing algorithm

Genotype-guided dosing algorithm

Non-genotype-guided dosing algorithm OTHER

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

Non-genotype-guided dosing algorithm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Utrecht Institute for Pharmaceutical Sciences: lead
• Utrecht University: collaborator
• Leiden University Medical Center: collaborator
• Erasmus Medical Center: collaborator
• University of Ulm: collaborator
• Newcastle University: collaborator
• University of Liverpool: collaborator
• LGC Limited: collaborator
• Uppsala University: collaborator
• Democritus University of Thrace: collaborator
• Elisabethinen Hospital: collaborator

Study Sites (2)

Democritus University of Thrace Medical School

Alexandropoulis, Greece

Location

Utrecht University

Utrecht, Netherlands

Location

Related Publications (17)

• van Schie RM, Wadelius MI, Kamali F, Daly AK, Manolopoulos VG, de Boer A, Barallon R, Verhoef TI, Kirchheiner J, Haschke-Becher E, Briz M, Rosendaal FR, Redekop WK, Pirmohamed M, Maitland van der Zee AH. Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design. Pharmacogenomics. 2009 Oct;10(10):1687-95. doi: 10.2217/pgs.09.125.

  PMID: 19842940 BACKGROUND

• Verhoef TI, Redekop WK, Darba J, Geitona M, Hughes DA, Siebert U, de Boer A, Maitland-van der Zee AH, Barallon R, Briz M, Daly A, Haschke-Becher E, Kamali F, Kirchheiner J, Manolopoulos VG, Pirmohamed M, Rosendaal FR, van Schie RM, Wadelius M; EU-PACT Group. A systematic review of cost-effectiveness analyses of pharmacogenetic-guided dosing in treatment with coumarin derivatives. Pharmacogenomics. 2010 Jul;11(7):989-1002. doi: 10.2217/pgs.10.74.

  PMID: 20602617 BACKGROUND

• van Schie RM, Jorgensen AL, de Boer A, Maitland-van der Zee AH; EU-PACT study group. Systematic review of pharmacogenetic warfarin dosing. J Gen Intern Med. 2009 Oct;24(10):1171. doi: 10.1007/s11606-009-1083-9. No abstract available.

  PMID: 19693633 BACKGROUND

• van Schie RM, Verhoef TI, Boejharat SB, Schalekamp T, Wessels JA, le Cessie S, Rosendaal FR, van der Meer FJ, de Boer A, Maitland-van der Zee AH. Evaluation of the effect of statin use on the acenocoumarol and phenprocoumon maintenance dose. Drug Metabol Drug Interact. 2012;27(4):229-34. doi: 10.1515/dmdi-2012-0024.

  PMID: 23096528 BACKGROUND

• Verhoef TI, Redekop WK, Hegazy H, de Boer A, Maitland-van der Zee AH; EU-PACT group. Long-term anticoagulant effects of CYP2C9 and VKORC1 genotypes in phenprocoumon users. J Thromb Haemost. 2012 Dec;10(12):2610-2. doi: 10.1111/jth.12007. No abstract available.

  PMID: 23016521 BACKGROUND

• Verhoef TI, Redekop WK, van Schie RM, Bayat S, Daly AK, Geitona M, Haschke-Becher E, Hughes DA, Kamali F, Levin LA, Manolopoulos VG, Pirmohamed M, Siebert U, Stingl JC, Wadelius M, de Boer A, Maitland-van der Zee AH; EU-PACT group. Cost-effectiveness of pharmacogenetics in anticoagulation: international differences in healthcare systems and costs. Pharmacogenomics. 2012 Sep;13(12):1405-17. doi: 10.2217/pgs.12.124.

  PMID: 22966889 BACKGROUND

• van Schie RM, el Khedr N, Verhoef TI, Teichert M, Stricker BH, Hofman A, Buhre PN, Wessels JA, Schalekamp T, le Cessie S, van der Meer FJ, Rosendaal FR, de Boer A, Maitland-van der Zee AH, Visser LE. Validation of the acenocoumarol EU-PACT algorithms: similar performance in the Rotterdam Study cohort as in the original study. Pharmacogenomics. 2012 Aug;13(11):1239-45. doi: 10.2217/pgs.12.101.

  PMID: 22920394 BACKGROUND

• van Schie RM, Babajeff AM, Schalekamp T, Wessels JA, le Cessie S, de Boer A, van der Meer FJ, van Meegen E, Verhoef TI, Rosendaal FR, Maitland-van der Zee AH; EU-PACT study group. An evaluation of gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol. J Thromb Haemost. 2012 May;10(5):767-72. doi: 10.1111/j.1538-7836.2012.04694.x.

  PMID: 22409277 BACKGROUND

• Verhoef TI, Redekop WK, Buikema MM, Schalekamp T, Van Der Meer FJ, Le Cessie S, Wessels JA, Van Schie RM, De Boer A, Teichert M, Visser LE, Maitland-Van Der Zee AH; EU-PACT Group. Long-term anticoagulant effects of the CYP2C9 and VKORC1 genotypes in acenocoumarol users. J Thromb Haemost. 2012 Apr;10(4):606-14. doi: 10.1111/j.1538-7836.2012.04633.x.

  PMID: 22252093 BACKGROUND

• Avery PJ, Jorgensen A, Hamberg AK, Wadelius M, Pirmohamed M, Kamali F; EU-PACT Study Group. A proposal for an individualized pharmacogenetics-based warfarin initiation dose regimen for patients commencing anticoagulation therapy. Clin Pharmacol Ther. 2011 Nov;90(5):701-6. doi: 10.1038/clpt.2011.186. Epub 2011 Sep 28.

  PMID: 22012312 BACKGROUND

• van Schie RM, Wessels JA, le Cessie S, de Boer A, Schalekamp T, van der Meer FJ, Verhoef TI, van Meegen E, Rosendaal FR, Maitland-van der Zee AH; EU-PACT Study Group. Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data. Eur Heart J. 2011 Aug;32(15):1909-17. doi: 10.1093/eurheartj/ehr116. Epub 2011 Jun 2.

  PMID: 21636598 BACKGROUND

• van Schie RM, Wessels JA, Verhoef TI, Schalekamp T, le Cessie S, van der Meer FJ, Rosendaal FR, Visser LE, Teichert M, Hofman A, Buhre PN, de Boer A, Maitland-van der Zee AH. Evaluation of the effect of genetic variations in GATA-4 on the phenprocoumon and acenocoumarol maintenance dose. Pharmacogenomics. 2012 Dec;13(16):1917-23. doi: 10.2217/pgs.12.174.

  PMID: 23215884 BACKGROUND

• Verhoef TI, Zuurhout MJ, van Schie RM, Redekop WK, van der Meer FJ, le Cessie S, Schalekamp T, de Boer A, Maitland-van der Zee AH. The effect of omeprazole and esomeprazole on the maintenance dose of phenprocoumon. Br J Clin Pharmacol. 2012 Dec;74(6):1068-9. doi: 10.1111/j.1365-2125.2012.04295.x. No abstract available.

  PMID: 22497277 BACKGROUND

• van Schie RM, de Boer A, Maitland-van der Zee AH. Implementation of pharmacogenetics in clinical practice is challenging. Pharmacogenomics. 2011 Sep;12(9):1231-3. doi: 10.2217/pgs.11.81. No abstract available.

  PMID: 21919599 BACKGROUND

• van Schie RM, Cascorbi I, Maitland-van der Zee AH. Conference Scene: Pharmacogenomics at the second PharmSciFair 2009: adverse drug reactions and clinical implementation. Pharmacogenomics. 2009 Sep;10(9):1389-91. doi: 10.2217/pgs.09.95.

  PMID: 19761363 BACKGROUND

• Baranova EV, Verhoef TI, Ragia G, le Cessie S, Asselbergs FW, de Boer A, Manolopoulos VG, Maitland-van der Zee AH; EU-PACT group. Dosing algorithms for vitamin K antagonists across VKORC1 and CYP2C9 genotypes. J Thromb Haemost. 2017 Mar;15(3):465-472. doi: 10.1111/jth.13615. Epub 2017 Feb 17.

  PMID: 28063245 DERIVED

• Verhoef TI, Ragia G, de Boer A, Barallon R, Kolovou G, Kolovou V, Konstantinides S, Le Cessie S, Maltezos E, van der Meer FJ, Redekop WK, Remkes M, Rosendaal FR, van Schie RM, Tavridou A, Tziakas D, Wadelius M, Manolopoulos VG, Maitland-van der Zee AH; EU-PACT Group. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med. 2013 Dec 12;369(24):2304-12. doi: 10.1056/NEJMoa1311388. Epub 2013 Nov 19.

  PMID: 24251360 DERIVED

MeSH Terms

Conditions

Venous Thromboembolism; Atrial Fibrillation

Condition Hierarchy (Ancestors)

Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Heart Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PharmD, PhD

Study Record Dates

• First Submitted: May 4, 2010
• First Posted: May 7, 2010
• Study Start: November 1, 2010
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: June 18, 2013

Record last verified: 2013-06

Locations

GR (1); NL (1)