Genotype-guided Strategy for Antithrombotic Treatment in Peripheral Arterial Disease.

NCT04619927 | Unknown Phase 4

• 1 other identifier: NL2020-7057
• Study Type: interventional
• Target: 2,276
• Locations: 1 country
• Sites: 11

Brief Summary

Rationale: Peripheral arterial disease (PAD) is a common presentation of atherosclerosis. For the prevention of adverse events related to arterial thrombosis in PAD patients, clopidogrel is recommended. Clopidogrel in itself is inactive and needs to be metabolized by cytochrome P450 2C19 (CYP2C19) into the active metabolite. About 30% of PAD patients receiving clopidogrel is carrying one or two CYP2C19 loss-of-function allele(s) and do not or to a limited extent convert the prodrug into its active metabolites, and are therefore at increased risk of adverse clinical events related to arterial thrombosis. We hypothesize that genotype-guided prescription of antithrombotic treatment reduces adverse clinical events related to arterial thrombosis. Objective: The primary aim of the GENPAD study is to evaluate the ability of genotype-guided antithrombotic treatment to reduce adverse clinical events related to arterial thrombosis in PAD patients. Secondary objectives are to evaluate the ability of genotype-guided antithrombotic treatment to reduce the separate elements of the primary composite outcome and to assess the risk of clinically relevant bleedings in patients allocated to the genotype-guided antiplatelet treatment versus standard clopidogrel prescription. Study design: A randomized, controlled, open label, multicenter trial. Study population: Patients (n=2276) with PAD consulting a vascular surgeon for diagnosis and/or treatment, receiving clopidogrel according to the guidelines. Intervention: Testing for carriage of the CYP2C19\*2 and \*3 loss-of-function alleles, followed by a genotype guided antithrombotic treatment with either clopidogrel 75mg once daily (normal metabolizers), clopidogrel 75mg twice daily (intermediate metabolizers), or low-dose rivaroxaban plus acetylsalicylic acid (poor metabolizers). Comparator: All patients receive clopidogrel 75mg once daily without pharmacogenetic guidance. Main study parameters/endpoints: The primary combined outcome is the occurrence of adverse clinical events related to arterial thrombosis at 24 months. The occurrence of major adverse cardiovascular events, major adverse limb events, death and clinically relevant bleedings are the secondary endpoints.

Conditions

Peripheral Arterial Disease

Outcome Measures

Primary Outcomes (1)

• The number of participants that experienced major adverse events

  The number of participants that experienced a major adverse cardiovascular events, major adverse limb events or death from any cause.

  24 months

Secondary Outcomes (4)

• The number of participants that experienced major adverse cardiovascular events

  24 months

• The number of participants that experienced major adverse limb events

  24 months

• The number of participants that experienced major bleeding

  24 months

• The number of participants that experienced clinically relevant bleeding

  24 months

Other Outcomes (3)

• The cost-effectiveness of a CYP2C19 genotype-guided antithrombotic treatment strategy versus standard clopidogrel treatment

  24 months

• The difference in mean health state scores

  24 months

• The difference in health-related quality of life scores

  24 months

Study Arms (2)

Intervention group

EXPERIMENTAL

The intervention includes testing of patients for carriage of the CYP2C19\*2 and \*3 allele (loss-of-function (LOF) alleles), followed by a genotype guided antithrombotic treatment with either clopidogrel 75mg (without LOF allele, normal metabolizers), clopidogrel 150mg (one LOF allele, intermediate metabolizers), or rivaroxaban 2.5mg twice daily plus acetylsalicylic acid 100mg (two LOF alleles, poor metabolizers).

Genetic: Direct CYP2C19 genotyping; Drug: Poor metabolisers; Drug: Intermediate metabolisers; Drug: Normal metabolisers and unknown metaboliser state

Comparison group

ACTIVE COMPARATOR

The comparison group will not be prescribed clopidogrel 75mg without preceding testing for carriage of the CYP2C19\*2 and \*3 loss-of-function alleles. CYP2C19 genotyping will be performed at the end of the study.

Genetic: CYP2C19 genotyping at the end of the study; Drug: Normal metabolisers and unknown metaboliser state

Interventions

Direct CYP2C19 genotyping GENETIC

CYP2C19 genotype will be determined by the Spartan RX CYP2C19 point-of-care system.

Intervention group

CYP2C19 genotyping at the end of the study GENETIC

Blood-based CYP2C19 genotyping will be performed at the end of the study

Comparison group

Poor metabolisers DRUG

Acetylsalicylic acid 100mg once daily plus rivaroxaban 2.5mg twice daily

Intervention group

Intermediate metabolisers DRUG

Clopidogrel 75mg twice daily

Intervention group

Normal metabolisers and unknown metaboliser state DRUG

Clopidogrel 75mg once daily

Comparison group; Intervention group

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \> 16 years
• Obtained written informed consent
• Indication for monotherapy clopidogrel 75mg once daily
• Ankle-brachial index \< 0.9 and/or toe brachial index \< 0.5
• Current or previous symptoms due to insufficient vascularization of one or two lower extremities, including intermittent claudication, pain at rest and/or gangrene (Rutherford category 1-6)
• Consulting a vascular surgeon for diagnosis, treatment and/or follow-up of PAD

You may not qualify if:

• known CYP2C19 genotype or metabolizer state
• treated with coumarins, Non-vitamin K Oral Anti-Coagulants, unfractionated heparin, low molecular weight heparins or double antiplatelet therapy with acetylsalicylic acid and a P2Y12 inhibitor for other indications
• contraindication for clopidogrel, acetylsalicylic acid and/or rivaroxaban
• pregnant or breastfeeding women
• unable to give informed consent (including not being able to understand the Dutch language)

Sponsors & Collaborators

• Radboud University Medical Center: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Academisch Ziekenhuis Groningen: collaborator
• Rijnstate Hospital: collaborator
• Bernhoven Hospital: collaborator
• Canisius-Wilhelmina Hospital: collaborator

Study Sites (11)

Gelre Ziekenhuizen

Apeldoorn, Netherlands

NOT YET RECRUITING

Rijnstate

Arnhem, 6815, Netherlands

RECRUITING

Ziekenhuis Gelderse Vallei

Ede, Netherlands

RECRUITING

Máxima Medisch Centrum

Eindhoven, Netherlands

NOT YET RECRUITING

Medisch Spectrum Twente

Enschede, Netherlands

NOT YET RECRUITING

UMC Groningen

Groningen, 9713 GZ, Netherlands

NOT YET RECRUITING

Ommelander Ziekenhuis

Groningen, Netherlands

NOT YET RECRUITING

Maastricht University Medical Center

Maastricht, Netherlands

NOT YET RECRUITING

Radboudumc

Nijmegen, 6525 GA, Netherlands

RECRUITING

Canisius Wilhelmina Hospital

Nijmegen, 6532 SZ, Netherlands

RECRUITING

Bernhoven

Uden, 5406 PT, Netherlands

RECRUITING

MeSH Terms

Conditions

Peripheral Arterial Disease

Condition Hierarchy (Ancestors)

Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Peripheral Vascular Diseases

Study Officials

• Michiel C Warlé, PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Loes H Willems, MD

CONTACT

0031 24 361 5333; genpad.heel@radboudumc.nl

Josephine Kranendonk, MD

CONTACT

0031 24 361 5333; genpad.heel@radboudumc.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: This is an open label trial.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A randomized, controlled, open label, multicenter trial.

Study Record Dates

• First Submitted: November 2, 2020
• First Posted: November 6, 2020
• Study Start: March 1, 2021
• Primary Completion: June 30, 2024
• Study Completion: December 31, 2024
• Last Updated: April 20, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Immediately after publication of the main paper for at least 15 years.
• Access Criteria: A steering committee, programme committee or project leader will be charged with approving data requests.

Locations

NL (11)