Clinical trial NCT04619927: Genotype-guided Strategy for Antithrombotic Treatment in Peripheral Arterial Disease.
Official title: Genotype-guided Strategy for Antithrombotic Treatment Versus Conventional Clopidogrel Therapy in Peripheral Arterial Disease.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Peripheral Arterial Disease
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Academisch Ziekenhuis Groningen
name: Rijnstate Hospital
name: Bernhoven Hospital
name: Canisius-Wilhelmina Hospital
First posted: 2020-11-06
Enrollment: 2276
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized, controlled, open label, multicenter trial.
Primary purpose: PREVENTION

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.

Detailed description: Rationale: Peripheral arterial disease (PAD) is a common presentation of atherosclerosis, resulting in intermittent claudication, pain at rest or gangrene. 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 and subsequent cardiovascular death. 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. Adverse clinical events of interest are major adverse cardiovascular events (myocardial infarction, stroke, transient ischemic arrack), major adverse limb events (acute/chronic limb ischemia of peripheral vascular intervention including amputation) and death. 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. Other objectives are to evaluate cost-effectiveness, to explore health state scores and health-related quality of life between study groups and metabolizer states and to set-up a biobank.

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. Health state, quality of life and medical consumption will be measured with validated questionnaire. Questionnaires will be used to assess which antithrombotic treatment the participant is receiving during follow-up, medication adherence and the occurrence of extramural adverse events at 6, 12, 24 and 36 months.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Participants will visit the hospital once for informed consent procedure, blood sample withdrawal and/or buccal sample collection This visit will be combined with a routine visit to the vascular surgeon or vascular laboratory. Patients might experience some discomfort while taking blood samples and buccal sample collection for a short amount of time. The follow-up of participants will range from 6 months (minimum) to 36 months (maximum). Participants are sent questionnaires at baseline and at 6, 12, 24 and 36 months, dependent on the duration of their follow-up. Completing the questionnaires will take approximately 30 minutes. Risks regarding the study are negligible and consist of the possible adverse events related to doubling the daily dose of clopidogrel or related to rivaroxaban and acetylsalicylic acid.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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)

Primary outcomes:
measure: The number of participants that experienced major adverse events
timeFrame: 24 months
Secondary outcomes:
measure: The number of participants that experienced major adverse cardiovascular events
timeFrame: 24 months
measure: The number of participants that experienced major adverse limb events
timeFrame: 24 months
measure: The number of participants that experienced major bleeding
timeFrame: 24 months
measure: The number of participants that experienced clinically relevant bleeding
timeFrame: 24 months
Other outcomes:
measure: The cost-effectiveness of a CYP2C19 genotype-guided antithrombotic treatment strategy versus standard clopidogrel treatment
timeFrame: 24 months
measure: The difference in mean health state scores
timeFrame: 24 months
measure: The difference in health-related quality of life scores
timeFrame: 24 months
Locations:
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen
city: Arnhem
country: Netherlands
facility: Rijnstate
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Máxima Medisch Centrum
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: UMC Groningen
city: Groningen
country: Netherlands
facility: Ommelander Ziekenhuis
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Nijmegen
country: Netherlands
facility: Radboudumc
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Hospital
city: Uden
country: Netherlands
facility: Bernhoven
Study officials:
affiliation: Radboud University Medical Center
name: Michiel C Warlé, PhD
role: PRINCIPAL_INVESTIGATOR
References: