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

Primary Purpose

Peripheral Arterial Disease

Status
Recruiting
Phase
Phase 4
Locations
Netherlands
Study Type
Interventional
Intervention
Direct CYP2C19 genotyping
CYP2C19 genotyping at the end of the study
Poor metabolisers
Intermediate metabolisers
Normal metabolisers and unknown metaboliser state
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Peripheral Arterial Disease

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Gelre Ziekenhuizen
  • RijnstateRecruiting
  • Ziekenhuis Gelderse ValleiRecruiting
  • Máxima Medisch Centrum
  • Medisch Spectrum Twente
  • UMC Groningen
  • Ommelander Ziekenhuis
  • Maastricht University Medical Center
  • RadboudumcRecruiting
  • Canisius Wilhelmina HospitalRecruiting
  • BernhovenRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Intervention group

Comparison group

Arm Description

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).

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

The number of participants that experienced major adverse cardiovascular events
The number of participants that experienced a myocardial infarction, stroke, transient ischemic attack or cardiovascular death.
The number of participants that experienced major adverse limb events
The number of participants that experienced acute limb ischemia, chronic limb ischemia or peripheral vascular intervention
The number of participants that experienced major bleeding
The number of participants that experienced major bleeding, including: 1) fatal bleeding, 2) symptomatic bleeding into a critical organ, 3) bleeding causing a fall in hemoglobin level of 20 g L-1 (1.24 mmol L-1) or more or leading to transfusion of two or more units of whole blood or red cells, and 4) bleeding into a surgical site requiring a second intervention.
The number of participants that experienced clinically relevant bleeding
The number of participants that experienced clinically relevant bleeding, including bleeding that led to: 1) hospitalization (including presentation to an acute care facility without an overnight stay), 2) a physician guided medical or surgical treatment for bleeding, or 3) a change in antithrombotic treatment.

Full Information

First Posted
November 2, 2020
Last Updated
April 19, 2022
Sponsor
Radboud University Medical Center
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development, Academisch Ziekenhuis Groningen, Rijnstate Hospital, Bernhoven Hospital, Canisius-Wilhelmina Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04619927
Brief Title
Genotype-guided Strategy for Antithrombotic Treatment in Peripheral Arterial Disease.
Acronym
GENPAD
Official Title
Genotype-guided Strategy for Antithrombotic Treatment Versus Conventional Clopidogrel Therapy in Peripheral Arterial Disease.
Study Type
Interventional

2. Study Status

Record Verification Date
January 2022
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2021 (Actual)
Primary Completion Date
June 30, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development, Academisch Ziekenhuis Groningen, Rijnstate Hospital, Bernhoven Hospital, Canisius-Wilhelmina Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Peripheral Arterial Disease

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
A randomized, controlled, open label, multicenter trial.
Masking
None (Open Label)
Masking Description
This is an open label trial.
Allocation
Randomized
Enrollment
2276 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Intervention group
Arm Type
Experimental
Arm Description
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).
Arm Title
Comparison group
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Genetic
Intervention Name(s)
Direct CYP2C19 genotyping
Intervention Description
CYP2C19 genotype will be determined by the Spartan RX CYP2C19 point-of-care system.
Intervention Type
Genetic
Intervention Name(s)
CYP2C19 genotyping at the end of the study
Intervention Description
Blood-based CYP2C19 genotyping will be performed at the end of the study
Intervention Type
Drug
Intervention Name(s)
Poor metabolisers
Intervention Description
Acetylsalicylic acid 100mg once daily plus rivaroxaban 2.5mg twice daily
Intervention Type
Drug
Intervention Name(s)
Intermediate metabolisers
Intervention Description
Clopidogrel 75mg twice daily
Intervention Type
Drug
Intervention Name(s)
Normal metabolisers and unknown metaboliser state
Intervention Description
Clopidogrel 75mg once daily
Primary Outcome Measure Information:
Title
The number of participants that experienced major adverse events
Description
The number of participants that experienced a major adverse cardiovascular events, major adverse limb events or death from any cause.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
The number of participants that experienced major adverse cardiovascular events
Description
The number of participants that experienced a myocardial infarction, stroke, transient ischemic attack or cardiovascular death.
Time Frame
24 months
Title
The number of participants that experienced major adverse limb events
Description
The number of participants that experienced acute limb ischemia, chronic limb ischemia or peripheral vascular intervention
Time Frame
24 months
Title
The number of participants that experienced major bleeding
Description
The number of participants that experienced major bleeding, including: 1) fatal bleeding, 2) symptomatic bleeding into a critical organ, 3) bleeding causing a fall in hemoglobin level of 20 g L-1 (1.24 mmol L-1) or more or leading to transfusion of two or more units of whole blood or red cells, and 4) bleeding into a surgical site requiring a second intervention.
Time Frame
24 months
Title
The number of participants that experienced clinically relevant bleeding
Description
The number of participants that experienced clinically relevant bleeding, including bleeding that led to: 1) hospitalization (including presentation to an acute care facility without an overnight stay), 2) a physician guided medical or surgical treatment for bleeding, or 3) a change in antithrombotic treatment.
Time Frame
24 months
Other Pre-specified Outcome Measures:
Title
The cost-effectiveness of a CYP2C19 genotype-guided antithrombotic treatment strategy versus standard clopidogrel treatment
Description
The costs per adverse event avoided for CYP2C19 genotype-guided antithrombotic treatment strategy compared to standard clopidogrel treatment
Time Frame
24 months
Title
The difference in mean health state scores
Description
Health state score measured by the EuroQol five-dimensional questionnaire five-level (EQ-5D-5L) will be determined at baseline and during follow-up. Patients score five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) on 5 levels (no problems, slight problems, moderate problems, severe problems and extreme problems), resulting in a descriptive score of 5 consecutive numbers. The validated Dutch tariff for the EQ-5D-5L will convert the descriptive score to a continuous score (range -1 to 1) in which a higher value represents a better health state than a lower value..
Time Frame
24 months
Title
The difference in health-related quality of life scores
Description
Health-related quality of life measured by the abbreviated World Health Organization Quality of life questionnaire (WHOQoL-Bref) will be determined at baseline and during follow-up. Patients score their quality of life with 26 questions on 4 domains (physical, psychological, social relationships and environment). Each question can be answered by 1 to 5. Scores are scaled in a positive direction (i.e. higher scores denote higher quality of life). The mean score of individual items within each domain, multiplied by 4, represents the domain score (range 4 to 20). The mean of the domain scores is the health-related quality of life score (range 4 to 20).
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Loes H Willems, MD
Phone
0031 24 361 5333
Email
genpad.heel@radboudumc.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Josephine Kranendonk, MD
Phone
0031 24 361 5333
Email
genpad.heel@radboudumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michiel C Warlé, PhD
Organizational Affiliation
Radboud University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Gelre Ziekenhuizen
City
Apeldoorn
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hessel CLJ Buscher, PhD
Facility Name
Rijnstate
City
Arnhem
ZIP/Postal Code
6815
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michel MPJ Reijnen, Prof
Facility Name
Ziekenhuis Gelderse Vallei
City
Ede
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hans JEM Sybrandy, MD
Facility Name
Máxima Medisch Centrum
City
Eindhoven
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maarten JA Loos, PhD
Facility Name
Medisch Spectrum Twente
City
Enschede
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Theo P Menting, PhD
Facility Name
UMC Groningen
City
Groningen
ZIP/Postal Code
9713 GZ
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clark JAM Zeebregts, Prof
Facility Name
Ommelander Ziekenhuis
City
Groningen
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Martijn L Dijkstra, PhD
Facility Name
Maastricht University Medical Center
City
Maastricht
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Barend ME Mees, Ass. Prof
Facility Name
Radboudumc
City
Nijmegen
ZIP/Postal Code
6525 GA
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michiel C Warlé, PhD
Facility Name
Canisius Wilhelmina Hospital
City
Nijmegen
ZIP/Postal Code
6532 SZ
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bianca Bendermacher, PhD
Facility Name
Bernhoven
City
Uden
ZIP/Postal Code
5406 PT
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andre S van Petersen, PhD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Data will be accessible through the Data Archiving and Networked Services Electronic Archiving System (DANS EASY) repository, using Dublin Cor metadata scheme
IPD Sharing Time Frame
Immediately after publication of the main paper for at least 15 years.
IPD Sharing Access Criteria
A steering committee, programme committee or project leader will be charged with approving data requests.

Learn more about this trial

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

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