Impact of CYP2C19 Genotype-guided Clopidogrel and Ticagrelor Treatment on Platelet Function Test and Metabolomics Profile

NCT05516784 | Completed Phase 4 DMC FDA Drug

• 1 other identifier: 56795
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

Several studies have shown that pharmacodynamic (PD) response varies between patients treated with clopidogrel and that individuals with reduced response have an increased risk of recurrent ischemic events, particularly in patients undergoing percutaneous coronary intervention. This is due to several factors influencing the response to clopidogrel, including genetic variations of the cytochrome P450 (CYP) 2C19 enzyme. Loss of function (LOF) carriers of the CYP2C19 gene are associated with the decreased generation of the active metabolite clopidogrel and decreased platelet inhibition, which translates to an increased rate of adverse cardiovascular events, particularly in the setting of percutaneous coronary intervention (PCI). Thus, drug regulatory authorities have cautioned about the decreased efficacy of clopidogrel among individuals with CYP2C19 LOF carriers and suggested using alternative therapies to inhibit p2Y12. Ticagrelor is a new generation P2Y12 receptor inhibitor with greater efficacy for PD and reduced rates of ischemic events compared with clopidogrel and are not affected by the CYP2C19 LOF polymorphism. However, in clinical practice, the genotype-guided selection strategy for the oral P2Y12 inhibitor has been limited despite intensive research efforts. This is due to the interaction of cardiovascular risk factors and molecular and biochemical complications that lead to poor response to platelet inhibitor therapy, which impedes physicians' ability to prescribe a more effective and personalized antiplatelet therapy. Therefore, we must move away from traditional approaches and use integrated systems biology study designs and disciplines to bridge the gap between genotype, phenotype, disease manifestation and/or recurrence. Pharmacometabolomics is a rapidly developing field that takes advantage of a systems pharmacology approach to probe the molecular pathways involved in drug response variability to understand metabolic changes and identify novel biomarkers that can be used to predict response more comprehensively. Using profiles of changes in metabolites can help establish drug exposure fingerprints and clarify the determinants of drug response. This study aims to investigate the Impact of pharmacogenetics-guided clopidogrel and ticagrelor treatment on platelet function test and its association with metabolomics in Coronary Artery Disease (CAD) patients undergoing PCI in Malaysia

Conditions

Coronary Artery Disease (CAD)

Outcome Measures

Primary Outcomes (1)

• Platelet Reactivity

  The primary endpoint is a Platelet reactivity index (PRI) measured by the ELISA-Based Vasodilator-Associated Stimulated Phosphoprotein Phosphorylation Assay 4hours/hospital discharge post randomization to clopidogrel vs ticagrelor. Vasodilator-stimulated phosphoprotein (VASP) measurement is the most specific approach to evaluate the extent to which P2Y12 receptors are functionally blocked by a P2Y12 antagonist.

  4 hours post loading dose

Secondary Outcomes (3)

• Participants With Any Event From the Composite of All-cause Mortality, and MI

  Randomization up to 30 days

• Participants With MI Event

  Randomization up to 30 days

• Participants With Major or Minor Bleeding

  First dosing up to 30 days

Study Arms (2)

Clopidogrel

ACTIVE COMPARATOR

The primary endpoint is the non-inferiority in platelet reactivity of clopidogrel versus ticagrelor among CYP2C19\*2 or \*3 allele carriers.

Drug: Clopidogrel; Drug: Ticagrelor

Ticagrelor

EXPERIMENTAL

The primary endpoint is the non-inferiority in platelet reactivity of clopidogrel versus ticagrelor among CYP2C19 CYP2C19\*2 or \*3 allele carriers.

Drug: Clopidogrel; Drug: Ticagrelor

Interventions

Clopidogrel DRUG

Comparison of platelet reactivity between clopidogrel and ticagrelor

Also known as: Plavix

Clopidogrel; Ticagrelor

Ticagrelor DRUG

Comparison of platelet reactivity between clopidogrel and ticagrelor

Also known as: Brilinta

Clopidogrel; Ticagrelor

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males or females.
• Age more than 18 and below 80 years.
• Patients with stable CAD planned for elective PCI.
• Thienopyridine naive for at least two weeks before admission.

You may not qualify if:

• Pregnant
• Any urgent/emergent coronary angiography procedure that would not allow for genetic testing to be performed before PCI
• Considered at high risk for bleeding
• History of ischemic or hemorrhagic stroke or transient ischemic attack
• Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with Ticagrelor): ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin
• History of ACS within 12 months of screening or need for revascularization
• Any acute or chronic unstable condition.
• Liver disease.
• Have increased bleeding risk, e.g., recent gastrointestinal bleed, uncontrolled high blood pressure, low platelet count.
• History of intolerance or allergy to ticagrelor or clopidogrel
• Patient on dialysis.

Sponsors & Collaborators

• Universiti Sains Malaysia: lead

Study Sites (1)

Department of Cardiology, Penang General Hospital

George Town, Pulau Pinang, 10990, Malaysia

Location

Related Publications (3)

• Akkaif MA, Daud NAA, Sha'aban A, Ng ML, Abdul Kader MAS, Noor DAM, Ibrahim B. The Role of Genetic Polymorphism and Other Factors on Clopidogrel Resistance (CR) in an Asian Population with Coronary Heart Disease (CHD). Molecules. 2021 Apr 1;26(7):1987. doi: 10.3390/molecules26071987.

  PMID: 33915807 BACKGROUND

• Akkaif MA, Sha'aban A, Daud NAA, Yunusa I, Ng ML, Sk Abdul Kader MA, Noor DAM, Ibrahim B. Coronary Heart Disease (CHD) in Elderly Patients: Which Drug to Choose, Ticagrelor and Clopidogrel? A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Cardiovasc Dev Dis. 2021 Sep 30;8(10):123. doi: 10.3390/jcdd8100123.

  PMID: 34677192 BACKGROUND

• Akkaif MA, Daud NAA, Noor DAM, Sha'aban A, Kader MASA, Ibrahim B. The Impact of CYP2C19 Genotype on the Platelet Reactivity Index (PRI) among Chronic Coronary Syndromes (CCS) Patients Undergoing Percutaneous Coronary Intervention (PCI): Affectability of Rapid Genetic Testing. Cardiovasc Drugs Ther. 2025 Apr;39(2):347-356. doi: 10.1007/s10557-024-07544-6. Epub 2024 Jan 15.

  PMID: 38224415 DERIVED

MeSH Terms

Conditions

Coronary Artery Disease

Interventions

Clopidogrel; Ticagrelor

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Adenosine; Purine Nucleosides; Purines; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Baharudin Ibrahim

  Faculty of Pharmacy, University of Malaya, Kuala Lumpur 50603, Federal Territory Malaysia

  PRINCIPAL INVESTIGATOR

• Nur Aizati Athirah Daud

  School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia

  PRINCIPAL INVESTIGATOR

• Mohammed Ahmed Akkaif

  School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia

  PRINCIPAL INVESTIGATOR

• Muhammed Ali Sk Abdul Kader

  Department of Cardiology, Penang General Hospital, Penang 10990, Malaysia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle investigator

Study Record Dates

• First Submitted: August 23, 2022
• First Posted: August 26, 2022
• Study Start: September 1, 2019
• Primary Completion: August 22, 2022
• Study Completion: August 22, 2022
• Last Updated: September 1, 2022

Record last verified: 2022-08

Locations

MY (1)