A Genomic Approach for Clopidogrel in Caribbean Hispanics

Stroke Clinical Trial

Official title:

Adopting a Precision Medicine Paradigm in Puerto Rico: Leveraging Ancestral Diversity to Identify Predictors of Clopidogrel Response in Caribbean Hispanics

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03419325
• Other study ID #: A4070417
• Secondary ID: 2U54MD007600-31
• Status: Active, not recruiting
• Phase: Early Phase 1
• Start date: September 1, 2020
• Est. completion date: December 30, 2023

Study information

• Verified date: May 2023
• Source: University of Puerto Rico
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Clopidogrel is a prescription medicine used to minimize blood clot formation in patients with cardiovascular disease, particularly those undergoing heart catheterization and stroke. A substantial amount of medical evidence has proven that patients with stroke or heart diseases can benefit from this medicine. However, significant variability in such expected benefits has been found among individuals receiving clopidogrel, with some patients not having the benefit of reduced complications and adverse cardiovascular events. Prior studies have demonstrated a significant association between certain variants on patient's genes (e.g., CYP2C19) and poor response to clopidogrel and, therefore, major adverse cardiovascular events. Variation in other genes and other factors such as platelet activation, weight, diabetes mellitus (a medical condition that produces high blood sugar), concomitant use of other drugs, and smoking status have also been proposed to be related to the same adverse outcomes. In this study, the investigators would like to determine a possible association between these genes and the response to the medication among Caribbean Hispanic cardiovascular patients on clopidogrel. In other populations, it is known that patients with certain genetic variants have lower or magnified responses to this medication when compared to those individuals taking the same dose and not carrying the genetic variations. However, a fundamental gap remains in understanding whether the genomic diversity of Caribbean Hispanics accounts for the observed high inter-individual variability of clinical outcomes to preventive dual antiplatelet therapy (DAPT) with clopidogrel.

Description:

Despite the substantial work in cardiovascular pharmacogenomics published over the past decade, a fundamental gap remains in understanding whether the genomic diversity of Caribbean Hispanics accounts for high inter-individual variability of clinical outcomes to preventive dual antiplatelet therapy (DAPT) with clopidogrel. Caribbean Hispanics are disproportionately affected by cardio-metabolic disorders, but with a limited expectation of benefits from existing genomic-based algorithms. The investigators will focus on clopidogrel to develop urgently-needed genomic-driven prescription guidelines for this population. To this purpose, the investigators will implement a treatment algorithm to guide DAPT in Caribbean Hispanics and will create a repository of genomic DNAs and fully annotated clinical and genomic datasets from Caribbean Hispanics with cardiovascular diseases. This proposal will also take a novel approach to definitively assess the admixture component and is also highly practical for the development of a clinical decision support (CDS) tool. The investigators will test the following hypothesis: There are unknown genetic variants that uniquely contribute to clopidogrel responsiveness in Caribbean Hispanics to such extent that a developed CDS tool that incorporates personal ethno-specific genotypes and ex vivo pharmacodynamics (PD) testing will help enable more precise recommendations for optimizing medical outcomes to antiplatelet therapy in this population. To test this hypothesis we will work with the following aim: To implement a treatment algorithm based on ex vivo PD and genetic test results to guide DAPT in Caribbean Hispanics.

This clinical study will be conducted over 2-3 years in 250 naive cardiovascular patients to be treated with DAPT for secondary prevention of thromboembolic events (i.e., to be compared to another set of 250 clopidogrel-treated patients from a matched non-concurrent standard-of-care cohort). It is expected that this study advances the adoption of a Precision Medicine (PM) paradigm for the benefit of Hispanic patients. The richer genetic variance in Latinos is likely to contribute substantially to variability in response to drug treatments, a component that will be missed by traditional studies within homogeneous populations. This addressable oversight is of great concern since it will tend to exacerbate the healthcare disparity already experienced by Hispanic populations in the US. Hispanics have been largely excluded from Precision Medicine initiatives, which increase dramatically the disparities in translating benefits from new findings in pharmacogenomics to this medically underserved population, exacerbating the existing inequity in healthcare services. Accordingly, the proposed research will expand the current understanding of the pharmacogenomics of Clopidogrel. Advancing knowledge in the under-investigated area of pharmacogenetics in minority populations will generate results that apply to personalize DAPT in the wider population as it moves, inevitably, toward increasing heterogeneity through admixed genomes.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 150
• Est. completion date: December 30, 2023
• Est. primary completion date: April 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

Inclusion Criteria:

• Caribbean Hispanics (Puerto Ricans, Dominicans or Cubans) residing in Puerto Rico, whose parents are also of Hispanic origin

• Both genders (Males/Females)

• Age =21

• Receiving Clopidogrel for therapeutic indications.

• No clinically active hepatic abnormality

• The ability to understand the requirements of the study

• The ability to comply with study procedures and protocol

• A female patient is eligible to enter the study if she is of child-bearing potential and not pregnant or nursing, or not of child-bearing potential

Exclusion Criteria:

• Non-Hispanic patients (race/ethnicity is self-reported by the patients)

• Currently enrolled in another active research protocols at the participating institutions

• BUN >30

• Creatinine >2.0 mg/dL

• Platelet count <100,000/mm3

• Nasogastric or enteral feedings

• Acute illness (e.g., sepsis, infection, anemia)

• HIV/AIDS, Hepatitis B patients

• Alcoholism and drug abuse

• Patients with any cognitive and mental health impairment

• Sickle cell patients

• Active malignancy

• Patients taking another antiplatelet

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Cardiovascular Disease (CVD)
• Cardiovascular Diseases
• Coronary Artery Disease
• Infarction
• Myocardial Infarction
• Peripheral Arterial Disease
• Peripheral Vascular Diseases
• Stroke

Intervention

Genetic:
• CYP2C19 test
Patients will be categorized into 4 groups based on the results of their genetic test for CYP2C19 as well as the residual platelet reactivity test (P2RY12 assay=PRU units) and DAPT treatments options will be recommended accordingly (i.e., through a Clinical Decision Support (CDS) tool that is based on a pharmacogenetic-driven algorithm and the PRU result).

Diagnostic Test:
• P2RY12 assay
Patients will be categorized into 4 groups based on the results of their genetic test for CYP2C19 as well as the residual platelet reactivity test (P2RY12 assay=PRU units) and DAPT treatments options will be recommended accordingly (i.e., through a Clinical Decision Support (CDS) tool that is based on a pharmacogenetic-driven algorithm and the PRU result).

Locations

Country	Name	City	State
Puerto Rico	University Hospital at Carolina	Carolina
Puerto Rico	Cardiovascular Hospital of Puerto Rico and the Caribbean	San Juan

Sponsors (3)

Lead Sponsor	Collaborator
University of Puerto Rico	Icahn School of Medicine at Mount Sinai, National Institute on Minority Health and Health Disparities (NIMHD)

Country where clinical trial is conducted

Puerto Rico, 

References & Publications (2)

Duconge J, Santiago E, Hernandez-Suarez DF, Monero M, Lopez-Reyes A, Rosario M, Renta JY, Gonzalez P, Ileana Fernandez-Morales L, Antonio Velez-Figueroa L, Arce O, Marin-Maldonado F, Nunez H, Melin K, Scott SA, Ruano G. Pharmacogenomic polygenic risk scor — View Citation

Hernandez-Suarez DF, Melin K, Marin-Maldonado F, Nunez HJ, Gonzalez AF, Gonzalez-Sepulveda L, Rivas-Tumanyan S, Naik H, Ruano G, Scott SA, Duconge J. Implementing a pharmacogenetic-driven algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics: protocol for a non-randomised clinical trial. BMJ Open. 2020 Aug 6;10(8):e038936. doi: 10.1136/bmjopen-2020-038936. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Major adverse cardiovascular events (MACE) reductions	MACE reductions will be the composite of all-cause death, MI (according to the universal definition), stroke or coronary revascularization.	six months after intervention
Secondary	number of patients with treatment-related cardiovascular (CV) death	death resulting from an acute myocardial infarction, sudden cardiac death, death due to heart failure, stroke, CV procedures, CV hemorrhage and other CV causes.	six months after intervention
Secondary	number of patients with treatment-related stent thrombosis	definite or confirmed stent thrombosis as proposed by the Academic Research Consortium (ARC): i.e., symptoms suggestive of an acute coronary syndrome and angiographic or pathologic confirmation of stent thrombosis.	six months after intervention
Secondary	Bleeding	as defined by Bleeding Academic Research Consortium (BARC) criteria	six months after intervention

External Links

•   Protocol for a non-randomised clinical trial that seeks to implement a PGx-driven algorithm to guide DAPT in Caribbean Hispanics.