Clinical trial NCT03419325: A Genomic Approach for Clopidogrel in Caribbean Hispanics
Official title: Adopting a Precision Medicine Paradigm in Puerto Rico: Leveraging Ancestral Diversity to Identify Predictors of Clopidogrel Response in Caribbean Hispanics
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Cardiovascular Disease (CVD)
Stroke
Acute Coronary Syndrome
Peripheral Arterial Disease
Coronary Artery Disease
Myocardial Infarction
Keywords: percutaneous coronary interventions (PCI)
secondary stroke prevention
dual antiplatelet therapy (DAPT)
Lead sponsor: University of Puerto Rico
Sponsor class: OTHER
Collaborators: name: National Institute on Minority Health and Health Disparities (NIMHD)
name: Icahn School of Medicine at Mount Sinai
First posted: 2018-02-01
Enrollment: 150
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: After being consented, patients will undergo rapid ex vivo platelet functional testing (i.e., residual platelet reactivity units, PRU, measured using the VerifyNow P2R12 assay for Clopidogrel response) and CYP2C19 genotyping. Patients will then be categorized into 4 groups based on tests results: 1) high on-treatment platelet reactivity (HTPR)/ CYP2C19 loss-of-function (LOF) alleles (i.e., presence of both HTPR and CYP2C19 LOF alleles); 2) HTPR/No-LOF (presence of HTPR, but no CYP2C19 LOF allele); 3) No-HTPR/LOF (presence of a CYP2C19 LOF allele, but no HTPR); 4) No-HTPR/No-LOF (absence of both HTPR and CYP2C19 LOF alleles).
Primary purpose: BASIC_SCIENCE

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Major adverse cardiovascular events (MACE) reductions
timeFrame: six months after intervention
Secondary outcomes:
measure: number of patients with treatment-related cardiovascular (CV) death
timeFrame: six months after intervention
measure: number of patients with treatment-related stent thrombosis
timeFrame: six months after intervention
measure: Bleeding
timeFrame: six months after intervention
Other outcomes:
Locations:
city: Carolina
country: Puerto Rico
facility: University Hospital at Carolina
city: San Juan
country: Puerto Rico
facility: Cardiovascular Hospital of Puerto Rico and the Caribbean
Study officials:
affiliation: University of Puerto Rico
name: Jorge Duconge, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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 score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach. Clin Transl Sci. 2021 Nov;14(6):2254-2266. doi: 10.1111/cts.13124. Epub 2021 Aug 20.
citation: Nunez-Medina H, Monero M, Torres LM, Leal E, Gonzalez-Sepulveda L, Mayor AM, Renta JY, Gonzalez-Garcia ER, Gonzalez A, Melin K, Scott SA, Ruano G, Hernandez-Suarez DF, Duconge J. Implementing a Pharmacogenomic-driven Algorithm to Guide Antiplatelet Therapy among Caribbean Hispanics: A non-randomized prospective cohort study. medRxiv [Preprint]. 2023 Dec 6:2023.12.05.23299547. doi: 10.1101/2023.12.05.23299547.
citation: Yang G, Gonzalez P, Monero M, Carrasquillo K, Renta JY, Hernandez-Suarez DF, Botton MR, Melin K, Scott SA, Ruano G, Roche-Lima A, Alarcon C, Ritchie MD, Perera MA, Duconge J. Discovery of Ancestry-specific Variants Associated with Clopidogrel Response among Caribbean Hispanics. medRxiv [Preprint]. 2023 Oct 2:2023.09.29.23296372. doi: 10.1101/2023.09.29.23296372.
citation: Monero-Paredes M, Feliu-Maldonado R, Carrasquillo-Carrion K, Gonzalez P, Rogozin IB, Roche-Lima A, Duconge J. Non-Random Enrichment of Single-Nucleotide Polymorphisms Associated with Clopidogrel Resistance within Risk Loci Linked to the Severity of Underlying Cardiovascular Diseases: The Role of Admixture. Genes (Basel). 2023 Sep 17;14(9):1813. doi: 10.3390/genes14091813.