A Genomic Approach for Clopidogrel in Caribbean Hispanics

NCT03419325 | Active Not Recruiting Early Phase 1 DMC FDA Drug

• 2 other identifiers: A40704172U54MD007600-31
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 2

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.

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)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• number of patients with treatment-related cardiovascular (CV) death

  six months after intervention

• number of patients with treatment-related stent thrombosis

  six months after intervention

• Bleeding

  six months after intervention

Study Arms (4)

HTPR/LOF

EXPERIMENTAL

Intervention: Genotyping (CYP2C19 assay) and P2RY12 testing to make decision on therapy. Presence of both high on-treatment platelet reactivity (HTPR) and CYP2C19 loss-of-function (LOF) alleles: An alternative therapy with either prasugrel or ticagrelor (in line with specific contraindications and precautions for each agent) will be strongly recommended for HPR/LOF patients, within next 5-7 days. Changes in DAPT will be at the discretion of the clinician. Treatment strategies and clinical outcomes will be evaluated up to 6-months.

Genetic: CYP2C19 test; Diagnostic Test: P2RY12 assay

HTPR/no-LOF

EXPERIMENTAL

Intervention: Genotyping (CYP2C19 assay) and P2RY12 testing to make decision on therapy. Presence of HTPR, but no CYP2C19 LOF allele found: An alternative therapy should be considered for HTPR/no-LOF patients, within next 5-7 days. Changes in DAPT will be at the discretion of the clinician. Treatment strategies and clinical outcomes will be evaluated up to 6-months.

Genetic: CYP2C19 test; Diagnostic Test: P2RY12 assay

no-HTPR/LOF

EXPERIMENTAL

Intervention: Genotyping (CYP2C19 assay) and P2RY12 testing to make decision on therapy. Presence of a CYP2C19 LOF allele, but no HTPR: An alternative therapy should be considered for no-HTPR/LOF patients, within next 5-7 days. Changes in DAPT will be at the discretion of the clinician. Treatment strategies and clinical outcomes will be evaluated up to 6-months.

Genetic: CYP2C19 test; Diagnostic Test: P2RY12 assay

No-HTPR/No-LOF

EXPERIMENTAL

Intervention: Genotyping (CYP2C19 assay) and P2RY12 testing to make decision on therapy. Absence of both HTPR and CYP2C19 LOF alleles: Maintaining clopidogrel for no-HPR/no-LOF patients. Changes in DAPT will be at the discretion of the clinician. Treatment strategies and clinical outcomes will be evaluated up to 6-months.

Genetic: CYP2C19 test; Diagnostic Test: P2RY12 assay

Interventions

CYP2C19 test GENETIC

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).

HTPR/LOF; HTPR/no-LOF; No-HTPR/No-LOF; no-HTPR/LOF

P2RY12 assay DIAGNOSTIC_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).

HTPR/LOF; HTPR/no-LOF; No-HTPR/No-LOF; no-HTPR/LOF

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Puerto Rico: lead
• National Institute on Minority Health and Health Disparities (NIMHD): collaborator
• Icahn School of Medicine at Mount Sinai: collaborator

Study Sites (2)

University Hospital at Carolina

Carolina, 00984, Puerto Rico

Location

Cardiovascular Hospital of Puerto Rico and the Caribbean

San Juan, 00926, Puerto Rico

Location

Related Publications (6)

• 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.

  PMID: 32764090 BACKGROUND

• 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.

  PMID: 34415683 RESULT

• 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.

  PMID: 38106133 RESULT

• 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.

  PMID: 37873439 RESULT

• 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.

  PMID: 37761953 RESULT

• Nunez-Medina HJ, 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-randomised clinical trial. BMJ Open. 2024 Sep 5;14(9):e084119. doi: 10.1136/bmjopen-2024-084119.

  PMID: 39242160 DERIVED

Related Links

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

MeSH Terms

Conditions

Cardiovascular Diseases; Stroke; Acute Coronary Syndrome; Peripheral Arterial Disease; Coronary Artery Disease; Myocardial Infarction

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Myocardial Ischemia; Heart Diseases; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Peripheral Vascular Diseases; Coronary Disease; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis

Study Officials

• Jorge Duconge, PhD

  University of Puerto Rico

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Proffesor, PhD

Model Details: 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).

Study Record Dates

• First Submitted: January 20, 2018
• First Posted: February 1, 2018
• Study Start: September 1, 2020
• Primary Completion: April 30, 2023
• Study Completion: December 30, 2024
• Last Updated: June 26, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: The investigators plan a submission of the study data to the dbGaP repository within the first three months of collection completion. Afterward, NIH is expected to release controlled-access human genomic data from this study no later than six months after the data have been submitted to dbGaP repository and cleaned, or at the time of acceptance of the first publication, whichever occurs first, without restrictions on publications or other dissemination of research findings.
• Access Criteria: As stated by guidelines, data will be made available in the database of Genotype and Phenotype (dbGaP) http://www.ncbi.nlm.nih.gov/gap through controlled-access. Accordingly, controlled-access data in dbGaP repository will be made available for secondary research only after investigators have obtained appropriate approval to use the requested data for their proposed projects.

Locations

PR (2)