Clinical Trials Logo

Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02345356
Other study ID # A4070215
Secondary ID 8G12MD007600
Status Completed
Phase
First received
Last updated
Start date January 2016
Est. completion date May 17, 2022

Study information

Verified date May 2022
Source University of Puerto Rico
Contact n/a
Is FDA regulated No
Health authority
Study type Observational

Clinical Trial Summary

Caribbean Hispanics are a population with a disproportionately high prevalence of cardio-metabolic disorders but with a limited expectation of benefits from current pharmacogenetic algorithms derived mainly in subjects of relatively pure ancestry. The investigators focus on warfarin responses to develop urgently-needed DNA-driven prescription guidelines for this population, who have arisen from European, West African and Amerindian genomic origins to produce a highly heterogeneous population. Our project combines admixture analysis and DNA-sequencing with development of more accurate rules for better predictability of warfarin dosing to immediately serve this medically underserved population.


Description:

Despite the substantial number of work published over the past years in different populations around the world, a fundamental gap remains in understanding whether and how genomic admixture and polymorphisms in warfarin-related pharmacogenes account for the high inter-individual dose variability observed in Caribbean Hispanic patients. In addition to being a medically underserved population, often marginally represented in clinical studies, Caribbean Hispanics are also a genomically heterogeneous population whose high level of admixture has produced a rich repertoire of combinatorial genotypes (e.g., CYP2C9*2/*5 + VKORC1-1639 A/A) that appear to challenge current pharmacogenetic-driven prescribing models. Our project takes a novel approach to definitively assess this admixture component and is also highly practical for its incorporation into a customized pharmacogenetic algorithm that will be implemented in "real-world" clinical settings through a web-based portal. Moreover, the project is also aimed at performing DNA-sequencing to identify those unknown variants on candidate pharmacogenes (i.e., CYP2C9 and VKORC1) that may contribute further to explain dose variability in Caribbean Hispanics. Shaped by strong preliminary data from a SC2 pilot project, the investigators will assess clinical validity and utility of an admixture-adjusted, pharmacogenetic-guided prescribing model for personalized prediction of effective warfarin dosing in Caribbean Hispanics, which also encompasses genetic (common and novel variants) and non-genetic clinical and demographic factors. The study will be conducted over 4 years in 300 patients with thromboembolic disorders receiving warfarin. Four collaborating/recruiting sites will be further connected through precise delivery of genotyping results and prescribing advice to clinicians via a web-based portal. Our novel assessment of genetic admixture will quantify the contribution of European, African and Amerindian ancestry, and the investigators will test whether this admixture component can explain the heritability that is currently missing in the response variability to this drug among Caribbean Hispanics. If successful in our target population, the same approach can ultimately render current pharmacogenomic models for clinical management of related thromboembolic conditions more accurate and predictive for other populations. The proposed research will advance and expand our understanding of how these clinically relevant variants affect the response to warfarin in an admixed population. Advancing knowledge in the important and under-investigated area of pharmacogenetics in minority populations will generate results that apply to personalize oral anticoagulation therapy in the wider population as it moves, inevitably, toward increasing heterogeneity through admixed genomes.


Recruitment information / eligibility

Status Completed
Enrollment 200
Est. completion date May 17, 2022
Est. primary completion date May 17, 2022
Accepts healthy volunteers No
Gender All
Age group 21 Years to 90 Years
Eligibility Inclusion Criteria: - Caribbean Hispanic origin (e.g., Puerto Ricans, Dominicans, Cubans), whose parents are Caribbean Hispanics as well - Age = 21 years and =90 years. - Willingness and ability to sign informed consent. - Able to be followed up over 3 months. - Expected duration of warfarin therapy of at least 3 months. - Anticoagulation management for the patient will be performed in-hospital and/or as an outpatient by clinicians (i.e., participating Physicians, PharmD) that will adhere to the study dosing algorithms and dose-titration plans. Exclusion Criteria: - Non-Hispanic patients (race/ethnicity is self-reported by the patients) - Age <21 years and >90 years. - Currently taking warfarin or any other new oral anticoagulant (e.g., Xarelto, Pradaxa, Eliquis, and Savaysa/Lixiana). - Prior warfarin therapy with known required stable dose. - Clinician opinion that warfarin dosing needs to be adjusted for reasons not accounted for by dosing algorithm (i.e., other than age, gender, body size, co-meds, comorbidities, diet, genetics, ancestry, INRs and target INR). - Abnormal baseline INR (off warfarin), e.g., due to liver disease, antiphospholipid antibody - Contraindication to warfarin treatment for at least 3 months. - Life expectancy of less than 1 year. - Pregnant women or childbearing women not using medically approved method of birth control. - Inability to follow-up on a regular basis with anticoagulation practitioners participating in trial. - Any factors likely to limit adherence to warfarin, (e.g., dementia, alcohol or substance abuse, plans to move in the next 3 months, history of unreliability in medication taking or appointment keeping, significant concerns about participation in the study from spouse, significant other, or family members, lack of support from primary health care provider). - Sickle cell, HIV-positive/ AIDS patients - Cognitive or other causes of inability to provide informed consent or follow study procedures. - Participating in another trial that prohibits participation in the current trial or planned enrollment in such a trial within the first 3 months of warfarin therapy. - Anemia: a reduction in Hg =2g/dl within 48 hours before randomization and requiring blood transfusions. - Creatinine Clearance (CrCL) = 15 mL/min. - Genotype (CYP2C9 or VKORC1) known to participant from prior testing.

Study Design


Intervention

Genetic:
Genotype-guided
Individual warfarin dose adjustments by using a pharmacogenetically driven algorithm
Other:
Standard-of-Care
Individual warfarin dose adjustments by using a clinically driven algorithm (standard care)

Locations

Country Name City State
Puerto Rico UPR University Hospital at Carolina Carolina
Puerto Rico UDH University Hospital at Centro Medico San Juan
United States Miami VA Healthcare System Miami Florida

Sponsors (3)

Lead Sponsor Collaborator
University of Puerto Rico Genomas, Inc, National Institute on Minority Health and Health Disparities (NIMHD)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (5)

Claudio-Campos K, Duconge J, Cadilla CL, Ruaño G. Pharmacogenetics of drug-metabolizing enzymes in US Hispanics. Drug Metab Pers Ther. 2015 Jun;30(2):87-105. doi: 10.1515/dmdi-2014-0023. Review. — View Citation

Claudio-Campos K, Labastida A, Ramos A, Gaedigk A, Renta-Torres J, Padilla D, Rivera-Miranda G, Scott SA, Ruaño G, Cadilla CL, Duconge-Soler J. Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study. Fro — View Citation

Claudio-Campos K, Orengo-Mercado C, Renta JY, Peguero M, García R, Hernández G, Corey S, Cadilla CL, Duconge J. Pharmacogenetics of healthy volunteers in Puerto Rico. Drug Metab Pers Ther. 2015 Dec;30(4):239-49. doi: 10.1515/dmpt-2015-0021. Review. — View Citation

Duconge J, Cadilla CL, Seip RL, Ruaño G. Why admixture matters in genetically-guided therapy: missed targets in the COAG and EU-PACT trials. P R Health Sci J. 2015 Sep;34(3):175-7. — View Citation

Duconge J, Ramos AS, Claudio-Campos K, Rivera-Miranda G, Bermúdez-Bosch L, Renta JY, Cadilla CL, Cruz I, Feliu JF, Vergara C, Ruaño G. A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics. PLoS One. 2016 Jan 8;11(1):e0145480. doi: 10.1371/journal.pone.0145480. eCollection 2016. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary time spent within therapeutic range percentage of time each patient spent within and out of the therapeutic range (TTR) during initiation, using the Rosendaal linear interpolation method. 6 months
Secondary number of warfarin dose adjustments number of warfarin dose adjustments during the first 12 weeks of therapy 12 weeks
Secondary time to stable anticoagulation time to get stabilization of warfarin doses based on achieving at least three consecutive INR measures within the range for the same average dose. 12 weeks
Secondary events-free time the number of days elapsed between warfarin initiation (date of prescription) and the occurrence of the first event of interest. For the purpose of this analysis, we will use a composite of multiple events that includes hospitalization rates (the first hospitalization due to any cause or due to bleeding or thromboembolism), first overanticoagulation (INR> 4) and first major or minor bleeding episode or ischemic stroke. 6 months
See also
  Status Clinical Trial Phase
Recruiting NCT05654272 - Development of CIRC Technologies
Terminated NCT04115735 - His Bundle Recording From Subclavian Vein
Completed NCT04571385 - A Study Evaluating the Efficacy and Safety of AP30663 for Cardioversion in Participants With Atrial Fibrillation (AF) Phase 2
Completed NCT05366803 - Women's Health Initiative Silent Atrial Fibrillation Recording Study N/A
Completed NCT02864758 - Benefit-Risk Of Arterial THrombotic prEvention With Rivaroxaban for Atrial Fibrillation in France
Recruiting NCT05442203 - Electrocardiogram-based Artificial Intelligence-assisted Detection of Heart Disease N/A
Completed NCT05599308 - Evaluation of Blood Pressure Monitor With AFib Screening Feature N/A
Completed NCT03790917 - Assessment of Adherence to New Oral anTicoagulants in Atrial Fibrillation patiEnts Within the Outpatient registrY
Enrolling by invitation NCT05890274 - Atrial Fibrillation (AF) and Electrocardiogram (EKG) Interpretation Project ECHO N/A
Recruiting NCT05316870 - Construction and Effect Evaluation of Anticoagulation Management Model in Atrial Fibrillation N/A
Recruiting NCT05266144 - Atrial Fibrillation Patients Treated With Catheter Ablation
Not yet recruiting NCT06023784 - The Impact of LBBAP vs RVP on the Incidence of New-onset Atrial Fibrillation in Patients With Atrioventricular Block N/A
Recruiting NCT05572814 - Transform: Teaching, Technology, and Teams N/A
Recruiting NCT04092985 - Smart Watch iECG for the Detection of Cardiac Arrhythmias
Completed NCT04087122 - Evaluate the Efficiency Impact of Conducting Active Temperature Management During Cardiac Cryoablation Procedures N/A
Completed NCT06283654 - Relieving the Emergency Department by Using a 1-lead ECG Device for Atrial Fibrillation Patients After Pulmonary Vein Isolation
Recruiting NCT05416086 - iCLAS™ Cryoablation System Post-Market Clinical Follow-up (PMCF) Study N/A
Completed NCT05067114 - Solutions for Atrial Fibrillation Edvocacy (SAFE)
Completed NCT04546763 - Study Watch AF Detection At Home
Completed NCT03761394 - Pulsewatch: Smartwatch Monitoring for Atrial Fibrillation After Stroke N/A