A Genomic Approach to Warfarin Dose Prescription in Admixed Caribbean Hispanics
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|ClinicalTrials.gov Identifier: NCT02345356|
Recruitment Status : Active, not recruiting
First Posted : January 26, 2015
Last Update Posted : March 30, 2020
|Condition or disease||Intervention/treatment|
|Atrial Fibrillation Deep Vein Thrombosis Cardiac Valvular Insufficiency Coagulopathies Pulmonary Embolism||Genetic: Genotype-guided Other: Standard-of-Care|
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.
|Study Type :||Observational|
|Actual Enrollment :||200 participants|
|Official Title:||A Randomized, Double-blind Clinical Trial of Anticoagulation Therapy With Warfarin in Caribbean Hispanics: Comparison Between an Admixture-adjusted Pharmacogenetic-driven Warfarin Dose Refinement Algorithm and the Standard of Care|
|Study Start Date :||January 2016|
|Estimated Primary Completion Date :||July 2020|
|Estimated Study Completion Date :||July 2020|
the standard clinical approach will be followed
Individual warfarin dose adjustments by using a clinically driven algorithm (standard care)
algorithmically guided personalized therapy of warfarin, using a pharmacogenetic model developed in Caribbean Hispanics
Individual warfarin dose adjustments by using a pharmacogenetically driven algorithm
- time spent within therapeutic range [ Time Frame: 6 months ]percentage of time each patient spent within and out of the therapeutic range (TTR) during initiation, using the Rosendaal linear interpolation method.
- number of warfarin dose adjustments [ Time Frame: 12 weeks ]number of warfarin dose adjustments during the first 12 weeks of therapy
- time to stable anticoagulation [ Time Frame: 12 weeks ]time to get stabilization of warfarin doses based on achieving at least three consecutive INR measures within the range for the same average dose.
- events-free time [ Time Frame: 6 months ]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.
Biospecimen Retention: Samples With DNA
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02345356
|United States, Florida|
|Miami VA Healthcare System|
|Miami, Florida, United States, 33125|
|UPR University Hospital at Carolina|
|Carolina, Puerto Rico, 00984|
|UDH University Hospital at Centro Medico|
|San Juan, Puerto Rico, 00936|
|Principal Investigator:||Jorge Duconge, PhD||University of Puerto Rico Medical Sciences Campus|
|Study Director:||Graciela M. Vega-Debien, BSc||University of Puerto Rico Medical Sciences Campus|
|Study Director:||Angel Lopez-Candales, MD||University of Puerto Rico Medical Sciences Campus|
|Study Chair:||Alga S. Ramos, PharmD||Miami VA Hospital|