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A Genomic Approach to Warfarin Dose Prescription in Admixed Caribbean Hispanics

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ClinicalTrials.gov Identifier: NCT02345356
Recruitment Status : Recruiting
First Posted : January 26, 2015
Last Update Posted : January 23, 2018
Sponsor:
Collaborators:
National Institute on Minority Health and Health Disparities (NIMHD)
Genomas, Inc
Information provided by (Responsible Party):
Jorge Duconge, University of Puerto Rico

Brief 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.

Condition or disease Intervention/treatment
Atrial Fibrillation Deep Vein Thrombosis Cardiac Valvular Insufficiency Coagulopathies Pulmonary Embolism Genetic: Genotype-guided Other: Standard-of-Care

Detailed 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.


Study Type : Observational
Estimated Enrollment : 300 participants
Observational Model: Case-Control
Time Perspective: Prospective
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 2019
Estimated Study Completion Date : July 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners

Group/Cohort Intervention/treatment
Standard-of-Care
the standard clinical approach will be followed
Other: Standard-of-Care
Individual warfarin dose adjustments by using a clinically driven algorithm (standard care)

Genotype-guided
algorithmically guided personalized therapy of warfarin, using a pharmacogenetic model developed in Caribbean Hispanics
Genetic: Genotype-guided
Individual warfarin dose adjustments by using a pharmacogenetically driven algorithm




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. number of warfarin dose adjustments [ Time Frame: 12 weeks ]
    number of warfarin dose adjustments during the first 12 weeks of therapy

  2. 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.

  3. 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
Buccal swabs


Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Caribbean Hispanics (e.g., Puerto Ricans, Dominicans, Cubans), whose parents are Caribbean Hispanics as well.
Criteria

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.

Information from the National Library of Medicine

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


Contacts
Contact: Jorge Duconge, PhD (787) 758-2525 ext 3006 jorge.duconge@upr.edu
Contact: Gualberto Ruano, MD (860) 545-3773 g.ruano@genomas.net

Locations
United States, Florida
Miami VA Healthcare System Recruiting
Miami, Florida, United States, 33125
Contact: Patricia Fernandez-Quevedo, PharmD, BCPS    305-575-7000 ext 3752    Patricia.Fernandez-quevedo@va.gov   
Contact: Alga S. Ramos, PharmD    787-360-5666    Alga.Ramos-Morales@va.gov   
Puerto Rico
UPR University Hospital at Carolina Recruiting
Carolina, Puerto Rico, 00984
Contact: Angel Lopez-Candales, MD    1 (412) 735-6631    angel.lopez17@upr.edu, candales33@gmail.com   
Principal Investigator: Kyle Melin, PharmD         
UDH University Hospital at Centro Medico Recruiting
San Juan, Puerto Rico, 00936
Contact: Angel Lopez-Candales, MD    1 (412) 735-6631    angel.lopez17@upr.edu, candales33@gmail.com   
Principal Investigator: Kyle Melin, PharmD         
Sponsors and Collaborators
University of Puerto Rico
National Institute on Minority Health and Health Disparities (NIMHD)
Genomas, Inc
Investigators
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

Publications of Results:
Other Publications:
Responsible Party: Jorge Duconge, PhD, MSc, BSc Pharm, Professor, University of Puerto Rico
ClinicalTrials.gov Identifier: NCT02345356     History of Changes
Other Study ID Numbers: A4070215
8G12MD007600 ( U.S. NIH Grant/Contract )
First Posted: January 26, 2015    Key Record Dates
Last Update Posted: January 23, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data sharing plan is fully described in the corresponding section of the protocol. A thorough description of appropriate use of the data to be shared in this study is provided in informed consent documents. Limitations on data use are also described therein and in this Institutional Certification. Safeguards to protect the data according to Federal standards for information protection will be implemented. 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. This research involves individual-level human data. We expect to share both genotypes and phenotype data as well as additional information necessary to interpret such data, and we propose a data sharing plan that complies with NIH guidelines for NIH-funded studies (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html) and the new NIH Genomic Data Sharing (GDS) Policy's scope (http://gds.nih.gov/03policy2.html).

Keywords provided by Jorge Duconge, University of Puerto Rico:
Pharmacogenomics
Warfarin
Caribbean Hispanics
Polymorphisms
Dosing Algorithm

Additional relevant MeSH terms:
Atrial Fibrillation
Thrombosis
Embolism
Pulmonary Embolism
Venous Thrombosis
Blood Coagulation Disorders
Hemostatic Disorders
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Lung Diseases
Respiratory Tract Diseases
Hematologic Diseases
Hemorrhagic Disorders
Warfarin
Anticoagulants