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Trial record 11 of 145 for:    warfarin AND therapeutic range

A Genomic Approach to Warfarin Dose Prescription in Admixed Caribbean Hispanics

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02345356
Recruitment Status : Recruiting
First Posted : January 26, 2015
Last Update Posted : February 12, 2019
Sponsor:
Collaborators:
National Institute on Minority Health and Health Disparities (NIMHD)
Genomas, Inc
Information provided by (Responsible Party):
Jorge Duconge, University of Puerto Rico

Tracking Information
First Submitted Date January 19, 2015
First Posted Date January 26, 2015
Last Update Posted Date February 12, 2019
Study Start Date January 2016
Estimated Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: December 23, 2015)
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.
Original Primary Outcome Measures
 (submitted: January 23, 2015)
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.
Change History
Current Secondary Outcome Measures
 (submitted: December 23, 2015)
  • 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.
Original Secondary Outcome Measures
 (submitted: January 23, 2015)
  • 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 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title A Genomic Approach to Warfarin Dose Prescription in Admixed Caribbean Hispanics
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
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.
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
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Buccal swabs
Sampling Method Non-Probability Sample
Study Population Caribbean Hispanics (e.g., Puerto Ricans, Dominicans, Cubans), whose parents are Caribbean Hispanics as well.
Condition
  • Atrial Fibrillation
  • Deep Vein Thrombosis
  • Cardiac Valvular Insufficiency
  • Coagulopathies
  • Pulmonary Embolism
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)
Study Groups/Cohorts
  • Standard-of-Care
    the standard clinical approach will be followed
    Intervention: Other: Standard-of-Care
  • Genotype-guided
    algorithmically guided personalized therapy of warfarin, using a pharmacogenetic model developed in Caribbean Hispanics
    Intervention: Genetic: Genotype-guided
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: January 23, 2015)
300
Original Estimated Enrollment Same as current
Estimated Study Completion Date July 2019
Estimated Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Eligibility 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.
Sex/Gender
Sexes Eligible for Study: All
Ages 21 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers No
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
Listed Location Countries Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT02345356
Other Study ID Numbers A4070215
8G12MD007600 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
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).
Responsible Party Jorge Duconge, University of Puerto Rico
Study Sponsor University of Puerto Rico
Collaborators
  • 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
PRS Account University of Puerto Rico
Verification Date February 2019