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Pharmacogenetics of Warfarin in Puerto Ricans.

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by University of Puerto Rico
Sponsor:
Collaborators:
Hartford Hospital
VA Caribbean Healthcare System
Information provided by (Responsible Party):
Jorge Duconge, University of Puerto Rico
ClinicalTrials.gov Identifier:
NCT01318057
First received: March 17, 2011
Last updated: January 5, 2014
Last verified: January 2014
  Purpose

Warfarin (Coumadin) is a prescribed "blood thinner" medication used to make the blood less thick in people with high risk of forming blood clots. Despite the various methods to monitor this drug, life-threatening bleeding is a common undesired effect and might result in patient death. Patients starting warfarin therapy may require several weeks or even months to reach the appropriate blood level of warfarin. This blind practice could place the patient at high risk. There are several demographic and clinical factors that significantly influence how much warfarin the patient needs to attain the desired response. Genes, which control hereditary traits, are also important. Now, the investigators know that by using the information encoded in patient's genes the investigators are able to individualize the therapy. Two genes are considered to be involved in warfarin response (CYP2C9 and VKORC1). This study proposes to ascertain what CYP2C9 and VKORC1 variants are present in warfarin-treated Puerto Rican patients. To this purpose, a novel physiogenomic array comprising 384 variants in 222 genes of cardio-metabolic relevance will be used so the investigators are able to determine the structure of the Puerto Rican population in terms of ancestral contributions and how the admixture may impact the prevalence of CYP2C9 and VKORC1 variants. Secondly, the investigators will assess the association of these variants to clinical responses in order to develop a better method of dose estimation. The expected result is the improvement of warfarin therapy in Puerto Ricans. The proposed study will fill a gap in the knowledge of warfarin pharmacogenetics, providing new information on the prevalence of CYP2C9 (metabolism) and VKORC1 (sensitivity) polymorphisms in Puerto Ricans as well as their role in the warfarin response variability observed in this admixed population.


Condition
Atrial Fibrillation
Deep Vein Thrombosis
Cardiac Valvular Insufficiency
Antiphospholipid Syndrome
Coagulopathy

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Pharmacogenetics of Warfarin in Puerto Rican Patients Using a Physiogenomics Approach.

Resource links provided by NLM:


Further study details as provided by University of Puerto Rico:

Primary Outcome Measures:
  • time to achieve stable warfarin dose [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    time to get a stable warfarin dose is defined by the time span (days) from the initial dose until achieving three consecutive INR measurements within therapeutic range (2-3 or 2.5-3.5, according to indication.


Secondary Outcome Measures:
  • time to first bleeding [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    time to first bleeding is defined as the time span (days) from the initiation of therapy until the first report of serious or life-threatening bleeding episode.

  • time to first INR>4 [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    time to first INR above 4 is an indicator of overanticoagulation that is defined as the time span (days) from the initiation of therapy until the first measurement of INR above 4.


Biospecimen Retention:   Samples With DNA

Whole fresh blood and Genomic DNA samples fom enrolled patients


Estimated Enrollment: 350
Study Start Date: February 2011
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts
Wild-Type
Wild-Type are those individuals who were non-carriers of any functional (loss-of-function)variant in CYP2C9 and/or VKORC1 genes
Carriers
Those patients who were identified as having any functional CYP2C9 and/or VKORC1 polymorphism

Detailed Description:

Warfarin is a frequently prescribed drug for both the treatment and prevention of thromboembolic complications. Although many reports have been published over the past years in different populations worldwide, there is a fundamental gap in understanding whether variations in CYP2C9 and VKORC1 genes account for the inter-individual variability in response to warfarin that is observed in Puerto Rican patients. This study is a first step toward the development of DNA-driven personalized guidelines for warfarin dose optimization in Puerto Rican patients with thromboembolic complications. Guided by strong preliminary data, this application will pursuit two specific aims: 1) Develop a physiogenomic (PG)-driven admixture analysis of 350 samples from a population of warfarin-treated Puerto Rican patients using the PG array in order to study the pharmacogenetics of warfarin in Puerto Ricans and 2) Determine whether combinatorial CYP2C9 and VKORC1 genotypes are associated with clinical phenotypes during warfarin therapy in Puerto Rican patients. Under the first aim, 350 DNA specimens from warfarin-treated Puerto Rican patients who consent to participate in this study will be genotyped at large-scale using a novel Illumina-based PG-array of 222 candidate genes from relevant cardio-metabolic and neuro-endocrine pathways in order to examine the population structure of Puerto Ricans and create a reference database of individual admixture, allele frequencies, linkage disequilibrium (LD) and haplotypes for pharmacogenetics studies. Noteworthy, this information remains to be determined in Puerto Ricans. Under the second aim, demographic and clinically relevant non-genetic data will be retrospectively collected from medical records of these patients in order to perform an association analysis between their previously obtained CYP2C9 and VKORC1 genotypes and the corresponding time to achieve stable warfarin dosing following survival analysis techniques and Cox proportional hazards model. Accomplishment of this specific aim will also give the basis for developing a DNA-guided warfarin dosing algorithm in Puerto Rican by using these patients as a learning sample. The long-term goal is to generate valuable information from the genetic background of Puerto Ricans in order to further validate the pharmacogenetic-driven warfarin dosing algorithm for this admixed population. The proposed research is significant because it is expected to advance and expand understanding of how these clinically relevant variants affect the way people from an admixed, under-served population respond to warfarin. This is an important and under-investigated area of pharmacogenetics in minority populations that will have potential applicability to personalize warfarin therapy.

  Eligibility

Ages Eligible for Study:   18 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Hispanic Puerto Rican patients from all geographic regions of the Island of Puerto Rico who are currently receiving a standard stable dose of warfarin at the anticoagulation clinic of the Veteran Affair Caribbean Healthcare System (VACHS)

Criteria

Inclusion Criteria:

  • Patients whose parents are both Puerto Ricans; male and female aged > 18 years old
  • Scheduled to receive the standard 5 mg/day oral dose of warfarin for therapeutic anti-coagulation in indications such as deep vein thrombosis (DVT) with or without Pulmonary Embolism (PE)
  • Atrial fibrillation (AF) or other arrhythmias, cardiac valvular replacement, and previously diagnosed coagulopathy
  • Hematocrit (Hct) > 40%
  • Blood Urea Nitrogen (BUN)/creatinine < 30/1.5 mg/dL
  • Patients having the ability to understand the requirements of the study and to comply with study procedures and protocol
  • Female patient is eligible to enter the study if she is of child-bearing potential but not pregnant or nursing, or not of child-bearing potential

Exclusion Criteria:

  • Patients currently enrolled in another active research protocol at the Veteran Affairs Caribbean Healthcare System (VACHS) Hospital
  • Blood Urea Nitrogen (BUN)/creatinine > 30/2.0 mg/dL
  • Active hepatic disease (defined by a Child-Pugh score above 10 points)
  • Ascites
  • Total bilirubin above 2.0 mg/dl
  • Serum albumin below 3.5 g/dl
  • Prothrombin time in seconds prolonged over control > 4
  • Hepatic encephalopathy
  • Prolonged diarrhea (three or more days)
  • Nasogastric or enteral feedings
  • Acute illness (e.g., sepsis, infection, anemia)
  • Lymphocyte function test (LFT)> 3x upper limit of normal (ULN)
  • Active malignancy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01318057

Contacts
Contact: Jorge Duconge, PhD 787-758-2525 ext 5418 jorge.duconge@upr.edu

Locations
Puerto Rico
Veteran Affair Caribbean Healthcare System Recruiting
San Juan, Puerto Rico, 00921
Principal Investigator: Giselle Rivera-Miranda, PharmD         
Sponsors and Collaborators
University of Puerto Rico
Hartford Hospital
VA Caribbean Healthcare System
Investigators
Principal Investigator: Giselle T Rivera-Miranda, PharmD VACHS at San Juan
Principal Investigator: Jorge Duconge, PhD University of Puerto Rico
  More Information

Publications:

Responsible Party: Jorge Duconge, PhD, MSc, BSc Pharm, Associate Professor, University of Puerto Rico
ClinicalTrials.gov Identifier: NCT01318057     History of Changes
Other Study ID Numbers: 1SC2HL110393-01A2, SC2HL110393
Study First Received: March 17, 2011
Last Updated: January 5, 2014
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by University of Puerto Rico:
Pharmacogenetics
Warfarin
Personalized Medicine
Puerto Ricans
Physiogenomics
Hispanics
Anticoagulants
Cardiovascular
Deep Vein Thrombosis with or without Pulmonary Embolism
Cardiac Valvular Replacement

Additional relevant MeSH terms:
Atrial Fibrillation
Antiphospholipid Syndrome
Blood Coagulation Disorders
Hemostatic Disorders
Thrombosis
Venous Thrombosis
Arrhythmias, Cardiac
Autoimmune Diseases
Cardiovascular Diseases
Embolism and Thrombosis
Heart Diseases
Hematologic Diseases
Hemorrhagic Disorders
Immune System Diseases
Pathologic Processes
Vascular Diseases
Warfarin
Anticoagulants
Hematologic Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014