Pharmacogenetics of Warfarin in Puerto Ricans.

January 19, 2015 updated by: Jorge Duconge, University of Puerto Rico

Pharmacogenetics of Warfarin in Puerto Rican Patients Using a Physiogenomics Approach.

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
350

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Puerto Rico
      • San Juan, Puerto Rico, 00921
        • Veteran Affair Caribbean Healthcare System

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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)

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
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

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
time to achieve stable warfarin dose
Time Frame: 6 months
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.
6 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
time to first bleeding
Time Frame: 6 months
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.
6 months
time to first INR>4
Time Frame: 6 months
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.
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Puerto Rico

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Heart, Lung, and Blood Institute (NHLBI)
Hartford Hospital
VA Caribbean Healthcare System

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Jorge Duconge, PhD, University of Puerto Rico
  • Principal Investigator: Giselle T Rivera-Miranda, PharmD, VACHS at San Juan

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
February 1, 2011

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 1, 2014

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 1, 2014

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 17, 2011

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 17, 2011

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 18, 2011

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 21, 2015

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 19, 2015

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 1SC2HL110393-01A2 (U.S. NIH Grant/Contract)
  • SC2HL110393 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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