Official Title: “A Randomized Controlled Trial to Assess the Clinical Benefits of a Pharmacogenetics-Guided Dosing Regimen for Calculating Warfarin Maintenance Dose”

Interethnic differences in warfarin dose requirements in the Asian population have been well described. Our previous studies showed that warfarin maintenance doses in our multi-ethnic population were closely related to patient demographics and genetic polymorphisms in cytochrome(CYP)P4502C9 and vitamin K epoxide reductase complex subunit 1(VKORC1). A retrospective regression model combining these predictors accounts for 57.8% of the variability in warfarin dose.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label

Hypothesis: We hypothesize that warfarin dose requirement could be more accurately predicted using a simplified genotyping procedure requiring the identification of a single CYP2C9 allele and a single nucleotide polymorphism of VKORC1 to discern between the 2 major haplotypes H1 and H7.

Aims: The aim is to compare the clinical benefits of genetics-guided dosing versus traditional trial and error dosing with protocol guided-adjustments. Two secondary objectives are (1) to prospectively evaluate a dosing algorithm built on demographics and genetic predictors; (2) to assess the feasibility of a simplified test for CYP2C9*3 and VKORC1 SNP in clinical practice.

Methodology: A randomized controlled trial targeted at accruing 100 patients with indication for wafarin therapy. The endpoint for comparing genetics-guided dosing against traditional dosing method at the anticoagulant clinic is the number of dosage titrations to achieve targeted International Normalized Ratio (INR) at 1, 2 and 3 months of initializing warfarin.

Upon reaching steady-state, pharmacokinetics of warfarin R- and S-isomers will be assessed for correlation with dose requirements based. An assay for easy identification of genetic polymorphisms required in this dosing regimen in a clinic setting will also be validated.

Significance: This concerted, multi-disciplinary effort to bring pharmacogenetics-based therapy from bench to bedside has the potential to reduce the efforts incurred with multiple dose titrations of the most commonly prescribed oral anticoagulant. With the aid of mathematical modeling, a simplified and more cost-effective genotyping method could be implementation for the future treatment and prophylaxis of thromboembolic diseases.

Intervention(s) in this Clinical Trial

• Drug: Warfarin Sodium

Inclusion Criteria:

• 1. At least 18 years of age
• 2. New indication for warfarin therapy
• 3. No previous history of liver disease; transaminases must be less than 3 times upper limit of normal and bilirubin within normal range
• 4. No previous history of malabsorption syndrome or chronic diarrheal conditions
• 5. Written, informed consent

Exclusion Criteria:

• 1. Uncontrolled hypertension
• 2. Peptic ulcer disease
• 3. Any other medical conditions as deemed unfit for warfarin therapy based on clinical judgement of primary physician

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National University Hospital, Singapore

Overall Clinical Trial Officials and Contacts

Boon Cher Goh, MBBS, MRCP Principal Investigator National University Hospital, Singapore  

Overall Contact: Boon Cher Goh 65-6772-4617 Boon_Cher_Goh@nuh.com.sg

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00700895

Study ID Number: PG01/11/06

ClinicalTrials.gov Identifier: NCT00700895

Health Authority: Singapore: Domain Specific Review Boards