Assessing the Clinical Benefits of a Pharmacogenetics-Guided Dosing Regiment for Calculating Warfarin Maintenance Dose

Indications for Warfarin Therapy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00700895
• Other study ID #: PG01/11/06
• Status: Recruiting
• Phase: Phase 3
• First received: June 18, 2008
• Last updated: June 6, 2016
• Start date: August 2006
• Est. completion date: August 2017

Study information

• Verified date: June 2016
• Source: National University Hospital, Singapore
• Contact: Boon Cher Goh
• Phone: 65-6772-4617
• Email: Boon_Cher_Goh[@]nuhs.com.sg
• Is FDA regulated: No
• Health authority: Singapore: Domain Specific Review BoardsSingapore: Health Sciences Authority
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 320
• Est. completion date: August 2017
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Indications for Warfarin Therapy

Intervention

Drug:
• Warfarin Sodium
All predicted warfarin dose will be administered by rounding down to the nearest 0.5 mg. Warfarin (Marevan®) is available as 1mg (brown), 3 mg (blue) and 5 mg (pink) oral tablets from GlaxoSmithKline Pte. Ltd.

Locations

Country	Name	City	State
Malaysia	University of Malaya Medical Centre	Kuala Lumpur
Singapore	National University Hospital	Singapore

Sponsors (1)

Lead Sponsor	Collaborator
National University Hospital, Singapore

Countries where clinical trial is conducted

Malaysia,  Singapore, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	No. of dosage titrations required to achieve targeted INR at 3 months of initializing warfarin.	1. Number of dosage titrations/adjustments required to achieve targeted International Normalized Ratio (INR) at 3 months of initializing warfarin. The number of titrations refers to the number of times warfarin dosage was adjusted when INR was out of target range (>1.9 and = 3.1) or in response to an adverse event or therapeutic failure. This endpoint will be compiled every 4 weeks, up to 3 months after the initialization of warfarin therapy	3 months	Yes
Secondary	pharmacokinetics of warfarin R- and S-enantiomers	Upon reaching steady-state, pharmacokinetics of warfarin R- and S-enantiomers will be determined for correlation with dose requirements and genotypes based on a single 5ml blood sample taken after achieving target INR without a change in dose for at least 3 months. Warfarin concentrations will be measured using a validated method through a high-performance liquid chromatography (HPLC) method modified from Henne et al.	3 months	No