Clinical trial NCT00700895: Assessing the Clinical Benefits of a Pharmacogenetics-Guided Dosing Regiment for Calculating Warfarin Maintenance Dose
Official title: A Randomized Controlled Trial to Assess the Clinical Benefits of a Pharmacogenetics-Guided Dosing Regimen for Calculating Warfarin Maintenance Dose
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Indications for Warfarin Therapy
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
First posted: 2008-06-19
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: No. of dosage titrations required to achieve targeted INR at 3 months of initializing warfarin.
timeFrame: 3 months
Secondary outcomes:
measure: pharmacokinetics of warfarin R- and S-enantiomers
timeFrame: 3 months
Other outcomes:
Locations:
city: Kuala Lumpur
country: Malaysia
facility: University of Malaya Medical Centre
city: Singapore
country: Singapore
facility: National University Hospital
Study officials:
affiliation: National University Hospital, Singapore
name: Boon Cher Goh, MBBS, MRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Syn NL, Wong AL, Lee SC, Teoh HL, Yip JWL, Seet RC, Yeo WT, Kristanto W, Bee PC, Poon LM, Marban P, Wu TS, Winther MD, Brunham LR, Soong R, Tai BC, Goh BC. Genotype-guided versus traditional clinical dosing of warfarin in patients of Asian ancestry: a randomized controlled trial. BMC Med. 2018 Jul 10;16(1):104. doi: 10.1186/s12916-018-1093-8.