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

This study is currently recruiting participants.
Verified June 2016 by Haematology-Oncology, National University Hospital, Singapore
Sponsor:
ClinicalTrials.gov Identifier:
NCT00700895
First Posted: June 19, 2008
Last Update Posted: June 7, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Haematology-Oncology, National University Hospital, Singapore
  Purpose
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.

Condition Intervention Phase
Indications for Warfarin Therapy Drug: Warfarin Sodium Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Controlled Trial to Assess the Clinical Benefits of a Pharmacogenetics-Guided Dosing Regimen for Calculating Warfarin Maintenance Dose

Resource links provided by NLM:


Further study details as provided by Haematology-Oncology, National University Hospital, Singapore:

Primary Outcome Measures:
  • No. of dosage titrations required to achieve targeted INR at 3 months of initializing warfarin. [ Time Frame: 3 months ]
    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


Secondary Outcome Measures:
  • pharmacokinetics of warfarin R- and S-enantiomers [ Time Frame: 3 months ]
    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.


Estimated Enrollment: 320
Study Start Date: August 2006
Estimated Study Completion Date: August 2017
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pharmacogenetics-guided dosing group
For patients randomized to the pharmacogenetics-guided dosing group, this 10mls of blood will be immediately sent for genotyping studies. Genotyping results will be available for pharmacogenetics-guided dosing within 3 working days, (ranging 3 to 5 days). During this period, if patients need to be initiated on anticoagulation, a low molecular weight heparin, Fraxiparine, will be given. Fraxiparine will be overlapped with warfarin for 2 to 3 days until target INR is achieved. Elective cases should have the pharmacogenetics-based warfarin dose available at the time of warfarin therapy.
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.
Other Name: Warfarin (Marevan®)
Experimental: Traditional dosing group
For patients randomized to the traditional dosing regime, the blood will be stored and genotyped retrospectively at the end of the study. Overlapping of warfarin with Fraxiparine or heparin till target INR is achieved is allowed for this group as per normal clinical practice. All warfarin dosage adjustments based on INR results will be according to the current protocol used by the NUH Anticoagulant Clinic.
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.
Other Name: Warfarin (Marevan®)

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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00700895


Contacts
Contact: Boon Cher Goh 65-6772-4617 Boon_Cher_Goh@nuhs.com.sg

Locations
Malaysia
University of Malaya Medical Centre Recruiting
Kuala Lumpur, Malaysia, 50603
Contact: Ping Chong Bee, MBBS    +603 7949 2741    bpingchong@gmail.com   
Principal Investigator: Ping Chong Bee, MBBS         
Singapore
National University Hospital Recruiting
Singapore, Singapore
Contact: Boon Cher Goh, MBBS, MRCP    65-6772-4617    Boon_Cher_Goh@nuhs.com.sg   
Principal Investigator: Boon Cher Goh, MBBS, MRCP         
Sponsors and Collaborators
National University Hospital, Singapore
Investigators
Principal Investigator: Boon Cher Goh, MBBS, MRCP National University Hospital, Singapore
  More Information

Responsible Party: Haematology-Oncology, Dr. Goh Boon Cher, National University Hospital, Singapore
ClinicalTrials.gov Identifier: NCT00700895     History of Changes
Other Study ID Numbers: PG01/11/06
First Submitted: June 18, 2008
First Posted: June 19, 2008
Last Update Posted: June 7, 2016
Last Verified: June 2016

Additional relevant MeSH terms:
Warfarin
Anticoagulants


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