An interventional study of TPMT genotyping; Drug: azathioprine or 6-mercaptopurine and azathioprine (AZA) or 6-mercaptopurine (6-MP) in Inflammatory Bowel Diseases, Crohn Disease and Ulcerative Colitis, sponsored by ZonMw: The Netherlands Organisation for Health Research and Development. Completed at 3 sites in Netherlands. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2014-03-28.
Sponsored by ZonMw: The Netherlands Organisation for Health Research and Development · Not applicable, Interventional, and Supportive care
The purpose of this study is to determine whether thiopurine S-methyltransferase (TPMT) genotyping prior to thiopurine use is cost-effective in patients with inflammatory bowel disease (IBD) in need of immune suppression.
The study is designed to test the hypothesis that optimization of initial thiopurine dose based on pre-treatment TPMT genotyping will maximize treatment efficacy and minimize adverse drug reactions (ADRs) resulting in reduced costs.
Immunosuppressives, e.g. azathioprine (AZA) and 6-mercaptopurine (6-MP), are important in induction of remission and long term treatment of (ulcerative) colitis and Crohn's disease when treatment with 5-aminosalicylates and corticosteroids fails. ADRs to immunosuppressive treatment, including myelosuppression and hepatotoxicity, are frequently (15-30%) observed. Genetic variation in the TPMT gene results in 10-11% of the general population in reduced and in 0.3-0.6% to negligible TPMT enzyme activity. In IBD patients, this genetic variation predicts 25-40% of the haematological ADRs necessitating tempering of thiopurine dose or discontinuation of treatment.
Pharmacogenetics aims at providing optimized drug treatment to patients by maximizing efficacy and minimizing adverse drug reactions (ADRs) based on genetic testing. Despite the proven value of pharmacogenetics in clinical practice, its use in medical care is still limited.
The best-established example of a pharmacogenetic test is genotyping of thiopurine S-methyltransferase (TPMT) in the treatment of patients with immunosuppressive thiopurines. Nonetheless, it is not used on a large scale in clinical practice so far, which might be due to: insufficient information transfer from research to clinic; lack of cost-effectiveness analyses (CEAs); lack of availability of (or access to) fast and/or cheap genotyping; or lack of test reimbursement by health insurance.
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Exclusion Criteria:
Pre-treatment TPMT genotyping to optimize initial thiopurine treatment dose. Intervention is based on the genotype.
Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine
Standard thiopurine treatment
Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP)
Assessment of the polymorphisms G238C, G460A, and A719G in a venous blood sample to identify functional genetic variants (TPMT\*2, \*3A, \*3C) of the TPMT gene (chromosome 6) associated with reduced or negligible TPMT enzyme activity. Patients are advised an initial treatment dose based on the enzyme activity: * Normal: AZA 2-2.5 mg/kg/day or 6-MP 1-1.5 mg/kg/day (standard care); * Reduced: AZA 1-1.25 mg/kg/day or 6-MP 0.5-0.75 mg/kg/day; * Negligible: AZA 0-0.2 mg/kg/day or 6-MP 0-0.1 mg/kg/day;
Also known as: Imuran, Puri-Nethol
Patients will be advised a standard initial treatment dose: * AZA 2-2.5 mg/kg/day or 6-MP 1-1.5 mg/kg/day (standard care);
Also known as: Imuran, Puri-Nethol
Haematological adverse drug reactions
Time frame: 0-5 months
Non-haematological Adverse Drug Reactions
Time frame: 0- 5 months
Clinical outcome (disease activity)
Time frame: 5 months
Treatment compliance
Time frame: 0 to 5 months
TPMT enzym activity
Time frame: at baseline
Therapeutic Drug Monitoring of TPMT Metabolites
Time frame: week 1 and 8
Health related quality of life
Time frame: 5 months
Cost-efficacy
Time frame: 5 months
This study is completed, as verified in Mar 2014. You cannot join it, but the record below documents what was studied.
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ZonMw: The Netherlands Organisation for Health Research and Development