Cost-effectiveness of TPMT Pharmacogenetics (TOPIC)

ZonMw: The Netherlands Organisation for Health Research and Development

Status: Completed

Conditions: Ulcerative Colitis; Inflammatory Bowel Diseases; Crohn Disease

Treatments: Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine; Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP)

Study type: Interventional

Funder types: Other

Identifiers

NCT00521950

CMO 2006/129

945-07-606

ABR NL13171.091.06

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 853 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age 18 or older
• Diagnosis of a form of IBD
• Indication for azathioprine/6-MP treatment
• Patient giving (written) informed consent

Exclusion criteria

• Previous treatment with azathioprine/6-MP
• Co-prescription of allopurinol (this treatment blocks xanthine oxidase, an enzyme important for thiopurine metabolism)
• Baseline leukocyte count less then 3x10^9 per litre
• Reduced liver function at baseline
• Reduced renal function at baseline
• Known TPMT phenotype (enzyme activity / Therapeutic Drug Monitoring) or genotype
• Pregnancy or breastfeeding

Trial design

Primary purpose: Supportive Care

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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853 participants in 2 patient groups

Intervention, TPMT genotyping

Experimental group

Description:

Pre-treatment TPMT genotyping to optimize initial thiopurine treatment dose. Intervention is based on the genotype.

Treatment:

Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine

control

Active Comparator group

Description:

Standard thiopurine treatment

Treatment:

Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP)