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Completed

NCT Number: NCT00521950

Cost-effectiveness of TPMT Pharmacogenetics

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.

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Key information

Conditions

Inflammatory Bowel Diseases Colitis Colitis, Ulcerative Colonic Diseases Crohn Disease Digestive System Diseases Gastroenteritis Gastrointestinal Diseases Intestinal Diseases Ulcerative Colitis

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Radboud University Medical Center, Nijmegen, Gelderland, Netherlands

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

TPMT genotyping; Drug: azathioprine or 6-mercaptopurine

Genetic

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;

Other names: Imuran, Puri-Nethol

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

Drug

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);

Other names: Imuran, Puri-Nethol

Primary outcomes

  1. Haematological adverse drug reactions

    Time frame: 0-5 months

Secondary outcomes

  1. Non-haematological Adverse Drug Reactions

    Time frame: 0- 5 months

  2. Clinical outcome (disease activity)

    Time frame: 5 months

  3. Treatment compliance

    Time frame: 0 to 5 months

  4. TPMT enzym activity

    Time frame: at baseline

  5. Therapeutic Drug Monitoring of TPMT Metabolites

    Time frame: week 1 and 8

  6. Health related quality of life

    Time frame: 5 months

  7. Cost-efficacy

    Time frame: 5 months

Sponsors and collaborators

Lead sponsor

ZonMw: The Netherlands Organisation for Health Research and Development

Other

Collaborators

  • Radboud University Medical Center

Registry information

Official study title

Pharmacogenetic Testing in the Clinical Setting: is Screening for TPMT Genotype a Cost-effective Treatment Strategy? - The First Prospective Randomized Controlled Trial Within the Dutch Health Care System.

Acronym: TOPIC

Important dates

Study start
2007
Primary completion
2011
Study completion
2011
First posted
Aug 28, 2007
Registry last updated
Mar 28, 2014

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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