Cost-effectiveness of TPMT Pharmacogenetics (TOPIC)

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. Read our disclaimer for details. Identifier: NCT00521950
Recruitment Status : Completed
First Posted : August 28, 2007
Last Update Posted : March 28, 2014
Radboud University
Information provided by (Responsible Party):
Marieke Coenen, Radboud University

August 27, 2007
August 28, 2007
March 28, 2014
September 2007
December 2011   (Final data collection date for primary outcome measure)
Haematological adverse drug reactions [ Time Frame: 0-5 months ]
Cost-efficacy [ Time Frame: 5 months ]
Complete list of historical versions of study NCT00521950 on Archive Site
  • 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 ]
  • (Haematological) Adverse Drug Reactions [ Time Frame: 1, 2, 4, 6, 8 weeks and 5 months ]
  • Clinical outcome (disease activity) [ Time Frame: 5 months ]
  • Health related quality of life [ Time Frame: 5 months ]
  • Treatment compliance [ Time Frame: 0 to 5 months ]
Not Provided
Not Provided
Cost-effectiveness of TPMT Pharmacogenetics
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.

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.

Not Applicable
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
  • Inflammatory Bowel Diseases
  • Crohn Disease
  • Ulcerative Colitis
  • Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine

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

    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
  • Experimental: Intervention, TPMT genotyping
    Pre-treatment TPMT genotyping to optimize initial thiopurine treatment dose. Intervention is based on the genotype.
    Intervention: Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine
  • Active Comparator: control
    Standard thiopurine treatment
    Intervention: Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP)

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
December 2011
December 2011   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
Contact information is only displayed when the study is recruiting subjects
CMO 2006/129
ABR NL13171.091.06
Not Provided
Not Provided
Marieke Coenen, Radboud University
ZonMw: The Netherlands Organisation for Health Research and Development
Radboud University
Study Director: Barbara Franke, PhD Radboud University
Study Chair: Hans Scheffer, PhD Radboud University
Principal Investigator: Corine J van Marrewijk, MSc Radboud University
Principal Investigator: Dirk J de Jong, MD PhD Radboud University
Study Chair: Marieke JH Coenen, PhD Radboud University
Study Chair: Henk-Jan Guchelaar, PhD Leiden UMC
Study Chair: Luc Derijks, PhD Maxima MC Veldhoven
Study Chair: Olaf Klungel, PhD UMC Utrecht
Study Chair: André Verbeek, PhD Radboud University
Study Chair: Sita Vermeulen, MSc Radboud University
Radboud University
March 2014

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