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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

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Inflammatory Bowel Diseases Crohn Disease Ulcerative Colitis Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP) Not Applicable

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 853 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Official 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.
Study Start Date : September 2007
Actual Primary Completion Date : December 2011
Actual Study Completion Date : December 2011

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Intervention, TPMT genotyping
Pre-treatment TPMT genotyping to optimize initial thiopurine treatment dose. Intervention is based on the genotype.
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

Active Comparator: control
Standard thiopurine treatment
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

Primary Outcome Measures :
  1. Haematological adverse drug reactions [ Time Frame: 0-5 months ]

Secondary Outcome Measures :
  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 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

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 identifier (NCT number): NCT00521950

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Radboud University Medical Center
Nijmegen, Gelderland, Netherlands, 6500 HB
Bernhoven Hospital
Oss, Netherlands, 5342 BT
Bernhoven Hospital
Veghel, Netherlands, 5461 AA
Sponsors and Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development
Radboud University
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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
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Marieke Coenen, PhD, Radboud University Identifier: NCT00521950    
Other Study ID Numbers: 945-07-606
CMO 2006/129
ABR NL13171.091.06
First Posted: August 28, 2007    Key Record Dates
Last Update Posted: March 28, 2014
Last Verified: March 2014
Keywords provided by Marieke Coenen, Radboud University:
Cost Effectiveness
Inflammatory Bowel Diseases
Crohn Disease
Ulcerative Colitis
Randomized Controlled Trials
Additional relevant MeSH terms:
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Crohn Disease
Colitis, Ulcerative
Intestinal Diseases
Inflammatory Bowel Diseases
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Pathologic Processes
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Antirheumatic Agents