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Cost-effectiveness of TPMT Pharmacogenetics (TOPIC)

This study has been completed.
Sponsor:
Collaborator:
Radboud University
Information provided by (Responsible Party):
Marieke Coenen, Radboud University
ClinicalTrials.gov Identifier:
NCT00521950
First received: August 27, 2007
Last updated: November 29, 2012
Last verified: November 2012
History of Changes
  Purpose

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 Intervention
Inflammatory Bowel Diseases
Crohn Disease
Ulcerative Colitis
 Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine
Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP)

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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.

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Radboud University:

Primary Outcome Measures:
  • Cost-efficacy [ Time Frame: 5 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • (Haematological) Adverse Drug Reactions [ Time Frame: 1, 2, 4, 6, 8 weeks and 5 months ] [ Designated as safety issue: Yes ]
  • Clinical outcome (disease activity) [ Time Frame: 5 months ] [ Designated as safety issue: No ]
  • Treatment compliance [ Time Frame: 0 to 5 months ] [ Designated as safety issue: No ]
  • TPMT enzym activity [ Time Frame: at baseline ] [ Designated as safety issue: No ]
  • Therapeutic Drug Monitoring of TPMT Metabolites [ Time Frame: week 1 and 8 ] [ Designated as safety issue: No ]
  • Health related quality of life [ Time Frame: 5 months ] [ Designated as safety issue: No ]

Enrollment: 853
Study Start Date: September 2007
Study Completion Date: December 2011
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00521950

Locations
Netherlands
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
Investigators
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
  More Information

Additional Information:
Department of Human Genetics Nijmegen  This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party: Marieke Coenen, PhD, Radboud University
ClinicalTrials.gov Identifier: NCT00521950     History of Changes
Other Study ID Numbers: 945-07-606, CMO 2006/129, ABR NL13171.091.06
Study First Received: August 27, 2007
Last Updated: November 29, 2012
Health Authority: Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Radboud University:
Pharmacogenetics
Cost Effectiveness
Inflammatory Bowel Diseases
 Crohn Disease
Ulcerative Colitis
Randomized Controlled Trials

Additional relevant MeSH terms:
Colitis
Colitis, Ulcerative
Crohn Disease
Inflammatory Bowel Diseases
Intestinal Diseases
Ulcer
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Pathologic Processes
6-Mercaptopurine
Azathioprine
 Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Antirheumatic Agents

ClinicalTrials.gov processed this record on June 18, 2013