Cost-effectiveness of TPMT Pharmacogenetics (TOPIC)

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.

Study Overview

• Status: Completed
• Conditions: Inflammatory Bowel Diseases; Crohn Disease; Ulcerative Colitis
• Intervention / Treatment: Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine; Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP)

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.

• Study Type: Interventional
• Enrollment (Actual): 853
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Oss, Netherlands, 5342 BT
    • Bernhoven Hospital
  • Veghel, Netherlands, 5461 AA
    • Bernhoven Hospital
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500 HB
      • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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: Puri-Nethol; Imuran
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: Puri-Nethol; Imuran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Haematological adverse drug reactions	0-5 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Non-haematological Adverse Drug Reactions	0- 5 months
Clinical outcome (disease activity)	5 months
Treatment compliance	0 to 5 months
TPMT enzym activity	at baseline
Therapeutic Drug Monitoring of TPMT Metabolites	week 1 and 8
Health related quality of life	5 months
Cost-efficacy	5 months

Collaborators and Investigators

• Sponsor: ZonMw: The Netherlands Organisation for Health Research and Development
• Collaborators: Radboud University Medical Center
• Investigators: Study Director: Barbara Franke, PhD, Radboud University Medical Center; Study Chair: Hans Scheffer, PhD, Radboud University Medical Center; Principal Investigator: Corine J van Marrewijk, MSc, Radboud University Medical Center; Principal Investigator: Dirk J de Jong, MD PhD, Radboud University Medical Center; Study Chair: Marieke JH Coenen, PhD, Radboud University Medical Center; 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 Medical Center; Study Chair: Sita Vermeulen, MSc, Radboud University Medical Center

Publications and helpful links

General Publications

• Wong DR, Coenen MJ, Derijks LJ, Vermeulen SH, van Marrewijk CJ, Klungel OH, Scheffer H, Franke B, Guchelaar HJ, de Jong DJ, Engels LG, Verbeek AL, Hooymans PM; TOPIC Recruitment Team. Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease. Aliment Pharmacol Ther. 2017 Feb;45(3):391-402. doi: 10.1111/apt.13879. Epub 2016 Dec 12.
• Wong DR, Coenen MJ, Vermeulen SH, Derijks LJ, van Marrewijk CJ, Klungel OH, Scheffer H, Franke B, Guchelaar HJ, de Jong DJ, Engels LG, Verbeek AL, Hooymans PM; TOPIC recruitment team. Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease. J Crohns Colitis. 2017 Feb;11(2):175-184. doi: 10.1093/ecco-jcc/jjw130. Epub 2016 Jul 9.
• Coenen MJ, de Jong DJ, van Marrewijk CJ, Derijks LJ, Vermeulen SH, Wong DR, Klungel OH, Verbeek AL, Hooymans PM, Peters WH, te Morsche RH, Newman WG, Scheffer H, Guchelaar HJ, Franke B; TOPIC Recruitment Team. Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease. Gastroenterology. 2015 Oct;149(4):907-17.e7. doi: 10.1053/j.gastro.2015.06.002. Epub 2015 Jun 11.

Helpful Links

• Department of Human Genetics Nijmegen

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: August 27, 2007
• First Submitted That Met QC Criteria: August 27, 2007
• First Posted (Estimate): August 28, 2007

Study Record Updates

• Last Update Posted (Estimate): March 28, 2014
• Last Update Submitted That Met QC Criteria: March 27, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Keywords: Ulcerative Colitis; Randomized Controlled Trials; Cost Effectiveness; Pharmacogenetics; Crohn Disease; Inflammatory Bowel Diseases
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Ulcer; Inflammatory Bowel Diseases; Crohn Disease; Intestinal Diseases; Colitis; Colitis, Ulcerative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Mercaptopurine; Azathioprine
• Other Study ID Numbers: 945-07-606; CMO 2006/129; ABR NL13171.091.06