Clinical trial NCT00521950: Cost-effectiveness of TPMT Pharmacogenetics
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Inflammatory Bowel Diseases
Crohn Disease
Ulcerative Colitis
Keywords: Pharmacogenetics
Cost Effectiveness
Inflammatory Bowel Diseases
Crohn Disease
Ulcerative Colitis
Randomized Controlled Trials
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Radboud University Medical Center
First posted: 2007-08-28
Enrollment: 853
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

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 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

Primary outcomes:
measure: Haematological adverse drug reactions
timeFrame: 0-5 months
Secondary outcomes:
measure: Non-haematological Adverse Drug Reactions
timeFrame: 0- 5 months
measure: Clinical outcome (disease activity)
timeFrame: 5 months
measure: Treatment compliance
timeFrame: 0 to 5 months
measure: TPMT enzym activity
timeFrame: at baseline
measure: Therapeutic Drug Monitoring of TPMT Metabolites
timeFrame: week 1 and 8
measure: Health related quality of life
timeFrame: 5 months
measure: Cost-efficacy
timeFrame: 5 months
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
state: Gelderland
city: Oss
country: Netherlands
facility: Bernhoven Hospital
city: Veghel
country: Netherlands
facility: Bernhoven Hospital
Study officials:
affiliation: Radboud University Medical Center
name: Barbara Franke, PhD
role: STUDY_DIRECTOR
affiliation: Radboud University Medical Center
name: Hans Scheffer, PhD
role: STUDY_CHAIR
affiliation: Radboud University Medical Center
name: Corine J van Marrewijk, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Medical Center
name: Dirk J de Jong, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Medical Center
name: Marieke JH Coenen, PhD
role: STUDY_CHAIR
affiliation: Leiden UMC
name: Henk-Jan Guchelaar, PhD
role: STUDY_CHAIR
affiliation: Maxima MC Veldhoven
name: Luc Derijks, PhD
role: STUDY_CHAIR
affiliation: UMC Utrecht
name: Olaf Klungel, PhD
role: STUDY_CHAIR
affiliation: Radboud University Medical Center
name: André Verbeek, PhD
role: STUDY_CHAIR
affiliation: Radboud University Medical Center
name: Sita Vermeulen, MSc
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.