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| ID | Type | Description | Link |
|---|---|---|---|
| CMO 2006/129 | |||
| ABR NL13171.091.06 |
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| Name | Class |
|---|---|
| Radboud University Medical Center | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intervention, TPMT genotyping | Experimental | Pre-treatment TPMT genotyping to optimize initial thiopurine treatment dose. Intervention is based on the genotype. |
|
| control | Active Comparator | Standard thiopurine treatment |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TPMT genotyping; Drug: azathioprine or 6-mercaptopurine | Genetic | 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:
|
| Measure | Description | Time Frame |
|---|---|---|
| Haematological adverse drug reactions | 0-5 months |
| Measure | Description | Time Frame |
|---|---|---|
| Non-haematological Adverse Drug Reactions | 0- 5 months | |
| Clinical outcome (disease activity) | 5 months | |
| Treatment compliance |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Barbara Franke, PhD | Radboud University Medical Center | Study Director |
| Hans Scheffer, PhD | Radboud University Medical Center | Study Chair |
| Corine J van Marrewijk, MSc | Radboud University Medical Center | Principal Investigator |
| Dirk J de Jong, MD PhD | Radboud University Medical Center | Principal Investigator |
| 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 |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Radboud University Medical Center | Nijmegen | Gelderland | 6500 HB | Netherlands | ||
| Bernhoven Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27943397 | Derived | 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. | |
| 27402913 |
| Label | URL |
|---|---|
| Department of Human Genetics Nijmegen | View source |
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| ID | Term |
|---|---|
| D015212 | Inflammatory Bowel Diseases |
| D003424 | Crohn Disease |
| D003093 | Colitis, Ulcerative |
| ID | Term |
|---|---|
| D005759 | Gastroenteritis |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
| D007410 | Intestinal Diseases |
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| ID | Term |
|---|---|
| D001379 | Azathioprine |
| D015122 | Mercaptopurine |
| ID | Term |
|---|---|
| D013872 | Thionucleosides |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D011687 | Purines |
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|
|
| azathioprine (AZA) or 6-mercaptopurine (6-MP) | Drug | Patients will be advised a standard initial treatment dose:
|
|
|
| 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 |
| Study Chair |
| Oss |
| 5342 BT |
| Netherlands |
| Bernhoven Hospital | Veghel | 5461 AA | Netherlands |
| 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. |
| 26072396 | Derived | 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. |
| D003092 | Colitis |
| D003108 | Colonic Diseases |
| D006574 |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D013438 | Sulfhydryl Compounds |