Cost-effectiveness of TPMT Pharmacogenetics

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Inflammatory Bowel Diseases, Crohn Disease, Ulcerative Colitis

Intervention / Treatment
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* Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine
* Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention, TPMT genotyping<br>Pre-treatment TPMT genotyping to optimize initial thiopurine treatment dose. Intervention is based on the genotype. | Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine<br>* 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;<br>* Other names: Puri-Nethol;|
| Active Comparator: control<br>Standard thiopurine treatment | Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP)<br>* 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);<br>* Other names: Puri-Nethol;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacogenetics, Cost Effectiveness, Inflammatory Bowel Diseases, Crohn Disease, Ulcerative Colitis, Randomized Controlled Trials