Cost-effectiveness of TPMT Pharmacogenetics

Ulcerative Colitis Clinical Trial

— TOPIC  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00521950
• Other study ID #: 945-07-606
• Secondary ID: CMO 2006/129ABR
• Status: Completed
• Phase: N/A
• First received: August 27, 2007
• Last updated: March 27, 2014
• Start date: September 2007
• Est. completion date: December 2011

Study information

• Verified date: March 2014
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: Medical Ethics Review Committee (METC)Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 853
• Est. completion date: December 2011
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Colitis, Ulcerative
• Crohn Disease
• Inflammatory Bowel Diseases
• Intestinal Diseases
• Ulcerative Colitis

Intervention

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;

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);

Locations

Country	Name	City	State
Netherlands	Radboud University Medical Center	Nijmegen	Gelderland
Netherlands	Bernhoven Hospital	Oss
Netherlands	Bernhoven Hospital	Veghel

Sponsors (2)

Lead Sponsor	Collaborator
ZonMw: The Netherlands Organisation for Health Research and Development	Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Haematological adverse drug reactions		0-5 months	Yes
Secondary	Non-haematological Adverse Drug Reactions		0- 5 months	Yes
Secondary	Clinical outcome (disease activity)		5 months	No
Secondary	Treatment compliance		0 to 5 months	No
Secondary	TPMT enzym activity		at baseline	No
Secondary	Therapeutic Drug Monitoring of TPMT Metabolites		week 1 and 8	No
Secondary	Health related quality of life		5 months	No
Secondary	Cost-efficacy		5 months	No

External Links

•   Department of Human Genetics Nijmegen