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AzTrials

Inflammatory Bowel DiseasesTOPICNCT00521950

Cost-effectiveness of TPMT Pharmacogenetics

A study testing TPMT genotyping; Drug: azathioprine or 6-mercaptopurine and azathioprine (AZA) or 6-mercaptopurine (6-MP) in people with Inflammatory Bowel Diseases and Crohn Disease, run by ZonMw: The Netherlands Organisation for Health Research and Development at 3 sites in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
TPMT genotyping; Drug: azathioprine or 6-mercaptopurine and azathioprine (AZA) or 6-mercaptopurine (6-MP)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
853 participants
Where
3 sitesNetherlands
Study dates
Sep 2007to Dec 2011
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age 18 or older
  • Diagnosis of a form of IBD
  • Indication for azathioprine/6-MP treatment
  • Patient giving (written) informed consent

Who cannot join

  • 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

Trial locations and contacts

3 sites in 1 country.

Netherlands3 sites

  • Radboud University Medical Center

    Nijmegen, Gelderland, 6500 HB

  • Bernhoven Hospital

    Oss, 5342 BT

  • Bernhoven Hospital

    Veghel, 5461 AA

Other trials in Netherlands

About this study

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.

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.

Read the 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.

Being tested
TPMT genotyping; Drug: azathioprine or 6-mercaptopurine, azathioprine (AZA) or 6-mercaptopurine (6-MP)
Keywords
Pharmacogenetics, Cost Effectiveness, Inflammatory Bowel Diseases, Crohn Disease, Ulcerative Colitis, Randomized Controlled Trials
Medical subject headings
Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TPMT genotyping; Drug: azathioprine or 6-mercaptopurineGenetic

    Also called Imuran, Puri-Nethol

    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;

  • azathioprine (AZA) or 6-mercaptopurine (6-MP)Drug

    Also called Imuran, Puri-Nethol

    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);
Study groups in NCT00521950
Study groupRoleWhat they receive
Intervention, TPMT genotypingExperimentalPre-treatment TPMT genotyping to optimize initial thiopurine treatment dose. Intervention is based on the genotype.
Receives: Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine
controlActive comparatorStandard thiopurine treatment
Receives: Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Haematological adverse drug reactions

    Measured: 0-5 months

Secondary outcomes (7)

  1. Non-haematological Adverse Drug Reactions

    Measured: 0- 5 months

  2. Clinical outcome (disease activity)

    Measured: 5 months

  3. Treatment compliance

    Measured: 0 to 5 months

  4. TPMT enzym activity

    Measured: at baseline

  5. Therapeutic Drug Monitoring of TPMT Metabolites

    Measured: week 1 and 8

  6. Health related quality of life

    Measured: 5 months

  7. Cost-efficacy

    Measured: 5 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Aug 2007 (estimated)
  2. Study startSep 2007
  3. Primary completionDec 2011
  4. Study completionDec 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Supportive care
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
853 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00521950
Sponsor's protocol ID
945-07-606
Other IDs
CMO 2006/129, ABR NL13171.091.06
Acronym
TOPIC
Status last verified
Mar 2014
First submitted
27 Aug 2007
Last updated
28 Mar 2014
Results posted
No
Data monitoring committee
No

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.

    PubMed 27943397

  • 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.

    PubMed 27402913

  • 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.

    PubMed 26072396

Questions about this trial

What is this clinical trial studying?

A study testing TPMT genotyping; Drug: azathioprine or 6-mercaptopurine and azathioprine (AZA) or 6-mercaptopurine (6-MP) in people with Inflammatory Bowel Diseases and Crohn Disease, run by ZonMw: The Netherlands Organisation for Health Research and Development at 3 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Mar 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Haematological adverse drug reactions (time frame: 0-5 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00521950, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Mar 2014; AzTrials last refreshed its copy on 27 Oct 2026.

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