Colitis, Ulcerative
Conditions
Keywords
Therapeutic Drug Monitoring, Mercaptopurine (6-MP), Thiopurine, Efficacy
Brief summary
This project is a double-blind, randomized, placebo-controlled, multicenter trial in the Netherlands. The aim of this study is to investigate the therapeutic efficacy of optimized 6-mercaptopurine (6-MP) in ulcerative colitis patients. Therapeutic drug monitoring (TDM) will be performed in order to optimize treatment outcomes and objective endoscopic endpoints will be used.
Detailed description
Subjects will receive treatment with oral prednisone 40 mg/day for 2 weeks, followed by fixed tapering over 6 weeks. Half of the subjects will be randomized to concomitant 6-MP 1-1.5 mg/kg/day and half will receive concomitant placebo treatment. During the entire course of the trial all subjects will receive maintenance treatment with 5-ASA in an oral dose of at least 2 gram per day. Subjects will be subjected to one colonoscopy at baseline and one sigmoidoscopy in week 52 in order to assess endoscopic disease activity. Data will be collected using electronic case report forms (eCRF) with Castor EDC. Quality and data validation procedures will be applied to ensure the validity and accuracy of the clinical database. Monitoring of the study will be done according to the GCP guidelines and following a monitoring plan. The financier of the study, ZonMw Goed Gebruik Geneesmiddelen, has the right to perform an audit if seen necessary.
Interventions
DRUGMercaptopurine (Purinethol)
DRUGPlacebo
DRUGMesalamine
DRUGPrednisone
Sponsors
ZonMw: The Netherlands Organisation for Health Research and Development
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Confirmed diagnosis of UC by endoscopy and histopathology 2. Patients between 18 and 80 years of age 3. Active disease, despite oral treatment with at least 2g/day 5-ASA 4. Treatment with oral corticosteroids is required
Exclusion criteria
1. Prior treatment with thiopurines 2. Prior treatment with biologics (e.g. anti-TNF agents and vedolizumab) 3. Current pregnancy (a pregnancy test will be performed if necessary according to the treating physician) 4. Chronic Obstructive Pulmonary Disease (COPD) 5. Acute coronary heart disease 6. (Bacterial) gastroenteritis has to be treated first 7. Coagulation disorders 8. Active malignancy 9. History of colonic dysplasia/cancer 10. Extensive colonic resection, i.e. subtotal colectomy with \<15 cm colon in situ 11. Concomitant therapy with drugs interfering with MP metabolism, like allopurinol, ribavirin or anti-epileptics. 12. Known systemic fungal infections or parasitic infections have to be treated first 13. Known duodenal or ventricular ulcus 14. Substance abuse, such as alcohol (\> 80 gram/day - one standard glass contains 10 gram of alcohol), I.V. drugs and inhaled drugs. If the subject has a history of substance abuse, to be considered for inclusion into the protocol, the subject must have abstained from using the abused substance for at least 2 years. Subjects receiving methadone within the past 2 years are also excluded 15. Positive tuberculosis screen (when a screening is performed at the discretion of the treating physician) 16. Active hepatitis B virus or hepatitis C virus infection defined as a positive anti-HCV, HBsAg and/or anti-HBcore screening. 17. Leucopenia (Neutrophil count \< 1,8x10\^9/L) 18. Thrombopenia (Platelets \< 90x10\^9/L) 19. Elevated liver enzymes (\>2x ULN) 20. Abnormal renal function (eGFR\< 30 mL/min) 21. Other conditions which in the opinion of the investigator may interfere with the subject's ability to comply with the study procedure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical and endoscopic remission | After 52 weeks of treatment | Defined as a SCCAI-score ≤ 4, a UCEIS-score ≤ 3 and a total Mayo score ≤ 2, with no individual subscore \>1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| (Serious) Adverse Events | Continue during 52 weeks of treatment | Occurrence of (serious) adverse events ((S)AE) |
| Leukocyte counts | Every 6 weeks during 52 weeks of treatment | — |
| Liver function tests | Every 6-12 weeks during 52 weeks of treatment | — |
| Occurrence of subjective thiopurine intolerance | Every 6-12 weeks during 52 weeks of treatment | — |
| 6-MMP levels | Every 6-12 weeks during 52 weeks of treatment | — |
| Occurrence of treatment failure | Continue during 52 weeks of treatment | — |
| Occurrence of upscaling treatment | Continue during 52 weeks of treatment | Occurrence of upscaling treatment to biologicals (anti-TNF agents or vedolizumab) |
| Treatment costs | Every 3 months during 52 weeks of treatment | Budget-impact analysis and cost-utility analysis |
| 6-TGN levels | Every 6-12 weeks during 52 weeks of treatment | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Disease specific quality of life | Every 3 months during 52 weeks of treatment | Quality of life measured by use of the IBD questionnaire (IBDQ) |
Countries
Netherlands
Contacts
Primary ContactMark Löwenberg, MD, PhD
Backup ContactSara van Gennep, MD
Outcome results
None listed