Mercaptopurine Therapy in Ulcerative Colitis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Efficacy of Optimized Thiopurine Therapy in Ulcerative Colitis (OPTIC)

Conditions
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Colitis, Ulcerative

Intervention / Treatment
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* Drug: Mercaptopurine (Purinethol)
* Drug: Placebo
* Drug: Mesalamine
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of UC by endoscopy and histopathology Patients between 18 and 80 years of age Active disease, despite oral treatment with at least 2g/day 5-ASA Treatment with oral corticosteroids is required Exclusion Criteria: Prior treatment with thiopurines Prior treatment with biologics (e.g. anti-TNF agents and vedolizumab) Current pregnancy (a pregnancy test will be performed if necessary according to the treating physician) Chronic Obstructive Pulmonary Disease (COPD) Acute coronary heart disease (Bacterial) gastroenteritis has to be treated first Coagulation disorders Active malignancy History of colonic dysplasia/cancer Extensive colonic resection, i.e. subtotal colectomy with <15 cm colon in situ Concomitant therapy with drugs interfering with MP metabolism, like allopurinol, ribavirin or anti-epileptics. Known systemic fungal infections or parasitic infections have to be treated first Known duodenal or ventricular ulcus 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 Positive tuberculosis screen (when a screening is performed at the discretion of the treating physician) Active hepatitis B virus or hepatitis C virus infection defined as a positive anti-HCV, HBsAg and/or anti-HBcore screening. Leucopenia (Neutrophil count < 1,8x10^9/L) Thrombopenia (Platelets < 90x10^9/L) Elevated liver enzymes (>2x ULN) Abnormal renal function (eGFR< 30 mL/min) Other conditions which in the opinion of the investigator may interfere with the subject's ability to comply with the study procedure

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Mercaptopurine (Purinethol)<br>Mercaptopurine (Purinethol),1-1.5 mg/kg/day oral, 52 weeks & Prednisone, 40 mg/day oral, 2 weeks, followed by fixed tapering over 6 weeks OR budesonide (cortiment) 9 mg/day during 8 weeks & Mesalamine, 2 g/day oral, 52 weeks. | Drug: Mercaptopurine (Purinethol)<br> <br> * Other names: Purinethol;Drug: Mesalamine<br> <br> * Other names: Salofalk;Drug: Prednisone<br> <br> |
| Placebo Comparator: Placebo<br>Placebo, 1-1.5 mg/kg/day, 52 weeks & Prednisone, 40 mg/day oral, 2 weeks, followed by fixed tapering over 6 weeks OR budesonide (cortiment) 9 mg/day during 8 weeks & Mesalamine, 2 g/day oral, 52 weeks. | Drug: Placebo<br> <br> Drug: Mesalamine<br> <br> * Other names: Salofalk;Drug: Prednisone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical and endoscopic remission | Defined as a SCCAI-score ≤ 4, a UCEIS-score ≤ 3 and a total Mayo score ≤ 2, with no individual subscore >1. | After 52 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Serious) Adverse Events | Occurrence of (serious) adverse events ((S)AE) | Continue during 52 weeks of treatment | 
| 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-TGN levels |  | 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 | Occurrence of upscaling treatment to biologicals (anti-TNF agents or vedolizumab) | Continue during 52 weeks of treatment | 
| Treatment costs | Budget-impact analysis and cost-utility analysis | Every 3 months during 52 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Therapeutic Drug Monitoring, Mercaptopurine (6-MP), Thiopurine, Efficacy