Comparison of Methotrexate vs Placebo in Corticosteroid-dependent Ulcerative Colitis

Study Overview
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Brief Summary
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PHASE: II TYPE OF STUDY : With direct benefit DESCRIPTIVE: Multicenter, randomized, double-blind study INCLUSION CRITERIA: Steroid-dependent ulcerative colitis OBJECTIVES: To show superiority of methotrexate vs placebo in inducing steroid-free remission in steroid-dependent ulcerative colitis STUDY TREATMENTS: Methotrexate 1 intramuscular injection (25 mg) per week Placebo 1 intramuscular injection per week NUMBERS OF PATIENTS: 55 patients in each group, i.e. a total of 110 patients INCLUSION PERIOD: 24 months STUDY DURATION: 36 months EVALUATION CRITERIA: Remission without steroids, immunosuppressives and without colectomy at 16 weeks of treatment.

Detailed Description
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Ulcerative colitis (UC) is a chronic inflammatory bowel disease that slightly reduces life expectancy, strongly reduces its quality and can lead to serious complications such as acute colitis, dysplasia and colon cancer. About 40'000 patients are affected in France Among them, 15% suffer from a chronic active form that often leads to an extended steroid therapy, and its known side effects. Azathioprine has already proven its efficacy in this indication but brings a lasting remission without steroid in only 41% of the patients (1-4). What are the medications available for the patients who failed in maintaining a remission with azathioprine ? Cyclosporin is designed for severe or steroid-resistant forms. (5). The results of two recent studies have showed that infliximab is more efficacious than placebo in active UC (6, 7). Infliximab is expensive, its efficacy in steroid-dependent UC has not been specifically tested yet, and its tolerance on the long term remains uncertain. Methotrexate proved its efficacy in Crohn's disease with an intramuscular dose of 25mg/week (8). In UC a controlled trial has been negative with an oral dose of 12.5mg/week (9). Another study compared mercaptopurine, methotrexate (15mg/week) and 5-aminosalicylate in 72 steroid-dependent patients with CD or UC (10). The remission rates obtained were 58% after 30 weeks with methotrexate (not significantly different from 5-ASA) and 14% after 106 weeks (not significantly different from 5-ASA). Few data are available on the efficacy of methotrexate in UC, at a dose which is active in Crohn's disease (25mg intramuscular/week). Several uncontrolled series have been published, including 91 patients whose remission failed under azathioprine. Methotrexate is cheap and its patent has fallen in the public domain. Only institutional research will be able to finance a study in this new indication. This is a prospective, controlled, randomized, double-blind study of methotrexate with an intramuscular dose of 25mg/week vs placebo in patients with steroid-dependent UC. This multicenter study will take place under the aegis of the Therapeutic Study Group for Inflammatory Digestive Diseases (G.E.T.A.I.D.) and with the help of the gastroenterologists network of the CIC. The issue of this study is important. If the hypothesis is borne out, a cheap, efficacious medication will be available for chronic active UC.

Official Title
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A Controlled, Randomized, Double-blind, Multicenter Study, Comparing Methotrexate vs Placebo in Corticosteroid-dependent Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: methotrexate
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: UC diagnosed according to the Lennard-Jones criteria (Appendix 1) with endoscopic colorectal lesions, whatever their extension may be A Mayo Disease Activity Index £ 4, with no item >1 for the clinical part of the score and from 0 to 2 for the endoscopic part at the time of inclusion Steroid-dependence defined by at least 1 unsuccessful attempt to stop systemic steroid therapy during the last 12 weeks. Steroid therapy might have been completely stopped if it has been restarted within the last 30 days To be receiving a treatment of prednisone at a dose between 10 and 40mg, stable for at least 2 weeks at the time of inclusion Under an adequate contraception for male or female subjects of childbearing potential Exclusion Criteria: Indication to a colectomy. Alcoholism (more than 21 glasses per week for male subjects and 14 glasses per week for female subjects). 1 glass corresponds to 3 cl of strong alcohol, 10 cl glass of wine or a half pint of beer. Pregnant or breast-feeding female subjects. No efficacious contraception. NSAIDS or cotrimoxazole intake upon inclusion, or probenecid intake within 1 month prior to inclusion. Anti-TNFa treatment within 2 months prior to inclusion. Azathioprine, mercaptopurine, cyclosporin or thalidomide within 1 month prior to inclusion. Modification of mesalazine or olsalazine dosage within 1 month prior to inclusion. Chronic (broncho) pneumopathy. Renal failure (creatinaemia > upper limit of normal laboratory values limit). Liver disease apart from primary sclerosing cholangitis. Unexplained rise higher than twice the normal level for transaminases, alkaline phosphatases and/or bilirubin. Folate level < normal level. Past history of malignant condition (including leukaemia, lymphoma and myelodysplasia) except for baso-cellular cutaneous cancers.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1<br>Methotrexate IM or SC 25 mg/week vs placebo IM or SC for 24 weeks | Drug: methotrexate<br>* 25 mg per week IM or SC during 24 weeks<br>|
| Placebo Comparator: 2<br>1 IM or SC of placebo per week during 24 weeks | Drug: placebo<br>* one intramuscular injection per week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission without steroids, immunosuppressives and without colectomy |  | week 16 |