Clinical trial NCT00498589: Comparison of Methotrexate vs Placebo in Corticosteroid-dependent Ulcerative Colitis
Official title: A Controlled, Randomized, Double-blind, Multicenter Study, Comparing Methotrexate vs Placebo in Corticosteroid-dependent Ulcerative Colitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ulcerative Colitis
Lead sponsor: Centre Hospitalier Universitaire de Besancon
Sponsor class: OTHER
First posted: 2007-07-10
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: * 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Remission without steroids, immunosuppressives and without colectomy
timeFrame: week 16
Secondary outcomes:
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: University Hospital of Vienna
city: Bruxelles
country: Belgium
facility: ULB - Cliniques Saint Luc
city: Amiens
country: France
facility: CHU Amiens - Hôpital Nord
city: Avignon
country: France
facility: CH Avignon
city: Besançon
country: France
facility: Centre Hospitalier Universitaire de Besançon
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand - Hôpital Hotel Dieu
city: Clichy
country: France
facility: APHP - Hôpital Beaujon
city: Le Kremlin Bicetre
country: France
facility: APHP - Hôpital Bicêtre
city: Lille
country: France
facility: CHRU Lille - Hôpital Huriez
city: Nantes
country: France
facility: CHU Nantes - Hôpital Hôtel Dieu
city: Nice
country: France
facility: CHU Nice - Hôpital de l'Archet 2
city: Paris
country: France
facility: APHP - Hôpital Saint Louis
city: Paris
country: France
facility: APHP - Hôpital Saint Antoine
city: Paris
country: France
facility: APHP - Hôpital Cochin
city: Pessac
country: France
facility: CHU Bordeaux - Hôpital Haut L'Eveque
city: Rouen
country: France
facility: CHU Rouen - Hôpital Charles Nicolle
city: Saint Priest
country: France
facility: CHU St Etienne - Hôpital NOrd
city: Toulouse
country: France
facility: CHU Toulouse - Hôpital Rangueil
city: Tel aviv
country: Israel
facility: Sheba Medical Center
city: Rozzano , Milano
country: Italy
facility: Istituto Clinico Humanitas
city: San Giovanni Rotondo
country: Italy
facility: Ospedale Casa Sollievo Della Sofferenza
city: Leiden
country: Netherlands
facility: LUMC
Study officials:
affiliation: CHU Besançon
name: Franck Carbonnel
role: PRINCIPAL_INVESTIGATOR
References:
citation: Carbonnel F, Colombel JF, Filippi J, Katsanos KH, Peyrin-Biroulet L, Allez M, Nachury M, Novacek G, Danese S, Abitbol V, Bossa F, Moreau J, Bommelaer G, Bourreille A, Fumery M, Roblin X, Reinisch W, Bouhnik Y, Brixi H, Seksik P, Malamut G, Farkkila M, Coulibaly B, Dewit O, Louis E, Deplanque D, Michetti P, Sarter H, Laharie D; European Crohn's and Colitis Organisation; Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives. Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis. Gastroenterology. 2016 Feb;150(2):380-8.e4. doi: 10.1053/j.gastro.2015.10.050. Epub 2015 Nov 26.