Comparison of Methotrexate vs Placebo in Corticosteroid-dependent Ulcerative Colitis

NCT ID: NCT00498589

Last Updated: 2015-02-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 110 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-09-30
• Study Completion Date: 2014-06-30

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.

Conditions

Ulcerative Colitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

1

Methotrexate IM or SC 25 mg/week vs placebo IM or SC for 24 weeks

Group Type: PLACEBO_COMPARATOR

methotrexate

Intervention Type: DRUG

25 mg per week IM or SC during 24 weeks

2

1 IM or SC of placebo per week during 24 weeks

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

one intramuscular injection per week

Interventions

methotrexate

25 mg per week IM or SC during 24 weeks

Intervention Type: DRUG

placebo

one intramuscular injection per week

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centre Hospitalier Universitaire de Besancon

OTHER

Sponsor Role: lead

Responsible Party

Franck Carbonnel

PU-PH

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Franck Carbonnel

Role: PRINCIPAL_INVESTIGATOR

CHU Besançon

Locations

University Hospital of Vienna

Vienna, , Austria

ULB - Cliniques Saint Luc

Brussels, , Belgium

CHU Amiens - Hôpital Nord

Amiens, , France

CH Avignon

Avignon, , France

Centre Hospitalier Universitaire de Besançon

Besançon, , France

CHU Clermont-Ferrand - Hôpital Hotel Dieu

Clermont-Ferrand, , France

APHP - Hôpital Beaujon

Clichy, , France

APHP - Hôpital Bicêtre

Le Kremlin-Bicêtre, , France

CHRU Lille - Hôpital Huriez

Lille, , France

CHU Nantes - Hôpital Hôtel Dieu

Nantes, , France

CHU Nice - Hôpital de l'Archet 2

Nice, , France

APHP - Hôpital Saint Louis

Paris, , France

APHP - Hôpital Saint Antoine

Paris, , France

APHP - Hôpital Cochin

Paris, , France

CHU Bordeaux - Hôpital Haut L'Eveque

Pessac, , France

CHU Rouen - Hôpital Charles Nicolle

Rouen, , France

CHU St Etienne - Hôpital NOrd

Saint-Priest, , France

CHU Toulouse - Hôpital Rangueil

Toulouse, , France

Sheba Medical Center

Tel Aviv, , Israel

Istituto Clinico Humanitas

Rozzano , Milano, , Italy

Ospedale Casa Sollievo Della Sofferenza

San Giovanni Rotondo, , Italy

LUMC

Leiden, , Netherlands

Countries

Austria; Belgium; France; Israel; Italy; Netherlands

References

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.

Reference Type: DERIVED

PMID: 26632520 (View on PubMed)

Other Identifiers

GETAID 2006-1

Identifier Type: -

Identifier Source: org_study_id