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* = Presenting author

OP023 Methotrexate for corticosteroid-dependent ulcerative colitis: results of a placebo randomized controlled trial.

F. Carbonnel*1, J.F. Colombel2, J. Filippi3, K. Katsanos4, L. Peyrin-Biroulet5, M. Allez6, M. Nachury7, 8, G. Novacek9, S. Danese10, V. Abitbol11, F. Bossa12, J. Moreau13, G. Bommelaer14, A. Bourreille15, J.L. Dupas16, X. Roblin17, Y. Bouhnik18, W. Reinisch9, 19, M. Farkkila20, H. Brixi21, P. Seksik22, G. Malamut23, B. Coulibaly24, O. Dewit25, E. Louis26, D. Deplanque27, P. Michetti28, H. Sarter27, D. Laharie29

1APHP Paris Sud University , Gastroenterology, Le Kremlin Bicêtre, France, 2Icahn Medical School of Medicine at Mount Sinai, , IBD center, New York, United States, 3University Hospital of Nice Archet 2, Gastroenterology, Nice, France, 4University of Ioannina School of Medical Sciences, Gastroenterology, Ioannina, Greece, 5University Hospital of Nancy, Gastroenterology, Nancy, France, 6Saint Louis Hospital APHP, Gastroenterology, Paris, France, 7University hospital of Lille, Gastroenterology, Lille, France, 8University hopsital of Besançon, Gastroenterology, Besançon, France, 9Medizinische Universität Wien, Gastroenterology, Vienna, Austria, 10Istituto Clinico Humanitas, Gastroenterology, Milano, Italy, 11Cochin University Hospital, Gastroenterology, Paris, France, 12Cancer Research and Cure Institute "Casa Sollievo Sofferenza", Gastroenterology, San Giovanni Rotondo, Italy, 13Rangueil University Hospital, Gastroenterology, Toulouse, France, 14University Hospital of Clermont Ferrand, Gastroenterology, Clermont Ferrand, France, 15Insitut des Maladies de l'Appareil Digestif, , Gastroenterology, Nantes, France, 16Amiens University Hospital, Gastroenterology, Amiens, France, 17University hospital of Saint Etienne, Gastroenterology, Saint Etienne, France, 18University hospital of Beaujon APHP, Gastroenterology, Clichy, France, 19Mc Master University , Gastroenterology, Hamilton, Canada, 20University Hospital of Helsinki, Gastroenterology, Helsinki, Finland, 21University hospital of Reims, Gastroenterology, Reims, France, 22University Hospital of Saint Antoine, APHP, Gastroenterology, Paris, France, 23Hôpital Européen Geroges Pompidou, APHP, Gastroenterology, Paris, France, 24General hospital of Avignon, Gastroenterology, Avignon, France, 25UCL Saint Luc, Gastroenterology, Bruxelles, Belgium, 26University hospital of Liège, Gastroenterology, Liège, Belgium, 27University hospital of Lille, Biostatistics and Clinical Research, Lille, France, 28Clinique de la Source, Gastroenterology, Lausanne, Switzerland, 29University hospital of Bordeaux, Gastroenterology, Bordeaux, France

Background

There is no controlled trial of parenteral methotrexate (MTX) in ulcerative colitis (UC). We conducted a prospective, controlled, randomized, double-blind trial of intra-muscular or subcutaneous MTX at a dose of 25mg/week vs placebo in patients with steroid-dependent UC.

Methods

Eligible patients had active or inactive UC and were on prednisone at a daily dose of 10 to 40 mg at inclusion. Exclusion criteria were resistance to oral steroids, need for colectomy, alcohol consumption, pulmonary, renal or liver disease, obesity or diabetes mellitus, pregnant or breast-feeding female subjects, infection with HIV, HBV, HCV, a past history of malignant condition, use of other immunosuppressants within 1 month prior to inclusion or anti-TNF treatment within 2 months prior to inclusion. The primary endpoint was success at week 16 as defined by a Mayo score < or = 2 with no item >1, complete steroid withdrawal with a forced tapering regimen, and no need for other IS, anti TNF or colectomy. Secondary endpoints were success at week 24, success at week 16 and 24, mucosal healing (Mayo endoscopic subscore = 0 or 1), clinical remission (Mayo clinical subscore < or =χ2 with no item>1) without steroids and no need for other IS, anti TNF or colectomy at week 16 and/or 24. Endpoints were compared using chi square tests. The analysis was performed on an intent-to-treat basis. We expected a success rate of 45% with methotrexate and 20% with placebo. One hundred and ten patients were deemed sufficient to show a statistically significant difference with a 80% power and an alpha risk of 5% (bilateral test).

Results

One hundred and eleven patients (59 male, median age 42) were included in 26 European centers: 60 were randomized to the MTX arm and 51 to the placebo arm. Median dose of prednisone was 25 mg/d at inclusion. Rates of success at week 16 were 32% of patients among patients given MTX vs 20% among patients given placebo (difference 12.1% [CI 95%: -4.0%; +28.1%]; p=0.15). Clinical remission without steroids and no need for other IS, anti TNF or colectomy at week 16 was observed in 42% of patients given MTX vs 23.5% of patients given placebo (difference 18.1% [IC 95%: 1.1%; 35.2%]; p=0.04). The other secondary endpoints were not significant. Mucosal healing was observed in 35% of patients given MTX vs 25.5% of patients given placebo (difference 9.5% [CI 95%: -7.5% ; + 26.5]; p= 0.28). Rates of serious adverse events were 10% in the MTX group and 6% in the placebo group (p =0.5).

Table

Medians with P-values for comparison to control group
Coagulation parameterDay 1Day 5Week 4Week 8–12Controls
Fibrinogen g/L5.6 (<0.0001)3.9 (0.017)4 (0.34)3.3 (0.11)3.1
FVIII U/ml2.21 (<0.0001)2.3 (<0.0001)1.57 (0.0027)1.355 (0.296)1.29
vWF IU/ml1.67 (<0.0001)1.495 (<0.0001)1.32 (0.0001)1.225 (0.0035)0.79
ETP nM.min1777 (0.0003)1815 (0.0003)1714 (0.0192)1732 (0.0056)1368
Extem MCF mm47.5 (<0.0001)48 (0.0001)55 (0.0319)56 (0.18)68.5
Extem MCF mm74.5 (<0.000)71 (0.0008)69.5 (0.0516)68.5 (0.22)67
Extem &alpha; °80.5 (<0.0001)80 (<0.0001)78.5 (0.0139)79 (0.0531)76
Fibtem MCF mm36 (<0.0001)27 (<0.0001)21.5 (0.0028)20 (0.0079)16

Conclusion

Treatment with parenteral MTX was not significantly superior to placebo for the primary endpoint. However it induced clinical remission without steroids in a significantly larger percentage of patients with steroid dependent UC than placebo.