Clinical trial NCT00542152: Study Comparing Cyclosporine With Infliximab in Steroid-refractory Severe Attacks of Ulcerative Colitis
Official title: A Randomized, Multicenter Open Label Study Comparing Cyclosporine With Infliximab in Steroid-refractory Severe Attacks of Ulcerative Colitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Ulcerative Colitis
Steroid Refractory
Keywords: IBD
Ulcerative colitis
refractory to steroids
Lead sponsor: Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
Sponsor class: OTHER
First posted: 2007-10-10
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: PHASE: IV

TYPE OF STUDY: With direct benefit.

DESCRIPTIVE: Multicenter, randomized, open label study.

INCLUSION CRITERIA: Steroid-refractory ulcerative colitis.

OBJECTIVES: To compare the efficacy of cyclosporine with infliximab in steroid- refractory attacks of ulcerative colitis.

STUDY TREATMENTS:Cyclosporine 2mg/kg/day intravenous(IV)for 7days then Neoral 4mg/kg/day orally for 3 months. Infliximab 5mg/kg at Weeks 0, 2 and 6.

NUMBER OF PATIENTS: 50 patients in each group i.e. a total of 100 patients.

INCLUSION PERIOD: 24 months.

STUDY DURATION: 27 months.

MAIN EVALUATION CRITERIA:

Clinical response at D7 according to the Lichtiger Index score AND Clinical Remission at D98 according to the Mayo Disease Activity Index score

SECONDARY EVALUATION CRITERIA:

Clinical remission at D98 (according to the Mayo Disease Activity Index score) Endoscopic response Colectomy rate Tolerance


Eligibility criteria: Inclusion Criteria:

* Age \> 18 years.
* Diagnosis of UC according to Lennard-Jones criteria (Appendix 1).
* Endoscopically demonstrated colorectal lesions localized above the anal margin and extending at least up to 15cm proximally.
* Severe acute flare of UC with a Lichtiger Index score \> 10.
* Refractoriness to high dose intravenous steroid therapy (≥ 0.8 mg/kg/d of methylprednisolone or equivalent) given for at least 5 days.
* Adequate contraception for male or female subjects of childbearing potential, which will be continued throughout the study and at least 3 months after study termination.

Exclusion Criteria:

* Pregnant or breast-feeding woman.
* Previous treatment with cyclosporine or infliximab.
* Azathioprine or 6-mercaptopurine treatment initiated more than 4 weeks before inclusion.
* Indication for immediate surgery.
* History of colorectal dysplasia.
* Diagnosis of Crohn's disease.
* Positive stool tests for amoebiasis and/or positive bacteriological culture for Salmonella, Shigella, Yersinia and Campylobacter and/or presence of Clostridium difficile B toxin in the stools.
* Renal failure (creatininemia \> upper limit of normal laboratory value).
* Uncontrolled high blood pressure.
* HIV, HBV viral infection (except the presence of positive anti-HBs antibodies) with serology not older than 3 months.
* Uncontrolled bacterial or active viral infection.
* Past medical history of malignant condition in the last 5 years (including leukaemia, lymphoma and myelodysplasia) except for baso-cellular cutaneous cancers.
* Past medical history of myocardial infarction or heart failure.
* Intradermal reaction to Tuberculin (Tubertest® 5 units) \> 5mm.
* Active tuberculosis
* Untreated latent tuberculosis (see national recommendations. Appendix 2).
* Abnormal blood count with polynuclear neutrophils \< 1,500 G/L or white cells \< 3,000, or platelets \< 100,000 G/L.
* Unexplained rise higher than 3 times the normal level for transaminases, alkaline phosphatases and/or higher than twice the normal level for bilirubin.
* Non-compliant subjects.
* Participation in another therapeutic study.

Primary outcomes:
measure: % of patients with treatment failure defined as: absence of clinical response at D7 or absence of remission without steroids at D98 or relapse or severe adverse event leading to treatment interruption or colectomy or fatality between D0 and D98
timeFrame: Day 7
Secondary outcomes:
measure: % of patients in clinical response % patients in remission Lichtiger Index score MDAI score Time to discharge Endoscopic response colectomy rate Steroid dosage. Number of adverse events CMV infection
timeFrame: D98
Other outcomes:
Locations:
city: Bruxelles
country: Belgium
facility: Hopital Erasme
city: Bruxelles
country: Belgium
facility: Ulb - Clinique Saint Luc
city: Gent
country: Belgium
facility: Gent University Hospital
city: Leuven
country: Belgium
facility: Leuven University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Amiens
country: France
facility: Chu Amiens
city: Avignon
country: France
facility: Ch Avignon
city: Besancon
country: France
facility: Chu Besancon
city: Caen
country: France
facility: CHU CAEN
city: Clermont-ferrand
country: France
facility: Chu Clermont-Ferrand
city: Clichy
country: France
facility: Hopital Beaujon
city: Colombes
country: France
facility: Hopital Louis Mourrier
city: Creteil
country: France
facility: Hopital Henri Mondor
city: Le Kremlin Bicetre
country: France
facility: Hopital Bicetre
city: Lille
country: France
facility: Chru Lille
city: Marseille
country: France
facility: Chu Marseille - Hopital Nord
city: Montfermeil
country: France
facility: Ch Le Raincy Montfermeil
city: Nantes
country: France
facility: Chu Nantes
city: Nice
country: France
facility: CHU NICE
city: Paris
country: France
facility: Hopital Lariboisiere
city: Paris
country: France
facility: Hopital Saint Louis
city: Paris
country: France
facility: Hopital St Antoine
city: Paris
country: France
facility: Hopital Cochin
city: Paris
country: France
facility: Hopital Georges Pompidou
city: Paris
country: France
facility: Hopital Bichat
city: Paris
country: France
facility: Institut Mutualiste Montsouris (Imm)
city: Pessac
country: France
facility: Hopital Haut Leveque
city: Pierre Benite
country: France
facility: CHU LYON
city: Reims
country: France
facility: Chu Reims
city: Rennes
country: France
facility: Chu Rennes
city: Rouen
country: France
facility: Chu Rouen
city: St Etienne
country: France
facility: Chu Saint Etienne
city: Strasbourg
country: France
facility: Chu Strasbourg
city: Toulouse
country: France
facility: Chu Toulouse
city: Tours
country: France
facility: Chu Tours
city: Vandoeuvre Les Nancy
country: France
facility: Chu Nancy
city: Milano
country: Italy
facility: Istituto Clinico Humanitas
city: Barcelona
country: Spain
facility: Hospital Clinic
city: Barcelona
country: Spain
facility: Hospital Mutua de Terressa
city: Madrid
country: Spain
facility: Hospital de la Princesa
city: Madrid
country: Spain
facility: Hospital Ramon Y Cajal
Study officials:
affiliation: Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
name: David LAHARIE, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: EDWARDS FC, TRUELOVE SC. THE COURSE AND PROGNOSIS OF ULCERATIVE COLITIS. Gut. 1963 Dec;4(4):299-315. doi: 10.1136/gut.4.4.299.
citation: Truelove SC, Willoughby CP, Lee EG, Kettlewell MG. Further experience in the treatment of severe attacks of ulcerative colitis. Lancet. 1978 Nov 18;2(8099):1086-8. doi: 10.1016/s0140-6736(78)91816-0.
citation: D'Haens G, Lemmens L, Geboes K, Vandeputte L, Van Acker F, Mortelmans L, Peeters M, Vermeire S, Penninckx F, Nevens F, Hiele M, Rutgeerts P. Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology. 2001 May;120(6):1323-9. doi: 10.1053/gast.2001.23983.
citation: Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994 Jun 30;330(26):1841-5. doi: 10.1056/NEJM199406303302601.
citation: Van Assche G, D'Haens G, Noman M, Vermeire S, Hiele M, Asnong K, Arts J, D'Hoore A, Penninckx F, Rutgeerts P. Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology. 2003 Oct;125(4):1025-31. doi: 10.1016/s0016-5085(03)01214-9.
citation: Arts J, D'Haens G, Zeegers M, Van Assche G, Hiele M, D'Hoore A, Penninckx F, Vermeire S, Rutgeerts P. Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis. Inflamm Bowel Dis. 2004 Mar;10(2):73-8. doi: 10.1097/00054725-200403000-00002.
citation: Actis GC, Bresso F, Astegiano M, Demarchi B, Sapone N, Boscaglia C, Rizzetto M. Safety and efficacy of azathioprine in the maintenance of ciclosporin-induced remission of ulcerative colitis. Aliment Pharmacol Ther. 2001 Sep;15(9):1307-11. doi: 10.1046/j.1365-2036.2001.01019.x.
citation: Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol. 1999 Jun;94(6):1587-92. doi: 10.1111/j.1572-0241.1999.01149.x.
citation: Ardizzone S, Maconi G, Russo A, Imbesi V, Colombo E, Bianchi Porro G. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut. 2006 Jan;55(1):47-53. doi: 10.1136/gut.2005.068809. Epub 2005 Jun 21.
citation: Shibolet O, Regushevskaya E, Brezis M, Soares-Weiser K. Cyclosporine A for induction of remission in severe ulcerative colitis. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD004277. doi: 10.1002/14651858.CD004277.pub2.
citation: Jarnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlen P, Granno C, Vilien M, Strom M, Danielsson A, Verbaan H, Hellstrom PM, Magnuson A, Curman B. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology. 2005 Jun;128(7):1805-11. doi: 10.1053/j.gastro.2005.03.003.
citation: Su C, Salzberg BA, Lewis JD, Deren JJ, Kornbluth A, Katzka DA, Stein RB, Adler DR, Lichtenstein GR. Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol. 2002 Oct;97(10):2577-84. doi: 10.1111/j.1572-0241.2002.06026.x.
citation: Gornet JM, Couve S, Hassani Z, Delchier JC, Marteau P, Cosnes J, Bouhnik Y, Dupas JL, Modigliani R, Taillard F, Lemann M. Infliximab for refractory ulcerative colitis or indeterminate colitis: an open-label multicentre study. Aliment Pharmacol Ther. 2003 Jul 15;18(2):175-81. doi: 10.1046/j.1365-2036.2003.01686.x.
citation: Kohn A, Prantera C, Pera A, Cosintino R, Sostegni R, Daperno M. Infliximab in the treatment of severe ulcerative colitis: a follow-up study. Eur Rev Med Pharmacol Sci. 2004 Sep-Oct;8(5):235-7.
citation: Eidelwein AP, Cuffari C, Abadom V, Oliva-Hemker M. Infliximab efficacy in pediatric ulcerative colitis. Inflamm Bowel Dis. 2005 Mar;11(3):213-8. doi: 10.1097/01.mib.0000160803.44449.a5.
citation: Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005 Dec 8;353(23):2462-76. doi: 10.1056/NEJMoa050516.
citation: Laharie D, Bourreille A, Branche J, Allez M, Bouhnik Y, Filippi J, Zerbib F, Savoye G, Vuitton L, Moreau J, Amiot A, Cosnes J, Ricart E, Dewit O, Lopez-Sanroman A, Fumery M, Carbonnel F, Bommelaer G, Coffin B, Roblin X, van Assche G, Esteve M, Farkkila M, Gisbert JP, Marteau P, Nahon S, de Vos M, Lambert J, Mary JY, Louis E; Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives. Long-term outcome of patients with steroid-refractory acute severe UC treated with ciclosporin or infliximab. Gut. 2018 Feb;67(2):237-243. doi: 10.1136/gutjnl-2016-313060. Epub 2017 Jan 4.
citation: Laharie D, Bourreille A, Branche J, Allez M, Bouhnik Y, Filippi J, Zerbib F, Savoye G, Nachury M, Moreau J, Delchier JC, Cosnes J, Ricart E, Dewit O, Lopez-Sanroman A, Dupas JL, Carbonnel F, Bommelaer G, Coffin B, Roblin X, Van Assche G, Esteve M, Farkkila M, Gisbert JP, Marteau P, Nahon S, de Vos M, Franchimont D, Mary JY, Colombel JF, Lemann M; Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet. 2012 Dec 1;380(9857):1909-15. doi: 10.1016/S0140-6736(12)61084-8. Epub 2012 Oct 10.