Study Comparing Cyclosporine With Infliximab in Steroid-refractory Severe Attacks of Ulcerative Colitis

Condition(s) targeted: Steroid-refractory Severe Attack of Ulcerative Colitis

Intervention: CYCLOSPORINE VS INFLIXIMAB (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives

Official(s) and/or principal investigator(s):
David LAHARIE, MD, Principal Investigator, Affiliation: GETAID

Overall contact:
David LAHARIE, MD, Phone: 05 57 65 64 38, Email: david.laharie@chu-bordeaux.fr

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

Official title: A Randomized, Multicenter Open Label Study Comparing Cyclosporine With Infliximab in Steroid-refractory Severe Attacks of Ulcerative Colitis

Study design: Allocation: Randomized, Control: Uncontrolled, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: % 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

Secondary outcome: % 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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

David LAHARIE, MD, Phone: 05 57 65 64 38, Email: david.laharie@chu-bordeaux.fr

Hopital Erasme, Bruxelles 1070, Belgium; Active, not recruiting

Ulb - Clinique Saint Luc, Bruxelles 1200, Belgium; Recruiting
Olivier DEWIT, MD, Phone: 00327642822, Email: olivier.dewit@clin.ucl.ac.be
OLIVIER DEWIT, MD, Sub-Investigator

Gent University Hospital, Gent 9000, Belgium; Active, not recruiting

Leuven University Hospital, Leuven 3000, Belgium; Recruiting
Geert VAN ASSCHE, MD,PhD, Phone: +32 16 344218, Email: gert.vanassche@uzleuven.be
Gert VAN ASSCHE, MD, PhD, Principal Investigator

CHU LIEGE - Sart Tilman, Liege 4000, Belgium; Active, not recruiting

Helsinki University Hospital, Helsinki 00029, Finland; Recruiting
Maarti FARKKILA, MD,PhD, Phone: + 358 504271622, Email: martti.farkkila@hus.fi
Martti FARKKILA, MD,PhD, Principal Investigator

Kuopio University Hospital, Kuopio 70211, Finland; Active, not recruiting

Päijät-Häme CENTRAL HOSPITAL, Lahti 15850, Finland; Active, not recruiting

Oulu University Hospital, Oulu 90220, Finland; Active, not recruiting

Seinäjoki Central Hospital, Seinäjoki 60220, Finland; Active, not recruiting

Tampere University Hospital, Tampere 33521, Finland; Active, not recruiting

Turku University Hospital, Turku 20520, Finland; Active, not recruiting

Chu Amiens, Amiens 80054, France; Recruiting
Jean-Louis DUPAS, MD,PhD, Phone: +33 3 22 66 82 08, Email: dupas.jean-louis@chu-amiens.fr
Martine LECONTE, Phone: +33 3 22 66 82 14
JEAN LOUIS DUPAS, MD, Principal Investigator

Ch Avignon, Avignon 84000, France; Active, not recruiting

Chu Besancon, Besancon 25030, France; Recruiting
Maria NACHURY, MD, Phone: +33 3 81 66 82 54, Email: mnachury@chu-besancon.fr
Maria NACHURY, MD, Principal Investigator

Hopital Avicennes, Bobigny 93200, France; Active, not recruiting

Chu Caen, Caen 14033, France; Active, not recruiting

Chu Clermont-Ferrand, Clermont-ferrand 63003, France; Recruiting
Gilles BOMMELAER, MD,PhD, Phone: +33473750523, Email: gbommelaer@chu-clermontferrand.fr
Gilles BOMMELAER, MD,PhD, Principal Investigator

Hopital Beaujon, Clichy 92110, France; Recruiting
Yoram BOUHNIK, MD,PhD, Phone: +33 1 40 87 56 00, Email: yoram.bouhnik@bjn.aphp.fr
YORAM BOUHNIK, MD,PhD, Principal Investigator
Alain ATTAR, MD, Sub-Investigator
Carmen STEFANESCU, MD, Sub-Investigator
Xavier TRETON, MD, Sub-Investigator

Hopital Louis Mourrier, Colombes 92700, France; Recruiting
Benoit COFFIN, MD,PhD, Phone: +33147606061, Email: benoit.coffin@lmr.ap-hop-paris.fr
Benoit COFFIN, MD,PhD, Principal Investigator
Pauline JOUET, MD, Sub-Investigator
Jean-Marc SABATE, MD, Sub-Investigator

Hopital Henri Mondor, Creteil 94010, France; Recruiting
Jean-Charles DELCHIER, MD,PhD, Phone: +33149812351, Email: jean-charles.delchier@hmn.aphp.fr
Jean-Charles DELCHIER, MD,PhD, Principal Investigator
Elise CHANTELOUP, MD, Sub-Investigator
Hélène PILLANT, MD, Sub-Investigator

Hopital Bicetre, Le Kremlin Bicetre 94275, France; Active, not recruiting

Chru Lille, Lille 59037, France; Recruiting
Jean-Frédéric COLOMBEL, MD,PhD, Phone: +33 3 20 44 47 14, Email: jean-frederic-colombel@chru-lille.fr
Géraldine MEULIN, Phone: +33 3 20 44 56 20, Email: g-meulin@chru-lille.fr
Jean-Frédéric COLOMBEL, MD,PhD, Principal Investigator
Gwenola VERNIER-MASSOUILLE, MD, Sub-Investigator
Vincent MAUNOURY, MD, Sub-Investigator

Chu Marseille - Hopital Nord, Marseille 13915, France; Active, not recruiting

Ch Le Raincy Montfermeil, Montfermeil 93370, France; Recruiting
Stéphane NAHON, MD, Phone: +33141708121, Email: snahon@ch-montfermeil.fr
Stéphane NAHON, MD, Principal Investigator

Chu Nantes, Nantes 44093, France; Recruiting
Arnaud BOURREILLE, MD, Phone: +33202400830, Email: arnaud.boureille@chu-nantes.fr
Arnaud BOURREILLE, MD, Principal Investigator
Mathurin FLAMANT, MD, Sub-Investigator

Chu Nice, Nice 06202, France; Recruiting
Xavier HEBUTERNE, MD,PhD, Phone: +33492066168, Email: hebuterne.x@chu-nice.fr
Xavier HEBUTERNE, MD,PhD, Principal Investigator
Jérome FILIPPI, MD, Sub-Investigator

Hopital St Antoine, Paris 75012, France; Recruiting
Jacques COSNES, MD, PhD, Phone: +33 1 49 28 31 70, Email: jacques.cosnes@sat.aphp.fr
Jacques COSNES, MD, PhD, Principal Investigator
Philippe SEKSIK, MD, Sub-Investigator
Laurent BEAUGERIE, MD, PhD, Sub-Investigator

Hopital Saint Louis, Paris 75010, France; Recruiting
Marc LEMANN, MD, PhD, Phone: 33 1 42 49 95 97, Email: marc.lemann@sls.aphp.fr
Marc LEMANN, MD, PhD, Principal Investigator
Mathieu ALLEZ, MD, PhD, Sub-Investigator
Jean-Marc GORNET, MD, Sub-Investigator

Hopital Lariboisiere, Paris 75010, France; Recruiting
Philippe MARTEAU, MD,PhD, Phone: +33149952579, Email: philippe.marteau@lrb.aphp.fr
Philippe MARTEAU, MD,PhD, Principal Investigator
Jessica COELHO, MD, Sub-Investigator

Institut Mutualiste Montsouris (Imm), Paris 75674, France; Active, not recruiting

Hopital Georges Pompidou, Paris 75015, France; Active, not recruiting

Hopital Cochin, Paris 75014, France; Active, not recruiting

Hopital Bichat, Paris 75018, France; Active, not recruiting

Hopital Haut Leveque, Pessac 33604, France; Recruiting
David LAHARIE, MD, Phone: +33 5 57 65 64 38, Email: david.laharie@chu-bordeaux.fr
Sylvie RAZAIRE, Phone: +33 5 57 65 63 11
David LAHARIE, MD, Principal Investigator

Chu Lyon, Pierre Benite 69495, France; Active, not recruiting

Chu Reims, Reims, France; Active, not recruiting

Chu Rennes, Rennes 35033, France; Active, not recruiting

Chu Rouen, Rouen 76031, France; Recruiting
Eric LEREBOURS, MD,PhD, Phone: +33232888101, Email: eric.lerebours@chu-rouen.fr
Eric LEREBOURS, MD,PhD, Principal Investigator
Guillaume SAVOYE, MD, Sub-Investigator

Chu Saint Etienne, St Etienne 42270, France; Recruiting
Xavier ROBLIN, MD, Phone: +33 4 77 82 83 20, Email: xavier.roblin@chu-st-etienne.fr
Xavier ROBLIN, MD, Principal Investigator

Chu Strasbourg, Strasbourg 67091, France; Active, not recruiting

Chu Toulouse, Toulouse 31403, France; Recruiting
Jacques MOREAU, MD, Phone: +33561322764, Email: moreau.j@chu-toulouse.fr
Jacques MOREAU, MD, Principal Investigator

Chu Tours, Tours 37044, France; Active, not recruiting

Chu Nancy, Vandoeuvre Les Nancy 54500, France; Active, not recruiting

Istituto Clinico Humanitas, Milano 20089, Italy; Not yet recruiting
Silvio DANESE, MD, Email: sdanese@hotmail.com
Silvio DANESE, MD, Principal Investigator

Hospital Clinic, Barcelona 08036, Spain; Recruiting
Elena RICART GOMEZ, MD,PhD, Phone: +3493 2275418, Email: ericart@clinic.ub.es
Elena RICART GOMEZ, MD,PhD, Principal Investigator

Hospital Mutua de Terressa, Barcelona 08221, Spain; Active, not recruiting

Hospital Ramon Y Cajal, Madrid 28034, Spain; Recruiting
Antonio LOPEZ SAN ROMAN, MD, Phone: +34913368305, Email: alopezs@meditex.es
Antonio LOPEZ SAN ROMAN, MD, Principal Investigator

Related publications:

EDWARDS FC, TRUELOVE SC. THE COURSE AND PROGNOSIS OF ULCERATIVE COLITIS. Gut. 1963 Dec;4:299-315.

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.

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.

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.

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.

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.

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.

Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol. 1999 Jun;94(6):1587-92.

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. Epub 2005 Jun 21.

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. Review.

Järnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlén P, Grännö C, Vilien M, Ström M, Danielsson A, Verbaan H, Hellström 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.

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.

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.

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.

Eidelwein AP, Cuffari C, Abadom V, Oliva-Hemker M. Infliximab efficacy in pediatric ulcerative colitis. Inflamm Bowel Dis. 2005 Mar;11(3):213-8.

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.

Starting date: June 2007
Last updated: September 11, 2009