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

Ulcerative Colitis Clinical Trial

— CYSIF  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00542152
• Other study ID #: GETAID 2006-3
• Status: Completed
• Phase: Phase 4
• First received: October 8, 2007
• Last updated: August 30, 2011
• Start date: June 2007
• Est. completion date: October 2010

Study information

• Verified date: August 2011
• Source: Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)France: Institutional Ethical Committee
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 115
• Est. completion date: October 2010
• Est. primary completion date: June 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Steroid Refractory
• Ulcer
• Ulcerative Colitis

Intervention

Drug:
• CYCLOSPORINE VS INFLIXIMAB
Cyclosporine 2mg/kg/day intravenous for 7 days then Neoral 4mg/kg/day orally for 3 months. Infliximab 5mg/kg at weeks 0, 2 and 6

Locations

Country	Name	City	State
Belgium	Hopital Erasme	Bruxelles
Belgium	Ulb - Clinique Saint Luc	Bruxelles
Belgium	Gent University Hospital	Gent
Belgium	Leuven University Hospital	Leuven
Finland	Helsinki University Hospital	Helsinki
France	Chu Amiens	Amiens
France	Ch Avignon	Avignon
France	Chu Besancon	Besancon
France	CHU CAEN	Caen
France	Chu Clermont-Ferrand	Clermont-ferrand
France	Hopital Beaujon	Clichy
France	Hopital Louis Mourrier	Colombes
France	Hopital Henri Mondor	Creteil
France	Hopital Bicetre	Le Kremlin Bicetre
France	Chru Lille	Lille
France	Chu Marseille - Hopital Nord	Marseille
France	Ch Le Raincy Montfermeil	Montfermeil
France	Chu Nantes	Nantes
France	CHU NICE	Nice
France	Hopital Bichat	Paris
France	Hopital Cochin	Paris
France	Hopital Georges Pompidou	Paris
France	Hopital Lariboisiere	Paris
France	Hopital Saint Louis	Paris
France	Hopital St Antoine	Paris
France	Institut Mutualiste Montsouris (Imm)	Paris
France	Hopital Haut Leveque	Pessac
France	CHU LYON	Pierre Benite
France	Chu Reims	Reims
France	Chu Rennes	Rennes
France	Chu Rouen	Rouen
France	Chu Saint Etienne	St Etienne
France	Chu Strasbourg	Strasbourg
France	Chu Toulouse	Toulouse
France	Chu Tours	Tours
France	Chu Nancy	Vandoeuvre Les Nancy
Italy	Istituto Clinico Humanitas	Milano
Spain	Hospital Clinic	Barcelona
Spain	Hospital Mutua de Terressa	Barcelona
Spain	Hospital de la Princesa	Madrid
Spain	Hospital Ramon Y Cajal	Madrid

Sponsors (1)

Lead Sponsor	Collaborator
Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives

Countries where clinical trial is conducted

Belgium,  Finland,  France,  Italy,  Spain, 

References & Publications (16)

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. — View 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. Epub 2005 Jun 21. — View 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. — View 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. — View 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. — View Citation

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

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. — View 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. — View 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. — View 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. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. — View 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. Review. — View 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. — View 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. — View 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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	% 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		Day 7	No
Secondary	% 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		D98	No

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