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

Purpose

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

Condition	Intervention	Phase
Ulcerative Colitis Steroid Refractory	Drug: CYCLOSPORINE VS INFLIXIMAB	Phase 4


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Randomized, Multicenter Open Label Study Comparing Cyclosporine With Infliximab in Steroid-refractory Severe Attacks of Ulcerative Colitis

Resource links provided by NLM:

Genetics Home Reference related topics: ulcerative colitis

MedlinePlus related topics: Ulcerative Colitis

Drug Information available for: Cyclosporine Infliximab

U.S. FDA Resources

Further study details as provided by Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives:

Primary Outcome Measures:

% 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 [ Time Frame: Day 7 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

% 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 [ Time Frame: D98 ] [ Designated as safety issue: No ]


Enrollment:	115
Study Start Date:	June 2007
Study Completion Date:	October 2010
Primary Completion Date:	June 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: CICLO Cyclosporine will be administered by continuous intravenous infusion at the initial dose regimen of 2mg/kg per day. After 24 hours of treatment, cyclosporine trough level will be measured and the dose adapted in order to obtain a cyclosporinaemia level between 150 and 250 ng/ml. Cyclosporinaemia will be reassessed every 48 hours for the duration of the continuous intravenous treatment.	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 Other Names: Cyclosporine (IV)= Brand Name = Sandinuum Cyclosporine (PO)= brand name = Neoral Infliximab (IV)= brand name= Remicade
Active Comparator: INFLIXIMAB INFLIXIMAB (REMICADE) Infliximab in the form of a freeze-dried compound is conditioned in 100mg vials. Treatment will first be reconstituted in 250ml isotonic saline solution, and slowly infused at the dose of 5mg/kg in 2 hours. In patients with clinical response at D7 (Lichtiger Index score < 10 for 2 consecutive days), two additional infliximab infusions will be administered at the dose of 5mg/kg at D14 and D42.	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 Other Names: Cyclosporine (IV)= Brand Name = Sandinuum Cyclosporine (PO)= brand name = Neoral Infliximab (IV)= brand name= Remicade

Arms

Assigned Interventions

Active Comparator: CICLO

Cyclosporine will be administered by continuous intravenous infusion at the initial dose regimen of 2mg/kg per day.

After 24 hours of treatment, cyclosporine trough level will be measured and the dose adapted in order to obtain a cyclosporinaemia level between 150 and 250 ng/ml. Cyclosporinaemia will be reassessed every 48 hours for the duration of the continuous intravenous treatment.

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

Other Names:

Cyclosporine (IV)= Brand Name = Sandinuum
Cyclosporine (PO)= brand name = Neoral
Infliximab (IV)= brand name= Remicade

Active Comparator: INFLIXIMAB

INFLIXIMAB (REMICADE) Infliximab in the form of a freeze-dried compound is conditioned in 100mg vials. Treatment will first be reconstituted in 250ml isotonic saline solution, and slowly infused at the dose of 5mg/kg in 2 hours.

In patients with clinical response at D7 (Lichtiger Index score < 10 for 2 consecutive days), two additional infliximab infusions will be administered at the dose of 5mg/kg at D14 and D42.

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

Other Names:

Cyclosporine (IV)= Brand Name = Sandinuum
Cyclosporine (PO)= brand name = Neoral
Infliximab (IV)= brand name= Remicade

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00542152

Show 41 Study Locations

Sponsors and Collaborators

Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives

Investigators


Principal Investigator:	David LAHARIE, MD	Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives

More Information

Additional Information:

Related Info This link exits the ClinicalTrials.gov site

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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, Färkkilä M, Gisbert JP, Marteau P, Nahon S, de Vos M, Franchimont D, Mary JY, Colombel JF, Lémann M; Groupe d'Etudes Thérapeutiques 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.


Responsible Party:	Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
ClinicalTrials.gov Identifier:	NCT00542152 History of Changes
Other Study ID Numbers:	GETAID 2006-3
Study First Received:	October 8, 2007
Last Updated:	August 30, 2011
Health Authority:	France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) France: Institutional Ethical Committee

Keywords provided by Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives:


IBD Ulcerative colitis refractory to steroids

Additional relevant MeSH terms:


Colitis Ulcer Colitis, Ulcerative Gastroenteritis Gastrointestinal Diseases Digestive System Diseases Colonic Diseases Intestinal Diseases Pathologic Processes Inflammatory Bowel Diseases Infliximab Cyclosporine	Cyclosporins Dermatologic Agents Gastrointestinal Agents Antirheumatic Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antifungal Agents Anti-Infective Agents Calcineurin Inhibitors

ClinicalTrials.gov processed this record on September 30, 2016

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