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

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

Conditions
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Ulcerative Colitis, Steroid Refractory

Intervention / Treatment
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* Drug: CYCLOSPORINE VS INFLIXIMAB


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CICLO<br>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<br>* 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<br>* Other names: Infliximab (IV)= brand name= Remicade;|
| Active Comparator: INFLIXIMAB<br>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<br>* 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<br>* Other names: Infliximab (IV)= brand name= Remicade;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| % 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| % 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IBD, Ulcerative colitis, refractory to steroids