A Randomized, Multicenter Open Label Study Comparing Early Administration of Azathioprine Plus IFX to Steroids Plus Azathioprine for Acute Severe Colitis

A Randomized, Multicenter Open Label Study Comparing Early Administration of Azathioprine Plus Infliximab to Corticosteroids Plus Azathioprine for Acute Severe Colitis

PHASE : IV TYPE OF STUDY : With direct benefit. DESCRIPTIVE : Multicentre, randomized, open label study. INCLUSION CRITERIA : Acute severe ulcerative colitis. OBJECTIVES : To compare the efficacy and safety of early administration of the combination therapy with infliximab and azathioprine with steroids and azathioprine in patients with acute severe ulcerative colitis treated with intravenous steroids.

STUDY TREATMENTS : All patients :

Intravenous steroids (0.8 mg/kg/day of methylprednisolone or equivalent) for 5 days.

Combination therapy arm:

Infliximab 5 mg/kg plus Azathioprine 2-2.5 mg/kg/day.

Azathioprine arm:

Steroids tapering for 3 months and Azathioprine 2-2.5 mg/kg/day.

NUMBER OF PATIENTS : 73 patients in each group i.e. a total of 146patients. RECRUITMENT PERIOD : 36 months STUDY DURATION : 12 months

PRIMARY END POINT : Treatment failure is defined by:

• Absence of steroid-free remission at W52 according to the total Mayo Disease Activity Index score
• OR Absence of mucosal healing (Mayo endoscopic subscore 0-1)
• OR Adverse event leading to treatment interruption
• OR Colectomy
• OR Death
• OR Infliximab withdrawal in the combination therapy group OR Infliximab introduction in the azathioprine group SECONDARY END POINT: - Clinical response and remission at D7, W14 and W52 (according to Lichtiger score and total Mayo Disease Activity Index score)
• Endoscopic and histological response
• Mucosal healing (partial endoscopic Mayo subscore 0)
• Colectomy rate
• Adverse events rate
• Fecal calprotectin
• Health-economic outcome

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 (Endoscopic Mayo subscore ≥ 2).
• Acute flare requiring hospitalization
• Severe acute flare of UC with a Lichtiger Index score > 10 at Day -3
• 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.

3.2 EXCLUSION CRITERIA

• Pregnant or breast-feeding woman.
• Previous treatment with infliximab.
• Treatment with adalimumab or golimumab within 8 weeks before randomization
• Treatment with vedolizumab within 4 weeks before randomization
• Azathioprine or 6-mercaptopurine treatment initiated more than 4 weeks before screening.
• Ongoing intravenous steroids for more than 96 hours at time of the screening
• Contraindication for anti-TNF therapy
• Indication for immediate surgery.
• History of colorectal dysplasia.
• Diagnosis of Crohn's disease or indeterminate colitis
• 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 or positive interferon-gamma release assay (Quantiferon®)
• 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.
• Severe acute or chronic medical or psychiatric condition that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in judgement of the investigator, would make the subject inappropriate for entry in this study.
• Subjects who, in the opinion of the investigator, will be uncooperative or unable to comply with study procedures.
• Participation in another clinical trial.