Elsevier

The Lancet

Volume 380, Issue 9857, 1–7 December 2012, Pages 1909-1915
The Lancet

Articles
Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial

https://doi.org/10.1016/S0140-6736(12)61084-8Get rights and content

Summary

Background

Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs for this indication.

Methods

In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov (NCT00542152).

Findings

115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI −7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events.

Interpretation

Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience.

Funding

Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.

Introduction

Ulcerative colitis is a chronic inflammatory disorder of the colon characterised by mucosal ulceration, rectal bleeding, diarrhoea, and abdominal pain.1 In 15–25% of cases, patients present with severe colitis that necessitates admission to hospital.2, 3 Intravenous corticosteroids are the conventional medical treatment in this circumstance. However, roughly 40% of patients are resistant to treatment.4, 5 Previously, colectomy was the only available option for these patients. The development of ciclosporin, a calcineurin inhibitor that selectively inhibits T-cell immunity, and infliximab, a monoclonal antibody that targets tumour necrosis factor α, has provided effective alternatives to surgery.6, 7, 8 However, no randomised controlled trials have been done to compare the efficacy and safety of ciclosporin with those of infliximab, and thus practice guidelines do not state which treatment is preferable.9, 10 Assuming that ciclosporin was superior to infliximab, we compared the efficacy and safety of these drugs in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids.

Section snippets

Study design and patients

Our 98 day randomised, parallel, open-label trial compared ciclosporin with infliximab in patients admitted to hospital with severe colitis. We did our trial at 27 centres in France, Spain, Belgium, and Finland from June 1, 2007, to Aug 31, 2010. The study was designed by investigators from the Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID).

Patients were consecutively recruited. Eligible patients were at least 18 years of age and had an acute severe flare of

Results

Of the 115 randomly assigned patients, 58 were assigned to the ciclosporin group and 57 to the infliximab group (figure 1). Four of these patients had major inclusion deviations (ie, did not meet eligibility criteria)—one patient in the infliximab group received 0·50 mg/kg per day of intravenous methylprednisolone for 2 days only before initiation of infliximab, whereas in the ciclosporin group, before initiation one patient received 0·42 mg/kg per day of intravenous methylprednisolone for 5

Discussion

Contrary to our initial hypothesis, ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids (panel). Responses at day 7 and colectomy rates at day 98 were similar in both groups, and both drugs were well tolerated.

The efficacy of ciclosporin in our trial was similar to that noted in previous clinical trials.6, 7 The efficacy of infliximab in refractory ulcerative colitis is somewhat controversial. Three

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