Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

Abstract

SummaryBackgroundInfliximab and ciclosporin are of similar efficacy in treating acute severe ulcerative colitis, but there has been no comparative evaluation of their relative clinical effectiveness and cost-effectiveness.MethodsIn this mixed methods, open-label, pragmatic randomised trial, we recruited consenting patients aged 18 years or older at 52 district general and teaching hospitals in England, Scotland, and Wales who had been admitted, unscheduled, with severe ulcerative colitis and failed to respond to intravenous hydrocortisone within about 5 days. Patients were randomly allocated (1:1) to receive either infliximab (5 mg/kg intravenous infusion given over 2 h at baseline, and again at 2 weeks and 6 weeks after the first infusion) or ciclosporin (2 mg/kg per day by continuous infusion for up to 7 days, followed by twice-daily tablets delivering 5·5 mg/kg per day for 12 weeks). Randomisation used a web-based password-protected site, with a dynamic algorithm to generate allocations on request, thus protecting against investigator preference or other subversion, while ensuring that each trial group was balanced by centre, which was the only stratification used. Local investigators and participants were aware of the treatment allocated, but the chief investigator and analysts were masked. Analysis was by treatment allocated. The primary outcome was quality-adjusted survival—ie, the area under the curve (AUC) of scores from the Crohn's and Ulcerative Colitis Questionnaire (CUCQ) completed by participants at baseline, 3 months, and 6 months, then every 6 months from 1 year to 3 years. This trial is registered with the ISRCTN Registry, number ISRCTN22663589.FindingsBetween June 17, 2010, and Feb 26, 2013, 270 patients were recruited. 135 patients were allocated to the infliximab group and 135 to the ciclosporin group. 121 (90%) patients in each group were included in the analysis of the primary outcome. There was no significant difference between groups in quality-adjusted survival (mean AUC 564·0 [SD 241·9] in the infliximab group vs 587·0 [226·2] in the ciclosporin group; mean adjusted difference 7·9 [95% CI −22·0 to 37·8]; p=0·603). Likewise, there were no significant differences between groups in the secondary outcomes of CUCQ scores, EQ-5D, or SF-6D scores; frequency of colectomy (55 [41%] of 135 patients in the infliximab group vs 65 [48%] of 135 patients in the ciclosporin group; p=0·223); or mean time to colectomy (811 [95% CI 707–912] days in the infliximab group vs 744 [638–850] days in the ciclosporin group; p=0·251). There were no differences in serious adverse reactions (16 reactions in 14 participants receiving infliximab vs ten in nine patients receiving ciclosporin); serious adverse events (21 in 16 patients vs 25 in 17 patients); or deaths (three in the infliximab group vs none in the ciclosporin group).InterpretationThere was no significant difference between ciclosporin and infliximab in clinical effectiveness.FundingNIHR Health Technology Assessment programme.

Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia

“…Cyclosporine has long been shown as an effective rescue therapy in corticosteroid‐refractory acute severe colitis . An open‐labeled study comparing the two drugs did not show any significant difference in outcome, and this was confirmed in the CONSTRUCT study . Therefore, the choice of treatment is based on factors such as local availability, cost of therapy, and physician preference, whether patients have been unsuccessfully treated with thiopurines previously .…”

Healthcare professionals’ views of the use and administration of two salvage therapy drugs for acute ulcerative colitis: a nested qualitative study within the CONSTRUCT trial

“…Future research should focus on exploring findings from this study across a greater number and wide range of trial sites. It would also be beneficial to explore, following publication of the main trial findings, how views may have changed in the light of equal effectiveness across the two trial drugs being shown 29. How will this influence the preferences stated here and will it affect professionals’ decision-making between the two?…”

Optimal management of acute severe ulcerative colitis

“…Although the CONSTRUCT trial did not find any difference in the length of stay with either therapy, patients and physicians noted greater treatment satisfaction with IFX 52. It seems very likely that the current evolution in our understanding and application of pharmacokinetics of IFX in ASUC will shape and favour the use of IFX as preferred salvage therapy in most units.…”

“…There was no statistically significant difference between the two for the primary end point as well as the secondary end point of colectomy rates, time to colectomy, serious adverse events or death. IFX, however, was associated with a greater cost of treatment as compared with ciclosporin 52. That said, biosimilars to IFX are now available and cost of therapy is reducing.…”