OP33 Results of a randomised controlled trial to evaluate Interleukin 1 blockade with anakinra in patients with acute severe ulcerative colitis (IASO)
Raine, T.(1)*;Vaja, S.(2);Subramanian, S.(1);Brezina, B.(1);Probert, C.S.(3);Steel, A.(3);Lofthouse, M.(3);Speight, R.A.(4);Lamb, C.(4);Sebastian, S.(5);Kane, J.(5);Thut, J.(5);Din, S.(6);Arnott, I.(6);Smith, L.(6);Galea, J.(7);Hendy, P.(8);Flores, L.(9);Selinger, C.(10);Onoviran, F.(10);Steed, H.(11);Green, M.(12);Williams, J.(13);Jairath, V.(14);Qian, W.(2);Pavey, H.(2);Champion, K.(2);Dowling, F.(2);Thomas, M.(2);Wolf, K.(2);Davis-Wilkie, C.(2);Parkes, M.(1);Kaser, A.(15);
(1)Cambridge University Hospitals NHS Foundation Trust, Department of Gastroenterology, Cambridge, United Kingdom;(2)Cambridge University Hospitals NHS Foundation Trust, Cambridge Clinical Trials Unit, Cambridge, United Kingdom;(3)Royal Liverpool University Hospital, Department of Gastroenterology, Liverpool, United Kingdom;(4)Royal Victoria Infirmary, Department of Gastroenterology, Newcastle, United Kingdom;(5)Hull University Teaching Hospitals, IBD Unit, Hull, United Kingdom;(6)Western General Hospital- NHS Lothian, IBD Unit, Edinburgh, United Kingdom;(7)Cardiff and Vale University Health Board- Cardiff, Neurosurgery, Cardiff, United Kingdom;(8)Chelsea and Westminster NHS Trust, Department of Gastroenterology, London, United Kingdom;(9)Chelsea and Westminster NHS Trust, Research and Development, London, United Kingdom;(10)St James University Hospital, Department of Gastroenterology, Leeds, United Kingdom;(11)University of Wolverhampton, Department of Gastroenterology, Wolverhampton, United Kingdom;(12)The Royal Wolverhampton NHS Trust, Department of Gastroenterology, Wolverhampton, United Kingdom;(13)Swansea University, Department of Medicine, Swansea, United Kingdom;(14)Western University, Department of Gastroenterology, London, Canada;(15)University of Cambridge, Department of Medicine, Cambridge, United Kingdom; The IASO trial investigators
Background
Acute severe ulcerative colitis (ASUC) is a severe manifestation of ulcerative colitis (UC) that requires hospitalisation. Despite significant advances in therapeutic options for UC and in the medical management of steroid-refractory ASUC, the initial treatment paradigm for ASUC has not changed since the 1950s and is based on the use of intravenous (IV) corticosteroids. Approximately 50% of patients do not respond and require further medical or surgical therapy. Interleukin 1 (IL-1) has been identified as a key mediator of colonic inflammation and plays a pivotal role in local activation of neutrophils and a number of downstream inflammatory mediators. The IL-1 axis has been repeatedly identified as a therapeutic target in UC. The Interleukin 1 (IL-1) blockade in Acute Severe Colitis (IASO) trial investigated whether antagonism of IL-1 signalling could improve outcomes in patients with ASUC.
Methods
We performed a phase II, multicentre randomised (1:1), placebo-controlled, double-blinded trial of IL-1 blockade with short-duration anakinra, given alongside IV corticosteroids to adult patients hospitalised with suspected or confirmed ASUC. The primary outcome was the incidence of medical (ie infliximab/ciclosporin) or surgical rescue therapy (colectomy) within 10 days following the commencement of IV corticosteroid therapy. Secondary outcomes included disease activity, time to clinical response, time to rescue therapy, colectomy incidence by day 98 post IV corticosteroids and safety. The trial aimed to recruit 214 patients across 20 sites in the UK. Prespecified analyses were performed for feasibility and for futility.
Results
At the time of the prespecified interim futility analysis, 113 patients had been randomised, 55 to placebo, and 58 to anakinra (figure 1). The incidence of medical or surgical rescue therapy by day 10 was higher in the anakinra group than in the placebo group (43% vs 26%). The incidence of colectomy by day 98 was higher in the anakinra group (11% vs 4%). These differences were not statistically significant. Logistic models containing a mixture of baseline stratification factors did not suggest that the need for rescue therapy would be reduced with anakinra treatment and on the advice of the independent data monitoring committee, the trial was terminated for futility. There was a higher incidence of adverse event in the placebo group, the most common was worsening of ulcerative colitis.
Conclusion
This trial shows that adding anakinra to current standard care with IV corticosteroids in patients with ASUC did not reduce the need for rescue therapy or colectomy. This suggests that IL-1 blockade is not a therapeutic target in ASUC. There were no safety concerns with anakinra treatment. 