Title: IASO: A phase II randomised placebo controlled double blind trial of Interleukin 1 blockade in Acute Severe Colitis
Funder: Department of Health and Social Care

Abstract: Acute severe ulcerative colitis (ASUC) is an acute inflammatory pathology, with significant morbidity, associated with neutrophilic infiltration of the colon and inflammatory cytokine release, including interleukin-1 (IL-1). IASO is a randomised, double blind placebo controlled trial in patients hospitalised with ASUC. IASO will test whether anakinra, a recombinant IL-1 receptor antagonist, given in addition to standard care with intravenous (IV) corticosteroids, benefits patients. Patients hospitalised with ASUC (defined using the widely recognised criterion of a modified Truelove and Witts severity index (MTWSI) >10) will be randomised 1:1 to anakinra (100mg IV loading dose then twice daily 100mg subcutaneous (SC) dosing) or placebo. This dose achieves plasma and tissue concentrations sufficient to block elevated levels of IL-1 seen in ASUC. Randomisation will be stratified on concomitant immunomodulator prescription, using web-based allocation to prepackaged drug/placebo packs to maintain blinding. Treatment with drug/placebo will be initiated within 36 hours of the commencement of IV corticosteroids. In line with international guidelines, treating clinicians will be required to assess the need for additional immunosuppressant therapy (‘rescue therapy’) against criteria of clinical response between day 3-5 after commencement of IV steroid therapy. The primary endpoint will be the need for initiation of medical or surgical rescue therapy (by day 10, in order to capture any delayed starts). Secondary endpoints include requirement for colectomy (by day 98, in line with previous studies) and measurements of disease activity. Exploratory endpoints include validated quality of life measures and outcomes at 1 year, as well as a detailed study of biological effects, including plasma and tissue concentrations of IL-1 pathway mediators, a transcriptomic analysis of response and microbial analysis of stool. Anakinra has a strong safety record in several large studies, but there are no reports of its use in UC. Therefore IASO includes a strong framework for safety monitoring. Feasibility will be assessed with an early analysis after the randomisation of the first 20 patients with specific stop/go outcomes assessed by an independent data monitoring committee (iDMC) which will advise the steering committee (TSC) on proceeding with the main phase (further 194 patients, 20 sites, 35 months). During this main phase, an interim analysis will be performed after 100 patients have been randomised; statistical testing of evidence for futility as well as safety data will be provided to the iDMC which will advise the TSC on whether to proceed. Hospitalisation with ASUC affects around 3,600 people in the UK each year with significant associated morbidity and healthcare costs. Despite this, patients with ASUC are typically excluded from clinical trials in UC and only a handful of small studies have been performed in non-steroid refractory ASUC. Nevertheless, steroid failure is common, with around 50% of patients requiring rescue therapy and 20-40% ultimately requiring colectomy. If successful, this trial will challenge a paradigm of medical care for the first 3-5 days of admission that has remained unchanged and largely unresearched since the 1950s and may result in fewer patients requiring rescue therapy, reduced colectomy rates and shorter hospital stays. This would have benefits for patients and potential health economic benefits, that could begin to be realised immediately

Lay abstract: Ulcerative colitis (UC) is an inflammatory condition of the large bowel associated with diarrhoea, pain and bleeding that affects 120,000 people in the UK. Patients at the most severe extreme, who are hospitalised with acute severe UC (ASUC), have largely been excluded from clinical trials. Therefore limited research into new treatments for this patient group has taken place. Consequently, the initial management of ASUC has remained unchanged since 1955, and involves giving steroids through a drip. Around half these patients do not improve after 3-5 days and need ‘rescue therapy’ with strong drugs to suppress the immune system. For those receiving rescue therapy, there is a 50% chance of needing major surgery to remove the large bowel. This surgery results in the need for an external drain for the faecal material through the skin (stoma), as well as long-term physical and psychological complications. Long hospital stays and surgery are expensive, and, together with the high cost of rescue therapy, result in a typical cost of the hospital stay of over £6000 for each patient. In ASUC the bowel becomes congested with blood cells called neutrophils. These cells contribute to inflammation. Neutrophils are stimulated by a molecule called interleukin-1 (IL-1). IL-1 is a messenger molecule made in the body, which reaches high levels in inflamed bowel. Anakinra is a drug that blocks IL-1. It is used to treat rheumatoid arthritis, has an excellent safety record and is cheap. Therefore, because IL-1 is present in the diseased bowel, because it is known to activate the same cells that are also present, and because these cells cause damage when activated, blocking IL-1 with anakinra might help prevent bowel damage in ASUC. Indeed, anakinra successfully treats bowel inflammation in animal tests. However, it has never been used to treat ASUC. Together with a patient steering group, we designed a study to test if anakinra might help patients with ASUC. 214 patients admitted to 20 acute NHS hospitals in the UK, will all get the current best care with steroids, but will also receive injections of either anakinra or placebo (dummy drug). Patients will have an equal chance of being treated with anakinra or placebo and neither patients nor doctors will know which treatment is being given. At the end of the trial, the proportion of patients in the two groups needing rescue therapy will be compared. We will also measure the rates of surgery and effects on quality of life. The study design has a strong emphasis on safety, with an independent monitoring committee and a number of planned analyses during the study to detect any harm to patients. Our patient steering group have reviewed the study plan, will sit on the committee overseeing the study, and will make sure that patients receive all the information they need during the study. We will share results fully with scientific and patient communities through scientific papers and patient newsletters. If successful, this study may offer a new, effective, low-cost treatment for patients with ASUC that could be rapidly adopted for patients around the world.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL