Professor El-Omar has selected Dr Sailish Honap to do the next #GUTBlog. Dr Honap is the first author on this ‘Recent Advances in Clinical Practice’ paper and is a Research fellow in Inflammatory Bowel Disease at King’s College London, UK.

The #GUTBlog focusses on the paper “Acute severe ulcerative colitis (ASUC) trials: the past, the present and the future” which was published in paper copy in Gut in October 2024.

Dr Honap writes about the paper below:

“Unlike the ever-expanding list of novel therapies available for the treatment of moderate to severe UC, ASUC – a medical emergency that still carries a risk of mortality – has been left behind. First line therapy with intravenous corticosteroids remains unchanged for the past 70 years and for the third of patients that respond poorly to steroids, gastroenterologists are presented with only two established treatment options for medical rescue (ciclosporin and infliximab), each with their own list of limitations. Up to a half of patients with UC are hospitalised with a disease flare at some point and there is a real unmet need for this IBD subpopulation who are typically excluded from industry-sponsored confirmatory trials of novel drugs.

Advancing drug development and accurately determining the safety and efficacy of a compound rests on robustly designed clinical trials. To this end, our systematic review broadly sought to achieve two objectives: first, to examine what interventions have been tried and tested for ASUC in randomised trials. And second, to review how these interventions were tested by evaluating trial designs and endpoints that could be optimised for future trial conduct. It was a privilege to work alongside a team of senior trialists that lead the field of IBD to complete this undertaking.

The first part of the manuscript takes the reader on a historical journey starting from the landmark cortisone trial in the 1950s, through subsequent decades exploring various hypotheses. In total, 23 distinct therapies tested in 33 randomised trials were identified. While RCTs in the latter part of the 20th century focused on corticosteroids, dietary restrictions and antimicrobial therapy, the late 1990s and the turn of the millennium saw the focus shifted toward calcineurin inhibitors and monoclonal antibodies. As we know, trials in the present era have studied and continue to study novel dosing strategies and more recently, the JAK inhibitor drug class.

The second part of the paper looked at trial design. Perhaps as expected, we found a lack of consensus across multiple domains, which raised numerous unaddressed questions. First, defining trial populations. Eligibility criteria helps ensure safety but should also ensure the homogeneity of the study group to unmask the effect of the drug and at the same time be generalisable to the broader population. How should ASUC be defined? Should we use the Truelove and Witts criteria, or the Lichtiger score (or modified versions of these), or perhaps another instrument that better reflects the advanced therapy-exposed patients we see admitted today? Shouldn’t we also incorporate objective measures, particularly endoscopy, to define baseline disease activity? And then, trial design and endpoints. How should corticosteroids be handled prior to enrolment and following discharge? What about masking and unmasking in such trials of an acutely unwell group? What are the most suitable primary and secondary endpoints for ASUC trials? How should clinical response, clinical remission and treatment failure be defined and when should they be assessed?

Our study found substantial variation for each of the aforementioned points and many more. ASUC trials are notoriously difficult to conduct given the acuity of the study population, and such discrepancies in trial design impede clinical research efforts to identify novel therapies. There is a clear need for a consensus and a collaborative effort in this area among academics, sponsors and regulatory bodies to provide a degree of uniformity and clarity. At present, there is little guidance for trial design methodology in this high risk population. The next project was to run the first international consensus to provide clear position statements on these key areas to optimise the conduct of future ASUC clinical trials. This work is currently under review at the time of writing this #GUTBlog so watch this space!”

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@Sash_Honap Dr Sailish Honap