Title: Phase IIb, randomised, double-blind, placebo-controlled, multi-centre trial of infliximab with transcriptomic biomarker and mechanism evaluation in patients with acute pancreatitis
Funder: Department of Health and Social Care

Abstract: Acute pancreatitis (AP) is a common condition without licensed specific therapy that presents very substantial unmet clinical need characterised by severe pain and gastrointestinal dysfunction, leading to inpatient care that can be prolonged and complicated by organ failure and death. Tumour necrosis factor-a (TNFa) is a central cytokine in AP that drives the deleterious local and systemic immune responses in human AP, inhibition of which greatly reduces the likelihood and severity of AP. We will conduct a randomized clinical trial to test the hypothesis that early intravenous administration of the TNFa inhibitor infliximab is an effective, safe treatment to improve the outcome of AP - Randomised treatment of Acute Pancreatitis with Infliximab: Double-blind, placebo-controlled, multi-centre phase II trial: RAPID-I. RAPID-I will be a Phase IIb trial of 5 mg/kg or 10 mg/kg infliximab given as a single intravenous dose within 12 h of admission for mild, moderate or severe AP. Dosing within 12 h will ensure optimum inhibition of TNFa and potential to impact on all grades of severity. Up to 290 patients will be recruited equally between the three groups at six primary and up to 12 further NHS sites. We will use an adaptive design with two interim analyses, to determine on the basis of efficacy and/or safety whether to drop one treatment arm or stop the trial. The primary outcome measure of RAPID-I will be serum C-reactive protein levels on days 2, 4, 7, 14 and 28, summarised by area under the curve (AUC). Secondary outcome measures will include clinical and laboratory parameters, pancreatic contrast-enhanced CT at 14 +/- 2 days and length of stay. Six months set-up is anticipated prior to recruitment over 24 months, with follow up of 90 days, then a further seven months for completion of data collation, laboratory assessments, analyses and reporting. An economic analysis adopting a health and personal social service perspective will be used to estimate the cost-effectiveness of infliximab. We will also determine (a) validity of an expression signature of three genes that accurately predicts AP severity on admission; (b) efficacy mechanisms from gene expression differences between placebo and treatment arms, identifying a signature predictive of treatment response; (c) safety data from the impact of infliximab on gene expression of essential components of adaptive immunity. The human and financial costs of AP are very great, with no therapy to ameliorate AP. The case for high quality trials in AP is compelling. The research costs of this proposal are dwarfed by the health burden presented by AP.

Lay abstract: Acute pancreatitis is a common, severely debilitating disease of the pancreas that causes intense abdominal pain and may lead to multiple organ failure. Those suffering from the disease may need help with breathing, heart and kidney function. One out of twenty patients with acute pancreatitis dies, more likely in those who develop organ failure. Treatment can be prolonged, often with extended stays in hospital of many weeks. Recovery is slow and may take years. To date many drugs have been used to treat acute pancreatitis, but none cures the illness or accelerates recovery. In this programme we are testing a drug called Infliximab, which is made from natural protein and is currently used to treat bowel and joint disease. Infliximab operates by blocking an important process in the progression of the disease. This process leads to inflammation in both the pancreas and other parts of the body. In the proposed programme, infliximab is given within half a day of a patient arriving in hospital, much earlier than with other drugs tested in acute pancreatitis. The test programme follows NHS best practice, randomised trial procedures to ensure that the results are valid and recognised by hospitals and medical professionals alike. In support of this goal, patients are helping in the planning, undertaking and reporting of the programme. The name of the trial in this programme is RAPID-I, which highlights giving the drug early when it may be most effective. There are two additional aspects of the programme. One is investigation of possible links between inherited genes and the development of acute pancreatitis, and the other is investigation of possible links between the way inherited genes work and and the way infliximab works. Any information gained from these aspects of the programme will help target the right treatment to the right patients who develop acute pancreatitis and in understanding if, how and why treatment with Infliximab works. If Infliximab is found to be beneficial in the treatment of acute pancreatitis, major improvements in the health of a large number of NHS patients will be made possible, reducing patient suffering and hospital requirements for these patients with significant savings in NHS costs.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL