Phase IIb, randomised, double-blind, placebo-controlled, multi-centre trial of infliximab with transcriptomic biomarker and mechanism evaluation in patients with acute pancreatitis

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.