A Randomized Trial Comparing Rectal Indomethacin Alone Versus a Combination of Rectal Indomethacin and Oral Tacrolimus for Post-ERCP Pancreatitis Prophylaxis

Background: In the US alone, almost 700,000 endoscopic retrograde cholangiopancreatographies (ERCPs) are performed each year, and the utilization of ERCP over the last 10 years has increased due to the established therapeutic benefit of the procedure. The most common complication of ERCP is the development of post-ERCP pancreatitis (PEP). Depending on whether the ERCP is performed in average or high-risk patients, the incidence of PEP ranges from 3-15%. The average Medicare reimbursement for PEP is approximately $6,000 and the estimated annual cost burden of PEP is in excess of $200 million. Anti-inflammatory prophylaxis with rectal indomethacin and pancreatic duct stenting has been shown to reduce both the incidence of PEP and PEP severity. Yet, PEP remains a common complication due to the suboptimal efficacy of these current preventative modalities. The primary reason for the lack of progress in PEP prophylaxis is the lack of novel approaches to target the underlying mechanisms of PEP.

In the initiation of acute pancreatitis, calcium is released by acinar cells, the main parenchymal cell of the pancreas. Central to this pathway is the activation of the heterodimeric calcium-dependent serine, threonine phosphatase calcineurin (Cn). In addition to experimental evidence, recent clinical reports have demonstrated lower rates of PEP in transplant patients taking Cn inhibitors. To gain an understanding of this phenomenon, the investigators performed a search of the electronic medical records at the University of Pittsburgh Medical Center, from 2005 to 2013, for patients who underwent ERCP and found that tacrolimus users had close to a 50% reduction in PEP rates compared to non-tacrolimus users (13.2% to 6.9%). A recent retrospective study showed similar results. While these observations are subject to several confounders, including co-morbidity and polypharmacy, the overall data provides both an experimental and clinical premise for investigating the efficacy of Cn inhibitors in PEP.

In this trial, the investigators test the overarching hypothesis that tacrolimus, administered as an oral loading bolus just prior to ERCP, will provide additive PEP prophylaxis to the current standard of care, rectal indomethacin.

Hypothesis: H1: A combination of oral tacrolimus and rectal indomethacin is superior to the use of rectal indomethacin alone, for the prevention of post-ERCP pancreatitis among high-risk individuals.

H2: Oral tacrolimus is superior to placebo for the prevention of post-ERCP pancreatitis among non-high-risk individuals.