Rectal Indomethacin and Oral Tacrolimus Versus Combination to Prevent Post-ERCP Pancreatitis (INTRO)

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

This research is being done to see if using oral tacrolimus before endoscopy, can prevent pancreatitis that may occur after ERCP (a type of gastrointestinal endoscopy).

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. Sample size justification: Based on the information from the earlier controlled trials, the Investigators assume that the PEP incidence will be 7% in the Rectal Indomethacin group and it will be reduced to 3% by the additional use of oral tacrolimus in combination with rectal indomethacin A two-sided α=0.05, and a power of 0.8, will require 926 patients for the comparison between the combination of oral tacrolimus and rectal indomethacin versus rectal indomethacin alone among high-risk individuals. Since 20% of patients undergoing ERCP are expected to be at high risk based on the investigators' prior experience, the investigators estimate that the total number of patients needed to undergo ERCP is 4630. Adjusting for a 5% drop-out rate, the sample size needed will be 4874. Recruitment and Consenting: Patients scheduled to undergo ERCP will be screened for patient-based inclusion/exclusion criteria and will be consented to before the start of ERCP. Randomization: The randomization schedule is centrally generated at Johns Hopkins University. Patients will be stratified by the participating center. Within each stratum randomly varying block sizes of 30-50 will be used. Patients and treating physicians will be blinded for the treatment allocation. This will be ensured by directly delivering the list of randomly generated numbers to the investigational drug pharmacies. Statistical Plan: The baseline characteristics of age, sex, comorbidity, American Society of Anesthesiologists (ASA) score, ERCP indication, PEP risk factors, and the use of other prophylactics (e.g. Intravenous Fluids) will be reported. Data will be presented in percentages for categorical variables. Continuous variables will be presented as mean with standard deviation (normal distribution) or median with interquartile range (skewed distribution). The modified intention-to-treat (ITT) principle will be applied to the primary analysis. That is, all randomized patients will be analyzed according to the patients' original treatment allocation, regardless of study protocol violations. The only patients excluded from the analysis will be those in whom the duodenum was not reached and the papilla was not manipulated (e.g., in case of upper gastrointestinal stenosis, aspiration risk, restless patient) or follow-up could not be performed for 5 days. Because these patients will not ultimately undergo an ERCP, there is no risk of PEP. A two-tailed P value of less than 0.05 is considered to be statistically significant.

Tacrolimus Capsule 1-2 hours prior to the endoscopy Rectal Indomethacin immediately after ERCP, in high-risk patients

Placebo Capsule 1-2 hours prior to the endoscopy Rectal Indomethacin immediately after ERCP, in high-risk patients

Incidence of PEP as defined by the consensus guidelines as New or increased abdominal pain that is clinically consistent with a syndrome of acute pancreatitis Amylase or lipase ≥ 3x the upper limit of normal 24 hours after the procedure Hospitalization or prolongation of existing hospitalization for at least 2 days

PEP severity grading will be based on the modified Atlanta Criteria. Mild PEP: Hospitalization ≤3 days without organ failure, local or systemic complications. Moderate PEP: Hospitalization 4-10 days with transient organ failure that resolves within 48 hours and/or local or systemic complications. Severe PEP: Hospitalization >10 days with development of pancreatic necrosis or pseudocyst, persistent (>48 hours) single or multiple organ failure, and/or need for additional endoscopic, percutaneous, or surgical intervention for pancreatitis-related complications.

Inclusion Criteria: Any patient who is undergoing endoscopic retrograde cholangiopancreatography (ERCP) at any of the participating centers, is at least 18 years old and provides informed consent can be included in the study. Exclusion Criteria: Unwillingness or inability to consent for the study. Pregnancy Breastfeeding mother Chronic calcific pancreatitis ERCP for biliary stent exchange or removal ERCP in a patient with prior biliary sphincterotomy, but without anticipated pancreatogram. Biliary intervention in a patient with pancreas divisum. Standard contraindications to tacrolimus or NSAID use. Current tacrolimus or immune modulator use. Chronic kidney disease with glomerular filtration rate (GFR) < 30 or acute kidney injury. Absence of rectum. Acute pancreatitis within 30 days of ERCP. Pancreatic head malignancy. Sphincter of Oddi dysfunction (Type 3).

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