Stent vs. Indomethacin for Preventing Post-ERCP Pancreatitis

NCT02476279 | Completed Phase 3 Results DMC

• 1 other identifier: U01DK104833-01
• Study Type: interventional
• Target: 1,950
• Locations: 2 countries
• Sites: 20

Brief Summary

Background: Pancreatitis is the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP), accounting for substantial morbidity, occasional mortality, and increased health care expenditures. Until recently, the only effective method of preventing post-ERCP pancreatitis (PEP) had been prophylactic pancreatic stent placement (PSP), an intervention that is costly, time consuming, technically challenging, and potentially dangerous. The investigators recently reported the results of a large randomized controlled trial demonstrating that rectal indomethacin, a non-steroidal anti-inflammatory drug, reduced the risk of pancreatitis after ERCP in high-risk patients, most of whom (\>80%) had received a pancreatic stent. Secondary analysis of this RCT suggested that subjects who received indomethacin alone were less likely to develop PEP than those who received a pancreatic stent alone or the combination of indomethacin and stent, even after adjusting for underlying differences in subject risk. If indomethacin were to obviate the need for PSP, major clinical and cost benefits in ERCP practice could be realized. Objective: To assess whether rectal indomethacin alone is non-inferior to the combination of rectal indomethacin and prophylactic pancreatic stent placement for preventing post-ERCP pancreatitis in high-risk cases. Methods: Comparative effectiveness multi-center non-inferiority trial of rectal indomethacin alone vs. the combination of rectal indomethacin and prophylactic pancreatic stent placement for the prevention of post-ERCP pancreatitis in high-risk patients. One thousand four hundred and thirty subjects at elevated risk for PEP who would normally receive a pancreatic stent for prophylaxis will be randomized to indomethacin alone or the combination of indomethacin and PSP. The proportion of patients developing PEP and moderate-severe PEP will be compared. In addition, the investigators will establish a quality-assured central repository of biological specimens obtained from study participants, permitting future translational research elucidating the molecular and genetic mechanisms of PEP, as well as the mechanisms by which non-steroidal anti-inflammatory drugs prevent this complication.

Conditions

Post-ERCP Pancreatitis

Outcome Measures

Primary Outcomes (1)

• The Proportion of Subjects in Each Study Group With Post-ERCP Pancreatitis

  Post-ERCP pancreatitis (PEP) was based on a widely validated consensus definition that was applied as a diagnostic framework. In this consensus definition, PEP is diagnosed if there was new onset (or increase) of pain in the upper abdomen, elevation in pancreatic enzymes of at least three times the upper limit of normal 24 h after the procedure, and hospitalization for at least two nights. The outcome was independently adjudicated by 3 ERCP experts at non-enrolling centers based on review of the medical records for study participants who were hospitalized with any adverse event within 2 days of the ERCP. Medical records were redacted of all information that could potentially reveal study group assignment, including radiology reports. The consensus definition was applied as a diagnostic framework so that adjudicators could use their best judgment in cases that did not strictly satisfy the criteria. PEP was declared if there was agreement between at least two of the three adjudicators.

  Within 48 hours after ERCP

Secondary Outcomes (1)

• The Proportion of Subjects in Each Study Group With Moderate-severe Post-ERCP Pancreatitis

  Within one month of ERCP

Study Arms (2)

Indomethacin alone

EXPERIMENTAL

Indomethacin 100 mg rectally immediately after ERCP

Other: Indomethacin 100 mg rectally immediately after ERCP, NO prophylactic pancreatic stent placement

Indomethacin+pancreatic stent

ACTIVE COMPARATOR

Indomethacin 100 mg rectally immediately after ERCP AND prophylactic pancreatic stent placement

Other: Indomethacin 100 mg rectally immediately after ERCP AND prophylactic pancreatic stent placement

Interventions

Indomethacin 100 mg rectally immediately after ERCP, NO prophylactic pancreatic stent placement OTHER

Indomethacin alone

Indomethacin 100 mg rectally immediately after ERCP AND prophylactic pancreatic stent placement OTHER

Indomethacin+pancreatic stent

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Any patient undergoing ERCP in whom pancreatic stent placement is planned for post-ERCP pancreatitis prevention, is ≥ 18 years old, who provides informed consent, AND:
• Has one of the following:
• Clinical suspicion of or known sphincter of Oddi dysfunction
• History of post-ERCP pancreatitis (at least one prior episode of pancreatitis after ERCP)
• Pancreatic sphincterotomy
• Pre-cut (access) sphincterotomy (freehand pre-cut and septotomy)
• Difficult cannulation: cannulation duration ≥ 6 minutes (starting at time of initial papillary engagement with at least 25% of the time in contact with the papilla) AND/OR ≥ 6 cannulation attempts (defined as sustained contact with papilla lasting at least 1 second).
• Short-duration (≤ 1 min) balloon dilation of an intact biliary sphincter.
• Or has at least 2 of the following:
• Age \< 50 years old \& female gender
• History of recurrent pancreatitis (at least 2 episodes)
• ≥3 pancreatic injections
• Pancreatic acinarization
• Pancreatic brush cytology

You may not qualify if:

• Ampullectomy
• Cases in which a pancreatic stent must be placed for therapeutic intent
• Unwillingness or inability to consent for the study
• Pregnancy
• Breast feeding mother
• Standard contraindications to ERCP
• Allergy to Aspirin or NSAIDs
• Known renal failure (Cr \> 1.4 mg/dl)
• Ongoing or recent (within 2 weeks) hospitalization for gastrointestinal hemorrhage
• Ongoing or recent (within 1 week) hospitalization for acute pancreatitis
• Known chronic calcific pancreatitis
• Pancreatic head malignancy
• Procedure performed on major papilla/ventral pancreatic duct in patient with pancreas divisum (no manipulation of minor papilla)
• ERCP for biliary stent removal or exchange without anticipated pancreatogram
• Subjects with prior biliary sphincterotomy now scheduled for repeat biliary therapy without anticipated pancreatogram

Sponsors & Collaborators

• Medical University of South Carolina: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (20)

Univesrity of Southern California

Los Angeles, California, United States

Location

University of Colorado

Denver, Colorado, United States

Location

The Florida Hospital

Orlando, Florida, United States

Location

Emory University

Atlanta, Georgia, United States

Location

Northwestern University

Chicago, Illinois, United States

Location

University of Kansas

Kansas City, Kansas, United States

Location

Johns Hopkins University

Baltimore, Maryland, United States

Location

University of Michigan

Ann Arbor, Michigan, United States

Location

Washington University

St Louis, Missouri, United States

Location

Dartmouth University

Lebanon, New Hampshire, United States

Location

Case Western Reserve University

Cleveland, Ohio, United States

Location

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States

Location

Oregon Health & Science University

Portland, Oregon, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Location

Medical University of South Carolina

Charleston, South Carolina, United States

Location

Vanderbilt University

Nashville, Tennessee, United States

Location

Virginia Mason Medical Center

Seattle, Washington, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Location

University of Calgary

Calgary, Canada

Location

McGill University

Montreal, Canada

Location

Related Publications (2)

• Elmunzer BJ, Foster LD, Serrano J, Cote GA, Edmundowicz SA, Wani S, Shah R, Bang JY, Varadarajulu S, Singh VK, Khashab M, Kwon RS, Scheiman JM, Willingham FF, Keilin SA, Papachristou GI, Chak A, Slivka A, Mullady D, Kushnir V, Buxbaum J, Keswani R, Gardner TB, Forbes N, Rastogi A, Ross A, Law J, Yachimski P, Chen YI, Barkun A, Smith ZL, Petersen B, Wang AY, Saltzman JR, Spitzer RL, Ordiah C, Spino C, Durkalski-Mauldin V; SVI Study Group. Indomethacin with or without prophylactic pancreatic stent placement to prevent pancreatitis after ERCP: a randomised non-inferiority trial. Lancet. 2024 Feb 3;403(10425):450-458. doi: 10.1016/S0140-6736(23)02356-5. Epub 2024 Jan 11.

  PMID: 38219767 DERIVED

• Elmunzer BJ, Serrano J, Chak A, Edmundowicz SA, Papachristou GI, Scheiman JM, Singh VK, Varadarajulu S, Vargo JJ, Willingham FF, Baron TH, Cote GA, Romagnuolo J, Wood-Williams A, Depue EK, Spitzer RL, Spino C, Foster LD, Durkalski V; SVI study group and the United States Cooperative for Outcomes Research in Endoscopy (USCORE). Rectal indomethacin alone versus indomethacin and prophylactic pancreatic stent placement for preventing pancreatitis after ERCP: study protocol for a randomized controlled trial. Trials. 2016 Mar 3;17(1):120. doi: 10.1186/s13063-016-1251-2.

  PMID: 26941086 DERIVED

MeSH Terms

Interventions

Indomethacin

Intervention Hierarchy (Ancestors)

Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

Potential unmasking events occurred and could have influenced care. Decay in secondary outcome blinding, as unblinded clinician could resume care of patient after 48 h. Adjudicators provided radiographic information when assessing PEP severity, which may have influenced decision making. Unblinded endoscopists made procedural decisions, possibly altered according to study arm. Findings may not be applicable to community endoscopists since all sites were tertiary referral centers.

Results Point of Contact

• Title: Dr. B. Joseph Elmunzer
• Organization: Division of Gastroenterology & Hepatology, Medical University of South Carolina

elmunzer@musc.edu

8437926982

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: June 15, 2015
• First Posted: June 19, 2015
• Study Start: September 1, 2015
• Primary Completion: January 25, 2023
• Study Completion: January 25, 2023
• Last Updated: June 12, 2024
• Results First Posted: May 8, 2024

Record last verified: 2024-04

Locations

US (18); CA (2)