Stent vs. Indomethacin for Preventing Post-ERCP Pancreatitis

Phase 3

Completed

• Conditions: Post-ERCP Pancreatitis
• Interventions: Other: Indomethacin 100 mg rectally immediately after ERCP, NO prophylactic pancreatic stent placement; Other: Indomethacin 100 mg rectally immediately after ERCP AND prophylactic pancreatic stent placement

• Registration Number: NCT02476279
• Lead Sponsor: Medical University of South Carolina

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.

Detailed Description

The purpose of the SVI study is to determine whether or not rectal indomethacin has no important loss of efficacy as compared to the combination of rectal indomethacin and prophylactic pancreatic stent placement in patients undergoing high-risk ERCP who require pancreatic stent placement (PSP) for the sole purpose of pancreatitis prevention. The primary efficacy endpoint is defined as post-ERCP pancreatitis defined per consensus (Altanta) criteria. Another way of stating the trial's purpose is that the proportion of subjects with post-ERCP pancreatitis on rectal indomethacin alone is not more than that of the combination of rectal indomethacin and prophylactic PSP by more than a pre-specified absolute amount (i.e., the non-inferiority margin).

This is a blinded, two-armed non-inferiority trial where eligible patients will be randomized to either the combination treatment or indomethacin alone. Participants will be randomized during the ERCP procedure after eligibility is confirmed, and receive indomethacin at the time of randomization. The primary efficacy endpoint of post-ERCP pancreatitis within 2 days from randomization will be assessed by an independent adjudication panel. The participant follow-up period is 30 days from randomization.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2015-06-15
• Study First Submitted QC: 2015-06-16
• Study First Posted: 2015-06-19
• Study Start: 2015-09
• Primary Completion: 2023-01-25
• Study Completion: 2023-01-25
• Status Verified: 2024-04
• Results First Submitted: 2024-04-15
• Results First Submitted QC: 2024-04-15
• Results First Posted: 2024-05-08
• Last Update Submitted: 2024-05-14
• Last Update Posted: 2024-06-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1950

Inclusion Criteria

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:

1. Clinical suspicion of or known sphincter of Oddi dysfunction

2. History of post-ERCP pancreatitis (at least one prior episode of pancreatitis after ERCP)

3. Pancreatic sphincterotomy

4. Pre-cut (access) sphincterotomy (freehand pre-cut and septotomy)

5. 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).

6. Short-duration (≤ 1 min) balloon dilation of an intact biliary sphincter.

   Or has at least 2 of the following:

7. Age < 50 years old & female gender

8. History of recurrent pancreatitis (at least 2 episodes)

9. ≥3 pancreatic injections

10. Pancreatic acinarization

11. Pancreatic brush cytology

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Exclusion Criteria

1. Ampullectomy
2. Cases in which a pancreatic stent must be placed for therapeutic intent
3. Unwillingness or inability to consent for the study
4. Pregnancy
5. Breast feeding mother
6. Standard contraindications to ERCP
7. Allergy to Aspirin or NSAIDs
8. Known renal failure (Cr > 1.4 mg/dl)
9. Ongoing or recent (within 2 weeks) hospitalization for gastrointestinal hemorrhage
10. Ongoing or recent (within 1 week) hospitalization for acute pancreatitis
11. Known chronic calcific pancreatitis
12. Pancreatic head malignancy
13. Procedure performed on major papilla/ventral pancreatic duct in patient with pancreas divisum (no manipulation of minor papilla)
14. ERCP for biliary stent removal or exchange without anticipated pancreatogram
15. Subjects with prior biliary sphincterotomy now scheduled for repeat biliary therapy without anticipated pancreatogram
16. Anticipated inability to follow protocol
17. Absence of rectum

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Indomethacin alone	Indomethacin 100 mg rectally immediately after ERCP, NO prophylactic pancreatic stent placement	Indomethacin 100 mg rectally immediately after ERCP
Indomethacin+pancreatic stent	Indomethacin 100 mg rectally immediately after ERCP AND prophylactic pancreatic stent placement	Indomethacin 100 mg rectally immediately after ERCP AND prophylactic pancreatic stent placement

Primary Outcome Measures

Name	Time	Method
The Proportion of Subjects in Each Study Group With Post-ERCP Pancreatitis	Within 48 hours after ERCP	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.

Secondary Outcome Measures

Name	Time	Method
The Proportion of Subjects in Each Study Group With Moderate-severe Post-ERCP Pancreatitis	Within one month of ERCP	Moderate or severe post-ERCP pancreatitis was based on the consensus definition as a diagnostic framework. For the severity assessment, radiographic information was made available to the adjudicators. The severity was defined as mild post-ERCP pancreatitis resulting in a hospitalization of ≤3 days, moderate post-ERCP pancreatitis resulting in a hospitalization of 4-10 days, and severe post-ERCP pancreatitis resulting in a hospitalization of \> 10 days, or leading to the development of pancreatic necrosis or pseudocyst, or requiring percutaneous or surgical intervention. The outcome was declared if there was agreement between at least two of the three adjudicators.

Trial Locations

Locations (20)

The Ohio State University Wexner Medical Center; 🇺🇸 Columbus, Ohio, United States

Univesrity of Southern California; 🇺🇸 Los Angeles, California, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States

University of Kansas; 🇺🇸 Kansas City, Kansas, United States

Washington University; 🇺🇸 Saint Louis, Missouri, United States

Dartmouth University; 🇺🇸 Lebanon, New Hampshire, United States

University of Calgary; 🇨🇦 Calgary, Canada

McGill University; 🇨🇦 Montreal, Canada

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Case Western Reserve University; 🇺🇸 Cleveland, Ohio, United States

Vanderbilt University; 🇺🇸 Nashville, Tennessee, United States

Virginia Mason Medical Center; 🇺🇸 Seattle, Washington, United States

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States

University of Colorado; 🇺🇸 Denver, Colorado, United States

The Florida Hospital; 🇺🇸 Orlando, Florida, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States