Stent vs. Indomethacin for Preventing Post-ERCP Pancreatitis (SVI)

Stent vs. Indomethacin for Preventing Post-ERCP Pancreatitis: The SVI Trial

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.

Study Overview

• Status: Completed
• Conditions: Post-ERCP Pancreatitis
• Intervention / Treatment: 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

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.

• Study Type: Interventional
• Enrollment (Actual): 1950
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Calgary, Canada
    • University of Calgary
  • Montreal, Canada
    • McGill University
• United States
  • California
    • Los Angeles, California, United States
      • Univesrity of Southern California
  • Colorado
    • Denver, Colorado, United States
      • University of Colorado
  • Florida
    • Orlando, Florida, United States
      • The Florida Hospital
  • Georgia
    • Atlanta, Georgia, United States
      • Emory University
  • Illinois
    • Chicago, Illinois, United States
      • Northwestern University
  • Kansas
    • Kansas City, Kansas, United States
      • University of Kansas
  • Maryland
    • Baltimore, Maryland, United States
      • Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States
      • University of Michigan
  • Missouri
    • Saint Louis, Missouri, United States
      • Washington University
  • New Hampshire
    • Lebanon, New Hampshire, United States
      • Dartmouth University
  • Ohio
    • Cleveland, Ohio, United States
      • Case Western Reserve University
    • Columbus, Ohio, United States
      • The Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States
      • Oregon Health & Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States
      • University of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States
      • Vanderbilt University
  • Washington
    • Seattle, Washington, United States
      • Virginia Mason Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Indomethacin alone; Indomethacin 100 mg rectally immediately after ERCP	Other: Indomethacin 100 mg rectally immediately after ERCP, NO prophylactic pancreatic stent placement
Active Comparator: Indomethacin+pancreatic stent; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Proportion of Subjects in Each Study Group With Moderate-severe Post-ERCP Pancreatitis	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.	Within one month of ERCP

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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. Erratum In: Trials. 2020 Jun 3;21(1):471. doi: 10.1186/s13063-020-04458-0.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2015
• Primary Completion (Actual): January 25, 2023
• Study Completion (Actual): January 25, 2023

Study Registration Dates

• First Submitted: June 15, 2015
• First Submitted That Met QC Criteria: June 16, 2015
• First Posted (Estimated): June 19, 2015

Study Record Updates

• Last Update Posted (Actual): June 12, 2024
• Last Update Submitted That Met QC Criteria: May 14, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pancreatic Diseases; Pancreatitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Reproductive Control Agents; Gout Suppressants; Tocolytic Agents; Indomethacin
• Other Study ID Numbers: U01DK104833-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No