Rectal Indomethacin Versus Rectal Indomethacin and Sublingual Nitrate for PEP Prevention

Rectal Indomethacin Versus Rectal Indomethacin and Sublingual Nitrate to Prevent Post-ERCP Pancreatitis: a Multicentre, Non-inferiority, Double-blind, Randomised Trial

Patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) are at risk for post-ERCP pancreatitis (PEP), which is associated with adverse outcomes. Combination prophylaxis strategies are increasingly investigated to prevent PEP more effectively, and studies have confirmed the benefits. Two randomized controlled trials revealed that combination prophylaxis with rectal NSAIDs and sublingual nitrate has reduced PEP rates to 5.6%-6.7% in average-risk patients. However, there was concern regarding the safety of sublingual nitrate with reports of significant increasing the risk of hypotesion (rate of 54.9%) and headache (rate of 4.1%) as compared with placebo.

As a safety drug, rectal administration of one dose NSAIDs is recommended as basic chemoprophylaxis in common or high-risk patients in guidelines. Results from previous studies showed rectal administration of NSAIDs significantly reduced PEP rate to 4-5.3% in average-risk patients. Although the difference in demographics, study design and outcomes definition, evidence was obtained that rectal NSAIDS was associated with similar PEP rate as combination prophylaxis with rectal NSAIDs and sublingual nitrate. However, evidence is lacking from large, randomized clinical trials indicating that efficiency of PEP prevention with rectal NSAIDs alone is not inferior to with combination prophylaxis. The investigators conduct this trial to investigate the hypothesis that rectal NSAIDs alone is non-inferior to the combination prophylaxis in terms of PEP prevention, but with reduce side effect.

Study Overview

• Status: Active, not recruiting
• Conditions: Post-ERCP Acute Pancreatitis
• Intervention / Treatment: Drug: Isosorbide Dinitrate 5 MG; Drug: Indomethacin 100 MG; Drug: Sublingual Placebo; Drug: Rectal placebo

• Study Type: Interventional
• Enrollment (Actual): 2700
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Fujian
    • Xiamen, Fujian, China
      • Xiamen Humanity Hospital
  • Gansu
    • Lanzhou, Gansu, China, 730030
      • Lanzhou University Second Hospital
  • Shaanxi
    • Xi'an, Shaanxi, China, 710032
      • Xi'an Central Hospital
    • Xi'an, Shaanxi, China, 710032
      • Xijing hoapital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients (age, 18-80 y) with native papilla planned for diagnostic or therapeutic ERCP were eligible for enrollment in the study.

Exclusion Criteria:

• contraindications to ERCP;
• allergy to nitrates or NSAIDs;
• currently on nitrate medication;
• receiving NSAIDs within 7 days;
• not suitable for indomethacin eg, gastrointestinal hemorrhage within the past 4 weeks, renal dysfunction (creatinine level >1.4 mg/dL) or the presence of coagulopathy before the procedure (international normalized ratio > 1.5);
• acute pancreatitis within 3 days;
• pregnant or breastfeeding women;
• unwilling or inability to provide consent.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rectal indomethacin and sublingual nitrate; All patients without contraindications should receive sublingual isosorbide dinitrate within 5 min before ERCP. All patients without contraindications should receive rectal indomethacin within 30 min before ERCP.	Drug: Isosorbide Dinitrate 5 MG; All patients without contraindications should receive sublingual isosorbide dinitrate tablet within 5 minutes before ERCP.; Drug: Indomethacin 100 MG; All patients without contraindications should receive rectal indomethacin within 30 min before ERCP.
Active Comparator: Rectal indomethacin and sublingual placebo; All patients without contraindications should receive sublingual placebo within 5 min before ERCP. All patients without contraindications should receive rectal indomethacin within 30 min before ERCP.	Drug: Indomethacin 100 MG; All patients without contraindications should receive rectal indomethacin within 30 min before ERCP.; Drug: Sublingual Placebo; All patients without contraindications should receive sublingual placebo within 5 minutes before ERCP.
Active Comparator: Rectal placebo and sublingual nitrate; All patients without contraindications should receive sublingual isosorbide dinitrate within 5 min before ERCP. All patients without contraindications should receive rectal placebo within 30 min before ERCP.	Drug: Isosorbide Dinitrate 5 MG; All patients without contraindications should receive sublingual isosorbide dinitrate tablet within 5 minutes before ERCP.; Drug: Rectal placebo; All patients without contraindications should receive rectal placebo within 30 min before ERCP.
Placebo Comparator: Rectal placebo and sublingual placebo; All patients without contraindications should receive sublingual placebo within 5 min before ERCP. All patients without contraindications should receive rectal placebo within 30 min before ERCP.	Drug: Sublingual Placebo; All patients without contraindications should receive sublingual placebo within 5 minutes before ERCP.; Drug: Rectal placebo; All patients without contraindications should receive rectal placebo within 30 min before ERCP.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of post-ERCP Pancreatitis	The diagnosis of PEP was established if there was new onset of upper abdominal pain associated with an increased amylase or lipase level of at least 3 times the upper limit of normal range at 24 hours after the procedure, and hospitalization for at least 2 nights. Doctors are advised to use cross-sectional imaging to identify ambiguous PEP.	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of moderate to severe PEP	The severity classification of pancreatitis was defined according to the criteria of Cotton et al and the revised Atlanta criteria.	14 days
Other adverse events	Adverse effects of indomethacin, including gastrointestinal bleeding and renal failure. Adverse effects of nitrates, including hypotension, headache and dizziness. Other post-ERCP adverse events including cholangitis, bleeding, and perforation. Any other adverse outcomes possibly related to ERCP or experimental drugs that required hospital admission or a prolonged hospital stay for further management.	14 days

Collaborators and Investigators

• Sponsor: Air Force Military Medical University, China

Publications and helpful links

General Publications

• Sotoudehmanesh R, Eloubeidi MA, Asgari AA, Farsinejad M, Khatibian M. A randomized trial of rectal indomethacin and sublingual nitrates to prevent post-ERCP pancreatitis. Am J Gastroenterol. 2014 Jun;109(6):903-9. doi: 10.1038/ajg.2014.9. Epub 2014 Feb 11.
• Tomoda T, Kato H, Ueki T, Akimoto Y, Hata H, Fujii M, Harada R, Ogawa T, Wato M, Takatani M, Matsubara M, Kawai Y, Okada H. Combination of Diclofenac and Sublingual Nitrates Is Superior to Diclofenac Alone in Preventing Pancreatitis After Endoscopic Retrograde Cholangiopancreatography. Gastroenterology. 2019 May;156(6):1753-1760.e1. doi: 10.1053/j.gastro.2019.01.267. Epub 2019 Feb 14.
• Ding J, Jin X, Pan Y, Liu S, Li Y. Glyceryl trinitrate for prevention of post-ERCP pancreatitis and improve the rate of cannulation: a meta-analysis of prospective, randomized, controlled trials. PLoS One. 2013 Oct 1;8(10):e75645. doi: 10.1371/journal.pone.0075645. eCollection 2013.
• Luo H, Zhao L, Leung J, Zhang R, Liu Z, Wang X, Wang B, Nie Z, Lei T, Li X, Zhou W, Zhang L, Wang Q, Li M, Zhou Y, Liu Q, Sun H, Wang Z, Liang S, Guo X, Tao Q, Wu K, Pan Y, Guo X, Fan D. Routine pre-procedural rectal indometacin versus selective post-procedural rectal indometacin to prevent pancreatitis in patients undergoing endoscopic retrograde cholangiopancreatography: a multicentre, single-blinded, randomised controlled trial. Lancet. 2016 Jun 4;387(10035):2293-2301. doi: 10.1016/S0140-6736(16)30310-5. Epub 2016 Apr 28.
• Luo H, Wang X, Zhang R, Liang S, Kang X, Zhang X, Lou Q, Xiong K, Yang J, Si L, Liu W, Liu Y, Zhou Y, Wang S, Yang M, Chen W, Han Y, Shang G, Yang X, He Y, Zou Q, Guo W, Dai Y, Zeng W, Zhu X, Gong R, Li X, Nie Z, Wang Q, Wang L, Pan Y, Guo X, Fan D. Rectal Indomethacin and Spraying of Duodenal Papilla With Epinephrine Increases Risk of Pancreatitis Following Endoscopic Retrograde Cholangiopancreatography. Clin Gastroenterol Hepatol. 2019 Jul;17(8):1597-1606.e5. doi: 10.1016/j.cgh.2018.10.043. Epub 2018 Oct 31.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2020
• Primary Completion (Anticipated): May 30, 2022
• Study Completion (Anticipated): December 30, 2022

Study Registration Dates

• First Submitted: June 8, 2020
• First Submitted That Met QC Criteria: June 8, 2020
• First Posted (Actual): June 11, 2020

Study Record Updates

• Last Update Posted (Actual): October 22, 2020
• Last Update Submitted That Met QC Criteria: October 20, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: ERCP; nitrate; NSAIDs; PEP; indomethacin; Post-ERCP pancreatitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pancreatic Diseases; Pancreatitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; 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; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Reproductive Control Agents; Gout Suppressants; Tocolytic Agents; Nitric Oxide Donors; Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate; Indomethacin
• Other Study ID Numbers: KY20200522-4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No