Rectal Indomethacin Versus Rectal Indomethacin and Sublingual Nitrate for PEP Prevention

Study Overview
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Brief Summary
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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.

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

Conditions
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Post-ERCP Acute Pancreatitis

Intervention / Treatment
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* Drug: Isosorbide Dinitrate 5 MG
* Drug: Indomethacin 100 MG
* Drug: Sublingual Placebo
* Drug: Rectal placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ERCP, Post-ERCP pancreatitis, PEP, NSAIDs, indomethacin, nitrate