Randomized Trial of Rectal Indomethacin and Papillary Spray of Epinephrine Versus Rectal Indomethacin to Prevent Post-ERCP Pancreatitis (INDIEH)

A Randomized Trial of Rectal Indomethacin and Papillary Spray of Epinephrine Versus Rectal Indomethacin to Prevent Post-ERCP Pancreatitis in High Risk Patients

This research is being done to see if using a combination of rectal indomethacin and epinephrine spray during endoscopy, can prevent pancreatitis that may occur after ERCP (a type of gastrointestinal endoscopy).

Study Overview

• Status: Completed
• Conditions: Post-ERCP Acute Pancreatitis
• Intervention / Treatment: Drug: Rectal Indomethacin; Drug: Epinephrine

Detailed Description

Background: Post-ERCP pancreatitis (PEP) is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP) with an estimated incidence of 3-7% among average risk patients and 15-20% among patients at high risk for developing PEP. Around 500,000 - 700,000 ERCPs are performed annually in U.S. Even with a modest incidence of 5%, PEP results in approximately $150 million in healthcare costs in the US alone.

A recent landmark controlled trial demonstrated the superiority of rectal nonsteroidal antiinflammatory drug - NSAIDs (indomethacin) over placebo in preventing PEP among patients at high risk for PEP. Also, epinephrine sprayed on the major duodenal papilla was shown to reduce the incidence of PEP in multiple studies. Our group performed a network meta-analysis (NMA) which simultaneously compared 16 drugs evaluated in 99 randomized controlled trials with 25,313 patients, to determine their relative efficacy using direct and indirect comparisons. Interestingly, the NMA ranked epinephrine as the best performing drug, followed by rectal NSAIDs and nafamostat.

Indomethacin acts on pancreatic inflammation while epinephrine sprayed on duodenal papilla keeps the pancreatic duct open by reducing papillary edema. The use of these drugs in combination may potentially synergistically reduce or further reduce the incidence of PEP.

Hypothesis: A combination of papillary spray of epinephrine and rectal indomethacin is superior to the use of rectal indomethacin alone, for PEP prophylaxis among patients at high risk for PEP.

Sample size justification: Based on the information from earlier controlled trials, the Investigators assume that PEP incidence will be 10% in the rectal NSAID arm (Group A) and it will be reduced to 5% by the additional use of papillary spray of epinephrine (Group B). Therefore, a total of 474 patients in each arm, or 948 patients in total, will be required to see a 50% difference between the groups with a power of 0.8 and two sided alpha of 0.05.

Recruitment and Consenting: Patients scheduled to undergo ERCP will be screened for patient based inclusion / exclusion criteria and will be consented, in the private waiting area of the endoscopy units.

Randomization procedures and delivery of drugs: During ERCP performed according to standard clinical care, if the endoscopist determines that the patient meets the criteria for 'high-risk', the study coordinator will randomize the patient to either group A or B in a 1:1 fashion using a web-based central randomization system. Randomization will be stratified by each center and a randomly varying block size will be used. The patients will be randomized to either Group A - Patients will receive 20 ml of normal saline sprayed on the duodenal papilla and surrounding regions of edema, over a period of 1 minute using any ERCP cannulation catheter, at the end of procedure, just before the withdrawal of endoscope; followed by 100 mg of rectal indomethacin OR Group B - Patients will receive 20 ml of 0.02% epinephrine sprayed on the duodenal papilla and surrounding regions of edema, over a period of 1 minute using any ERCP cannulation catheter, at the end of procedure, just before the withdrawal of endoscope; followed by 100 mg of rectal indomethacin.

Statistical Plan: For the statistical analysis of primary end point, the difference in proportion of PEP among the two groups will be calculated by stratifying the site and by combining patients from all sites, as separate analyses. A two sided p-value of <0.05 will be considered statistically significant. The severity of PEP, mortality and other complications related to PEP will also be compared among the two groups. The data on the risk factors of PEP, incidence of PEP will be used for the development of PEP risk

Data and safety monitoring board (DSMB) charter: An Independent DSMB, clinical trial monitor (safety officer) will be formed consisting of five endoscopists from India and U.S., with expertise in biostatistics and clinical trial methodology. DSMB will review study related documentation including and not limited to, protocol, standard operating procedures, consent form, data entry forms; monitor study performance, will ensure adherence to good clinical practice guidelines and regulatory requirements; and will make appropriate recommendations to the investigators. All adverse events, will be reported to the safety officer by the study coordinators at each center. Blinded interim analysis will be performed at 33% and 66% of the sample size. If the PEP incidence or complication rate is >25% in any of the treatment groups, DSMB will break randomization code and will terminate the study. During interim analysis, if a statistically significant difference is found between the two groups (p<0.001), the study will be terminated for ethical considerations.

• Study Type: Interventional
• Enrollment (Actual): 948
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • Chandigarh, India, 160012
    • Post Graduate Institute of Medical Education and Research
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500082
      • Asian Institute of Gastroenterology
  • West Bengal
    • Kolkata, West Bengal, India, 700054
      • Apollo Gleneagles Hospitals
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Medical Institutions

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Major inclusion criteria (If patients meet at least 1 of the criteria):

  1. History of PEP
  2. Pancreatic sphincterotomy
  3. Pre-cut sphincterotomy
  4. Difficult cannulation (>5 attempts / 10 minutes to cannulate)
  5. Failed cannulation
  6. Pneumatic dilation of an intact sphincter
  7. Sphincter of Oddi dysfunction of Type I or Type II

• Minor inclusion criteria (If patients meet at least 2 of the criteria):

  1. Age < 50 & Female gender
  2. History of acute pancreatitis (at least 2 episodes)
  3. >/= 3 pancreatic injections (with at least 1 injection in tail)
  4. Pancreatic acinarization
  5. Pancreatic Brush Cytology

Exclusion Criteria:

1. Unwillingness or inability to consent for the study
2. Age < 18 years
3. Intrauterine pregnancy
4. Breastfeeding mother
5. Standard contraindications to ERCP
6. Allergy / hypersensitivity to aspirin or NSAIDs or epinephrine
7. Chronic renal disease (Cr > 1.4)
8. Active or recent (within 4 weeks) gastrointestinal hemorrhage
9. Acute pancreatitis (lipase peak) within 72 hours
10. Known chronic calcific pancreatitis
11. Pancreatic head mass
12. Receiving pancreatic duct stent placement for any indication
13. Procedure performed on major papilla/ventral pancreatic duct in patients with pancreas divisum
14. ERCP for pancreatic/biliary stent removal or exchange without anticipated pancreatogram
15. Subject with prior biliary sphincterotomy now scheduled for repeat biliary therapy without anticipated pancreatogram
16. Anticipated inability to follow protocol
17. Sphincter of Oddi dysfunction of Type III

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
Active Comparator: Rectal Indomethacin only; Patients in this group will receive 20 ml of normal saline sprayed on the duodenal papilla and surrounding regions of edema, over a period of 1 minute using any ERCP cannulation catheter, at the end of procedure, just before the withdrawal of endoscope; followed by 100 mg of rectal indomethacin.	Drug: Rectal Indomethacin; Other Names: Indocin; NSAIDs
Active Comparator: Rectal Indomethacin plus papillary spray of Epinephrine; Patients in this group will receive 20 ml of 0.02% epinephrine sprayed on the duodenal papilla and surrounding regions of edema, over a period of 1 minute using any ERCP cannulation catheter, at the end of procedure, just before the withdrawal of endoscope; followed by 100 mg of rectal indomethacin.	Drug: Rectal Indomethacin; Other Names: Indocin; NSAIDs; Drug: Epinephrine; Other Names: Adrenaline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Who Developed Post-ERCP Pancreatitis	The primary outcome variable of interest is the incidence of post ERCP pancreatitis (PEP) as defined by the consensus guidelines as 1) New or increased abdominal pain that is clinically consistent with a syndrome of acute pancreatitis and 2) amylase or lipase ≥ 3x the upper limit of normal 24 hours after the procedure and 3) Hospitalization or prolongation of existing hospitalization for at least 2 days.	24 hours after ERCP

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Who Developed Severe Post-ERCP Pancreatitis	Severity of PEP defined using the consensus grading as Mild PEP that results in hospitalization (or prolongation of existing hospitalization) for ≤3 days. Moderate PEP will be defined as PEP that results in hospitalization (or prolongation of existing hospitalization) for 4-10 days. Severe PEP will be defined as PEP that results in hospitalization (or prolongation of existing hospitalization) for > 10 days, or leads to the development of pancreatic necrosis or pseudocyst, or requires additional endoscopic, percutaneous, or surgical intervention.	up to 30 days after ERCP

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: Postgraduate Institute of Medical Education and Research; Asian Institute of Gastroenterology, India; American Society for Gastrointestinal Endoscopy; Apollo Gleneagles Hospitals, Kolkata
• Investigators: Principal Investigator: Vikesh K Singh, M.D., M.Sc., Johns Hopkins University

Publications and helpful links

General Publications

• Elmunzer BJ, Scheiman JM, Lehman GA, Chak A, Mosler P, Higgins PD, Hayward RA, Romagnuolo J, Elta GH, Sherman S, Waljee AK, Repaka A, Atkinson MR, Cote GA, Kwon RS, McHenry L, Piraka CR, Wamsteker EJ, Watkins JL, Korsnes SJ, Schmidt SE, Turner SM, Nicholson S, Fogel EL; U.S. Cooperative for Outcomes Research in Endoscopy (USCORE). A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012 Apr 12;366(15):1414-22. doi: 10.1056/NEJMoa1111103.
• Akshintala VS, Hutfless SM, Colantuoni E, Kim KJ, Khashab MA, Li T, Elmunzer BJ, Puhan MA, Sinha A, Kamal A, Lennon AM, Okolo PI, Palakurthy MK, Kalloo AN, Singh VK. Systematic review with network meta-analysis: pharmacological prophylaxis against post-ERCP pancreatitis. Aliment Pharmacol Ther. 2013 Dec;38(11-12):1325-37. doi: 10.1111/apt.12534. Epub 2013 Oct 20.
• Xu LH, Qian JB, Gu LG, Qiu JW, Ge ZM, Lu F, Wang YM, Li YM, Lu HS. Prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis by epinephrine sprayed on the papilla. J Gastroenterol Hepatol. 2011 Jul;26(7):1139-44. doi: 10.1111/j.1440-1746.2011.06718.x.
• Matsushita M, Takakuwa H, Shimeno N, Uchida K, Nishio A, Okazaki K. Epinephrine sprayed on the papilla for prevention of post-ERCP pancreatitis. J Gastroenterol. 2009;44(1):71-5. doi: 10.1007/s00535-008-2272-8. Epub 2009 Jan 22.
• Kamal A, Akshintala VS, Talukdar R, Goenka MK, Kochhar R, Lakhtakia S, Ramchandani MK, Sinha S, Goud R, Rai VK, Tandan M, Gupta R, Elmunzer BJ, Ngamruengphong S, Kumbhari V, Khashab MA, Kalloo AN, Reddy DN, Singh VK. A Randomized Trial of Topical Epinephrine and Rectal Indomethacin for Preventing Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis in High-Risk Patients. Am J Gastroenterol. 2019 Feb;114(2):339-347. doi: 10.14309/ajg.0000000000000049.

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Actual): December 2, 2016
• Study Completion (Actual): December 2, 2016

Study Registration Dates

• First Submitted: April 14, 2014
• First Submitted That Met QC Criteria: April 15, 2014
• First Posted (Estimate): April 16, 2014

Study Record Updates

• Last Update Posted (Actual): November 1, 2017
• Last Update Submitted That Met QC Criteria: October 2, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pancreatic Diseases; Pancreatitis; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic 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; Adrenergic alpha-Agonists; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Gout Suppressants; Adrenergic beta-Agonists; Tocolytic Agents; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Epinephrine; Indomethacin
• Other Study ID Numbers: IRB00034715 (Other Identifier: Johns Hopkins Medicine IRB)