Randomized Trial of Rectal Indomethacin and Papillary Spray of Epinephrine Versus Rectal Indomethacin to Prevent Post-ERCP Pancreatitis
Condition: Post-ERCP Acute Pancreatitis
MeSH terms: Pancreatitis
Study type: Interventional

Summary: 
      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).
    

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.
    

Intervention name(s): Rectal Indomethacin; Epinephrine
Intervention type(s): Drug; Drug
Other intervention name(s): Indocin; NSAIDs; Adrenaline
Intervention MeSH terms: Indomethacin; Epinephrine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention