Comparative Effectiveness Between Indomethacin and Pancreatic Stenting in the Prevention of Post ERCP Pancreatitis

Study Overview
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Brief Summary
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Post ERCP pancreatitis (PEP) occurs in 4 to 5% of patients and is associated with significant morbidities and occasional mortalities. The use of rectall administered indomethacin and pancreatic duct stent (PDS) placement have independently been proven to reduce PEP. The comparative effectiveness of the two methods has however not been studied. It is argued that in the context of indomethacin, the placement of a PDS is unnecessary. Advocates for PDS insertion however believe that mechanical decompression of the pancreatic duct is critical in the prevention of pancreatitis. The investigators propose a multi-centre randomised controlled trial to compare the use of rectal indomethacin to PDS insertion in high risk patients in the prevention of PEP.

Detailed Description
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Background of research Pancreatitis is the most common complication after Endoscopic retrograde cholangiopancreatography (ERCP). It occurs in approximately 5% of patients. The risk can approach 20 to 30% in those with known pre- and intra-procedural risk factors. Three in 100 patients with post ERCP pancreatitis (PEP) consequently die. The placement of pancreatic duct stent and the use of rectal administered indomethacin have both been independently shown to reduce PEP. The placement of a pancreatic duct stent has been for a long time considered the gold standard in the prophylaxis against PEP. In a meta-analysis of 8 RCTs that compared the use of pancreatic duct stents to no treatment, pancreatic duct stenting in high risk patients reduces incidence of PEP by approximately 5 fold. In a landmark study by Elmunzer et al., rectal administered indomethacin was shown to reduce PEP (52 of 307 patients,16.9% to 27 of 295 patients, 9.2%, P=0.005). In the trial, >80% received pancreatic duct stents in addition to rectal indomethacin. Overall there have been 7 RCTs on the use of rectal indomethacin all showing benefits with its use, 3 with PDS and 4 without. In the literature, there has been no direct comparison between the use of rectal indomethacin alone and insertion of PDS. In a secondary analysis of the trial by Elmunzer et al., PEP following the use of rectal indomethacin alone was less compared with the placement of PDS. In a meta-analysis by Akbar et al. pooling 29 studies (22 PDS and 7 indomethacin), the use of rectal indomethacin alone was associated with fewer PEP when compared to insertion of PDS on an indirect comparison using network metaanalysis (OR 0.48, 95%CI 0.26-0.87). The more favorable results with rectal indomethacin alone raised the question if PDS insertion is necessary. Furthermore, in another secondary analysis, patients after failed PDS insertion had a 34.7% rate of pancreatitis. In contrary, the rate of pancreatitis was 16.4% in those after successful PDS and 12.1% after no attempt at PDS insertion. The SVI (stent versus indomethacin) trial (NCT024762279) by the US cooperative for Outcomes Research in Endoscopy (USCORE) group is an ongoing non-inferiority trial that compares indomethacin alone to the combination of indomethacin and PDS in 1430 high risk patients with the primary outcome of pancreatitis. The trial tests the hypothesis that PDS is no longer necessary in the context of rectal indomethacin. The rationale for the trial has been based on the secondary analysis of the Elmunzer trial and the network analysis aforementioned. The investigators argue that the relative merits of rectal indomethacin and PDS placement have not been established. There may have been substantial difference in the baseline risks between the trials using either rectal indomethacin and PDS placement alone. The small number of RCTs over the use of rectal indomethacin may have overestimated its beneficial effect especially among patients at lower risk of PEP. A direct comparison in the form of a RCT to compare effectiveness of both treatment modalities is required. The insertion of PDS may continue to be important in patients contraindicated for the use of NSAIDs. Research plan and methodology The investigators hypothesize that rectal administration of indomethacin is not inferior to placement of a pancreatic duct stent in the prevention of pancreatitis after ERCP in high risk patients. In patients randomised to receive pancreatic duct stents, the investigators sought to determine the success rate with PDS insertion and outcomes following successful or unsuccessful PDS insertion. In addition, the investigators analyse possible factors to PEP in both cohorts of patients on either indomethacin or PDS.

Official Title
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Comparative Effectiveness Between Rectally Administered Indomethacin and Pancreatic Stenting in the Prevention of Post Endoscopic Retrograde Cholangio-panceaticography (ERCP) Pancreatitis: a Randomized Trial

Conditions
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Post ERCP Pancreatitis

Intervention / Treatment
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* Device: pancreatic stenting
* Drug: Indomethacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: presence of one of the following risk factors for Post ERCP Pancreatitis sphincter of Oddi dysfunction history of PEP, pancreatic instrumentation or sphincterotomy, precut sphincterotomy, difficult cannulation defined by >5 cannulation attempts the use of double wire technique in bile duct access at least 2 of the followings including i) female age<50 ii) 3 pancreatograms iii) acinarization (contrast injection to tail fo pancreas). iv） normal bilirubin； v）guidewire to the tail of pancreas or secondary branches. Exclusion Criteria: patients intended for pancreatic stenting e.g. those with pancreatic duct strictures, ampullectomy, without informed consents from patient or next of kin age <18 pregnant or lactating women patients with altered anatomy except except Billroth I and II gastrectomy contraindications to the use of NSAIDs such as those with active gastrointestinal bleeding, renal failure (serum creatinine > 140) known NSAID allergy incipient heart failure.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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
Interventional Model Description: rectal indomethacin 100 mg to be administered before or after ERCP a PD stent to be inserted during ERCP (a 3 to 5 cm 5Fr single pigtail pancreatic duct stent without inner flap is used, the stent is inserted after deep cannulation of pancreatic duct with a .025 or .035 wire) or a PD stent plus rectal indomethacin 100 mg before or after ERCP In patients randomized to receive PD stenting, the number of attemtps is limited to 5.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: indomethacin<br>rectal indomethacin 100 mg to be administered before or after ERCP | Drug: Indomethacin<br>* rectally administered indomethacin before or after ERCP<br>* Other names: indocid;|
| Experimental: pancreatic stenting<br>a PD stent to be inserted during ERCP (a 3 to 5 cm 5Fr single pigtail pancreatic duct stent without inner flap is used, the stent is inserted after deep cannulation of pancreatic duct with a .025 or .035 wire) | Device: pancreatic stenting<br>* a PD stent to be inserted during ERCP (a 3 to 5 cm 5Fr single pigtail pancreatic duct stent without inner flap is used, the stent is inserted after deep cannulation of pancreatic duct with a .025 or .035 wire)<br>|
| Experimental: indomethacin plus pancreatic stenting<br>[rectal indomethacin 100 mg to be administered before or after ERCP] plus [a PD stent to be inserted during ERCP (a 3 to 5 cm 5Fr single pigtail pancreatic duct stent without inner flap is used, the stent is inserted after deep cannulation of pancreatic duct with a .025 or .035 wire] | Device: pancreatic stenting<br>* a PD stent to be inserted during ERCP (a 3 to 5 cm 5Fr single pigtail pancreatic duct stent without inner flap is used, the stent is inserted after deep cannulation of pancreatic duct with a .025 or .035 wire)<br>Drug: Indomethacin<br>* rectally administered indomethacin before or after ERCP<br>* Other names: indocid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| post-ERCP pancreatitis | Percentage of Participants with post ERCP pancreatitis | 30 days | 
| high severity of post-ERCP pancreatitis | Percentage of Participants with high severity of post-ERCP pancreatitis using the Clavian-Dindo classification (1 / 2 / 3 / 3a / 3b / 4 / 4a/ 4b / 5) | 30 days | 
| pancreatitis with complications | Percentage of Participants with pancreatitis with complications using Atlanta classification (Mild / Moderate / Severe / Critical ) | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hospital stay | period of hospitalisation (days) | 30 days | 
| endoscopic intervention due to PEP | Percentage of Participants with endoscopic intervention due to Post ERCP pancreatitis | 30 days | 
| radiologic intervention due to PEP | Percentage of Participants with radiologic intervention due to Post ERCP pancreatitis | 30 days | 
| surgery due to PEP | Percentage of Participants with Surgical intervention due to Post ERCP pancreatitis | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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post ERCP panceatitis, rectal indomethacin, pancreatic stents