Rectally Administered Indomethacin to Prevent Post-ESWL-pancreatitis (RIPEP)
Phase: PHASE4
Conditions: Pancreatitis
Sponsor: Changhai Hospital

Protocol 
Supplement to: Rectal Indomethacin to Prevent Post-ESWL Pancreatitis: The RIPEP 
Randomized Clinical Trial

 
1 Title 
Rectal Indomethacin to Prevent Post ESWL-pancreatitis  
2 Trial registration 
NCT02797067, registered on May 29th, 2016, and was initially released on May 31st, 2016 
3 Protocol version and summary of amendments to the original 
protocol and SAP through course of study 
Version: 20171220A 
Issue date: 20 December 2017 
5/10/2017: 
1. Sample size increased from 1116 total subjects to 1370 total subjects because statistical power 
was recalculated. 
12/20/2017: 
The definition of the primary outcome, post-ESWL pancreatitis, is changed to the Revised Atlanta 
International consensus from Cotton’s criteria. Patients were identified as post-ESWL pancreatitis 
if meeting two out of three criteria: pain consistent with acute pancreatitis; amylase or lipase>3 
times normal limit; characteristic findings on imaging. 
4 Roles and responsibilities 
YYQ and NR drafted the manuscript. NR and JYG participated in the enrollment of patients in the 
study. YYQ and CW performed the sample size calculation. WBZ, LX, JP and XYT participated in 
the acquisition of data. HC, LHH, HW and BL lead the site-specific recruitments and carried out 
the study interventions. ZDJ, DW, YQD and LWW participated in the design of the study. ZL and 
ZSL conceived the project and led the study. ZL obtained funding of the study. All authors had 
access to the study data and reviewed and approved the final manuscript. 
5 Background 
Chronic pancreatitis encompasses a wide range of progressive fibro-inflammatory processes of the 
exocrine pancreas that eventually lead to damage of the gland, leading to abdominal pain, endocrine 
(diabetes) and exocrine insufficiency (steatorrhea). Pancreatic duct stones, a common complication 
of chronic pancreatitis, develop during the natural course of disease and are observed in 90% 

 
patients [1]. Current treatment options include endoscopic therapy, extracorporeal shock wave 
lithotripsy (ESWL) and surgery. ESWL disintegrates the stones as a compensatory role thus 
facilitating main pancreatic duct (MPD) sphincterotomy, stricture dilatation, stone extraction and 
MPD stenting during endoscopic retrograde cholangiopancreatography (ERCP) [2,3]. The 
European Society of Gastrointestinal Endoscopy (ESGE) recommends ESWL as a first step, 
immediately followed by endoscopic extraction of stone fragments for treating patients with 
uncomplicated, painful chronic pancreatitis and radiopaque stones of 5 mm or more obstructing the 
MPD [4]. Although proved as safe, effective and noninvasive in stone fragmentation [5–8], ESWL 
can still cause adverse events, which can be classified as complications and transient adverse events 
(TAEs), depending on the severity. Based on previous published studies, major complications were 
classified into five groups: post-ESWL pancreatitis, bleeding, infection, steinstrasse and perforation 
[6, 9]. It is reported that the rate of post-ESWL pancreatitis ranges from 6.3 to 12.5% [1]. According 
to previous data in our center, post-ESWL pancreatitis was the most common complication, with an 
overall occurrence rate of 6.8% for the first ESWL sessions. Some cases may need specific medical 
treatment or prolonged hospitalization, high medical expenditure and may even be life-threatening 
[9]. 
Compared to ESWL, complications of ERCP have been widely studied and the prevention strategies 
have been particularly analyzed by prior studies. Post-ERCP pancreatitis (PEP) also proved to be 
the most common complication with a reported incidence ranging from 3.6 to 15.1% in large-scale 
studies [10]. To date, various prophylactic procedures have been applied while prophylactic 
pancreatic stent (PPS) placement and rectally administered nonsteroidal anti-inflammatory drugs 
(NSAIDs) are promising for decreasing the rate and severity of PEP [11–16]. The strongly 
prophylactic effect of NSAIDs has prompted the European Society of Comparative 
Gastroenterology (ESGE), the Japanese Society of Hepato-Biliary-Pancreatic Surgery and The 
Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy (ASGE) 
to recommend the intrarectal administration of NSAIDs in all cases undergoing ERCP without 
contraindications [17–19]. Furthermore, Luo et al. have conducted a multicenter randomized 
controlled trial and demonstrated that pre-procedural rectal administration of indomethacin in 
unselected patients reduced the overall occurrence of PEP compared with a risk-stratified and post-
procedural strategy [20]. 

 
As there are few research regarding the incidence and prophylaxis of post-ESWL complications and 
given the potential clinical and economic benefit, we designed this prospective, randomized, 
double-blinded, placebo-controlled trial to investigate whether rectally administered indomethacin 
can effectively decrease the incidence and severity of post-ESWL pancreatitis as well as any 
associated adverse events, thus benefiting patients treated with pancreatic ESWL. 
6 Objectives 
To investigate whether rectal indomethacin can effectively decrease the incidence and severity of 
post-extracorporeal shock wave lithotripsy (ESWL) pancreatitis as well as associated transient 
adverse events, thus benefiting patients treated with pancreatic ESWL. 
7 Trial design 
The RIPEP trial is designed as a prospective, randomized, double-blinded, placebo-controlled 
clinical trial.  
8 Study setting 
The study is conducted in Changhai Hospital, which is a tertiary referral center and the largest 
digestive endoscopy center performing pancreatic ESWL in China. 
9 Eligibility criteria 
Inclusion criteria 
All patients (aged 18 years or older) with chronic pancreatitis treated with ESWL for pancreatic 
stones. ESWL is performed for the clearance of radiopaque obstructive MPD stones larger than 5 
mm located at the head/body of the pancreas. 
Exclusion criteria 
1) Readmitted to the hospital during enrollment of the study; 
2) Suspected or established malignancy; 
3) Pancreatic ascites; 
4) Receiving NSAIDs within 7 days;  
5) Contraindications to ESWL; 
6) Contraindication or allergy to NSAIDs (including gastrointestinal hemorrhage within 4 weeks 
or renal dysfunction with serum creatinine > 120 μmol/L); 

 
7) Presence of coagulopathy or received anticoagulation therapy within 3 days;  
8) Acute pancreatitis within 3 days; 
9) Known active cardiovascular or cerebrovascular disease; 
10) Unwilling or unable to provide consent; 
11) Pregnant or breastfeeding women; 
12) Being without a rectum (i.e., status post-total proctocolectomy). 
10 Interventions 
If inclusion/exclusion criteria are met and written informed consent has been obtained, the subject 
will be randomized to receive either a 100-mg indomethacin suppository or identical-appearing 
placebo. Glycerin suppositories used in our study are produced by department of pharmacy, 
Changhai Hospital, making them identical in appearance to indomethacin suppositories. Patients 
enrolled receive suppositories without packaging, making it possible that patients enrolled and 
performing endoscopists are all blinded to the assignment despite of the different packaging. The 
suppository will be administered within 30 min before ESWL by a trained research nurse blinded 
to the type of suppository labeled with allocation sequence. Randomization will occur in a 1:1 
fashion with a random number table generated by the investigator, making it possible that all the 
patients and staff endoscopists are blinded to the treatment assigned to each participant. 
ESWL will be performed by two endoscopists (HC and HW) using an electromagnetic lithotripter 
with bi-dimensional fluoroscopic targeting facility. The pretreatment procedure is similar to that for 
ERCP. Intravenously administered remifentanil combined with dexmedetomidine is administered 
for analgesia during the procedure. 
Patients are to be placed in the supine position or tilted to their right side at an angle of 30°. An 
intensity ranging from 1 to 6 was used with a frequency of 60–120 shocks per min during the 
procedure, and the exposure is limited to a maximum of 5000 shock waves per session. The duration 
of each session is 60–90 min. Routinely, it was set at an intensity of 6 with a frequency of 120 
shocks per min and a total of 5000 shock waves per session. The fragmentation of the stones is 
monitored by fluoroscopy during the pancreatic ESWL session. Vital signs of the patients will be 
closely monitored and procedure related parameters, intensity, frequency, duration and 
fragmentation efficacy, will be recorded by the performing endoscopists during and right after 

 
ESWL. 
After the ESWL, patients will be kept under surveillance for up to 24 h. A Visual Analogue Scale 
(VAS) before and after the procedure will be recorded. Serum amylase, routine hematology and 
biochemical tests will be measured in all study patients 3 and 24 h after the procedure and 
subsequently at clinical discretion. If new abdominal pain appears at any moment during the 
surveillance period, the amylase level will be measured. If abdominal pain suggests strongly that 
acute pancreatitis is present, but the serum amylase activity is less than three times the upper limit 
of normal, as may be the case with delayed presentation, imaging will be required to confirm the 
diagnosis of acute pancreatitis. All complications will be captured during hospitalization. Repeated 
ESWL sessions will be performed over consecutive days until the stones have been successfully 
fragmented, which is defined as stones broken into fragments ≤2 or 3 mm, or by the demonstration 
at X-ray of decreased stone density, increased stone surface, and heterogeneity of the stone which 
may fill the MPD and adjacent side branches. ERCP is routinely performed one or two days after 
the last session of ESWL or after complete recovery from post-ESWL complications for the 
clearance and visualization of the MPD. 
Patients who develop post ESWL/ERCP pancreatitis will be treated with standardized guideline-
based management for acute pancreatitis overseen by the treating physician. Usually most of the 
patients developed mild to moderate post-ESWL pancreatitis based on previous treatment, and no 
specific strategy was provided before the procedure. The management of patients with acute 
pancreatitis after the procedure includes closely monitored general supportive care consisted of 
adequate fluid resuscitation, supplemental oxygen, correction of electrolyte and metabolic 
imbalances and effective pain control. Efforts to rest pancreas includes fasting, nasogastric suction, 
proton pump inhibitors, somatostatin, and octreotide. Gabexate mesilate is used to reduce activated 
proteases. Prophylactic antibiotics is also used for prevention of infection. Appropriate treatment is 
provided once complications occur. 
11 Outcomes* 
Primary outcome 
The primary outcome is the incidence of post-ESWL pancreatitis. 

 
Patients were identified as post-ESWL pancreatitis if meeting two out of three criteria: pain 
consistent with acute pancreatitis; amylase or lipase>3 times normal limit; characteristic findings 
on imaging, in according to the Revised Atlanta International consensus. 
Secondary outcomes 
The secondary outcomes include the incidence of moderate to severe post-ESWL pancreatitis, 
asymptomatic hyperamylasemia and post-ESWL complications. The related definition and 
stratification of post-ESWL complications is shown in Table 1. 
 
*For patients undergoing more than one ESWL session during hospital admission, only the result 
of the first procedure will be included into analysis, and for patients readmitted only the first 
admission will be considered for enrollment. 
 
Table 1 Definitions of major complications of ESWL 
Complications 
Mild 
Moderate 
Severe 
Post-ESWL pancreatitis  
 
 
 
 
Two of the following: 
a) Pain consistent with 
acute pancreatitis; b) 
Amylase or lipase > 3 
times normal limit; c) 
Characteristic imaging 
findings, requires 
admission or extension 
of planned admission 
from 2 days to 3 days 
Requires hospitalization 
of 4 – 10 days  
 
Hospitalization for > 10 
days, pseudocyst, or 
intervention 
(percutaneous drainage 
or surgery)  
 
 
Bleeding 
Clinical evidence of 
bleeding, hemoglobin 
drop < 3 g, no 
transfusion  
Transfusion of ≤ 4 units, 
no angiographic 
intervention, or surgery  
Transfusion of ≥ 5 units 
or intervention 
(angiographic or 
surgical)  
Infection 
> 38 °C for 24 – 48 
hours  
Requires > 3 days of 
hospital treatment  
Abscess, septic shock, or 
intervention 
(percutaneous drainage 
or surgery)  
Steinstrasse 
Severe abdominal pain 
without other post-
ESWL complications  
Combined with other 
complications, or 
requires > 3 days of 
hospital treatment 
Combined with other 
complications; 
hospitalization for > 10 
days, or surgery  

 
Perforation 
Possible, or very slight 
leak of fluid, treatable 
with fluids and suction 
for≤ 3 days  
Any definite perforation 
treated medically for 4 – 
10 days  
Medical treatment for > 
10 days or intervention 
(percutaneous or 
surgical)  
 
12 Timeline 
See Fig.1. 
 
Figure 1. Schedule of enrolment, interventions and assessments. 
13 Sample size 
This trial is a superiority trial. According to our previous retrospective studies, post-ESWL 
pancreatitis occurred in about 6.8% of the patients for the first ESWL sessions and accounting for 
69.4% of complications in our center [9]. We estimate that 1370 patients (685 per arm), including a 
possible withdrawal rate of 5%, will provide a 50% reduction in the incidence of post-ERCP 
pancreatitis, corresponding to a relative risk of 0.5 with a two-tailed alpha of 0.05 and a power of 
80%.  
14 Recruitment 
All adult patients admitted with CP will be considered for inclusion into the study during their 

 
hospital admission in Changhai Hospital. The research members will screen the electronic medical 
record system every day to find the appropriate patients. Once a potential subject is found, the 
subject will be seen and examined by the research members. Once identified meeting the eligibility 
criteria, he or she will be invited to participate in the study. Written informed consent will be 
obtained from every patient. All subjects have the right to refuse or withdraw from the study without 
giving any reasons. 
15 Allocation 
After enrollment, patients will be randomized to receive either 100 mg of indomethacin 
suppositories or identical-appearing glycerin suppositories in a 1:1 ratio within 30min before the 
procedure by a trained research nurse. The randomization schedule was generated by the 
investigator using a random number table, making it possible that patients enrolled and performing 
endoscopists are all blinded to the treatment protocol assigned. 
16 Data management 
Data collection 
Clinical data regarding baseline characteristics (including age, sex, etiology, smoking status, 
complications, previous pancreatic surgery, and previous ERCP, etc., as listed in Table 2) and 
outcomes will be collected during hospital admission using a case record form (CRF). CRFs will be 
filled out by study group personnel blinded to group assignments.  
All clinical data from individual subjects will be de-identified and given a study number. The study 
number will serve as a link between the data and the subject’s identifiable information. The data 
will only be accessed by the primary investigator and research assistants. 
 
Table 2 Demographic and clinical characteristics of CP patients in the study 
Age 
   At onset of chronic pancreatitis 
   At diagnosis of chronic pancreatitis 
   At pancreas stone 
   At enrollment 
Sex 
Smoking status 
Etiology 

 
   Alcoholic CP 
   Idiopathic CP 
   Hereditary (Familial) CP 
   Metabolic 
   Traumatic  
   Others 
Complications 
   Diabetes 
   Steatorrhea  
   Pseudocyst 
   Common Bile Duct obstruction or stricture 
   Duodenal stenosis 
   Pancreatic fistula 
   Portal hypertension 
Previous pancreas surgery 
Previous ERCP 
Radiolucent stone 
 
Descriptive statistics and analysis 
All analyses will be performed on an intention-to-treat basis. For continuous variables, tests of data 
normality will be carried out using the Shapiro–Wilk test. Normally distributed variables will be 
presented as mean ± standard deviation (SD) and compared using Student’s t-tests. Non-normally 
distributed variables will be presented as median (interquartile range, IQR) and compared using 
Mann–Whitney U tests. Categorical variables will be presented as frequencies and percentages. Chi-
squared analysis or Fisher’s exact test will be used for comparison of categorical variables. Two-
sided P values less than 0.05 are considered statistically significant. Post hoc subgroup analyses of 
the primary outcome based on potential risk factors of ESWL identified earlier will be performed, 
including age, sex, main etiology, diabetes, and steatorrhea. Comparisons will be represented with 
relative risk (RR) and nominal 95 percent confidence intervals (CI). All statistical analyses will be 
performed using SPSS (version 23.0). 
17 Instruments 
Data collection, handling, record keeping 
Source documents provide evidence of participant involvement, consent and permit collection of 
the data acquired. Source documents will be retained at the investigator’s site and may include but 

 
are not limited to, consent forms, current medical records and laboratory results. All data will be 
primarily stored in a secure, locked room within the department of gastroenterology at Changhai 
Hospital, Shanghai. Only study staff will have access to these source documents. All study staff and 
investigators will endeavor to protect the rights of the study’s participants to privacy and informed 
consent.  
Case Report Forms 
CRFs will be treated as confidential documents and held securely in accordance with regulations. 
CRFs shall be restricted to those personnel approved by the Chief Investigator. The investigator 
shall sign the CRF to confirm the accuracy of the data recorded. 
Record Retention and Archiving 
The investigator will maintain all records and documents regarding the conduct of the study. These 
will be retained for at least 5 years, or for longer if required. If the responsible investigator is no 
longer able to maintain the study records, a second person will be nominated to take over this 
responsibility. 
18 Monitoring 
The data will be monitored every twelve months by the Data Safety Monitoring Committee (DSMC) 
which is independent of the trial organizers. The protocol adherence, the progress of the trial and 
the safety parameters will be accessed by the DSMC. All physicians who are involved in the study 
will be asked to report any potential adverse events during the study. These adverse events will be 
collected and discussed with the DSMC every twelve months. The outcome of the meeting of the 
monitoring committee will be sent to the ethics committee and the physicians who are involved with 
the study. Any death will be reported directly to the DSMC and is discussed about the cause of death. 
19 Ethics approval 
Ethical approval is obtained from Changhai Institutional Review Board. (CHEC2016-096) 
20 Informed consents 
Written informed consent will be obtained from each patient before randomization by his/her 
attending doctor.  
21 Protocol amendments 

 
Any subsequent amendments of the protocol need to be approved by the relevant ethical bodies 
before the implementation.  
22 Declaration of interests 
The authors declare that they have no competing interests. 
23 Dissemination 
We aim to present the results of these findings to national and international conferences. We also 
hope to disseminate finding by submitting results for publication in peer-reviewed journals. 
 
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