Stent vs. Indomethacin for Preventing Post-ERCP Pancreatitis: The SVI Trial
Phase: PHASE3
Conditions: Post-ERCP Pancreatitis
Sponsor: Medical University of South Carolina

SVI PROTOCOL 
 
CONFIDENTIAL 
 
MUSC.V6 February 2021 
 
Stent vs. Indomethacin for Preventing Post-ERCP 
Pancreatitis:  The SVI Trial 
 
 
 
A Multicenter Randomized Non-Inferiority Clinical Trial of 
Rectal Indomethacin Alone 
vs. 
Indomethacin & Prophylactic Pancreatic Stent Placement 
for Preventing Post-ERCP Pancreatitis in High-Risk Cases 
 
NCT02476279 
 
STUDY GROUP CHAIR 
B. Joseph Elmunzer, MD, MSc. 
Peter Cotton Professor of Medicine and Endoscopic Innovation 
Medical University of South Carolina 
 
 
Protocol Amendment 6: February 15, 2021 
Protocol History: 
Original Protocol: September 7, 2015 
Protocol Amendment 1: November 5, 2015 
Protocol Amendment 2: March 28, 2016 
Protocol Amendment 3: July 6, 2016 
Protocol Amendment 4: October 16, 2016 
Protocol Amendment 5: January 17, 2019 
 
 
Supported by: 
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
National Institutes of Health (NIH) 
 
 

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Investigators’ Agreement 
 
I have read the attached clinical protocol titled "Stent vs. Indomethacin for Preventing Post-ERCP 
Pancreatitis: The SVI Trial" revised in February 15, 2021 and agree to conduct the protocol as written 
in this document.  
 
I agree to comply with the Declaration of Helsinki/Tokyo/Venice on Experimentation in Humans 
as required by the United States Food and Drug Administration regulations, Code of Federal 
Regulations parts 50, 56, 312, ICH Good Clinical Practice Guidelines and all other applicable 
guidelines. 
 
I understand this document contains confidential information of the Department of 
Gastroenterology and Hepatology at the Medical University of South Carolina and cannot be 
disclosed to anyone other than study team members and members of the Institutional Review 
Board or Ethical Committee.   
 
I agree to ensure that this information will not be used for any purpose other than the evaluation 
or conduct of this clinical trial without the prior written permission of the Study Chairpersons. 
 
 
_________________________________ 
 
 
_____________________________ 
Signature of Principal Investigator 
 
 
 
Date 
 
 
_________________________________ 
 
 
 
Printed name of Principal Investigator 
 
 
 
_________________________________ 
 
 
______________________________ 
Signature of Co-Principal Investigator 
 
 
Date 
(When applicable) 
 
 
 
_________________________________ 
Printed name of Co-Principal Investigator 
(When applicable) 
 

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TABLE OF CONTENTS 
1.0 
SUMMARY .............................................................................................................................. 1 
1.1 
Acronyms .............................................................................................................................. 3 
2.0 
OBJECTIVES............................................................................................................................ 4 
2.1 
Primary .................................................................................................................................. 4 
2.2 
Secondary .............................................................................................................................. 4 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 4 
3.1 
Background ........................................................................................................................... 4 
3.2 
Rationale ............................................................................................................................... 6 
4.0 
STUDY PLAN .......................................................................................................................... 7 
4.1 
Study Design ......................................................................................................................... 7 
4.2 
Study Sites ............................................................................................................................. 7 
4.3 
Recruitment ........................................................................................................................... 7 
4.4 
Estimated Study Duration and Timeline ............................................................................... 7 
5.0 
ELIGIBILITY CRITERIA ........................................................................................................ 7 
5.1 
Inclusion Criteria ................................................................................................................... 7 
5.2 
Exclusion Criteria .................................................................................................................. 8 
6.0 
SUBJECT RECRUITMENT ..................................................................................................... 8 
6.1 
Screening of Potential Subjects ............................................................................................. 8 
7.0 
SUBJECT CONSENT ............................................................................................................... 9 
7.1 
Pre-Consent Eligibility Assessment ...................................................................................... 9 
7.2 
Presentation of Informed Consent ......................................................................................... 9 
8.0 
STUDY PROCEDURES ........................................................................................................... 9 
8.1 
Screening/Baseline Visit ....................................................................................................... 9 
8.1.1 
Informed Consent .......................................................................................................... 9 
8.1.2 
Medical History & Record Review ............................................................................. 10 
8.2 
Endoscopic Retrograde Cholangiopancreatography (ERCP) ............................................. 10 
8.2.1 
Participating endoscopists ........................................................................................... 10 
8.2.2 
ERCP & Follow Up .................................................................................................... 10 
8.2.3 
ERCP Procedure ......................................................................................................... 10 
8.2.4 
Randomization ............................................................................................................ 10 
8.2.5 
Indomethacin Administration ..................................................................................... 11 
8.2.6 
Pancreatic Stent Placement ......................................................................................... 11 
8.2.7 
Intra-procedural Intravenous Fluid Administration .................................................... 11 
8.2.8 
Maintenance of the Blind ............................................................................................ 12 
8.3 
Follow-Up Assessments ...................................................................................................... 12 
8.3.1 
Immediate Post-Procedure Care, Observation, and Discharge ................................... 13 
8.3.2 
Post-Intervention Evaluations ..................................................................................... 13 
8.4 
Biorepository ....................................................................................................................... 13 

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8.5 
ERCP Skills ......................................................................................................................... 14 
9.0 
PROCEDURE FOR UNBLINDING ...................................................................................... 14 
10.0 
DISCONTINUATION OF PARTICIPATION ....................................................................... 14 
10.1 
Subject Withdrawal ............................................................................................................. 14 
10.2 
Subject Removal from Study .............................................................................................. 15 
10.3 
Procedure for Discontinuation ............................................................................................ 15 
10.4 
Subject Lost to Follow-Up .................................................................................................. 15 
10.5 
Re-entering the Study .......................................................................................................... 15 
10.6 
Subject Transfers ................................................................................................................. 15 
11.0 
OUTCOMES DEFINITIONS ................................................................................................. 15 
11.1 
Primary ................................................................................................................................ 15 
11.2 
Secondary ............................................................................................................................ 16 
12.0 
DATA COLLECTION, MANAGEMENT, AND QUALITY CONTROL PROCEDURES . 16 
12.1 
Data Management ............................................................................................................... 16 
12.2 
Site Monitoring ................................................................................................................... 17 
12.3 
Data Security and Confidentiality ....................................................................................... 17 
13.0 
STATISTICAL CONSIDERATIONS .................................................................................... 17 
13.1 
Non-inferiority Margin ........................................................................................................ 17 
13.2 
Sample Size Calculation...................................................................................................... 18 
13.3 
Statistical Analyses ............................................................................................................. 19 
13.4 
Interim Analysis .................................................................................................................. 19 
13.5 
Data and Safety Monitoring Plan (DSMP) ......................................................................... 19 
14.0 
REGULATORY AND ETHICAL OBLIGATIONS .............................................................. 20 
14.1 
Informed Consent ................................................................................................................ 20 
14.2 
Institutional Review Board/Research Ethics Board ............................................................ 20 
14.2.1 
Initial Review and Approval ....................................................................................... 20 
14.2.2 
Amendments ............................................................................................................... 21 
14.2.3 
Annual Renewal .......................................................................................................... 21 
14.2.4 
Pre-Study Documentation Requirements .................................................................... 21 
14.3 
Subject Confidentiality ........................................................................................................ 21 
15.0 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ........................................................... 21 
15.1 
Study Termination ............................................................................................................... 21 
16.0 
ORGANIZATIONAL INFRASTRUCTURE ......................................................................... 21 
16.1 
Executive Committee .......................................................................................................... 21 
16.2 
Steering Committee ............................................................................................................. 22 
16.3 
Standing Committees .......................................................................................................... 22 
16.4 
Statistical and Data Management Center ............................................................................ 22 
16.5 
Medical Safety Monitor ...................................................................................................... 23 
16.6 
Data and Safety Monitoring Board ..................................................................................... 23 
17.0 
REFERENCES ........................................................................................................................ 23 

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1.0 
SUMMARY 
Protocol Title 
Stent vs. Indomethacin for Preventing Post-ERCP Pancreatitis 
Acronym 
SVI 
Clinical Trial Phase 
Phase III 
Study Sites 
Approximately 20 clinical centers in the United States and 
Canada 
Study Period 
Planned enrollment period – 7.5 years 
Planned duration of the study – 8 years 
Study Population 
Patients undergoing high-risk ERCP who require pancreatic 
stent placement for the sole purpose of pancreatitis 
prevention. 
Primary Study Objective 
To assess whether rectal indomethacin alone is non-inferior to 
the combination of rectal indomethacin and prophylactic 
pancreatic stent placement (PSP) for preventing post-ERCP 
pancreatitis (PEP) in high-risk cases. 
Secondary Study Objective 
To establish a repository of whole blood, serum, plasma, 
urine, duodenal fluid, and stool from study subjects that will 
allow future translational research elucidating the molecular 
and genetic mechanisms of PEP, as well as the mechanisms 
by which non-steroidal anti-inflammatory drugs prevent this 
complication. 
Study Design 
A comparative effectiveness, multi-center, randomized, 
double blind, non-inferiority study of rectal indomethacin 
alone vs. the combination of rectal indomethacin and 
prophylactic pancreatic stent placement for the prevention of 
post-ERCP pancreatitis in high-risk cases.  
Sample Size 
A maximum sample size of 2180 subjects (1090 in each arm) 
will be needed for 85% power to rule out that the upper two-
sided 95% confidence limit for the absolute difference 
between the two groups is greater than 5% in favor of 
combination therapy. 
Inclusion Criteria 
Any patient undergoing ERCP in whom pancreatic stent 
placement is planned for post-ERCP pancreatitis prevention, 
is ≥ 18 years old, who provides informed consent, AND: 
Has one of the following: 
1. Clinical suspicion of or known sphincter of Oddi 
dysfunction 
2. History of post-ERCP pancreatitis (at least one prior 
episode of pancreatitis after ERCP) 

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3. Pancreatic sphincterotomy 
4. Pre-cut (access) sphincterotomy (including septotomy) 
5. Difficult cannulation: cannulation duration ≥ 6 minutes 
(starting at time of initial papillary engagement with at 
least 25% of the time in contact with the papilla) 
AND/OR ≥ 6 cannulation attempts (defined as sustained 
contact with papilla lasting at least 1 second).  
6. Short-duration (≤ 1 min) balloon dilation of an intact 
biliary sphincter.  
Or has at least 2 of the following: 
7. Age < 50 years old & female gender 
8. History of recurrent pancreatitis (at least 2 episodes) 
9. ≥3 pancreatic injections 
10. Pancreatic acinarization  
11. Pancreatic brush cytology 
Exclusion Criteria 
1. Ampullectomy 
2. Cases in which a pancreatic stent must be placed for 
therapeutic intent 
3. Unwillingness or inability to consent for the study 
4. Pregnancy 
5. Breast feeding mother 
6. Standard contraindication to ERCP 
7. Allergy to Aspirin or NSAIDs  
8. Ongoing or recent (within 1 week) hospitalization for 
acute pancreatitis, or known ongoing biochemical or 
anatomic evidence of unresolved pancreatic injury. 
9. Known chronic calcific pancreatitis 
10. Suspected pancreatic head malignancy 
11. Procedure performed on major papilla/ventral pancreatic 
duct in patient with pancreas divisum (no manipulation of 
minor papilla) 
12. ERCP for biliary stent removal or exchange without 
anticipated pancreatogram  
13. Subjects with prior biliary sphincterotomy now scheduled 
for repeat biliary therapy without anticipated 
pancreatogram  
14. Anticipated inability to follow protocol 
15. Absence of rectum 
Study Intervention and 
Follow-up 
Subjects will undergo ERCP per clinical indication. During 
the procedure, if the attending endoscopist determines that 

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inclusion criteria have been met and none of the exclusion 
criteria are present, the subject will be randomized to receive a 
100 mg of rectal indomethacin (two 50 mg suppositories) only 
or the combination of prophylactic stent and 100 mg of rectal 
indomethacin. Subjects will be contacted at 5 and 30 days 
after the ERCP to assess for the development of outcome 
events.  
Primary Outcome Measure 
The primary endpoint is post-ERCP pancreatitis, defined per 
consensus (Atlanta) criteria: 1) New or increased pain in the 
upper abdomen 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 
(at least night of ERCP & next night). This outcome will be 
adjudicated by a blinded panel. 
Statistical Analysis for 
Primary Outcome Measure 
An intention-to-treat approach will be the primary basis for 
analysis of the primary outcome measure. The two-sided 95% 
upper confidence bound of the risk difference in the observed 
proportion of patients developing post-ERCP pancreatitis 
between the two treatment groups will be calculated. 
1.1 
Acronyms 
DSMB 
Data and Safety Monitoring Board 
DSMP 
Data and Safety Monitoring Plan 
ERCP 
Endoscopic Retrograde Cholangiopancreatography 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
MoP –  
Manual of Procedures 
MSM 
Medical Safety Monitor 
MUSC 
Medical University of South Carolina 
NCI 
National Cancer Institute 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
NIH 
National Institutes of Health 
NSAIDs  Non-Steroidal Anti-Inflammatory Drugs 
OPRR 
Office for Protection from Research Risks 
PEP 
Post-ERCP Pancreatitis 
PI 
Principal Investigator 

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PSP 
Pancreatic Stent Placement  
RCT 
Randomized Controlled Trial 
REB 
Research Ethics Board 
SAE 
Severe Adverse Event 
SC 
Steering Committee 
SDMC 
Statistical & Data Management Center 
SOD 
Sphincter of Oddi Dysfunction 
SSL 
Secure Socket Layer 
SVI 
Stent vs. Indomethacin 
UM 
University of Michigan 
2.0 
OBJECTIVES 
2.1 
Primary 
To assess whether rectal indomethacin alone is non-inferior by a pre-specified amount therapeutic 
effect to the combination of rectal indomethacin and prophylactic pancreatic stent placement (PSP) 
for preventing post-ERCP pancreatitis (PEP) in high-risk cases. 
2.2 
Secondary 
1. To assess whether rectal indomethacin alone is non-inferior by a pre-specified amount 
therapeutic effect to the combination of rectal indomethacin and PSP for decreasing the 
severity of PEP in high-risk cases. 
2. To establish a repository of whole blood, serum, plasma, urine, duodenal fluid, and stool from 
study subjects that will allow future translational research elucidating the molecular and 
genetic mechanisms of PEP, as well as the mechanisms by which non-steroidal anti-
inflammatory drugs prevent this complication. 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Background 
Post-ERCP Pancreatitis remains a significant public health issue: 
Pancreatitis is the most frequent complication of endoscopic retrograde cholangiopancreatography 
(ERCP) occurring in 2-10% of cases1 and accounting for substantial morbidity, occasional 
mortality, and increased health care expenditures. Twelve percent of those who develop post-
ERCP pancreatitis (PEP) will follow a severe clinical course that results in prolonged 
hospitalization or additional interventions, leading to significant patient suffering.2 It has been 
estimated that over 700,000 ERCP procedures are performed in the United States annually. 
Assuming a mid-range post-ERCP pancreatitis rate of 5%, over 35,000 cases of PEP occur in the 
US each year. Average Medicare reimbursement for PEP is approximately $6000, resulting in an 
estimated annual cost burden in excess of $200 million. 
Preventing post-ERCP pancreatitis:  

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Until recently, only pancreatic stent placement (PSP) had been shown to be effective in preventing 
PEP.3,4 PSP has become common clinical practice in the United States,5,6 however it remains 
technically challenging, time consuming, and costly.7-10 Moreover, attempting to place a pancreatic 
stent with subsequent failure actually increases the risk of PEP above baseline by inducing injury 
to the pancreas.11,12 Additionally, studies demonstrating the efficacy of PSP were conducted at 
referral centers by expert endoscopists who are highly skilled in pancreatic intervention – clinical 
outcomes from broader practices are not available and it seems likely that the effectiveness of PSP 
may be lower in less expert hands – and the risks higher, potentially mitigating the benefits of this 
intervention.  
Recently, we reported the results of our multi-center double-blind, randomized, controlled trial 
(RCT) demonstrating that rectal administration of indomethacin, a non-steroidal anti-
inflammatory drug (NSAID), significantly reduces the incidence and severity of PEP in high-risk 
cases.13 On the background of a prior meta-analysis showing that rectal NSAIDs are effective in 
preventing PEP,14 as well as the 2010 European Society of Gastrointestinal Endoscopy guidelines 
recommending rectal NSAIDs to all patients undergoing ERCP,15 this groundbreaking study, 
funded through the NIH-NIDDK R21 mechanism, has immediately, broadly, and meaningfully 
impacted clinical practice worldwide by convincing the GI community that rectal indomethacin 
has a concrete, beneficial role in ERCP practice. Several recent meta-analyses have confirmed the 
effectiveness of rectal NSAIDs for preventing post-ERCP pancreatitis, and existing practice 
guidelines recommend their use in all patients undergoing ERCP.  
Rectal indomethacin could replace pancreatic stent placement for preventing PEP:  
The aforementioned RCT enrolled 602 patients at elevated risk for PEP, most of whom (>80%) 
had undergone pancreatic stent placement. Secondary analysis revealed that those who received 
indomethacin and a pancreatic stent (n=247) had a PEP rate of 9.7% compared to 16.1% in subjects 
who received a stent alone (n=249) (p=0.04). Therefore, this trial showed that indomethacin 
confers protection in addition to PSP, however there are no studies examining whether 
indomethacin is effective when administered instead of PSP. If indomethacin were to obviate the 
need for pancreatic stent placement, major clinical and cost benefits in ERCP practice could be 
realized (see below).  
To further explore this possibility, we performed a post hoc, hypothesis-generating analysis of our 
indomethacin RCT which suggested that subjects who received indomethacin alone were less 
likely to develop PEP than those who received a pancreatic stent alone or the combination of 
indomethacin and stent, even after adjusting for underlying differences in subject risk.16 
Additionally, a recent network meta-analysis comparing the data supporting PSP with those 
supporting prophylactic NSAIDs demonstrated that rectal NSAIDs alone are not inferior to the 
combination of NSAIDs and PSP for preventing PEP.17  
Prophylactic pancreatic stent placement is thought to reduce the risk of PEP by relieving pancreatic 
ductal hypertension that develops due to procedure-induced edema and stenosis of the pancreatic 
orifice.1,8,9 PSP, however, is not completely effective because orifice edema is only one of several 
relevant pathophysiologic mechanisms in PEP. Other factors, such as chemical, allergic, 
enzymatic, and infectious injury are also likely to contribute to PEP,1 and may be induced or 
potentiated by the process of placing a pancreatic stent. Indeed, the superiority of indomethacin 
mono-prevention over any strategy involving PSP is biologically plausible because the 
indomethacin strategy avoids manipulation of the pancreatic orifice and instrumentation of the 
pancreatic duct.  

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3.2 
Rationale 
The SVI trial is a natural next step in the advancement of our understanding of PEP prevention by 
answering a critically important clinical question: can we replace an invasive and costly 
preventive intervention with a safe and inexpensive one? 
Potential impact of replacing PSP with rectal indomethacin prophylaxis: 
Research focusing on whether PSP remains necessary in the era of indomethacin prophylaxis is 
critical because replacing prophylactic stent placement by indomethacin mono-prevention in 
clinical practice has the following major potential advantages: 
1. Improving clinical outcomes by avoiding the phenomenon of attempted but failed PSP, which 
is associated with a high rate of PEP by causing pancreatic orifice injury but providing no 
ductal decompression.11,12 As mentioned, PSP is generally (but not universally) successful and 
effective in expert hands, however there are no data evaluating the success rates and 
effectiveness of PSP in real-life practice – it is possible that this phenomenon of failed PSP is 
occurring more frequently than has been reported in clinical trials from expert research centers. 
2. Improving clinical outcomes by avoiding the significant non-pancreatitis complications 
induced by PSP. Complications such as stent migration and duct perforation occur in up to 4% 
of cases.4 Rare complications may also occur during follow-up upper endoscopy to retrieve 
retained stents. 
3. Improving clinical outcomes because indomethacin alone may actually be more effective for 
preventing PEP than any strategy that employs PSP. As mentioned above, a post hoc analysis 
of our indomethacin RCT revealed that, after adjusting for underlying imbalances in the 
prevalence of risk factors for PEP between groups, subjects who received indomethacin alone 
(7.1% PEP rate) appeared to be at lower risk for PEP than subjects who received no prophylaxis 
(23% PEP rate), those who received PSP alone (16% PEP rate), and those who received the 
combination of indomethacin and PSP (9.5% PEP rate).16 Indomethacin alone may be more 
effective than any strategy involving PSP because it avoids manipulation of the pancreatic 
orifice and instrumentation of the pancreatic duct, interventions that are necessary to place a 
pancreatic stent but are also known to contribute to pancreatitis. 
4. Substantially reducing healthcare expenditures by eliminating the cost of stent placement in 
most cases, as well as eliminating the need for follow-up abdominal radiography (to ensure 
spontaneous passage of the stent) and follow-up upper endoscopies to remove retained stents. 
A cost-benefit analysis using data from our indomethacin RCT, published literature, and 
publicly available cost data, revealed that a prevention strategy employing rectal indomethacin 
alone could save approximately $150 million annually in the United States compared with a 
strategy of PSP alone, and $85 million compared with a strategy of indomethacin and PSP.16 
5. Allowing broader delivery of care to more patients (particularly in resource-limited 
environments) by allowing additional time for other endoscopic procedures and interventions. 
Since PSP requires approximately 10 minutes to perform,10 indomethacin mono-prevention 
would save 1 million procedural minutes (or 16,666 procedure hours) annually in the US, 
beneficial to patients and endoscopy units alike. For example, the time saved by not placing 
pancreatic stents in high-risk ERCP cases would allow unit and physician manpower to 
perform over 20,000 additional screening colonoscopies in the United States annually 
(assuming 45 minutes per colonoscopy).   

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4.0 
STUDY PLAN 
4.1 
Study Design 
This is a comparative effectiveness, multi-center, randomized, double blind, non-inferiority study 
of rectal indomethacin alone vs. the combination of rectal indomethacin and prophylactic 
pancreatic stent placement for the prevention of post-ERCP pancreatitis in high-risk cases. 
4.2 
Study Sites 
The study will be conducted at approximately twenty tertiary care academic medical centers in the 
United States and Canada. Each study center will have a site PI who is responsible for the overall 
direction of the study at the site level, and a full study coordinator who will be responsible for 
consenting and enrolling patients, conducting follow-up, inputting data for local subjects, 
obtaining medical records for subjects hospitalized after ERCP, and procuring and processing bio-
samples. Additionally, the Statistical & Data Management Center (SDMC) team will include a 
senior statistician, statistical analyst, data manager, database programmer, project manager, and 
clinical monitor(s). The collective goal of this research team is to ensure the on-budget, on-time 
execution of the study with the highest possible ethical, regulatory, and scientific integrity.    
4.3 
Recruitment 
The SVI trial will enroll a maximum of 2180 patients over 7.5 years. Therefore, an enrollment goal 
of 3 patients per site per month is necessary. We believe that this enrollment requirement is 
achievable given the volume of high-risk ERCP with stent placement performed at each of the 
sites.  
4.4 
Estimated Study Duration and Timeline 
Initiation of Study 
3 months 
Subject Recruitment 
90 months 
Pre-Treatment/Treatment/Follow-up 1 month 
Site Close Out/Analysis and Reports 5 months 
Total: 
96 months 
5.0 
ELIGIBILITY CRITERIA 
5.1 
Inclusion Criteria 
Subjects must meet the following inclusion criteria to be eligible for enrollment into the trial: 
Any patient undergoing ERCP in whom pancreatic stent placement is planned for the purpose of 
PEP prevention, is ≥ 18 years old, who provides informed consent, AND: 
Has one of the following: 
1. Clinical suspicion of or known sphincter of Oddi dysfunction 
2. History of post-ERCP pancreatitis (at least one prior episode of pancreatitis after ERCP) 
3. Pancreatic sphincterotomy 
4. Pre-cut (access) sphincterotomy (including septotomy) 

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5. Difficult cannulation: cannulation duration ≥6 minutes (starting at time of initial papillary 
engagement with at least 25% of the time in contact with the papilla) AND/OR ≥6 cannulation 
attempts (defined as sustained contact with papilla lasting at least 1 second). 
6. Short-duration (≤ 1 min) balloon dilation of an intact biliary sphincter.  
Or has at least 2 of the following: 
7. Age < 50 years old & female gender 
8. History of recurrent pancreatitis (at least 2 episodes) 
9. ≥3 pancreatic injections 
10. Pancreatic acinarization, defined as opacification of pancreatic parenchyma with ductal 
contrast injection  
11. Pancreatic brush cytology 
5.2 
Exclusion Criteria 
1. Ampullectomy 
2. Cases in which a pancreatic stent must be placed for therapeutic intent 
3. Unwillingness or inability to consent for the study 
4.  Pregnancy 
5. Breast feeding mother 
6. Standard contraindications to ERCP 
7. Allergy to Aspirin or NSAIDs 
8. Ongoing or recent (within 1 week) hospitalization for acute pancreatitis, or known ongoing 
biochemical or anatomic evidence of unresolved pancreatic injury. 
9. Known chronic calcific pancreatitis 
10. Suspected pancreatic head malignancy 
11. Procedure performed on major papilla/ventral pancreatic duct in patient with pancreas 
divisum (no manipulation of minor papilla) 
12. ERCP for biliary stent removal or exchange without anticipated pancreatogram 
13. Subjects with prior biliary sphincterotomy now scheduled for repeat biliary therapy without 
anticipated pancreatogram 
14. Anticipated inability to follow protocol 
15. Absence of rectum 
6.0 
SUBJECT RECRUITMENT 
6.1 
Screening of Potential Subjects 
All patients presenting to participating study centers for ERCP will be screened before the 
procedure for the presence of pre-procedural exclusion criteria. If no pre-procedural exclusion 
criteria are present, the potential study subject will be interviewed by a research coordinator to 
evaluate for pre-procedural inclusion criteria and obtain informed consent.  
Ongoing study recruitment efforts at each center will include the maintenance of a Screen Failure 
Log for the purpose of documenting the center population from which the subjects in this trial are 

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drawn who are not eligible for the study. All patients in whom the consent process for the SVI 
Study is initiated but randomization is not performed will be recorded on the SVI Screen Failure 
Log. A reason for exclusion for each of the patients will be recorded. Further details on the 
completion of the Screen Failure Log are located in the SVI Manual of Procedures (MoP).   
7.0 
SUBJECT CONSENT  
7.1 
Pre-Consent Eligibility Assessment 
Eligibility assessment will include: 
1) Verification that all pre-procedural inclusion/exclusion criteria have been evaluated correctly; 
2) Evaluation and documentation of relevant medical history; 
3) Documentation of medication history;  
4) Verification that all required information has been documented;  
5) Signed and dated informed consent.  
7.2 
Presentation of Informed Consent 
Consent will be obtained by either the Principal Investigator or by individuals approved by the 
Principal Investigator and whose names and copy of their curriculum vitae have been submitted to 
the SDMC. The initial consent will be the most recent IRB/REB-approved version. During the 
consent process the objectives of the study, as well as the risks and benefits of enrolling will be 
explained in detail to potential subjects. 
Informed consent will be obtained from subjects in the pre-procedure preparation area at the time 
of obtaining ERCP consent, as part of normal patient care at the institution. The Informed Consent 
process will be documented in the subject record to include a review of the trial, the informed 
consent document, and that subject questions were answered prior to signature of the 
consent. Subjects will receive a copy of the signed and dated informed consent document and the 
original signed and dated consent form will be placed in the subject record. Original informed 
consent documents will be maintained on-file at each participating center. Once consented and 
enrolled into the trial, subjects will be issued a unique code to be used on data collection forms 
and other research records throughout the duration of the trial. Consent to procure outside medical 
records will also be obtained from study subjects in the event they are admitted to an outside 
facility after the ERCP.   
To maximize recruitment, all patients without exclusion criteria will be asked to consent for the 
study, even if they do not meet any pre-procedural inclusion criteria. This strategy will increase 
enrollment because a subset of subjects will only become eligible for the study on the basis of 
meeting one or more intra-procedural inclusion criteria. 
8.0 
STUDY PROCEDURES 
8.1 
Screening/Baseline Visit  
The following events will occur during the baseline screening visit, on the day of the procedure 
in the pre-ERCP preparation area or during a clinic visit preceding the ERCP.  
8.1.1 Informed Consent 

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A written informed consent form will be reviewed and signed by each subject before any study-
related procedures are performed.  Investigators or designated staff may discuss the availability of 
the study and the possibility for entry with a potential subject without first obtaining consent.  
8.1.2 Medical History & Record Review 
Study-relevant medical history will be reviewed and documented. This will include questions 
about past medical history, including the indication for ERCP, prior history of PEP, and recurrent 
pancreatitis.   
8.2 
Endoscopic Retrograde Cholangiopancreatography (ERCP) 
8.2.1 Participating endoscopists 
All study ERCPs will be performed or directly supervised by board certified gastroenterologists 
with specialized expertise in ERCP who are faculty physicians at participating study centers. A 
proportion of study cases will involve trainees at varying stages of ERCP proficiency. The extent 
of participation of the trainee in the study ERCP will be left to the discretion of the attending 
endoscopist, although the degree of trainee involvement in the case, including their involvement 
in the various components of the ERCP, will be formally collected.  
8.2.2 ERCP & Follow Up 
The activities and procedures that will occur during the ERCP, recovery period, and follow up are 
outlined, and each procedure described in detail below. 
8.2.3 ERCP Procedure  
• Standard Medical Procedure Consent (Non-Research):  Subjects will review and sign a 
standard medical ERCP consent form (non-research) prior to the ERCP procedure.    
• Pre-Procedure Preparation:  Patients will have been advised to prepare for the ERCP prior 
to arrival, including instructions not to eat or drink anything after midnight the night before the 
procedure, or 6-8 hours prior, depending on the time of the procedure. All ALLERGIES should 
be reviewed and reported prior to ERCP. Patients are also advised what, if any, medications to 
avoid and/or medications that may require dosing or time changes (i.e., Metformin, insulin, 
anticoagulants). If approved by the physician, a small amount of liquid may be allowed to 
swallow important medications.  
• ERCP Procedure:  Almost all components of the ERCP and related interventions, except for 
prophylactic pancreatic stent placement, will be dictated by the performing endoscopist. The 
endoscopists will only use  devices approved by the FDA or Health Canada during the ERCP. 
8.2.4 Randomization 
During the procedure, when one or more inclusion criteria have been met AND it has been 
determined that none of the exclusion criteria are present, AND the papilla (major or minor 
depending on indication) has been visualized and deemed accessible, the subject will be 
randomized to receive a 100 mg of rectal indomethacin (two 50mg suppositories) only or the 
combination of PSP and 100 mg of rectal indomethacin in a 1:1 fashion using a web-based 
electronic randomization system that will be accessed on a computer within the endoscopy suite. 
The randomization schedule will be generated centrally at the data coordinating center and will 
ensure treatment balance within site.  

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NOTE: SUBJECTS NOT MEETING ANY INCLUSION CRITERIA OR IDENTIFIED AS 
INELIGIBLE BASED ON EXCLUSION CRITERIA DURING THE ERCP WILL 
NOT BE RANDOMIZED.   
• Subjects in whom the consent process is initiated but are not consented will be recorded in the 
Screen Failure Log along with the reason for eligibility exclusion or unwillingness to provide 
consent.  
• Consented subjects who are not randomized will be recorded in the Screen Failure Log along 
with the reason for eligibility exclusion.  
• Consented subjects not eligible for randomization will receive continued medical treatment per 
standard of care at each institution and appropriate details will be documented in the subject 
research record. 
8.2.5 Indomethacin Administration 
Indomethacin suppositories will be administered to subjects in both study groups by an endoscopy 
nurse, technician, or the endoscopist at the time of randomization during the ERCP. Rectal 
indomethacin was selected (as opposed to diclofenac) because it is approved by the FDA and 
Health Canada and commercially available in the United States and Canada. This dose of 
indomethacin is congruent with all prior studies evaluating rectal NSAIDs in PEP prevention, 
wherein a 100 mg dose of rectal NSAIDs is administered in the peri-procedural period. The rectal 
route was selected on the basis of available clinical data suggesting that only rectal NSAIDs are 
effective in PEP prophylaxis, perhaps due to more rapid and complete bioavailability. Several 
recent meta-analyses have confirmed the effectiveness of rectal NSAIDs for preventing post-
ERCP pancreatitis, and existing practice guidelines recommend their use in all patients undergoing 
ERCP. 
8.2.6 Pancreatic Stent Placement 
Patients randomized to the PSP group will undergo stent placement at the appropriate time during 
the ERCP. The technique by which prophylactic pancreatic stents are placed and the type of stent 
used will not be directed by the study protocol but rather deferred to the judgment and expertise 
of the endoscopist. This approach is intended to mimic real-world practice, wherein variations in 
stent type, caliber, and length exist.18 Specific information regarding stent make/model, caliber, 
length, guidewire used, amount of time required for deployment, and difficulty of stent placement 
will be collected to allow exploratory analyses of how stent characteristics influence PEP risk. For 
cases in which a pancreatic stent is placed to facilitate biliary access (precut sphincterotomy over 
a stent) or pancreatic sphincterotomy, if the subject is randomized to the indomethacin alone group, 
the pancreatic stent will be removed before the termination of the case. 
8.2.7 Intra-Procedural Intravenous Fluid Administration 
Intravenous fluid (IVF) administration during the ERCP will be left to the discretion of the 
clinicians involved in the ERCP (attending endoscopist, trainee, anesthesia personnel). Since IVF 
type and rate may influence the development of the primary and secondary endpoints, all decisions 
regarding IVF administration made by the endoscopy team must be implemented prior to 
randomization. After randomization, unblinded study personnel should not recommend any 
changes in IVF administration. For example, an attending endoscopist may ask anesthesia 
personnel to increase the IVF rate once he/she determines that the case has become high risk due 

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to a difficult cannulation. However, no further changes can be recommended or made once 
randomization has occurred.  
After randomization, urgent changes in IVF administration in response to hemodynamic instability 
or volume overload will be dictated by anesthesia personnel. All efforts should be made to ensure 
that these anesthesia personnel are not aware of the overall purpose of the study nor are they fully 
aware of study group assignment.  
Specific information regarding IVF administration immediately before, during, and after the case 
will be collected in the CRF to allow exploratory analyses of how IVFs influence PEP risk. 
8.2.8 Maintenance of the Blind 
Since the endoscopist(s), endoscopy nurse, and technician/assistant involved in the ERCP will be 
aware of whether or not a stent was placed, these individuals will not be involved in the subsequent 
post-procedure care of the patient until at least 48 hours after the procedure, at which point the 
presence or absence of the primary endpoint (PEP) will have become apparent. This approach is 
critical to maintaining blinding (of patients, treating clinical personnel, and outcome assessors), 
which ensures equal co-interventions between study groups and unbiased adjudication of the 
primary outcome.  
In order to ensure blinding of 1) subjects, 2) healthcare providers making clinical decisions that 
may directly impact the primary endpoint (e.g. rate of intravenous fluid administration, amount of 
analgesics delivered, decision to keep the patient in the hospital a second night), and 3) those who 
will adjudicate the study outcomes, the endoscopy report and medical record will NOT state 
whether a stent was placed. Instead, the following statement will be input into the endoscopy 
report:  
“This patient was enrolled in study protocol #xxxxxx in which he/she was 
randomized to receive either a dose of indomethacin only or both indomethacin and 
a prophylactic pancreatic stent for the prevention of post-ERCP pancreatitis. If this 
patient received indomethacin and a stent, he/she will be contacted 1-4 weeks after 
the ERCP to arrange an abdominal XRAY that is necessary to ensure spontaneous 
passage of the pancreatic stent.” 
If a stent was indeed placed, 1-4 weeks after the procedure, the endoscopist or their clinical support 
personnel will contact the subject and deliver a requisition for an abdominal XRAY. Ensuring that 
the XRAY is performed, following up on the results, and removing retained stents will be the 
responsibility of the treating endoscopist and his/her support staff, as per standard clinical 
protocols. Patients who receive this requisition will be unblinded to study group assignment 
although this will occur after the primary endpoint has been established. This unblinding could 
theoretically impact development or assessment of the secondary endpoint, although subjects will 
be discouraged from mentioning their randomization assignment to study personnel during the 
30-day telephone visit.  
We realize that a small fraction of study subjects will undergo abdominal imaging within the first 
2 post-ERCP days, the results of which may provide the clinical care team with information 
pertaining to PSP. This is an unavoidable threat to blinding; however, we believe that this will 
occur in only a small percentage of enrolled subjects. 
8.3 
Follow-Up Assessments 

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8.3.1 Immediate Post-Procedure Care, Observation, and Discharge 
Subjects will be observed in the recovery area for as long as clinically appropriate after the 
termination of the procedure. To ensure that the unblinded endoscopist does not influence the care 
of a study subject, each participating endoscopist will have the option of implementing a provider-
specific post-procedure order set that is activated prior to randomization and executed uniformly 
regardless of a subject’s study group assignment. This order set may include intravenous fluid, 
analgesic, and antiemetic administration as well as parameters for hospital admission. If activated, 
all clinical decisions pertaining to the immediate post-procedure care of the subject and to hospital 
admission will be dictated primarily by this order set. If an order set is not available or has not 
been activated, the endoscopist will be responsible for designating a blinded clinician who will 
oversee the post-procedure care of the patient. In these cases, all post-procedure clinical decisions 
(including IVF and analgesic administration & the decision to admit to the hospital) will be 
dictated by this blinded healthcare provider. Once a patient is admitted, all clinical decisions will 
be made by an inpatient team that cannot include the endoscopist for at least 48 hours after the 
ERCP.  
Performing endoscopists are permitted to communicate with patients and their families/friends 
after the procedure as long as they do not provide any direct or indirect information about treatment 
group assignment.  
Performing endoscopists may ask that subjects be admitted to the hospital for observation or for 
additional post-procedure care depending on factors that occurred during the case which are 
unrelated to the study group assignment.  
8.3.2 Post-Intervention Evaluations 
A study coordinator will perform two follow-up contacts:  
1) 3-5 days after the ERCP and,  
2) 30 days after the ERCP.  
The goal of the first follow-up is to ascertain those data necessary to adjudicate the primary 
endpoint. The goal of the second follow-up is to ascertain those data necessary to adjudicate the 
secondary outcome and assess for delayed serious adverse events. Permission to procure outside 
medical records (in the event a subject is admitted to a non-study center) will have been obtained 
at the time of consent. 
Visit Windows: The timeline of the assessments is based on a start date of randomization. Although 
every attempt should be made to contact the subject at these pre-specified intervals, it is possible 
that the assessments may occur within a window around the intervals. The study data should 
always be collected regardless of its tardiness, however preferable windows are 3-5 days after 
ERCP for the first assessment, and 30 days +/- 5 days for the second assessment.  
Subjects’ medical records may be reviewed for up to 5 years after enrollment to review ERCP 
results, additional ERCP findings, hospitalizations, and laboratory or radiology data. Study 
samples (see below) and clinical data will be stored indefinitely as long as consent has not been 
withdrawn. 
8.4 
Biorepository 

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To improve our understanding of the mechanisms by which indomethacin protects against PEP, as 
well as to further explore the incompletely understood pathophysiology of PEP, we will establish 
a repository of whole blood, serum, plasma, urine, duodenal fluid, and stool specimens obtained 
from trial subjects on which future translational studies can be conducted.  
Biologic specimens will be obtained from the first 1430 study subjects (original sample size) who 
agree to donate their samples. Subsequently, collection of specimens will be optional and 
dependent on a combination of individual site resources and subject consent. Specimen storage 
and tracking will be handled by the Clinical Ligand Assay Service Satellite (CLASS) Biosample 
Repository at the University of Michigan. The CLASS repository is a professionally managed 
biosample repository described in more detail in the “Resources and Environment” section and at: 
http://swan.class.sph.umich.edu/html/fn_classovr.htm. The samples will then be transferred in 
increments to the NIDDK Central Repository for long term storage. 
Complete procedures for sample procurement, processing, labeling, storage, tracking, and sharing 
are detailed in the current version of the MoP available on WebDCU™. 
8.5 
ERCP Skills  
An assessment of endoscopic skill and correlation with ERCP outcomes may be performed in a 
subset of subjects enrolled in SVI. The endoscopic and fluoroscopic footage of ERCP procedures 
in SVI subjects may be recorded. Participating endoscopists will each submit 5-20 videos of 
themselves performing complete ERCP procedures. The endoscopists will be asked to submit 
consecutive SVI cases, with at least 3 cases in which a biliary and/or pancreatic sphincterotomy is 
performed. After quality assurance of the footage and removal of all identifiers and non-critical 
footage, each video will be distributed to other endoscopists for peer rating. The correlation 
between endoscopic skill and adverse events will be examined to more concretely understand this 
relationship and to elucidate the composition of a skillful ERCP. 
9.0 
PROCEDURE FOR UNBLINDING 
The medical safety monitor, clinical personnel treating the patient for the first 48 hours after ERCP, 
subject, and outcomes adjudicators are blinded to treatment assignment. Every effort should be 
made not to break the blind.   
In the event of either an accidental or deliberate unblinding event, the clinical site individual who 
was unblinded must report the incident within one (1) calendar day of the unblinding in 
WebDCUTM. The incident should not be discussed with other clinical site personnel.  
In those cases of an emergency where the medical management of the subject would change based 
on the study procedure, emergency unblinding is authorized. Refer to the SVI MoP for emergency 
unblinding procedures. 
10.0 
DISCONTINUATION OF PARTICIPATION 
10.1 Subject Withdrawal 
The subject has the right to voluntarily withdraw from the study at any time for any reason without 
prejudice to his/her future medical care by the physician or at the institution.  
If a subject withdraws consent, the date and reason for consent withdrawal should be documented. 
Subject data will be included in the analysis up to the date of the consent withdrawal.  

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A distinction should be made between subjects who fail to complete all forms on schedule or who 
miss some clinic visits and those who withdraw consent. Missed or rescheduled visits will be 
documented, but the subject will continue to be followed in the future according to protocol 
requirements, and all follow-up data will be included in the protocol-specified analysis. 
10.2 Subject Removal from Study 
Subjects may be removed from the study if any of the following events occur: 
(1) 
Significant protocol violation, either on the part of the subject or Investigator. 
(2) 
Refusal of the subject and/or the legal guardian to remain in the study (i.e. consent 
withdrawal). 
(3) 
If the physician or the Medical Safety Monitor believes it is in the subject's best interest to 
discontinue participation in the study. 
(4) 
Administrative reasons, e.g., MUSC or NIDDK termination of the study. 
10.3 Procedure for Discontinuation 
The procedure to be followed at the time a subject either discontinues participation or is removed 
from the study is: 
(1) 
Adverse event assessment. 
(2) 
Attempt to perform final follow-up evaluations. 
(3) 
Complete the End-of-Study form, including an explanation of why the subject is withdrawing 
or withdrawn. 
10.4 Subject Lost to Follow-Up 
All attempts to make contact with the subject will be documented in the study database. A plan of 
action for following up on subjects who cannot be contacted via telephone is outlined in the SVI 
Manual of Procedures. When all possible attempts to locate the subject have failed, that subject 
will be considered ‘lost to follow up’.  
10.5 Re-Entering the Study 
If a subject who has withdrawn from the study voluntarily expresses interest in returning to 
complete the study, the subject can be re-entered. 
10.6 Subject Transfers 
Whenever a subject's medical care transfers to another clinical setting, every attempt must be made 
to obtain continued follow-up data and information on self-administered forms. 
11.0 
OUTCOMES DEFINITIONS 
11.1 Primary 
The primary endpoint is post-ERCP pancreatitis, based on consensus (Atlanta) guidelines:19 1) 
New or increased pain in the upper abdomen 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 (at least the night of ERCP & following night).   

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Using these consensus guidelines as a diagnostic framework, three adjudicators will independently 
assess for the development of PEP based on review of a site-provided AE narrative and medical 
records for each study subject hospitalized within 2 days after the ERCP. The primary outcome 
will be adjudicated by an independent committee consisting of the MSM and two other voting 
members. To help the adjudicators assess post-procedure pain, the AE narrative and the pre and 
post-ERCP numeric pain scale results administered by the study coordinator will be available to 
the adjudicators. PEP will be declared if 2 of the 3 adjudicators determine that a subject has 
experienced post-ERCP pancreatitis. This committee-adjudicated outcome will be used for the 
primary analysis. Complete details of the outcomes adjudication process are available in the MoP. 
11.2 Secondary 
The secondary endpoint is moderate-severe post-ERCP pancreatitis, also defined on the basis of 
consensus guidelines: mild PEP is defined as pancreatitis that results in hospitalization (or 
prolongation of existing hospitalization) for ≤3 days. Moderate PEP – pancreatitis that results in 
hospitalization (or prolongation of existing hospitalization) for 4-10 days. Severe PEP – 
pancreatitis that results in hospitalization (or prolongation of existing hospitalization) for > 10 
days, or leads to the development of a pancreatic fluid collection, or requires additional 
endoscopic, percutaneous, or surgical intervention. This outcome will also be adjudicated by the 
independent panel. Subjects may be unblinded to study group assignment after 7 days (if they 
receive notification for pancreatic stent follow-up), and thus the study is only partly double-blinded 
for the secondary endpoint.  
12.0 
DATA 
COLLECTION, 
MANAGEMENT, 
AND 
QUALITY 
CONTROL 
PROCEDURES 
Comprehensive data coordinating functions for this clinical trial, including clinical monitoring, 
database development, web-based data entry and management, as well as the creation and export 
of study reports for the data and safety monitoring board (DSMB) will be provided by the SDMC 
at MUSC.  
12.1 Data Management  
Data management will be handled by the SVI SDMC which is housed in the Data Coordination 
Unit (DCU) in the Department of Public Health Sciences at the Medical University of South 
Carolina (MUSC). All study activities will be conducted in coordination with the study PI, the 
clinical sites, and NIDDK, and will use an electronic data acquisition method where all clinical 
data on randomized subjects will be entered by the site personnel in real time. The latest version 
of each CRF will be available as a PDF file on the study website for use as worksheets and source 
documents by study personnel.  
The study data will be managed (including data queries) by the SDMC using the WebDCU™ 
system. This user-friendly web-based database system, developed by the DCU, will be used for 
regulatory document management, subject randomization, data entry, data validation, project 
progress monitoring, subject tracking, site monitoring, user customizable report generation and 
secure data transfer. 
Upon entry of CRFs into the study database, quality control procedures will be applied at each 
stage of data handling in order to ensure compliance with GCP guidelines, integrity of the study 
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All sites will be monitored by the SDMC and site monitors will conduct periodic site visits to 
review source documents and case report form information. A quality assurance record audit will 
be implemented. Audit findings will be used to identify and correct problems. 
12.2 Site Monitoring 
The SVI Site Monitoring Plan will be guided by the FDA Guidance on Risk-Based Monitoring 
and will be a combination of remote and on-site monitoring. Briefly, the designated monitor(s) 
will be able to check regulatory documents and certain CRFs remotely and the SDMC will work 
with each site to develop the best plan (i.e., remote access to medical records or uploading files to 
WebDCU). In addition to remote monitoring, the monitor(s) will visit the Clinical Centers at 
specified intervals for the purposes of comparing source documents (such as hospital/clinical 
charts) to electronic Case Report Forms (CRFs) and database verification. This review will also 
verify adherence to local regulations for conducting clinical research, protocol eligibility criteria 
and protocol schedule, and to ensure the consistency, accuracy, and completeness of the data. At 
all times the monitor will ensure that subject confidentiality is maintained. The investigator agrees 
that he/she will ensure that any issues, problems, or need for corrections that arise during the 
conduct of the study will be resolved in a timely manner. Additional details are located in the 
current version of the SVI Manual of Procedures located in WebDCU™. 
12.3 Data Security and Confidentiality 
During the course of the trial, user access to the files with subject identifiers, treatment assignment 
and files with study outcomes will be restricted to core SDMC staff with any exceptions to be 
approved by the Executive Committee.  
In addition to use of passwords and other security measures, all documents containing identifying 
information on individuals or physicians are considered confidential materials and will be 
safeguarded to the greatest possible extent.  No information, which identifies a specific person, 
hospital, or physician, will be released to, or discussed with anyone other than study staff members. 
Because the SDMC uses a web-based system, source documents and CRFs will remain at the 
participating sites. The study database only identifies study subjects by unique study identification 
codes. All data will be stored in a manner that is HIPAA compliant, without the ability to track the 
information back to a specific subject except through a password protected system. All collected 
information about a subject will be stored by a unique identification code. All SDMC personnel 
are certified by the NIH Office of Human Subjects Research in the Protection of Human Research 
Subjects course. 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 Non-Inferiority Margin 
Given the high economic and opportunity costs associated with pancreatic stent placement, as well 
as the risks of attempted but unsuccessful insertion, we believe that rectal indomethacin would 
replace PSP in clinical practice if we can demonstrate that it results in less than a 5% greater PEP 
rate compared to the combination of indomethacin and PSP. The 5% threshold is referred to as the 
non-inferiority margin. 
The value of this margin is based on a combination of statistical reasoning and clinical judgment 
and was chosen to ensure that the overall PEP proportion of the new treatment (indomethacin 

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alone) demonstrates a clinically unimportant difference from the active comparator arm (the 
combination of stent and indomethacin) as well as a clinically relevant superiority over a putative 
placebo (i.e., stent alone).   
From a statistical perspective, the margin should retain at least 50% of the superiority of the 
combination of stent and indomethacin (the active control in the trial) when compared to stent 
alone.20,21 Our recent indomethacin RCT conducted in high-risk patients revealed that the absolute 
risk difference in the proportion of subjects with post-ERCP pancreatitis between those that 
received indomethacin plus stent versus those who received stent alone was 6.4% (95%CI: 0.5%, 
12.3%) (27). Therefore, taking a fraction of this value gives a non-inferiority margin (δ) of 3.2% 
(δ = .5*6.4).  
Independent to the statistical approach, a questionnaire was circulated to clinical stakeholders 
regarding how much better (in absolute terms) combination therapy would have to be in preventing 
PEP as compared to indomethacin alone to justify continuing the use of combination therapy in 
clinical practice.  Seven of 11 respondents said that combination therapy would have to be 10% 
more effective and the remaining 4 said that it had to be at least 5% more effective.  
Based on both the statistical and clinical information, the pre-specified non-inferiority margin was 
set at 5%. The clinical investigators unanimously judged that a difference in treatment effect of 
5% or greater constitutes an important difference between PEP proportions between the two 
treatment arms indicating that a strategy of indomethacin alone is inappropriate to adopt due to the 
higher risk of PEP.  Although the statistical guidance suggested a lower margin (3.2%), a non-
inferiority margin of 3.2% was considered impractical as it would require a sample size of 
approximately 1700 subjects per arm (to maintain the proposed 85% power), and it was strongly 
perceived by experts in the field that a margin of 5% would be adequate to definitively impact 
clinical practice if non-inferiority is declared.  
13.2 Sample Size Calculation 
The sample size is estimated using a confidence interval approach focusing on the upper 
confidence limit for a difference in proportions via simulation using nQuery.23 Based on results of 
our prior randomized controlled trial, the rate of PEP in subjects receiving the combination of 
indomethacin and PSP is estimated to be 9.5% for the risk-adjusted population and 9.7% of the 
unadjusted population.22 We chose to use the higher (unadjusted) proportion for a more 
conservative approach to sample size estimation. Based on this information, the study is powered 
to assure 85% likelihood of identifying less than a 5% absolute difference (non-inferiority margin) 
in PEP rates between the two treatment groups. For sample size estimation for a non-inferiority 
design, we set the independent proportions to be equal between the two treatment arms, the 
confidence level for the upper limit at 0.975 (equivalent to a one-sided 2.5% level test) and the 
upper limit of the confidence interval at 5% (NI margin). The maximum sample size required for 
randomization is 1300 subjects (650 per treatment group). Due to the potential non-adherence rate, 
the total sample size is inflated by 5% to account for a small probability of treatment crossovers 
or losses to follow-up. Thus, a total of 1430 subjects will need to be enrolled and randomized. The 
sample size was increased to a maximum of 2,180 in order to attain 85% power.  This increase 
was due to the DSMB recommendation based on the review of the planned blinded sample size 
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We recognize that sample size estimation is based on assumptions and if the control (i.e., 
combination arm) PEP rate is higher than 9.7% then we may begin to see a decrease in power.  To 
reduce the likelihood of an underpowered study due to incorrect sample size assumptions, a 
blinded sample size re-estimation will be conducted at the time of the first planned futility analysis 
(but prior to the futility analysis).  The study Statistical Analysis Plan (SAP) contains the details 
of this process. 
13.3 Statistical Analyses 
An intention-to-treat approach will be the primary basis for analysis. For the analysis of the 
primary and secondary endpoints, the two-sided 95% upper confidence bound (equivalent to the 
one-sided 97.5% upper confidence bound) of the observed risk difference in the proportion of 
patients developing post-ERCP pancreatitis (or moderate-severe PEP) between the two treatment 
groups (indomethacin alone – combination of indomethacin and PSP) will be calculated. 
Indomethacin alone will be declared non-inferior to combination therapy if the two-sided 95% 
upper confidence bound of the treatment difference is less than 5%. If indomethacin is found to be 
non-inferior, an analysis for superiority will be conducted using a one-sided two sample test for 
independent binomial proportions.24 
Exploratory subgroup analyses will be performed as specified in the Statistical Analysis Plan 
(SAP). These exploratory subgroup analyses will allow the development of hypotheses about 
subgroups of patients that may particularly benefit from PSP.  
All statistical analyses are outlined in the study Statistical Analysis Plan.  
13.4 Interim Analysis 
Two interim analyses for futility using conditional power will be conducted when approximately 
one-third (N~472) of the original sample size and one-half (N~1090) of the revised sample size 
(N=2180) have been evaluated for the primary outcome and all of the outcomes to be used in the 
analysis are adjudicated. The goal of the interim analysis plan is to determine whether to stop the 
trial early because it is unlikely to show non-inferiority at the final analysis. A conditional power 
will be calculated to assess the probability of observing non-inferiority at the final analysis 
conditional on the observed data and assumptions on the PEP event rates for the remainder of the 
trial. Conditional power will be calculated under two different assumptions: 1) the assumption that 
the PEP rates in the two treatment arms for the remainder of the trial will be the same as those 
hypothesized (pC=9.7%; pI=9.7%); and, 2) the assumption that the PEP rates observed at the 
interim analysis will be maintained for the remainder of the trial.   See the Statistical Analysis Plan 
for more details. 
13.5 Data and Safety Monitoring Plan (DSMP) 
Our previous large-scale RCT suggested that indomethacin alone may be more effective (safer) 
than any strategy involving PSP because it avoids manipulation of the pancreatic orifice and 
instrumentation of the pancreatic duct, interventions that are necessary to place a pancreatic stent 
but are known to contribute to pancreatitis.16 Nevertheless, PSP is routinely used in clinical 
practice for the prevention of PEP in high-risk cases. Our proposed comparative effectiveness 
study will randomize 50% of subjects to not receive a pancreatic stent even though one would 
likely have been placed in routine clinical practice. We are therefore ethically obligated to ensure 

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that withholding this intervention from high-risk patients as part of this study protocol is not 
causing excess harm.  
Study data and safety will be monitored by the NIDDK-appointed Data and Safety Monitoring 
Board (DSMB). This board serves in a consultative capacity to inform the NIDDK decisions 
regarding conduct of the study.  
The complete DSMP is presented in a separate safety monitoring plan document. In brief, there 
will be an independent medical safety monitor (MSM) who reviews in real-time all submitted 
serious adverse events and receives quarterly safety reports from the SDMC. The MSM will 
provide his/her review of the relevant SAEs regarding seriousness, relatedness and expectedness.  
Both the site and MSM entries will be presented to the DSMB. 
14.0 
REGULATORY AND ETHICAL OBLIGATIONS 
14.1 Informed Consent 
In accordance with US FDA regulations (21 CFR 50) and guidelines (Federal Register, May 9, 
1997, Vol. 62, Number 90–ICH Good Clinical Practice Consolidated Guideline), it is the 
investigator’s responsibility to ensure that legally effective informed consent is obtained from the 
participant before participating in an investigational study, after an adequate explanation of the 
purpose, methods, risks, potential benefits and participant responsibilities of the study. Procedures 
that are to be performed as part of the practice of medicine and which would be performed whether 
or not study entry was contemplated, such as for diagnosis or treatment of a disease or medical 
condition, may be performed and the results subsequently used for determining study eligibility 
without first obtaining consent. On the other hand, informed consent must be obtained prior to 
initiation of any screening procedures that are performed solely for the purpose of determining 
eligibility for research.  
Each subject must be given a copy of the signed and dated informed consent. The original signed 
consent must be retained in the institution’s records and is subject to review by the sponsor, 
coordinating center, the FDA or representative from another agency that performs the same 
function, and the IRB/REB responsible for the conduct of the institution. ICH Good Clinical 
Practice guidelines will be followed to the extent required by the FDA and Health Canada. 
Informed consent will be obtained by either the principal investigator or by individuals approved 
by the clinical center’s principal investigator and whose names have been submitted to the 
coordinating center. Informed consent will be obtained from the subject or subject’s legally 
acceptable representative after the details of the protocol have been reviewed. The individual 
responsible for obtaining consent will assure, prior to signing of the informed consent, that the 
subject has had all questions regarding therapy and the protocol answered. 
14.2 Institutional Review Board/Research Ethics Board 
In accordance with US FDA (21 CFR 56) and Health Canada regulations and guidelines (US 
Federal Register, May 9, 1997 Vol. 62 Number 90 - ICH Good Clinical Practice Consolidated 
Guideline), all research involving human subjects and changes to the research plan must be 
reviewed and approved by a local IRB/REB. 
14.2.1 Initial Review and Approval 

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A copy of the protocol, proposed informed consent form, other written subject information, and 
any proposed advertising material must be submitted to the Clinical Center’s IRB/REB for written 
approval.   
14.2.2 Amendments 
Protocol amendments may only be made with the prior approval of the SVI Executive Committee 
and the NIDDK. Substantive changes to the protocol require DSMB review prior to 
implementation. The Principal Investigator must agree to, and obtain approval from the IRB/REB 
for, all protocol amendments and revisions to the informed consent document as dictated by 
Executive Committee. The Principal Investigator at each clinical center must obtain approval from 
the IRB/REB for all revisions to the informed consent document, whether initiated by the 
investigator or Executive Committee.  
14.2.3 Annual Renewal  
The Principal Investigator will be responsible for obtaining annual IRB/REB approval renewal 
throughout the duration of the study. 
14.2.4 Pre-Study Documentation Requirements 
The Principal Investigator at each Clinical Center is responsible for uploading all required 
regulatory documents to the WebDCU™ for review by the SVI Project Manager or SDMC prior 
to recruitment. 
14.3 Subject Confidentiality 
The Principal Investigator at each Clinical Center must ensure that subject confidentiality is 
maintained. Enrolled subjects will be identified on any study documentation only by their initials 
and a study identification number generated by WebDCU™. 
15.0 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
15.1 Study Termination 
The study will be complete when all subjects have had their final study assessments. The sponsor 
or Executive Committee reserves the right to terminate the study if new information becomes 
available on the safety or efficacy of the study product or if such action is justified. 
If the Executive Committee terminates the study or individual study sites for the reasons given 
above, the investigator will provide any outstanding data or documentation (e.g., case report form 
pages) considered appropriate by the Coordinating Center at the time. 
The Clinical Center reserves the right to terminate the study according to the contract. The 
investigator is responsible for notifying the IRB/REB in writing of the trial’s completion or early 
termination.   
16.0 
ORGANIZATIONAL INFRASTRUCTURE 
16.1 Executive Committee 
The Executive Committee (EC) is composed of the study PI, the SDMC PI, the project manager, 
the NIDDK program officer, and the NIDDK project scientists. 

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The EC prepared the final protocol and will provide long-term scientific direction for the study at 
the operational level. The EC will advise and assist the SDMC on operational matters, monitor the 
performance of the clinical centers and communicate requests for any proposed ancillary changes 
in the protocol to the Project Scientist and the DSMB. The Executive Committee will review 
reports from the SDMC on performance of each participating institution to identify and implement 
solutions to problems that arise (in discussion with the Steering Committee). In addition, the 
collection, review and oversight of dissemination of SAE occurrences and other important events 
pertinent to the study will be the responsibility of the Executive Committee; as well as 
communication among all components of the study participants (e.g., SDMC, clinical centers, 
Steering Committee, DSMB).   
Throughout the study, the Executive Committee will meet monthly and ad hoc as needed. The 
Executive Committee will coordinate Investigator Meetings and/or continued training & 
education. Additional details including membership information are located in the current version 
of the SVI Manual of Procedures located on WebDCU™.  
16.2 Steering Committee 
The Steering committee (SC) is composed of the study PI, site PIs, SDMC PI, and the NIDDK 
project scientist. 
The SC has overall responsibility for assuring the scientific, clinical and ethical integrity of the 
study. The SC will meet on a regular basis, at least four times annually and in between as 
circumstances indicate.  This committee’s comprehensive list of duties/responsibilities is detailed 
in the current version of the SVI Manual of Procedures located on WebDCU™.  
16.3 Standing Committees 
Potential standing committees will be convened to address key study issues, such as the 
biorepository, ancillary studies, and publications. Further details regarding the standing 
committees can be found in Manual of Procedures located on WebDCU™.  
16.4 Statistical and Data Management Center 
The Statistical and Data Management Center (SDMC) is housed in the Department of Public 
Health Sciences Data Coordination Unit (DCU) at MUSC. Dr. Valerie Durkalski will assume 
overall responsibility of the SDMC (see budget justification). The SDMC will be responsible for 
the data management and analysis for the Trial. Specifically, they will: (1) develop the case report 
forms; (2) create and maintain the study database, including extensive error checking and subject 
registration/randomization; (3) develop and maintain a Data Management Plan; (4) assure data 
security and appropriate archiving of data files; (5) provide statistical support for the trial and 
produce interim and final reports to the Executive Committee and the DSMB; and (6) assist with 
the closeout of the Trial, including data transfers. The MUSC DCU, which will house the SDMC, 
has extensive experience with all aspects of data management for multicenter clinical trials, and is 
in full compliance with the Good Clinical Practice (GCP) guidelines and regulations for 
conducting clinical trials. All systems used in the management and storage of clinical trial data are 
maintained on site at the offices of DCU (refer to DCU Resource Page). The SDMC’s experience 
as a coordinating center for multicenter clinical studies of similar type has enabled the group to 
develop processes that minimize the burden on the site research personnel, and allow for an optimal 

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combination of technology and resources to ensure all aspects of the project are handled effectively 
and efficiently.  
16.5 Medical Safety Monitor 
The Medical Safety Monitor (MSM) is a licensed physician with relevant expertise who is 
independent of the research study. The independent MSM responsibilities include:  on-going 
review and familiarity with the SVI protocol; review of periodic cumulative safety monitoring 
reports to ensure the protocol is conducted safely and according to GCP and regulatory 
requirements; review of individual serious adverse event reports immediately after they are 
reported and on-going feedback regarding safety throughout the SVI study.   
16.6 Data and Safety Monitoring Board 
The monitoring of data quality and subject safety in this trial will be overseen by an appointed 
Data and Safety Monitoring Board (DSMB). The DSMB members are appointed by the NIDDK. 
The members will have a meeting with the PI and study statistician prior to study commencement 
to discuss the protocol as well as content and format of DSMB reports. The SDMC will prepare 
the requested reports at the pre-specified time intervals. Both open and closed reports will be 
distributed – open reports will be available to the Executive Committee members and will be 
blinded to treatment assignment while closed reports will only be available to the DSMB members 
and will only be unblinded upon request by the DSMB members. 
17.0 
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