SpHincterotomy for Acute Recurrent Pancreatitis (SHARP Trial)
Phase: NA
Conditions: Pancreatitis, Pancreas Divisum, Pancreatitis, Acute, Pancreatitis Idiopathic, Pancreas Inflamed
Sponsor: Oregon Health and Science University

SHARP 
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SHARP Trial  
SpHincterotomy for Acute Recurrent Pancreatitis Trial 
 
 
STUDY GROUP CO-CHAIRS 
 
Gregory A. Coté, MD, MS 
Professor of Medicine 
Oregon Health & Science University 
 
Dhiraj Yadav, MD, MPH 
Professor, Department of Medicine 
University of Pittsburgh 
 
Valerie Durkalski, MPH, PhD 
Professor, Department of Public Health Science 
Medical University of South Carolina 
 
 
Original Protocol 
Version 1.4, May 5, 2022 
 
SPONSOR and Collaborator 
 
 
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 
 National Institutes of Health (NIH) 

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i
Investigator's Agreement 
 
I have read the attached clinical protocol titled SHARP Trial and dated [05-May-2022] and agree 
to conduct the protocol as written in this document. 
 
I agree to comply with the Code of Federal Regulations Title 45 part 46; ICH Good Clinical 
Practice Guidelines; and all other applicable guidelines. 
 
I understand this document contains confidential information of the National Institute of Diabetes 
and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) and The Data 
Coordination Unit and cannot be disclosed to anyone other than members of my staff conducting 
this trial and members of my 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 National Institute of 
Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), 
Medical University of South Carolina, and The Data Coordination Unit. 
 
 
_________________________________ 
 
 
_____________________________ 
Signature of Principal Investigator 
 
 
 
Date 
 
 
_________________________________ 
 
 
 
Printed name of Principal Investigator 
 
 

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1. 
SUMMARY ............................................................................................................................ 1 
2. 
Study related Definitions ..................................................................................................... 1 
3. 
SIGNIFICANCE, BACKGROUND AND RATIONALE ..................................................... 2 
3.1 
Patients with recurrent acute pancreatitis (RAP) are at high risk for additional episodes 
and progression to chronic pancreatitis. ...................................................................................... 2 
3.2 
Pancreatic duct obstruction causes acute pancreatitis. .................................................... 2 
3.3 
Minor endoscopic sphincterotomy is widely performed for idiopathic RAP (iRAP). ... 3 
3.4 
RAP significantly impacts quality of life........................................................................ 4 
3.5 
Minor endoscopic sphincterotomy for iRAP is one of the highest risk indications for 
ERCP. 4 
3.5.1 
Immediate impact of empirical evidence supporting or refuting the use of ERCP. 4 
3.6 
Long-term risk of post-sphincterotomy stenosis of the minor papilla ............................ 5 
3.7 
Innovation ...................................................................................................................... 5 
4. 
OBJECTIVES ........................................................................................................................ 7 
4.1 
Primary outcome (Aim #1): Reduce the risk of subsequent acute pancreatitis episodes 
by 33%. ....................................................................................................................................... 7 
4.2 
Secondary outcome (Aim #2): To compare the incidence rate ratio of acute pancreatitis 
between treatment groups. .......................................................................................................... 7 
4.3 
Secondary outcome (Exploratory Aim #3): To compare changes in patient-centered 
outcomes between treatment groups. .......................................................................................... 7 
4.4 
Secondary outcome (Exploratory Aim #4): Progression to chronic pancreatitis and its 
sequelae. ...................................................................................................................................... 7 
4.5 
Secondary exploratory aims (Exploratory Aim #5): Biological and Data repository .... 7 
5. 
STUDY PLAN ....................................................................................................................... 7 
5.1 
Study Design ................................................................................................................. 7 
5.2 
Study Population .......................................................................................................... 8 
5.3 
Study Sites .................................................................................................................... 8 
5.4 
Estimated Study Duration ........................................................................................... 9 
6. 
ELIGIBILITY CRITERIA ...................................................................................................... 9 
6.1 
Inclusion Criteria ........................................................................................................... 9 
6.2 
Exclusion Criteria ......................................................................................................... 9 
6.3 
Discussion regarding enrollment criteria ...................................................................... 10 
7. 
PARTICIPANT RECRUITMENT ...................................................................................... 11 
7.1 
Methods ....................................................................................................................... 11 
8. 
PARTICIPANT ENROLLMENT ........................................................................................ 11 
8.1 
Presentation of Informed Consent ................................................................................ 11 
8.2 
Eligibility Assessment ................................................................................................ 11 
8.3 
Central Randomization .............................................................................................. 12 
9. 
STUDY PROCEDURE ...................................................................................................... 12 
9.1 
Baseline Assessments .............................................................................................. 13 
9.2 
Treatment Procedures ............................................................................................... 13 
9.3 
Observational cohort .................................................................................................. 16 
9.4 
Follow-up Procedures ................................................................................................ 16 
9.4.1 
30 day follow-up ................................................................................................. 16 
9.4.2 
18 Month Follow-up ........................................................................................... 17 
9.4.3 
Telephone follow-up .......................................................................................... 18 

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9.4.4 
First acute pancreatitis during follow-up .............................................................. 18 
9.4.5 
Subsequent acute pancreatitis follow-up .............................................................. 19 
9.5 
Maintenance of the blind ........................................................................................... 19 
9.6 
Guidelines for performing ERCP during the follow-up period. ................................... 20 
10.  DISCONTINUATION OF PARTICIPATION .................................................................... 21 
10.1 
Participant Withdrawal of Consent ............................................................................... 21 
10.2 
Participant Removal from Study Intervention/Procedures ........................................... 21 
11.  Risks to Subjects ................................................................................................................ 21 
12.  OUTCOMES DEFINITIONS ............................................................................................. 23 
12.1 
Aim #1 Subsequent acute pancreatitis. ......................................................................... 23 
12.2 
Aim #2. Incidence rate ratio. ......................................................................................... 24 
12.3 
Exploratory Aim #3. Patient-reported outcomes.. ........................................................ 24 
12.4 
Exploratory Aim #4. Progression to chronic pancreatitis. ............................................ 24 
12.5 
Secondary exploratory Aim #5. Biorepository. ............................................................ 24 
13.  DATA MANAGEMENT ...................................................................................................... 25 
13.1 
Site Monitoring ............................................................................................................ 25 
13.2 
Remote Monitoring of Informed Consent ..................................................................... 25 
13.3 
Data Management ...................................................................................................... 26 
13.4 
Data Security and Confidentiality ................................................................................. 26 
13.5 
Data Quality Assurance............................................................................................. 26 
14.  Adverse event reporting .................................................................................................... 26 
14.1 
Definition of Adverse Events and Serious Adverse Events .......................................... 26 
14.2 
Adverse Event Collection Period .................................................................................. 27 
14.3 
Reporting of Adverse Events .................................................................................... 27 
14.4 
Medical Safety Monitor .............................................................................................. 27 
14.5 
DSMB ........................................................................................................................... 28 
15.  STATISTICAL CONSIDERATIONS ................................................................................ 28 
15.1 
Sample Size and Power Estimation .............................................................................. 28 
Analysis Plan. ..................................................................................................................... 28 
15.2 
Treatment Allocation .................................................................................................. 28 
15.3 
Statistical Analyses .................................................................................................... 29 
15.4 
Observational Cohort ................................................................................................. 29 
16.  REGULATORY AND ETHICAL OBLIGATIONS ............................................................ 29 
16.1 
Informed Consent ....................................................................................................... 29 
16.2 
Single Institutional Review Board (SIRB) ................................................................... 30 
17.  ADMINISTRATIVE AND LEGAL OBLIGATIONS ......................................................... 30 
17.1 
Study Termination ...................................................................................................... 30 
17.2 
Study Documentation and Storage................................................................................ 31 
17.3 
Publication Policy ....................................................................................................... 31 
18.  REFERENCES ................................................................................................................... 32 

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1. 
SUMMARY 
This is a sham-controlled, single blinded with a blinded outcome assessment, multi-center, 
randomized clinical trial of endoscopic retrograde cholangiopancreatography (ERCP) with 
minor papilla endoscopic sphincterotomy (miES) for the treatment of recurrent acute 
pancreatitis (RAP) with pancreas divisum.  ERCP with miES is often offered in clinical 
practice to patients with RAP, pancreas divisum, and no other clear risk factors for their 
acute pancreatitis episodes.  We hypothesize that obstruction at the level of the minor 
papilla is one cause of RAP in pancreas divisum; miES will relieve the obstruction, thereby 
reducing the risk of a recurrent attack(s) of acute pancreatitis.  The trial requires a total 
sample size of approximately 234 subjects, and a planned enrollment period of 
approximately 3.5 years with total planned study duration of 5 years. 
 
2. 
STUDY RELATED DEFINITIONS 
 
LIST OF ABBREVIATIONS 
 
CECT  
contrast-enhanced computed tomography scan 
CRF 
 
case report form 
DCU 
 
Data Coordination Unit 
DSMB  
Data and Safety Monitoring Board 
ERCP  
endoscopic retrograde cholangiopancreatography 
EUS 
 
endoscopic ultrasound 
iRAP  
idiopathic recurrent acute pancreatitis 
miES  
minor papilla endoscopic sphincterotomy 
MRCP  
magnetic resonance cholangiopancreatography 
MRI 
 
magnetic resonance imaging  
MSM  
Medical Safety Monitor 
MUSC  
Medical University of South Carolina 
RAP 
 
recurrent acute pancreatitis 
SIRB  
Single Institutional Review Board 
TWEAK 
Tolerance, Worried, Eye-opener, Amnesia, and K/Cut down 
 
Acute pancreatitis. The definition of acute pancreatitis will be per consensus (Atlanta 
guidelines:)(Banks, Bollen et al. 2013) “The diagnosis of acute pancreatitis requires two 
of the following three features: (1) abdominal pain consistent with acute pancreatitis (acute 
onset of a persistent, severe, epigastric pain often radiating to the back); (2) serum lipase 
activity (or amylase activity) at least three times greater than the upper limit of normal; and 
(3) characteristic findings of acute pancreatitis on CECT and less commonly MRI or 
transabdominal ultrasonography.” 
 
Post-ERCP pancreatitis. The definition of post-ERCP pancreatitis will be per consensus 
Cotton criteria (Cotton, Eisen et al. 2010): 1) New or increased abdominal pain that is 
clinically consistent with a syndrome of acute pancreatitis, and 2) amylase or lipase ≥ 3x 
the upper limit of normal at least 24 hours after the procedure, and, 3) hospitalization (or 
prolongation of existing hospitalization) for at least 2 days. 
 
Recurrent acute pancreatitis (RAP). RAP will be defined as two or more discrete 
episodes of acute pancreatitis that occur >30 days apart with complete recovery from the 
first before commencement of the second episode.   
 

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Idiopathic RAP. A patient with RAP will be defined as idiopathic (iRAP) if no etiology is 
evident to the unblinded physician investigator after a thorough history, physical 
examination, routine laboratories (serum calcium, lipids (triglyceride level < 500mg/dL), 
liver chemistries), and cross-sectional imaging (transabdominal ultrasound and/or CECT).  
Patients with a history of current or previous smoking will be considered idiopathic if a 
second risk factor is absent.  
 
Pancreas divisum. A patient will be considered to have pancreas divisum anatomy if the 
dorsal and ventral pancreatic ducts have incomplete (incomplete pancreas divisum) or 
nonexistent fusion (complete pancreas divisum).(Stern 1986) 
 
Pancreas-related pain event. An episode of pancreatitis-type symptoms (most 
commonly pain) that requires emergency room or inpatient hospital evaluation. 
 
Calcific chronic pancreatitis. Defined as parenchymal or ductal calcifications identified 
on computed tomography or magnetic resonance imaging scan. 
 
Obstructive chronic pancreatitis. Defined as main pancreatic duct stone or main 
pancreatic duct stricture identified on computed tomography or magnetic resonance 
imaging scan, or endoscopic ultrasound. 
 
3. 
SIGNIFICANCE, BACKGROUND AND RATIONALE 
3.1 
Patients with recurrent acute pancreatitis (RAP) are at high risk for additional 
episodes and progression to chronic pancreatitis. 
Acute pancreatitis is among the most common gastrointestinal indications for 
hospitalization, and those suffering two or more episodes have a high risk of developing 
full-blown chronic pancreatitis.(Yadav and Lowenfels 2013, Peery, Crockett et al. 2015)  
There are ~150,000 incident cases of acute pancreatitis in the U.S. annually, and of these 
40-50,000 will suffer recurrent bouts.  Unlike most patients with chronic pancreatitis who 
present with irreversible fibrotic changes in the pancreas, patients with recurrent acute 
pancreatitis (RAP) are unique in that many do not have end organ morphological changes 
at the time of their clinical presentation.  However, patients with RAP have a substantial 
(10-40%) risk of progressing to chronic pancreatitis and its sequelae: chronic pain, 
malabsorption, diabetes mellitus, poor quality of life, and progression to pancreatic 
cancer.(Bang, Benfield et al. 2014, Sankaran, Xiao et al. 2015)  Many experts believe that 
“subclinical RAP” is the precursor for the majority of individuals who present with overt 
signs/symptoms of chronic pancreatitis.(Schneider and Whitcomb 2002, Aoun, Slivka et 
al. 2007, Aoun, Muddana et al. 2010)  Therefore, treatments to attenuate RAP are needed. 
 
3.2 
Pancreatic duct obstruction causes acute pancreatitis. 
Pancreas divisum occurs when the dorsal and ventral pancreatic ducts have 
incomplete or nonexistent fusion during early embryologic development.  For patients with 
pancreas divisum, the duct of Santorini drains the majority of the pancreas through an 
orifice (minor papilla) that is notably smaller than the orifice of a normal sphincter of Oddi 
(major papilla).  The duct of Santorini may have a narrow filamentous pathway to the duct 
of Wirsung or may drain a portion of the head independently.  Hence the concept was 
promulgated in the 1970s that in pancreas divisum there is an anatomic impediment to the 
drainage of pancreatic exocrine secretions, resulting in an obstructive pancreatopathy 
(Cotton 1980).  This is supported by RAP cohort studies where pancreas divisum is 
overrepresented compared to its expected baseline prevalence of 7-10%.(Coyle, Pineau 
et al. 2002, Gonoi, Akai et al. 2011) 

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Pancreatic duct obstruction and transient 
increases in intraductal pressure are 
believed to be potential triggers for acute 
pancreatitis, based on several concepts: 
1. Gallstone pancreatitis is caused by 
transient occlusion of the sphincter of 
Oddi 
and 
consequential 
pancreatic 
ductal hypertension.(Lerch, Saluja et al. 
1993)  Early decompression of the duct 
attenuates progression to pancreatic 
necrosis (Lerch, Saluja et al. 1993, 
Runzi, Saluja et al. 1993). 
2. In an animal model, sphincter of Oddi 
spasm induced by application of a topical 
cholinergic agonist increased intraductal 
pressure and acute pancreatitis (Chen, Thomas et al. 2000).  
3. Use of a prophylactic pancreatic stent reduces the likelihood of post-endoscopic 
retrograde cholangiopancreatography (ERCP) pancreatitis.(Sofuni, Maguchi et al. 2011)  
4. The amount and force while infusing bile acids or other solutions into the pancreatic duct 
causes acute pancreatitis in animal models and correlates with disease severity (Arendt, 
Hansler et al. 1996, Haciahmetoglu, Ertekin et al. 2008). 
5. Multiple pancreatic duct injections, contrast opacification extending to the pancreatic tail, 
and acinarization increase the risk of post-ERCP pancreatitis (Freeman, DiSario et al. 
2001). 
6. Pancreatic ductal adenocarcinoma and other tumors (e.g. intraductal papillary mucinous 
neoplams) cause acute pancreatitis by obstructing the pancreatic duct (Munigala, Kanwal 
et al. 2014). 
 
3.3 
Minor endoscopic sphincterotomy is widely performed for idiopathic RAP 
(iRAP). 
ERCP is a moderately high-risk intervention that has unproven benefit for patients with 
iRAP.  However, based on predominantly retrospective cohort studies and the notion that 
pancreas divisum anatomy predisposes some patients to acute pancreatitis, minor papilla 
endoscopic sphincterotomy (miES) is commonly performed in clinical practice.  Although 
the technique of miES has been performed for >30 years, there has been only one pilot, 
open-label, randomized trial of 19 patients with iRAP published over 20 years ago.(Lans, 
Geenen et al. 1992)  This study compared serial dilation of the minor papillary orifice via 
pancreatic stents – a surrogate for miES – vs. diagnostic ERCP.  After mean follow-up of 
29-32 months, 6/9 (67%) patients who underwent diagnostic only ERCP developed at 
least one bout of acute pancreatitis as compared to 1/10 (10%, p<0.05) that underwent 
serial pancreatic duct stent placement.  Serial stent placement has been replaced by miES 
in clinical practice since serial stenting requires multiple ERCPs and increases the risk of 
stent-associated main duct strictures.  
 
Several retrospective cohort studies also support the practice of miES for RAP in the 
setting of pancreas divisum, with >70% of patients in most studies reporting a significant 
improvement in their disease course (Gerke, Byrne et al. 2004, Attwell, Borak et al. 2006, 
Chacko, Chen et al. 2008, Borak, Romagnuolo et al. 2009, Crino, Bernardoni et al. 2017).  
While supporting the role of miES, these studies chose a subjective endpoint (self-
perceived improvement) despite their open-label design and absence of a sham 

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comparison group.  The controversy is a recurrent topic at national meetings, and opposite 
positions were nicely summarized after a debate at the 2006 meeting of the American 
Pancreatic Association (Fogel, Toth et al. 2007).  Both sides acknowledged the need for 
randomized trials, yet there has been little progress in clarifying the benefit of miES on 
iRAP with pancreas divisum over the past decade. 
 
In the North American Pancreatitis Studies (NAPS2), which prospectively ascertained 
patients from over 25 US centers from 2000-2014, pancreas divisum was identified by 
physicians as a risk factor in 14% (78/569) of RAP and 9% (110/1195) of chronic 
pancreatitis patients.  Any endotherapy, biliary or pancreatic sphincterotomy, and 
pancreatic duct stenting was performed more often in patients with divisum (Table 1, 
unpublished). 
 
3.4 
RAP significantly impacts quality of life. 
Acute pancreatitis causes significant pain, loss of productivity, and has a small but 
measurable risk of permanent morbidity and mortality.  The physical and mental burden 
on patients who have fully recovered from even one episode of acute pancreatitis is 
significant (Neoptolemos, Raraty et al. 1998, Soran, Chelluri et al. 2000, Halonen, Pettila 
et al. 2003, Hochman, Louie et al. 2006, Pezzilli, Morselli-Labate et al. 2009, Wright, 
Lochan et al. 2009).  Patients with iRAP and pancreas divisum and no objective evidence 
of chronic pancreatitis who were enrolled in a recent prospective cohort (FRAMES, 
sponsored by the NIDDK and led by Joe Romagnuolo, MD at MUSC; Gregory Cote was 
a sub-I at Indiana University) reported a Physical Component Score 0.5 standard 
deviations below the national average (Romagnuolo 2013).  Additionally, physical and 
mental quality of life in patients with RAP was intermediate between controls and chronic 
pancreatitis patients in the NAPS2 study, reinforcing the concept that RAP alone reduces 
quality of life.  Perhaps the best illustration of the RAP disease burden is the emerging 
practice of performing total pancreatectomy for individuals with iRAP in the absence of 
morphologic features of chronic pancreatitis: in a series of 49 individuals with iRAP 
undergoing total pancreatectomy, >80% demonstrated histological changes of chronic 
pancreatitis and >90% had intractable pain between acute pancreatitis episodes.(Bellin, 
Kerdsirichairat et al. 2016)  
 
3.5 
Minor endoscopic sphincterotomy for iRAP is one of the highest risk indications 
for ERCP. 
Post-ERCP pancreatitis is the most common complication of ERCP, occurring in 2-5% 
of all cases and at least 10% in high-risk patients (Dumonceau, Andriulli et al. 2014). The 
best way to prevent post-ERCP pancreatitis is not performing ERCP.  With the exception 
of difficult biliary cannulation, the strongest procedure-related risk factors for post-ERCP 
pancreatitis include injection or manipulation of the pancreatic duct and pancreatic 
sphincterotomy; both of these maneuvers are required when performing ERCP with miES, 
and are strong (7-fold increased risk) independent risk factors for post-ERCP 
pancreatitis.(Moffatt, Cote et al. 2011)  The highest risk indications for post-ERCP 
pancreatitis include the evaluation of iRAP and suspected sphincter of Oddi dysfunction, 
and are compounded by the ERCP-related risk of injection and duct manipulation. 
 
 
 
3.5.1 
Immediate impact of empirical evidence supporting or refuting the 
use of ERCP. 
The absence of viable medical therapies, the plausibility that improving 
pancreatic flow may improve the disease course, the available (but weak) 

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data in support of miES, and patients’ “desperation” have created the 
perfect storm for more than three decades of endoscopic intervention for 
iRAP.  This controversial practice affects thousands of Americans each 
year, and those enduring the complications of ERCP (and their associated 
costs) are impacted the greatest.  While these risks are acceptable if ERCP 
positively impacts the disease course, the only method to define the 
risk:benefit relationship is adequately powered, sham-controlled trials with 
long-term, standardized follow-up.  
 
The EPISOD study irrefutably showed that ERCP should not be performed 
for patients with sphincter of Oddi dysfunction type III (abdominal pain 
alone) (Cotton, Durkalski et al. 2014). This leaves sphincter of Oddi 
dysfunction type II and iRAP as the most prevalent, highest risk indications 
for ERCP.  Post-ERCP pancreatitis risk factors are multiplicative, so that 
performing an ERCP on a patient with iRAP + pancreas divisum requires 
pancreatic duct injection and manipulation, creating a “worst case scenario” 
from the standpoint of procedure risk.  Prevention of post-ERCP 
pancreatitis begins with validating the indications for ERCP that confer the 
greatest risk: the proposed SHARP trial will clarify whether or not ERCP 
should be performed for iRAP with pancreas divisum. 
 
3.6 
Long-term risk of post-sphincterotomy stenosis of the minor papilla 
A recognized risk of miES is the development of symptomatic post-sphincterotomy 
stenosis.  While large-scale, prospective studies with discrete criteria are lacking, rates of 
post-sphincterotomy stenosis are estimated to be 20% or higher (Elton, Howell et al. 1998, 
Heyries, Barthet et al. 2002, Joo, Yoon et al. 2009, Clarke, Slivka et al. 2012).  There are 
no objective definitions for post-sphincterotomy stenosis.  However, symptomatic post-
sphincterotomy stenosis is expected to result in either acute pancreatitis (aim #1) or 
pancreas-related pain event(s), defined as pancreatitis-type symptoms that prompt 
emergency room or inpatient hospital evaluation.  Differences in these outcomes 
(pancreatitis and pancreas-related pain events) between subjects randomized to 
EUS+ERCP with miES and EUS+sham will clarify whether the risk of post-sphincterotomy 
stenosis is outweighed by its benefit.  In this study, among subjects who undergo ERCP 
at randomization or follow-up, rates of post-sphincterotomy stenosis will be tracked as a 
secondary safety measure.  At the time of repeat ERCP, post-sphincterotomy stenosis will 
be defined by the need to perform minor papillary orifice treatment (re-do minor 
papillotomy or minor papillary orifice balloon dilation). 
 
3.7 
Innovation 
3.7.1 
First sham-controlled clinical trial for patients with iRAP. 
To date, there have been no sham-controlled intervention trials for patients 
with iRAP.  For a disease with numerous patient-centered endpoints that 
include quality of life, pain, and disability, a sham-controlled study is of 
paramount importance.  As compared to pharmacological interventions – 
none of which are on the immediate horizon and all of which would require 
indefinite administration – ERCP with miES is an attractive treatment 
modality for a sporadic disease such as RAP.  Given the promising 
preliminary data supporting its practice, only a sham-controlled, 
randomized trial with long-term follow-up can address whether or not miES 
reduces the risk of having another bout(s) of acute pancreatitis over time.  
A sham-controlled study will also be an ideal platform for the careful 

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collection of natural history data among patients assigned to the sham 
group.  The proposed rigorous experimental design will ensure robust and 
unbiased results.  
 
Irrespective of the primary outcome, the results will directly impact patient 
care: a study favoring miES will expand the use of this intervention 
internationally, whereas a study that shows no impact of miES in reducing 
the risk of a subsequent bout of acute pancreatitis will refute the practice 
of ERCP with miES and raise further questions about the role of ERCP for 
iRAP in standard ductal anatomy. 
 
3.7.2 
Assessment of several important clinical endpoints for patients with 
iRAP. 
Pancreas divisum is overrepresented in patients with iRAP (Fischer, 
Hassan et al. 2010, Gonoi, Akai et al. 2011) and pancreatitis susceptibility 
mutations such as in the cystic fibrosis transmembrane conductance 
regulator (CFTR) gene (Bertin, Pelletier et al. 2012, Ballard, Flueckiger et 
al. 2015).  Some have hypothesized that divisum protects against exocrine 
pancreas insufficiency during youth, and then later in life predisposes to 
RAP in patients with susceptibility mutations (Nicholson, Johnstone et al. 
2012).  The association between divisum and susceptibility mutations does 
not refute the potential benefit of miES in reducing the risk of future acute 
pancreatitis or other RAP sequelae.  A sham controlled, randomized trial 
will be the ideal format for the careful collection of data on known and 
potential covariates.  Other than pancreatitis susceptibility mutations, 
potential covariates that might impact the natural history of iRAP with 
pancreas divisum include smoking, age, number of previous attacks, main 
pancreatic duct diameter, and presence of definite chronic pancreatitis 
morphology.  This study protocol will exclude patients with RAP who have 
obstructive chronic pancreatitis (e.g., main duct strictures or stones) since 
treatment of these entities would not address the overarching question of 
this study: does miES reduce the risk of acute pancreatitis in patients with 
iRAP?  
 
 
3.7.3 
Foundation for additional research on unproven, high-risk indications 
for ERCP 
According to the American Society for Gastrointestinal Endoscopy, 
performing 
ERCP 
for 
an 
appropriate 
indication 
is 
strongly 
recommended.(Adler, Lieb et al. 2015)  The society’s Quality Indicators 
white paper states that “evaluation of pancreatitis of unknown etiology” 
remains an appropriate indication for ERCP; since MRI and EUS are widely 
accepted and less invasive diagnostic alternatives to ERCP, this 
recommendation assumes that miES confers benefit for patients with RAP 
and pancreas divisum as well as comparable benefits for patients with 
standard ductal anatomy.  Among ERCP experts and the majority of the GI 
community, currently available data are sufficient to support the practice of 
ERCP with miES for iRAP with pancreas divisum.  Clinical practice is very 
unlikely to change without executing a definitive trial measuring the effect 
of ERCP and miES on subsequent risk of having a recurrent bout of acute 
pancreatitis.  Results from this study will also stimulate future research on 
the therapeutic role of ERCP for standard duct anatomy, which has been 

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challenged by a recent, single center, open-label, randomized trial (n=89) 
of biliary sphincterotomy vs. biliary + pancreatic sphincterotomy for patients 
with iRAP.(Cote, Imperiale et al. 2012) 
 
 
4. 
OBJECTIVES 
4.1 
Primary outcome (Aim #1): Reduce the risk of subsequent acute pancreatitis 
episodes by 33%.  
To test this aim, we will compare the incidence of acute pancreatitis > 30 days after 
treatment allocation as the primary outcome measure, using the next attack of acute 
pancreatitis as a time-to-event outcome.  
 
4.2 
Secondary outcome (Aim #2): To compare the incidence rate ratio of acute 
pancreatitis between treatment groups. 
All randomized patients will be followed longitudinally until study completion, even if 
acute pancreatitis occurs during follow-up. A secondary benefit of miES may be a 
reduction in acute pancreatitis frequency, defined as the incidence rate (episodes/time 
pre- and post-randomization). Since baseline incidence rate is a probable predictor of 
post-randomization incidence rate, we will compare the incidence rate ratios between 
the two arms, keeping person-time equal between the pre/post periods. 
 
4.3 
Secondary outcome (Exploratory Aim #3): To compare changes in patient-
centered outcomes between treatment groups. 
The natural history of idiopathic RAP is primarily based on retrospective cohort studies 
with variable follow-up. We will measure relevant patient-centered outcomes, using 
validated instruments for each: pain, self-perceived quality of life, global impression of 
change, pain-related disability, and number and days of pain or pancreas-related 
hospitalizations. 
 
4.4 
Secondary outcome (Exploratory Aim #4): Progression to chronic pancreatitis 
and its sequelae. 
Although the proportion of patients who may transition to chronic pancreatitis during 
the proposed time period of the study will be low, we will quantify the progression to 
chronic pancreatitis during clinical care as an exploratory analysis. To accomplish this, 
we will perform a secretin-enhanced magnetic resonance imaging (MRI) study with 
magnetic resonance cholangiopancreatogram (MRCP) at 18 months after enrollment 
(for those eligible based on enrollment month). Also, we will measure the rates of new-
onset diabetes mellitus (using blood glucose and hemoglobin A1c) and exocrine 
insufficiency (using fecal elastase) at the same time. 
 
4.5 
Secondary exploratory aims (Exploratory Aim #5): Biological and Data 
repository 
Post hoc genetic analysis of the effect of known pathogenic mutations on natural 
history will be performed. Biological samples, MRI scans and data will be stored for 
future exploratory analyses of genetic, laboratory and radiological associations with 
outcomes. 
 
5. 
STUDY PLAN 
 
5.1 
Study Design 

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Following the informed consent process, patients diagnosed with iRAP and pancreas 
divisum will undergo an endoscopic ultrasound (EUS). During the EUS, the endoscopist 
will confirm the absence of exclusion criteria and reassess for the presence of pancreas 
divisum. If the patient meets all eligibility criteria, the patient will be randomized 1:1 to 
either EUS + sham or EUS + ERCP with miES. 
 
Development of post-ERCP pancreatitis will be assessed at the 30-day follow-up visit, 
which will occur at the study site.  
 
All patients will complete a follow-up study encounter on a semi-annual basis via a 
telephone visit until the end of the trial (a minimum of six months and maximum of 48 
months depending on enrollment year).  The month 18 visit will be in-person or virtually 
at the study site.  Other visits may be conducted by a blinded “central caller” or a blinded 
site coordinator. 
 
Blinded study personnel will complete the baseline clinical assessment, the Day 30 
follow-up visit and the planned 18-month patient visit.  This individual will also facilitate 
the process of randomization but remain masked to the assignment.  Other planned 
semiannual study assessments will be completed by a blinded central coordinator. If a 
patient develops acute pancreatitis or a pancreas-related pain event (see definitions in 
Section 8.6), a blinded local coordinator and physician will complete the applicable 
adverse event documentation. Subjects who experience acute pancreatitis or an acute 
pain event during the course of the study will be assessed for the need for treatment 
and will either be treated at the enrolling site or referred for treatment as appropriate. 
Please see the Manual of Procedures for clarification. 
 
Observational cohort 
In addition to the 234 randomized patients, approximately 100 patients with iRAP and 
pancreas divisum who meet all other eligibility criteria but who refuse randomization, 
refuse ERCP, or those in whom ERCP is not recommended by the unblinded physician 
investigator will be invited to participate in an observational cohort study.  Patients who 
provide consent will be followed for subsequent acute pancreatitis episodes (aim #1), 
systematic, semiannual assessments for patient-centered outcomes (aim #3), and clinical 
(observational) assessments for the interval development of chronic pancreatitis and 
exocrine or endocrine insufficiency (aim #4).  
 
5.2 
Study Population 
All patients with iRAP as defined per protocol will be screened for study eligibility.  The 
patient must have pancreas divisum (complete or incomplete) identified by radiographic 
imaging prior to randomization.  
 
5.3 
Study Sites 
In order to achieve a targeted enrollment of approximately 234 randomized subjects 
during a 3.5-year period, we have identified sites who are regional referral centers for 
pancreatobiliary endoscopy.  This would require approximately 67 patients/year at all 
sites, or 3-4 patients/year/site (assuming 16-20 enrolling sites).  The choice of centers is 
deliberate to include those with high ERCP volumes and expertise in therapeutic 
endoscopy and pancreatitis care.  The chosen centers include university-based and 
hospital-based practices; each site PI is a nationally or internationally recognized expert 
in ERCP, pancreatitis, or both. 
 

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5.4 
Estimated Study Duration 
In order to maximize follow-up data, we will follow all patients every 6 months until the 
end of Year 4.5 of the U01 funding period, when the database will be locked for analysis.  
We estimate starting enrollment within 6 months of the grant start date and completing 
enrollment over 3.5 years.  Assuming consistent enrollment, this would provide us with a 
minimum follow-up of 6 months and maximum follow-up of 48 months. 
 
6. 
ELIGIBILITY CRITERIA 
 
6.1 
Inclusion Criteria 
1) Patient must consent to be in the study and must have signed and dated an 
approved consent form. 
2) >18 years 
3) Two or more episodes of acute pancreatitis, with each episode meeting two of 
the following three criteria: 
 abdominal pain consistent with acute pancreatitis (acute onset of a 
persistent, severe, epigastric pain often radiating to the back) 
 serum lipase activity (or amylase activity) at least three times greater 
than the upper limit of normal 
 characteristic findings of acute pancreatitis on CECT, MRI or 
transabdominal ultrasonography 
4) At least one episode of acute pancreatitis within 24 months of enrollment 
5) Pancreas divisum confirmed by prior MRCP that is reviewed by an abdominal 
radiologist at the recruiting site. 
6) By physician assessment, there is no certain explanation for recurrent acute 
pancreatitis. 
7) Subjects must be able to fully understand and participate in all aspects of the 
study, including completion of questionnaires and telephone interviews, in the 
opinion of the clinical investigator. 
6.2 
Exclusion Criteria 
1) Prior minor papilla therapy (endoscopic or surgical) 
2) Calcific chronic pancreatitis, defined as parenchymal or ductal calcifications 
identified on computed tomography or magnetic resonance imaging scan that 
is reviewed by an expert radiologist at the recruiting site. 
3) Main pancreatic duct stricture* 
4) Presence of a structural etiology for acute pancreatitis, such as anomalous 
pancreatobiliary union, periampullary mass, or pancreatic mass lesion on 
imaging* 
5) Presence of a local complication from acute pancreatitis which requires 
pancreatogram 
6) Regular use of opioid medication for abdominal pain for the past three months 
7) Medication as the etiology for acute pancreatitis by physician assessment 
8) TWEAK score ≥ 4 
9) Hypertriglyceridemia, defined as a serum triglyceride level > 500mg/dL during 
a prior episode of acute pancreatitis 
10) Hypercalcemia, defined as a corrected serum calcium level > 10.5mg/dL 
associated with a prior episode of acute pancreatitis 
11) Clinical presentation consistent with type I or type II autoimmune pancreatitis 
12) Pregnancy (urine test) 
13) Low probability of follow-up on a regular basis to achieve study objectives 
14) Life expectancy < 6 months based on the opinion of the physician investigator 

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15) Incarceration 
 
*The possible presence of a pancreatic duct stricture or structural etiology for acute 
pancreatitis will be assessed for all subjects during review of the MRCP.  If no 
evidence of either exclusion is identified during review of MRCP, and all other 
eligibility criteria are met, subjects who consent to randomization will be scheduled 
for the pre-randomization EUS. Absence of pancreatic duct stricture and structural 
etiology will be confirmed during EUS before a subject can be randomized.   
  
6.3 
Discussion regarding enrollment criteria 
 
 
Exclusion criteria 2 and 3. Using these criteria, it is possible that some patients with 
early chronic pancreatitis will be included.  We will capture this information and consider 
appropriate secondary per protocol analyses; however, the primary analysis will be 
intention to treat which will include all randomized subjects.  Moreover, in the absence of 
calcifications, we will not exclude patients based on the number of EUS findings - rather, 
we will record the number and type of EUS criteria present, and during analysis determine 
if the number of EUS findings is a prognostic variable.  We elected deliberately not to use 
the Cambridge classification system since “moderate” changes of chronic pancreatitis by 
this system include irregularity and dilation of the main pancreatic duct.  For example, the 
presence of a Santorinicele (focal cystic dilation of the distal portion of the dorsal 
pancreatic duct, at the minor papilla) might be interpreted in this category.  These 
individuals represent an important subgroup who may benefit from miES.  Main pancreatic 
duct diameter – and the presence of a Santorinicele – will be measured in all subjects and 
is considered in the randomization scheme.  
 
Inclusion criterion 4. Requiring at least one attack in the previous 24 months: In clinical 
practice, it is uncommon for a patient with RAP to present for ERCP in the absence of 
having an episode in the past 24 months.  This criterion will assure that subjects 
randomized in SHARP have an adequate baseline incidence rate of acute pancreatitis 
episodes 
 
Exclusion criterion 6. Patients will be queried about their use of pain medications in the 
preceding 3 months. This criterion is meant to minimize the risk of enrolling subjects with 
chronic pain, in whom minor papilla sphincterotomy is not expected to help and in whom 
future endoscopic or surgical interventions are more likely.  Since these subsequent 
interventions would adversely impact the ascertainment of the primary outcome, these 
patients will be excluded. 
 
Exclusion criterion 8. The threshold at which alcohol causes acute pancreatitis is poorly 
understood and patient-dependent.  Therefore, we will rely on the TWEAK alcohol 
screening questionnaire, which defines harmful or at-risk alcohol use by a score of ≥ 
3.(Russell, Martier et al. 1996, Bradley, Boyd-Wickizer et al. 1998) TWEAK is an acronym 
for the 5 questions used in the questionnaire: Tolerance, Worry, Eye-opener, Amnesia, 
and “K”-ut down.  Since patients may modify their alcohol consumption after suffering from 
pancreatitis, wording of the TWEAK questions and the reference period will be “in the 
months before getting pancreatitis”.  We will use a higher threshold of ≥ 4 (rather than ≥ 
3) to allow evaluation of a modifying role of alcohol, while excluding patients with a high 
probability of having alcoholic pancreatitis.  Alcohol use will also be quantified during the 
baseline assessment, and its role on the natural history considered in the post hoc 

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analysis. 
 
 
7. 
PARTICIPANT RECRUITMENT 
 
7.1 
Methods 
The methods used for recruitment of participants in the study will be devoid of any 
procedures that may be construed as coercive.  The recruitment process will not involve 
any restrictions on sociodemographic factors including age, gender, or ethnic 
characteristics.  
 
The prevalence of RAP with pancreas divisum is balanced between men and women, 
although heavy alcohol use and smoking are more common among men.  Therefore, per 
our enrollment criteria, we anticipate our cohort will have more women than men (since 
heavy alcohol use is considered an etiology for RAP, and thus not idiopathic). We 
anticipate our cohort will reflect national trends in this regard.  We do not plan to actively 
pursue one sex, as we want our cohort to reflect the disease population.  The clinical 
centers selected from the study represent a diverse geographic spectrum.  Our clinical 
practice reflects our local regions in terms of minority populations, and we will recruit 
patients meeting eligibility criteria without discrimination. 
 
Participants will be recruited through the sites’ clinical practices and existing referral 
network.  Patients referred to the clinical practices of participating sites will be screened 
for a diagnosis of acute or recurrent acute pancreatitis, pancreas divisum or both.  Patients 
determined to be potentially eligible will be approached about study participation by their 
clinical care provider. It is expected that potentially eligible subjects will be approached 
regarding participation in the randomized trial well in advance of initiating randomization 
procedures to allow adequate time for the potential subject to consider the risks and 
benefits of participation. 
 
In addition, regional referring physician practices will be notified by letter of the SHARP 
study in order to refer potential subjects.  An informational video summarizing the purpose 
of the study and eligibility criteria will also be used as a recruitment tool and posted on 
widely used internet platforms, such as YouTube. It is expected that participating sites will 
approach all potentially eligible subjects regarding study participation. 
 
8. 
PARTICIPANT ENROLLMENT 
 
8.1 
Presentation of Informed Consent 
Consent will be obtained by either the Principal Investigator or by individuals 
delegated this responsibility by the Principal Investigator.  Informed consent is to be 
obtained from the participant according to Section 16.1 of this protocol.  Informed consent 
must be obtained prior to the initiation of any screening procedures that are performed 
solely for the purpose of determining eligibility for the study that would not have been 
performed as part of standard patient care at the Clinical Center.  
 
8.2 
Eligibility Assessment 
Any patient ≥ 18 years old who is believed to have iRAP and suspected pancreas 
divisum will be considered for inclusion in the study.  Prior to approaching a potential 
subject regarding study participation, study staff may review the existing available medical 

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records for evidence of exclusion criteria.  If no evidence of exclusion criteria is identified, 
the patient will be approached to discuss study participation.  
 
As in all trials, the goal is to achieve a high level of compliance with protocol 
requirements by assuring, during the eligibility assessment, that the potential participant 
is fully informed and agrees to the protocol requirements.  In addition, participants with a 
strong likelihood of non-adherence (e.g. for reasons such as difficulties in adhering to 
follow-up schedule) should not knowingly be enrolled.  Adherence of the clinical center 
staff to careful assessment of the participant’s understanding of the trial and a clinical 
center environment which supports the continued commitment of the participants are 
essential for the trial to be successfully completed. 
 
Conditional Eligibility: Once a subject has agreed to study participation and informed 
consent has been obtained and documented, research personnel begin screening 
procedures required to determine conditional eligibility.  Full eligibility for this trial cannot 
be assessed until EUS is performed immediately prior to randomization.  
 
The following will be performed to assess conditional eligibility: 
 
The TWEAK alcohol screening test will be administered.  A score of < 4 is required 
for study eligibility. 
 
Records of at least two previous attacks (including laboratory results and/or 
imaging studies) must be obtained and reviewed to determine if the attacks meet 
inclusion criteria. 
 
Films from a clinically indicated MRCP procedure must be reviewed with a 
radiologist at the recruiting site to confirm pancreas divisum, rule out definitive 
changes of calcific chronic pancreatitis, and to rule out other etiologies of acute 
pancreatitis. The MRCP procedure is performed as part of standard of care and 
will not be performed specifically for research purposes. 
 
Study personnel will interview the subject and review medical records to confirm 
remaining eligibility criteria. 
 
Pre-Randomization Screening Procedures: 
Additional procedures required to determine eligibility must be performed immediately 
prior to and during EUS at the Randomization/Treatment visit.   
 
Female subjects of child bearing potential must have a negative serum or urine 
pregnancy test within 2 days prior to EUS.  
 
During the EUS procedure, the investigator will confirm the absence of any 
previously unrecognized exclusion criteria.  This is the final step required to 
determine final eligibility. 
 
8.3 
Central Randomization 
Participants will be assigned to one of the treatment groups according to the 
randomization scheme described in Section 9. Randomization is accomplished 
electronically within the WebDCU™ system. The Clinical Center will enter the eligibility 
criteria into the electronic case report forms. If all eligibility criteria are met and no 
exclusion criteria are identified, the WebDCU™ system will assign treatment according to 
the pre-specified randomization scheme. 
    
9. 
STUDY PROCEDURE 
 

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9.1 
Baseline Assessments 
In addition to assessments related to eligibility, all patients will be administered the 
following questionnaires prior to the EUS: 
 
Demographics 
 
Previous pancreatitis episodes 
 
Smoking and alcohol use history 
 
Pancreatitis risk factors 
 
Pertinent medication utilization 
 
Quality of life (PROMIS29 and PROMIS Global) 
 
Pain assessment and related disability (PROMIS Nociceptive & 
Neuropathic Pain), and 
 
Opioid and other pain medication use 
 
Information about the subject’s medical history, including information about past 
pancreatitis episodes and pancreatitis risk factors will be collected from the subject’s 
medical record. 
If the subject has not already been diagnosed with diabetes mellitus, an assessment 
for diabetes mellitus will be performed at baseline (fasting or random blood glucose and 
hemoglobin A1c).  If the subject has not been diagnosed with exocrine insufficiency, 
subjects will undergo fecal elastase testing during the baseline assessment.  The 
diagnosis of diabetes mellitus will be established by use of antidiabetic medications or 
when a patient has abnormal values on two of the following tests or two abnormal values 
of the same test: a) fasting blood sugar ≥ 126 mg/dl; b) HbA1c ≥ 6.5%; c) random blood 
sugar ≥ 200 mg/dl.  
 
The diagnosis of exocrine pancreatic insufficiency will be established by a clinical history 
suggestive of steatorrhea, quantitative fecal fat > 7g/day, or fecal elastase concentration 
<100mcg/g of stool. See Biospecimen SOPs for details of sample collection, shipping, 
storage and testing. 
 
9.2 
Treatment Procedures 
 
Typically, randomization and study treatment procedures will be performed at a 
separate visit from the initial Screening/Baseline visit, during which consent is 
obtained.  However, these procedures may be performed on the same day if all 
medical records necessary to confirm eligibility are available at the time of the visit. 
 
Biospecimen collection 
Please refer to the SHARP Biospecimen SOP and section 12.5 for additional 
details.  Blood and urine specimens will be collected prior to the administration of 
anesthesia. 
 
Endoscopy and randomization 
During the EUS, an unblinded physician investigator will confirm the absence of 
exclusion criteria by reassessing for the presence of pancreas divisum and completing 
a standardized instrument documenting parenchymal and ductal changes in the 
pancreas.  From the stomach and using a linear echoendoscope, the pancreatic duct 
diameter should be measured in the neck (at the location of the portosplenic 
confluence), body, and tail.  The largest diameter will be entered as a stratification 
factor during randomization.  Prior to randomization, the unblinded physician 

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investigator should document the amount and type of intravenous fluids to be 
administered during the periprocedural period (irrespective of treatment allocation) 
under the assumption that the subject will be randomized.  This is done to preserve 
masking of subjects and blinded study staff. 
 
Unless a definitive obstructive lesion or any other exclusion criterion is identified during 
EUS, the patient will be randomized 1:1 to either EUS + sham or EUS + ERCP with 
miES. Subjects excluded from study participation during EUS will be treated per 
standard of care.   
 
Randomization procedure 
If all eligibility criteria are met, the study personnel will complete the randomization 
procedure using the WebDCU™ system.  Upon randomization, the WebDCU™ 
system will generate a numeric code that corresponds with a sealed envelope 
containing the subject’s treatment assignment.  Blinded study personnel may complete 
the randomization procedure in WebDCU™ and may retrieve the sealed envelope but 
will not open the envelope or be present when the envelope is opened.  The sealed 
envelope will be provided to an unblinded individual responsible for informing the 
unblinded investigator of the subject’s assignment.   
 
Minor papilla cannulation and pancreatography (EUS + ERCP with miES group) 
Subjects randomized to miES will undergo the procedure at the same time as EUS, 
under the same anesthetic. Indomethacin or diclofenac (100mg per rectum) will be 
administered for post-ERCP pancreatitis at the onset of the ERCP procedure in 
patients with no known allergy to indomethacin or diclofenac.  Rectal indomethacin 
and diclofenac reduces the risk of post-ERCP pancreatitis and is routinely 
administered to patients at high risk of post-ERCP pancreatitis. Techniques for minor 
papilla cannulation will be left to the discretion of the treating endoscopist.  In addition 
to standard techniques, other maneuvers to facilitate cannulation will be tracked using 
the ERCP case report form; these include the use of intravenous secretin and injection 
of methylene blue or other medium onto the surface of the duodenum to facilitate the 
identification of the minor papillary orifice.  Deep cannulation of the minor papilla will 
be defined as: 1) guidewire access at or beyond the pancreatic genu, and 2) ability to 
insert an ERCP catheter or sphincterotome completely through the minor papillary 
complex.  If both criteria are met, then deep cannulation will be defined as “successful.”  
Superficial cannulation will be defined by the ability to achieve one of these two 
maneuvers or only the performance of pancreatography.  Failed cannulation will be 
defined by the inability to perform a pancreatogram. 
 
In some cases, the endoscopist may perform a precut sphincterotomy using a needle 
knife sphincterotome (performance of a partial minor papilla sphincterotomy using a 
needle knife sphincterotome before deep cannulation is achieved) or wire-assisted 
access sphincterotomy (performance of a partial minor papilla sphincterotomy using a 
needle knife sphincterotome after achieving deep cannulation using a guidewire, but 
before deep cannulation with an ERCP catheter or sphincterotome can be achieved).  
The performance of these maneuvers to facilitate cannulation will be left to the 
discretion of the treating endoscopist and tracked on the ERCP case report form. 
 
There may be cases when deep minor papilla cannulation cannot be accomplished for 
technical reasons; the endoscopist should use their discretion in determining when 
additional efforts to achieve deep cannulation are considered futile.  Reasons for futility 

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will be detailed in the case report form. Inability to achieve deep minor papilla 
cannulation will be defined as a technical failure. It is expected that the endoscopist 
performing the procedure has a track record of high (>90%) technical success rate 
with native papilla cannulation.  To minimize the risk of technical failure, the treating 
physician may request the assistance of a colleague.  Trainees will not have hands on 
involvement during the procedure to which the subject is randomized. 
 
The extent of pancreatography (extent of injection) will also be left to the discretion of 
the treating endoscopist.  The injection should be adequate to confirm the presence of 
pancreas divisum, characterize its subtype (incomplete vs. complete), and to provide 
a measurement of the pancreatic duct diameter at least in the pancreatic head and 
neck.  The amount of contrast injected and the extent of pancreatic duct opacification 
will be recorded, as these are probable risk factors for post-ERCP pancreatitis.  
 
Minor papilla sphincterotomy (EUS + ERCP with miES group) 
The technique for miES will be left to the discretion of the study endoscopist.  
Techniques may include pull-type sphincterotomy, needle knife sphincterotomy over 
a pancreatic stent, dilation of the minor papilla orifice using a hydrostatic balloon 
catheter, or some combination of the above.  If none of these techniques can be 
executed, this will be classified as a technical failure.  The endoscopist may choose 
their preferred type of electrocautery (pure cut vs. blended cut current) as per their 
usual practice.  The extent of sphincterotomy will be per the discretion of the treating 
endoscopist, with every effort made to execute a complete incision of the minor papilla 
by extending the incision to the top or apex of the minor papilla complex – as identified 
endoscopically.  The study endoscopist will estimate the length of the incision (in mm); 
photo documentation of post-sphincterotomy minor papilla should not be performed in 
an effort to preserve blinding. 
 
The endoscopist is expected to place an FDA-approved pancreatic duct stent for 
prophylaxis (no larger than 5Fr in diameter), in an effort to minimize the risk of post-
ERCP pancreatitis.  The stent’s external characteristics (flange vs. pigtail), internal 
characteristics (with or without flanges), length, and diameter will be recorded. 
 
This technical approach is intended to mimic real-life practice and maximize the 
study’s external validity.  These variables will be tracked in order to determine their 
impact on study outcomes. 
 
 
Ultimately, the decision to abort the ERCP before deep minor papilla cannulation or 
completion of miES will be left to the discretion of the study endoscopist; conditions 
for this decision include futility and medical instability.  In the event of technical failure, 
a second attempt will not be performed unless the subject meets one of the guidelines 
detailed in Section 9.6. 
 
 
Unless methylene blue (or similar chromoendoscopy agent such as indigo carmine) 
has already been used to facilitate minor papilla cannulation, a minimum of 3mL of 
diluted dye will be injected into the duodenum.  If a prophylactic pancreatic duct stent 
cannot be deployed in the pancreatic duct, one should be deposited in the duodenal 
lumen (as done in the EUS + sham group) to minimize the risk of unblinding. 
 
EUS + Sham 

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Subjects randomized to EUS + sham will already be sedated and have undergone the 
diagnostic EUS.  The physician investigator will not make any attempts to achieve 
minor papilla cannulation, but photo document the minor papilla using a 
duodenoscope.  A minimum of 3mL of diluted dye will be injected into the duodenum.  
A small caliber (3, 4, or 5Fr) prophylactic pancreatic duct stent will be deposited into 
the duodenal lumen.  These maneuvers are performed to minimize the risk of 
unmasking.  
 
Since sham endoscopy is expected to take less time than ERCP with miES, the subject 
should remain in the endoscopy procedure room for a minimum of 30 minutes 
(including the time required to complete the EUS with photo documentation of the 
minor papilla).  Sedation will be stopped when the endoscopic procedure(s) is 
completed. 
 
9.3 
Observational cohort 
In addition to randomized subjects, we plan to enroll approximately 100 patients with 
iRAP and pancreas divisum who refuse randomization, those who refuse ERCP, or those 
in whom ERCP is not recommended by the blinded physician investigator into an 
observational cohort.  These subjects will be followed for subsequent acute pancreatitis 
episodes, systematic, semiannual assessments for patient-centered outcomes, and 
clinical (observational) assessments for the interval development of chronic pancreatitis 
and exocrine or endocrine insufficiency.  Subjects in the observational cohort will undergo 
follow-up imaging and laboratory testing (including pregnancy testing) at the discretion of 
the treating physician(s). 
 
Subjects enrolled into the observational cohort will follow the same follow-up schedule as 
patients who are randomized, with the following exceptions: 
 
No study-specific MRI/MRCP, and assessment of diabetes (endocrine) or 
exocrine insufficiency will be performed at 18 months. Therefore, these 
visits do not have to be in-person. 
 
9.4 
Follow-up Procedures 
The goal of the study is to achieve complete and accurate follow-up until completion of 
the trial. Appropriate compliance strategies should be implemented at clinical centers to 
encourage and support participants in protocol adherence. The ultimate success of this 
trial will depend upon the timely submission of complete and accurate data on all follow-
up forms. 
 
The Day 30 and 18-month follow-up visits will be completed as in-person, by telephone, 
or by virtual visits at the enrollment site.  Otherwise, planned semiannual study 
assessments will be completed by a blinded central coordinator with the assistance of 
blinded site coordinators on an as-needed basis. Central follow-up will be performed in a 
confidential manner, so that personal health identifiers required to complete remote follow-
up visits will be stored separate from the SHARP database. 
 
9.4.1 
30-day follow-up  
Blinded study personnel will direct the 30-day follow-up encounter, which 
will occur at the enrolling site, over the telephone or virtually. All 
randomized subjects will undergo an abdominal X-ray during this visit 
which is typically performed as part of clinical care to confirm spontaneous 
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will not have a pancreatic stent placed into the pancreatic duct, subjects in 
both groups will undergo an abdominal x-ray in order to maintain the blind. 
If a patient reports abdominal pain and a CT scan is ordered as part of the 
standard of care, the results of the CT scan can be used to confirm a stent 
has not been retained. 
 
If the stent is identified in the gastrointestinal tract but not in the pancreatic 
duct, the patient will not be notified; this reflects usual clinical care, since 
migrated stents in the small intestine or colon are not followed thereafter 
since their spontaneous passage is virtually assured.  If the stent is 
identified in the pancreatic duct, removal will be performed as part of the 
subject’s clinical care. 
 
In addition, blinded study personnel will assess the subject for adverse 
events that may have occurred since randomization. 
 
Development of post-ERCP pancreatitis will be an important assessment 
at the 30-day follow-up period.  Post-ERCP pancreatitis will be defined per 
consensus guidelines(Cotton, Eisen et al. 2010):  
1) New or increased abdominal pain that is clinically consistent with a 
syndrome of acute pancreatitis, and  
2) Amylase or lipase ≥ 3x the upper limit of normal at least 24 hours after 
the procedure, and  
3) Hospitalization (or prolongation of existing hospitalization) for at least 2 
days.  
 
The diagnosis of post-ERCP pancreatitis will be made based on review of 
medical records including clinical notes, results of lab tests and imaging 
studies. 
 
Subjects who develop post-ERCP pancreatitis will be managed per 
standard clinical practice by the unblinded physician investigator.  After 
recovery, subjects will continue to be followed per study protocol. 
 
9.4.2 
18 Month Follow-up 
At approximately 18 months post-randomization, subjects will undergo an 
MRI with intravenous contrast (gadolinium) and MRCP protocol with 
secretin (a pancreatic secretagogue) enhancement if available to assess 
for interval morphological and/or functional changes of chronic pancreatitis.  
Gadolinium may be withheld if the glomerular filtration rate is < 30 
mL/minute) or allergy.  If there is a contraindication to MRI, a pancreas 
protocol contrast-enhanced computed tomography (CECT) scan will be 
performed.  These images will be interpreted locally; de-identified images 
will be stored on a central radiology server at MUSC for future ancillary 
studies.  Each site will have their own methods for removing personal 
health identifiers including metadata, before submitting the films to the 
Statistical and Data Coordinating Center for storage.  If an MRI/MRCP had 
been performed within 6 months of these study time points, and is 
considered to be of adequate quality, then a repeat scan will be deferred. 
Images of MRI/MRCP scans, if performed at other intervals during the 
follow-up period, and available, will also be sent to a central radiology 

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server.  If the subject is pregnant at the 18-month encounter, the MRI will 
not be performed until post-partum. 
 
If the subject has not already been diagnosed with diabetes mellitus, 
assessment for diabetes mellitus will be performed at the 18-month follow-
up encounter (fasting or random blood glucose and hemoglobin A1c).  If 
the subject has not been diagnosed with exocrine insufficiency, subjects 
will undergo fecal elastase testing at the 18-month follow-up encounter. 
 
9.4.3 
Telephone follow-up (6 months, 12 months, 24 months, 30 months, 36 
months, 42 months, 48 months) 
In addition to in-person or virtual follow up visits completed at Day 30 and 
Month 18, subjects will complete a follow-up study visit by phone every 6 
months  until the end of the trial (a minimum of 1 year and maximum of 4 
years depending on enrollment year). These telephone visits may be 
conducted by a blinded “central caller” or by a site coordinator. The central 
caller will collect the following information since last contact:  
 
New hospitalizations or ER visits 
 
New diagnoses of medical conditions 
 
New medications 
 
Smoking and alcohol consumption 
 
Patient reported outcomes (PROMIS Global Health, 
PROMIS29, PROMIS Neuropathic, PROMIS Nociceptive Pain 
assessment and pain and disability, Best Guess Subject 
Assessment) 
   
Information collected by the central caller will be entered into the study 
database, where it can be reviewed by the enrolling site, which will be 
responsible for assessing and documenting reportable adverse events, 
events related to acute pancreatitis, and diagnoses of diabetes or exocrine 
insufficiency.  Subjects will be given the option to complete the patient 
reported outcome assessments online by entering responses on a secure 
website.  Subjects will access online assessments through a web link sent 
via email.  If a subject is unable or unwilling to complete assessments 
online, the central caller will administer these assessments during the call. 
 
9.4.4 
First acute pancreatitis during follow-up 
Subjects will be instructed to contact the enrolling site if they develop signs 
or symptoms suspicious for acute pancreatitis.  Blinded study personnel at 
the enrolling site will direct the follow-up if an enrolled subject develops 
signs or symptoms suspicious for acute pancreatitis (first episode) >30 
days after enrollment.  The decision to proceed with a clinical evaluation 
(e.g., laboratory testing, radiology, or referral to a medical facility for 
evaluation) will be made by a blinded site investigator who did not perform 
the index procedure and is unaware of the subject’s treatment allocation.  
Subjects will be given a standing order for laboratory testing and instructed 
to seek medical evaluation if symptoms reminiscent of their prior acute 
pancreatitis develop, and these symptoms are severe enough to interrupt 
their routine daily activities.  If the subject received care for signs or 
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records will be requested for review.  The blinded site investigator will 
determine if the subject’s episode meets study criteria for acute 
pancreatitis. 
 
Details of the acute pancreatitis event, such as need for and duration of 
hospitalization, presence of local and systemic complications of acute 
pancreatitis using the revised Atlanta criteria and treatment received will be 
assessed via history and review of medical records by the blinded 
coordinator and physician.  
 
9.4.5 
Subsequent acute pancreatitis follow-up 
Subsequent episodes of acute pancreatitis will be managed in a similar 
manner to the first.  To maintain consistency across centers, guidelines for 
recommending ERCP during the follow-up period are provided in Section 
9.6.  
 
9.5 
Maintenance of the blind 
 
In order to ensure blinding of 1) subjects, 2) healthcare providers making clinical 
decisions that may directly impact the primary endpoint, and 3) study coordinators who 
will obtain outcomes data, the medical record documentation will NOT state whether an 
ERCP with miES was performed.  Instead, the endoscopy report should include language 
indicating the subject’s participation in a blinded research study in which he/she may or 
may not have undergone the ERCP with miES procedure.  Sites who are unable to omit 
this information from medical record documentation must have a comparable method of 
preserving the blind via medical records in place.  Alternative methods must be approved 
by the SHARP Executive Committee.  
 
All sites will have a minimum of two physician investigators, of which one will serve as 
blinded investigator and one as unblinded investigator for each subject.  The investigator 
in the “blinded” and “unblinded” role may be consistent for all subjects or may alternate 
based on subject.    
 
For subjects randomized to EUS + ERCP with miES, the endoscopist should administer 
rectal indomethacin (all US sites) or diclofenac (non-US sites) for pancreatitis prophylaxis 
at the onset of ERCP.  This will minimize the likelihood that the subject will pass a visible 
suppository in the recovery room.  Since subjects randomized to EUS + ERCP with miES 
will undergo placement of a prophylactic pancreatic duct stent, all randomized subjects 
will require an abdominal X-ray at the Day 30 visit after ERCP to confirm spontaneous 
passage.  To maintain the blind, all subjects will undergo this procedure.  This will coincide 
with the first follow-up encounter to assess for adverse events. If the X-ray confirms 
retention of the stent in the pancreatic duct, it will be the responsibility of the unblinded 
physician investigator and his/her support staff to assure that the stent is removed 
endoscopically per clinical practice.  
 
To prevent unblinding, in the EUS + sham group, 3 ml of dilute dye such as methylene 
blue in US sites, or similar due in non-US sites will be injected into the duodenum and a 
plastic stent will be left in the duodenum.  In the EUS + ERCP with miES group, if dye was 
not used to assist in cannulation, 3 ml of dilute dye will be injected into the duodenum 
before the end of the procedure; in the EUS + ERCP with miES group, a stent will be left 
in the duodenum if one is not placed into the pancreatic duct. 

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Site study coordinators will be blinded to treatment allocation so that he/she may be 
involved in the follow-up assessments at Day 30, assist with data collection related to 
acute pancreatitis episodes and pancreas-related pain events, and during the 18-month 
follow-up visit. 
 
If a subject develops symptoms suggestive of acute pancreatitis more than 30 days after 
the randomization procedure, on-site assessments will be directed by a physician who 
was blinded to the treatment allocation.  Clinical decisions, including whether or not to 
obtain laboratory or radiographic testing for suspected acute pancreatitis, will not include 
the unblinded physician investigator.  A diagnosis of acute pancreatitis during follow-up 
will be determined by a healthcare provider who is unaware of the patient’s randomization 
group. 
 
In order to maintain blinding of subjects, all facility and professional charges associated 
with the randomization procedure will be billed to the research study.  
 
To test the effectiveness of blinding procedures, subjects and blinded study personnel will 
be asked at the 30-day follow-up assessment to which group they believe the subject has 
been assigned.  This question will be repeated at the Month 18 visit 
 
If the subject becomes aware of their treatment assignment at any point during study 
participation, this will be documented in the study database.  The subject will remain in the 
study and be part of the analysis population. 
 
9.6 
Guidelines for performing ERCP during the follow-up period. 
The following are guidelines to assist a blinded investigator who is evaluating subjects 
during the follow-up period.  Since the primary aim is to determine the effect of ERCP with 
miES on the probability of developing another bout of acute pancreatitis, which is a time-
dependent outcome measure, every effort should be made to avoid ERCPs during the 
follow-up period until this outcome has been reached.  
 
Definitions: 
 
Acute pancreatitis The definition of acute pancreatitis will be per consensus 
(Atlanta guidelines):(Banks, Bollen et al. 2013) “The diagnosis of acute pancreatitis 
requires two of the following three features: (1) abdominal pain consistent with acute 
pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to 
the back); (2) serum lipase activity (or amylase activity) at least three times greater 
than the upper limit of normal; and (3) characteristic findings of acute pancreatitis 
on CECT and less commonly MRI or transabdominal ultrasonography.” 
 
A pancreas-related pain event is defined as an episode of pancreatitis-type 
symptoms (most commonly pain) that requires emergency room or inpatient 
hospital evaluation. 
 
Guidelines for ERCP during the follow-up period: 
a) Two or more episodes of acute pancreatitis 
b) One episode of acute pancreatitis with local complication as defined by Atlanta 
criteria, that warrants pancreatogram 
c) One episode of acute pancreatitis plus at least one independent pancreas-
related pain event. 

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d) Interval development of symptomatic pancreatic duct obstruction (main duct 
stricture or stone) on cross sectional imaging 
e) Two or more pancreas-related pain events and minimum follow-up of 12 
months 
 
Ultimately the decision to recommend ERCP during the follow-up period is based on the 
best clinical judgement of a blinded physician investigator evaluating the subject. 
 
10. 
DISCONTINUATION OF PARTICIPATION 
 
10.1 Participant Withdrawal of Consent 
The participant has the right to voluntarily withdraw consent from the study at any 
time for any reason without prejudice to his/her future medical care by the physician or at 
the institution. For the occasional participant who withdraws consent, the date and reason 
for consent withdrawal should be documented. Participant data will be included in the 
analysis up to the date of the consent withdrawal.  
 
A distinction should be made between participants who fail to complete all forms on 
schedule or who miss some telephone visits and the withdrawal of consent.  Missed or 
rescheduled visits will be documented, but the participant will continue to be followed in 
the future according to protocol requirements, and all follow-up data will be included in the 
analysis. 
 
10.2 Participant Removal from Study Intervention/Procedures 
If a participant withdraws consent for the protocol intervention and/or study related 
procedures, document whether the participant is willing to allow the submission of 
continued follow-up information. This documentation should include whether the subject 
will continue to be willing to be contacted during follow up to complete all questionnaires, 
or at a minimum will be willing to be contacted to provide information on the occurrence of 
an acute pancreatitis event (primary outcome).  
 
11. 
RISKS TO SUBJECTS 
 
Randomization: Subjects will be assigned to receive the EUS + ERCP with miES 
procedure or EUS + sham procedure by chance.  One treatment group may prove to be 
less beneficial or have more risks than the other group.  
 
Blinding: To keep the study free from bias, the protocol has been carefully developed to 
minimize the risk of unmasking subjects and investigators responsible for evaluating 
subjects during follow-up. If a subject develops a medical problem where it is important 
for treating providers to know whether or not an ERCP was performed, there will be a 
mechanism in place for urgent unmasking of treating providers through the Statistical and 
Data Coordination Center (SDCC).   
 
Sham: Subjects in the sham group will not receive ERCP with sphincterotomy. While 
these subjects will not be exposed to the risks specific to ERCP, including post-ERCP 
pancreatitis, subjects will not receive the potential benefit which may occur from the ERCP 
procedure. 
 
Endoscopic ultrasound (EUS): All subjects will undergo EUS to evaluate for etiologies 
of RAP. The risks of EUS are similar to a standard esophagogastroduodenoscopy and 

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include perforation (<0.1%) and sedation-related cardiopulmonary complications (0.1-
0.5%). EUS is a routine diagnostic test performed in clinical practice for patients with iRAP. 
 
(ERCP) with minor papilla endoscopic sphincterotomy (miES): If randomized to 
ERCP with miES (approximately 50% of subjects), the procedure will be performed 
immediately after EUS and under the same anesthetic.  Subjects undergoing ERCP with 
miES will be at-risk for the ERCP-specific complications which include post-ERCP 
pancreatitis (10-20%), post-miES hemorrhage (1-2%), and post-sphincterotomy 
perforation (<1%).  The use of duodenoscopes has a very small risk of bacterial 
transmission (fewer than 100 reported cases of resistant infections potentially or definitely 
transmitted from duodenoscopes over many years, with approximately 500,000 ERCPs 
performed each year in the U.S.).  Echoendoscopes used to perform EUS (see above), 
have a similar elevator mechanism but the risk of bacterial transmission from 
echoendoscopes has not been defined.  ERCP with miES is performed for many patients 
with pancreas divisum and participation in this study will not expose them to a higher risk 
of ERCP-related complications than if the procedure were performed during standard 
clinical practice. 
 
Chromoendoscopy agents: The most common side effect of the proposed dye agents 
(Methylene Blue or Indigo Carmine) is abnormal urine color.  Less common side effects 
include diarrhea, frequent urination, nausea and vomiting, stomach cramps and fever.  
 
Magnetic 
resonance 
imaging 
(MRI) 
with 
magnetic 
resonance 
cholangiopancreatography (MRCP). Subjects will undergo an MRI with MRCP at month 
18 during the follow-up period (depending on their enrollment date).  Subjects who have 
a contraindication to MRI (subjects who have heart pacemakers, metal implants, or metal 
chips or clips in or around the eyeballs, artificial heart valves, metallic ear implants, bullet 
fragments, and chemotherapy or insulin pumps) will not participate in this component of 
the study.  There are no side effects of an MRI scan.  
 
Contrast Agent (Gadolinium): The contrast material used for an MRI exam, called 
gadolinium, does not contain iodine and is less likely to cause side effects or an allergic 
reaction.  There is a risk of an allergic reaction, so subjects will be queried about a prior 
history of allergy to gadolinium, fish, or shellfish (since a prior reaction to these foods 
increases the risk of an allergy to gadolinium).  In addition, gadolinium is excreted by the 
kidneys, so a serum creatinine level will be checked immediately prior to the MRI scan 
(glomerular filtration rate < 30mL/minute).  Gadolinium contrast agents may increase the 
risk of a rare, but serious, disease called nephrogenic systemic fibrosis in people with 
severe kidney failure.  Nephrogenic systemic fibrosis triggers thickening of the skin, 
organs and other tissues.  There is no effective treatment for this serious, debilitating 
disease. 
 
Secretin (administered during MRI/MRCP): Side effects from secretin are uncommon, 
but include flushing, nausea, vomiting, abdominal pain, upset stomach, diarrhea, and a 
remote (less than 1 in 100) chance of acute pancreatitis.  There is also a chance of an 
allergic reaction.  Contrast-enhanced computed tomography scan (CECT).  In subjects 
with a contraindication to MRI, a pancreas protocol CECT will be performed at month 18.  
The radiation exposure from one CECT (average dose = 10mSv) is roughly equivalent to 
the amount of radiation exposure one experiences from our natural surroundings in 3 
years. 
 

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Indomethacin or diclofenac: Potential side effects of this medication include peptic ulcer 
disease, kidney failure, heart attack, stroke, worsening of congestive heart failure or high 
blood pressure. However, a single dose of this medication is extremely unlikely to result 
in these effects. 
 
Stent Placement: It is possible for the stent to be placed within or migrate into the duct 
and cause pancreatitis, infection or perforation.  Migrated stents may require an operation 
for removal.  However, this is an extremely unlikely event.   
 
Abdominal X-ray: All randomized subjects will undergo an abdominal X-ray 
approximately 30 days after the randomization procedure.  An abdominal X-ray (average 
dose = 0.7mSv) is an exceedingly low risk test that requires no specific patient preparation 
www.xrayrisk.com).  The radiation exposure from one abdominal x-ray is roughly 
equivalent to the amount of radiation exposure one experiences from our natural 
surroundings in 100 days. 
 
Blood Draw: The risks of blood drawing include temporary discomfort from the needle 
stick, bruising, infection or clot in the vein.  Fainting could occur. 
 
Genetic Testing: The research participant could feel some stress from donating their 
samples for future research.  There is no intent to inform subjects, their family members 
or clinical care physicians of the results of future testing.  The risks of not knowing what is 
found include not being aware if there is treatment for the problem being studied. 
 
Loss of confidentiality: Protection of patient confidentiality is essential in human clinical 
trials.  A HIPAA compliant de-identification process will be utilized which includes a unique 
computer-generated study id for each enrolled subject.  Patient data maintained outside 
of the study site and within the WebDCU™ will be stored in a de-identified format with the 
key maintained with the local site PI.  Furthermore, at each local site study binders will be 
maintained in locked physical facilities and only accessible to authorized study team 
members to protect patient privacy. 
 
12. 
OUTCOMES DEFINITIONS 
 
12.1 Aim #1 Subsequent acute pancreatitis. The primary endpoint will be development 
of the first episode of acute pancreatitis during follow-up (following the 30-day post-
randomization visit).  The definition of acute pancreatitis will be the same as for study 
enrollment and per consensus (Atlanta guidelines):(Banks, Bollen et al. 2013) “The 
diagnosis of acute pancreatitis requires two of the following three features: 
(1) abdominal pain consistent with acute pancreatitis (acute onset of a persistent, 
severe, epigastric pain often radiating to the back); (2) serum lipase activity (or 
amylase activity) at least three times greater than the upper limit of normal; and (3) 
characteristic findings of acute pancreatitis on CECT and less commonly MRI or 
transabdominal ultrasonography.”  If the patient is evaluated at the participating 
institution where randomization occurred, a blinded physician will assess for and 
determine if each of the three criteria are present.  The blinded physician will diagnose 
acute pancreatitis if two of these three criteria are met.  If the patient is evaluated and 
treated at another facility (not the primary site of enrollment), a blinded site coordinator 
will collect medical records pertinent to the encounter(s).  These records will be 
reviewed by a blinded site physician at the participating institution where the 

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randomization procedure occurred.  After reviewing these records, the blinded 
physician will diagnose acute pancreatitis if two of these three criteria are met. 
 
12.2 Aim #2. Incidence rate ratio. The first secondary endpoint will be the incidence rate 
ratio of acute pancreatitis episodes.  The incidence rate ratio will be defined by the 
(number of acute pancreatitis episodes/time post-randomization) divided by the 
(number of acute pancreatitis episodes/time pre-randomization), keeping person-time 
equal between the pre/post periods. 
 
12.3 Exploratory Aim #3. Patient-reported outcomes. Pain related outcomes will include 
presence and pattern of pain, type of pain (neuropathic or nociceptive) using short 
form PROMIS instruments, opiate use (average use, recent use based on 30-day 
recall), and pain-related disability).  Quality of life will be measured using the PROMIS 
Global Health and PROMIS 29 instruments.  Patient’s Global Impression of Change 
will be measured using the PGIC scale.  Number and days of pain or pancreas-related 
hospitalizations will be quantified. 
 
12.4 Exploratory Aim #4. Progression to chronic pancreatitis. 
Interval development of chronic pancreatitis will be defined as the development of 
morphological changes of chronic pancreatitis during follow-up; specifically, the 
interval development of parenchymal or ductal calcifications or main pancreatic duct 
stricture.  These will be measured by radiographic interpretation of study MRI scans 
at month 18, or through other radiological imaging obtained during clinical care. 
 
Interval development of new-onset diabetes mellitus will be confirmed when a patient 
has abnormal values on two of the following tests or two abnormal values of the same 
test: a) Fasting blood sugar ≥ 126 mg/dl; b) HbA1c ≥ 6.5%; c) Random blood sugar ≥ 
200 mg/dl measured at month 18, or laboratory testing through routine clinical care, or 
are receiving antidiabetic medication(s) for treatment of diabetes mellitus.  
 
Interval development of exocrine pancreatic insufficiency will be defined using the 
fecal elastase test measured at month 18 (or laboratory testing through routine clinical 
care), defined as one fecal elastase concentration <100mcg/g stool or two values 
between 100-200 mcg/g stool. 
 
12.5 Exploratory Aim #5. Biorepository. 
The goal of biospecimen procurement (exploratory specific aim #4) is to establish a 
biorepository for future translational studies.  These studies would explore risk factors 
for recurrent acute pancreatitis, progression to chronic pancreatitis and its sequelae, 
and factors associated with response to miES.  We will collect blood and urine from 
subjects in both the randomized and observational cohorts who consent to 
participation in the biorepository.  All samples will be labeled with the SHARP study ID 
and no personal health identifiers. Samples collected at participating centers will be 
shipped to the University of Pittsburgh central biorepository and stored at this facility 
throughout the study period.  Following the SHARP trial, remaining samples will be 
shipped to a designated NIDDK Biosample Repository. 
 
All samples and data transferred to the Pittsburgh Repository will be under the 
custodianship of the SHARP PIs, although the study’s Steering Committee will have 
proprietary control of and exclusive access to the samples and data for an agreed-
upon period of time.  Subsequently, samples and data will be available to the wider 

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scientific community in accordance with the NIH policy on Data Sharing as well as the 
NIDDK policy for data sharing in multi-center and large single-center clinical studies. 
 
Biological samples from the biorepository will be used for targeted genotyping for the 
current study (in both randomized and non-randomized participants).  The genes 
analyzed will be determined by the study Steering Committee at the time of statistical 
analysis.  Refer to the SHARP Biospecimen SOPs document for additional 
information. 
 
Genomic Data Sharing Plan 
The SHARP trial is collecting biospecimens on all enrolled participants who provide 
written consent to allow biosamples to be used for future research by the SHARP 
investigators and the wider scientific community. All collected samples will be 
transferred for storage to a central repository at the University of Pittsburgh and only 
tracked by a unique study identifier. The SHARP investigators will have access to 
these samples for targeted genoyping during the grant funding period. No more than 
12 months after completion of the primary study analysis, the anonymized genotype 
data will be submitted to the NIH controlled-access database of Genotypes and 
Phenotypes (dbGaP).  
 
13. 
DATA MANAGEMENT 
 
13.1 Site Monitoring 
The 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.  The Site 
Monitoring Plan will detail the monitoring plan and will be part of the MOP. Briefly, the 
designated monitor(s) will be able to check regulatory documents and certain CRFs 
remotely and the DCU will work with each site to develop the best plan (i.e., remote access 
to medical records). 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. During both remote and on-site monitoring, the monitor will 
ensure that subject confidentiality is maintained and that PHI is protected. 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.  
 
13.2 Remote Monitoring of Informed Consent 
In an effort to review informed consent forms in a timely manner, enrolling sites will 
upload a pdf of the signed informed consent form, into the password protected clinical trial 
management system, WebDCUTM.  The PDF file will be linked to the subject ID but will be 
stored on a secure server separate from the study’s CRF data.  The secure server on 
which these files are stored is not backed up to prevent copies of files containing 
Individually identifiable health information from being copied and stored on non-SDCC 
back up servers.   The files on these servers can only be accessed by designated study 
personnel upon entry of a second password.  SDCC staff will remotely monitor the 
informed consent forms and issues identified will be relayed to the clinical site for 
corrective and preventative action.  After remote monitoring is complete, the PDF file 
containing the informed consent form will be permanently deleted from the secure server.  
If a subject must be re-consented, the process will repeat itself. 

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13.3 Data Management 
Data management will be handled by 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 PIs, the 
clinical sites, and NIDDK, and will use an electronic data acquisition method where all 
study specific clinical data 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 DCU using the WebDCU™ 
system.  This user-friendly web-based database system, developed by the DCU, will be 
used for regulatory document management, subject enrollment/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 data, and 
document processing system reliability.  All sites will be monitored by the DCU 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. 
 
13.4 Data Security and Confidentiality 
During the course of the trial, user access to the files with subject identifiers, and files 
with study outcomes will be restricted to core 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 DCU 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 DCU personnel have completed human subject protection training 
and good clinical practice training. 
 
13.5 Data Quality Assurance 
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 data and document processing system reliability.  These procedures are 
outlined in the Data Management Plan study document. 
 
14. 
ADVERSE EVENT REPORTING 
 
14.1 Definition of Adverse Events and Serious Adverse Events  

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An Adverse Event (AE) is any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of a medical treatment, device, or procedure regardless 
of whether it is considered related to the medical treatment, device, or procedures 
(attribution of unrelated, unlikely, possible, probable, or definite).  (For example, 
hyperventilation and dizziness during phlebotomy procedures) A Serious Adverse Event 
(SAE) is any adverse event that results in any of the following:  
a) Death  
b) In-patient hospitalization (for reasons other than observation) or prolongation of 
an existing hospitalization  
c) A persistent or significant disability or incapacity  
d) Congenital anomaly/birth defects  
 
The attribution of an AE or SAE characterizes its causal relationship to the study-related 
intervention/procedure as follows:  
a) Not Related  
b) Unlikely  
c) Reasonable Possibility  
d) Definitely  
 
The study will utilize the version of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) for Toxicity and Adverse Event reporting that is specified in the protocol.  
A copy of the CTCAE Criteria can be downloaded from the CTEP home page 
(http://ctep.info.nih.gov). 
14.2 Adverse Event Collection Period 
All AEs, non-serious AND serious, must be reported by the clinical site investigator(s) 
from randomization through Day 30.  Only SAEs must be reported through the end of the 
study period. 
 
14.3 Reporting of Adverse Events 
All AEs must be monitored and followed until they are adequately resolved or 
explained. The PI or the Study Coordinator at each Clinical Site is responsible for entering 
any and all reportable AEs into the database within the required timelines and updating 
the information (e.g., date of resolution, action taken) in a timely manner.  All reportable 
events must be submitted to WebDCU via the AE CRF within 5 days of first knowledge of 
the event.  Upon completion of the study protocol by the subject, premature withdrawal 
from the study by the subject, or the subject’s death, all information regarding each 
reportable event must be completed, if not done so earlier.  In the event of a subject death 
during study, that should be immediately reported and all possible efforts should be made 
by the site to obtain relevant records from the hospital or the subject’s primary care 
provider to determine the cause of death. 
 
14.4 Medical Safety Monitor 
An Independent Medical Safety Monitor has been appointed to review all serious 
adverse events (SAEs) reported during the study.  The MSM will adjudicate the 
relationship of the SAE to both the study intervention and the principles and intensity of 
overall care as described in the protocol as well as enter the expectedness of the reported 
SAE.  In addition, the MSM will regularly review aggregated AE data (provided by the 
SDCC).  The MSM will present any concerns regarding safety to the Study Executive 
Committee and the DSMB Liaison. 
 

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14.5 DSMB 
The SHARP study will have an independent Data and Safety Monitoring Board 
(DSMB) appointed by the NIDDK to oversee study patient safety.  The DSMB will receive 
reports on study progress and safety as well as data quality.  The DSMB will meet in 
person or by teleconference on a minimum of a semi-annual basis to monitor cumulative 
safety data and data quality.  
 
   
15. 
STATISTICAL CONSIDERATIONS 
 
15.1 Sample Size and Power Estimation 
Since the natural history of iRAP is poorly understood, risk estimates are based on 
previous small clinical trials and epidemiological studies. Based on a previous small trial 
of ERCP for RAP in pancreas divisum with limited (1-year) follow-up for the majority of 
patients, the probability of developing a third episode of AP is 70%.(Lans, Geenen et al. 
1992) Natural history studies specific to divisum are lacking, but retrospective cohort 
studies and one surgical series suggest the recurrence rate following minor papilla 
stenting, miES, or surgical sphincteroplasty are 15-50%(Attwell, Borak et al. 2006, 
Chacko, Chen et al. 2008, Borak, Romagnuolo et al. 2009, Crino, Bernardoni et al. 2017).  
Given the short-term risk of post-ERCP pancreatitis (~10%), costs of ERCP, and potential 
for post-sphincterotomy re-stenosis, we believe a minimum effect size of 33% (relative risk 
reduction) is of clinical relevance.  This effect size was agreed upon by the site principal 
investigators as the least clinically significant benefit for ERCP, considering the risks of 
ERCP and available data on this topic.  Since AP recurrence is variable and time sensitive, 
we propose a reduction in risk of subsequent acute pancreatitis during follow-up as the 
primary outcome, defined by the median time to acute pancreatitis recurrence (a time-to-
event measure). We assume the risk of recurrence within 12 months of randomization is 
60% in EUS + sham and 40% in EUS + ERCP with miES groups, with the median time to 
recurrence being 9.1 and 16.3 months for EUS + sham and EUS + ERCP with miES 
groups, respectively.  Assuming an exponential hazard, a 2-sided alpha error of 5%, power 
85%, and non-adherence of 20% (this includes technical crossovers when sphincterotomy 
cannot be performed and competing events/risks), the trial requires a total sample size of 
approximately 234 (n=117 per group).  
  
We recognize that sample size estimation is based on assumptions and if the event rate 
is lower than assumed, we may begin to see a decrease in power.  To reduce the likelihood 
of an underpowered study due to incorrect assumptions, a sample size re-estimation will 
be conducted during the enrollment period.  Details of this plan as well as all statistical 
considerations are outlined in the SHARP Statistical Analysis Plan.  
 
 
15.2 Treatment Allocation 
Enrolled patients will be assigned to either EUS + sham or EUS + ERCP with miES 
(1:1 randomization).  A dynamic stratification system will be implemented to ensure well-
balanced subgroups for the specified variables. Site, duct diameter (1, 2, 3, 4, 5, 6 or ≥ 7) 
and a dichotomized variable for number of attacks (1-2 vs ≥3) in the two years prior to 
randomization will be included in the randomization algorithm to ensure baseline balance 
between treatment arms.  The superior balancing characteristics of dynamic 
randomization over blocked randomization have been well established.  The 
randomization algorithm, which will be programmed into the data capture system, will 
employ biased-coin minimization and the variance method with stratification weights.  

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When a new patient is enrolled, the site will enter the stratification factor values into the 
eCRF (electronic case report form) on WebDCU™.  The details of the randomization 
algorithm are located in the Randomization Plan study document. 
 
15.3 Statistical Analyses 
The primary analysis of the trial will be done in accordance with the "intent-to-treat" 
(ITT) principle, i.e., all randomized participants will be included in the analysis.  This means 
that once a participant is randomized to an intervention group, the participant's data will 
be included in the primary analysis regardless of compliance with the protocol-specified 
intervention or follow-up requirements.     
 
A cox-proportional hazards model will be used to assess time to first occurrence of acute 
pancreatitis (primary outcome).  Subjects without an outcome event will be censored at 
the last known status or at the end of study time point.  We will adjust for duct diameter 
and number of attacks in the past 24 months in the primary analysis.  Additional analyses 
will explore the impact of the other potential prognostic variables.  This study is designed 
to test the primary hypothesis.  However, it also offers the opportunity to conduct analyses 
to evaluate important additional patient outcomes.  Details of the full analysis plan are in 
the Statistical Analysis Plan document. 
 
15.4 Observational Cohort 
The observational cohort will aid in the interpretation of the findings of the randomized 
study.  We are most interested in comparing the two cohorts, randomized and 
observational, in terms of baseline characteristics that may cause bias.  These 
comparisons will be primarily descriptive.  Two-sided 95% confidence intervals will be 
constructed and hypothesis tests will be conducted at an alpha level of 0.05.   
 
Based on data from other endoscopic and surgical studies with sham arms, and 
correspondence with some of the authors(Larson, Blute et al. 1998, Moseley, O'Malley et 
al. 2002, Salem, Rotevatn et al. 2004, Cotton, Durkalski et al. 2014), we anticipate that 
anywhere between 25-50% of eligible subjects will decline to participate in the randomized 
study.  A sample size of 100 for the observational cohort was chosen based on enrollment 
projections for the randomized trial. 
 
 
16. 
REGULATORY AND ETHICAL OBLIGATIONS 
 
16.1 Informed Consent 
It is the investigator’s responsibility to ensure that 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 done 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 participant must be given a copy of the informed consent.  The original signed 
consent must be retained in the institution’s records and is subject to review by the 

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sponsor, DCU, representatives from regulatory agencies, and the IRB responsible for the 
conduct of the institution.   
 
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 DCU.  Informed consent will be obtained from the participant 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 participant has had all questions 
regarding therapy and the protocol answered. 
 
16.2 Single Institutional Review Board (SIRB)  
In accordance with US federal regulations and ICH Good Clinical Practice Consolidated 
Guideline) all research involving human subjects and changes to the research plan must 
be reviewed and approved by an IRB.   
 
Per NIH policy (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-094.html), the 
Medical University of South Carolina Institutional Review Board will serve as the Single 
Institutional Review Board for all participating U.S. sites.  The Single Institutional Review 
Board (SIRB) for multicenter protocols is the single IRB of record. 
 
The Medical University of South Carolina IRB will initiate reliance agreements with each 
relying institution.  The relying institution will be responsible for performing a local context 
review of the study to ensure that the protocol is appropriate and reasonable for their 
respective study populations. 
 
Each relying site must undergo SIRB review and obtain SIRB approval before initiating 
any study activities at the site.  SIRB approved study materials (such as informed consent 
documents, patient-facing materials, etc.) will not be provided to a site until that site has 
received SIRB approval. 
 
Study wide amendments and/or modifications to the study will not be initiated without prior 
written approval of the SIRB except when necessary to eliminate immediate hazards to 
patients. 
 
 
 
17. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
 
17.1 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 study is terminated, the investigator will provide any outstanding data or 
documentation related to the study at the time. 
 
The Clinical Center reserves the right to terminate the study according to the contract.  
The SHARP PIs are responsible for notifying the SIRB in writing of the trial’s completion 
or early termination.  A copy of the notification must be uploaded into the regulatory 
database as part of the study regulatory documents. 

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17.2 Study Documentation and Storage 
Source documents are the original or valid records of participant information from 
which case report form data are obtained.  These include, but are not limited to, reports of 
test results, hospital charts and medical records, and correspondence.  Case report form 
entries may be considered source data if the case report form is the site of original 
notation, such as the patient questionnaires or quality of life instrument.  
 
In June 2005, a new Federal law was implemented that extends the statute of limitations 
to six (6) years to bring forward an allegation of research misconduct.  In response to this 
extension, research records must be retained for a sufficient period to investigate an 
allegation of research misconduct - a minimum period of six (6) years.  An agreement 
must be in place between the Site Investigator and the Principal Investigator regarding 
records that may be destroyed. 
 
17.3 Publication Policy 
Investigators will be offered the opportunity to publish as a group or with recognition 
of individual authors.  This decision will be made before analyses are conducted.  Refer 
to the study Publication Policy for more details. 

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