Per-oral Pancreatoscopy-guided Lithotripsy vs. Extracorporeal Shock Wave Lithotripsy in Chronic Pancreatitis
Phase: NA
Conditions: Pancreatitis, Chronic
Sponsor: University of Colorado, Denver

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PI: Raj Shah 
Version Date: December 6, 2023 
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SARC Approved 5/8/2019 
 
Per-oral Pancreatoscopy-guided Lithotripsy vs. Extracorporeal Shock Wave 
Lithotripsy For Treating Symptomatic Main Pancreatic Duct Stones in Chronic 
Pancreatitis: A Multicenter Randomized Clinical Trial 
 
 
 
Lead Site: University of Colorado 
Version Date: December 6, 2023 

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Table of Contents 
Table of Contents ........................................................................................................................................ 2 
Synopsis ...................................................................................................................................................... 3 
List of Abbreviations ................................................................................................................................... 4 
Study Protocol............................................................................................................................................. 5 
Research Questions and Hypothesis .............................................................................................. 5 
Basic Design of the Study ................................................................................................................ 7 
Sample and Methodology ............................................................................................................... 7 
Subject Inclusion and Exclusion Criteria .......................................................................................... 9 
Inclusion Criteria: ...........................................................................................................9 
Exclusion Criteria: ..........................................................................................................9 
Study Steps ................................................................................................................................... 10 
Screening/Baseline Evaluation ..................................................................................... 10 
Consent ....................................................................................................................... 10 
Randomization ............................................................................................................ 10 
Treatment Regimens .................................................................................................... 10 
Outcome Determination .............................................................................................. 11 
Standard of Care/Research Procedure .......................................................................................... 12 
Subject and Study Stopping Criteria .............................................................................................. 12 
Data Collection Tool ...................................................................................................................... 13 
Data Analysis Plan ......................................................................................................................... 13 
Data and safety monitoring plan ................................................................................................... 14 
Definition of AEs, serious AEs, and unanticipated problems........................................... 14 
Procedures for documentation of adverse events .......................................................... 15 
Monitoring of Data ...................................................................................................... 16 
Feasibility/Recruitment Plan/Materials ....................................................................................... 16 
Training Plan .................................................................................................................................. 16 
 

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Synopsis 
 
Title 
Per-oral Pancreatoscopy-guided Lithotripsy vs. Extracorporeal Shock Wave 
Lithotripsy in Chronic Pancreatitis: A Multicenter Randomized Clinical Trial 
Investigative sites 
University of Colorado 
The Ohio State University 
Baylor St. Luke’s Medical Center 
Methodist Dallas Medical Center 
University of Minnesota 
University Health, San Antonio 
Indiana University  
Washington University School of Medicine  
 
Hypothesis 
The central hypothesis is that per-oral pancreatoscopy- guided lithotripsy is superior 
to extracorporeal shock wave lithotripsy in clearance of main pancreatic duct 
stones, thereby improving pain levels and quality of life in 
patients with chronic calcific pancreatitis. 
Primary Objective 
To demonstrate the superiority of per-oral pancreatoscopy over extracorporeal 
shock wave lithotripsy in clearance of main pancreatic duct stones in patients with 
chronic pancreatitis. Failure to remove any or all stones with the initial intervention 
will be an outcome recorded for the study. 
Secondary Objective 
To demonstrate the effect of stone clearance to reduce pain and opiate use and 
improve quality of life. 
Timeline 
Enrollment will be performed over a 24-month time period with follow-up 
performed at 1, 3, 6, 12, 18, and 24 months after ductal clearance. 
Primary Endpoint 
Main pancreatic duct stone complete clearance rate 
Secondary Endpoints 
• 
Change in quality of life 
• 
Change in pain scores 
• 
Change in opiate use 
• 
Number of procedures 
• 
Adverse Events related to therapies 
Study Design 
Multicenter randomized trial 
Sample Size 
150 patients 

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List of Abbreviations 
 
PD: pancreatic duct 
PPL: per oral pancreatoscopy-guided lithotripsy 
ESWL: extracorporeal shock-wave lithotripsy 
EHL: electrohydraulic lithotripsy 
LL: laser lithotripsy 
ERP: endoscopic retrograde pancreatography 
ERCP: endoscopic retrograde cholangiopancreatography  
AE: adverse event  
EUS: endoscopic ultrasound  
CT: computed tomography 
MRCP: magnetic resonance cholangiopancreatography 
KUB: kidneys-ureters-bladder radiograph

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Study Protocol 
Research Questions and Hypothesis 
Pain relief poses a significant challenge in patients with chronic pancreatitis given the paucity of effective 
medications and interventions. Approximately 50-90% of patients with chronic pancreatitis develop 
pancreatic duct (PD) stones which can obstruct the PD, causing ductal hypertension that can lead to severe 
pain.1 This pain is frequently treated with opiates, which not only pose a risk of addiction but are also 
associated with increased hospitalization rates.2 Traditional methods to remove PD stones include 
endoscopic retrograde pancreatography (ERP) with sphincterotomy, stricture dilation, and balloon or 
basket extraction and extracorporeal shock-wave lithotripsy (ESWL) for larger stones.3, 4 A potential 
benefit of ERP techniques over ESWL alone is the ability to treat underlying pancreatic duct strictures with 
therapeutic PD stenting to not only facilitate stone removal but potentially to help reduce stone 
recurrence by improving pancreatic juice flow.5, 6 As shown previously, use of ESWL alone without 
treatment of strictures is associated with a significantly higher stone recurrence rate.7 Furthermore, ESWL 
does not remove stone fragments and ERP techniques are required for this aspect of stone clearance.8 If 
ERP with PPL is performed it may obviate the need for ESWL except in special circumstance such as 
significantly impacted pancreatic stone burden in the head of the pancreas. 
These methods, however, may be limited by imprecision, limited ESWL availability for PD stone therapy in 
the US, requirement of multiple treatment sessions, and decreased efficacy in removing larger, impacted 
stones.9, 10 From a practical standpoint, the need to frequently outsource ESWL to urologists limits the 
ability of gastroenterologists to control the timing of these sessions and assess efficacy while potentially 
increasing patient costs, time commitment, and use of general anesthesia.11 If ineffective in stone 
clearance, surgery remains a last-resort option that is associated with high morbidity (18-53%) and 
mortality (0-4.55%).12 The introduction of per oral pancreatoscopy, or direct endoscopic visualization of 
the PD, has enabled targeted intraductal therapy, including electrohydraulic lithotripsy (EHL) and laser 
lithotripsy (LL) for these stones.13 None of these treatment methods have been studied in prospective 
trials and there is a lack of comparative data between ERCP techniques and ESWL in removing stones, 
whether they improve pain and quality of life, and reduce opiate use along with assessing financial costs. 
There is, therefore, a critical need to compare the efficacy of per oral pancreatoscopy-guided lithotripsy 
(PPL) with ESWL and determine which therapy provides better outcomes with a goal of less procedures 
and that is more cost-effective in removing difficult PD stones. Without such information, the treatment 
of main pancreatic duct stones associated with chronic pancreatitis will likely remain limited anecdotal and 
consisting of retrospective case series. 
Within the field of pancreatology, there exists legitimate equipoise regarding which treatment is more 
effective in removing pancreatic duct stones. ESWL has been performed for a longer period of time with 
a meta-analysis including 27 studies and 3189 patients demonstrating a 70% complete duct clearance rate 
with the use of ESWL.14 There have been far fewer studies involving PPL with a recent meta-analysis 
involving 302 patients in 10 studies found a 86% success rate in stone clearance.15 Importantly, a 
randomized study comparing the two techniques has not been performed and the only randomized study 

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comparing ESWL with endoscopy was completed in 2007 prior to the use of PPL.9 Therefore, while PPL 
appears to be safe and effective in the treatment of these stones, there are no prospective studies 
evaluating its efficacy and given the relative efficacy of both techniques, a head-to-head randomized study 
is needed to determine which modality is optimal for patients with chronic pancreatitis. 
Currently, treatment of these PD stones in the US is often dictated by the resources and expertise available 
at each center. Both ESWL and PPL are considered standard of care treatments with the European Society 
for Gastrointestinal Endoscopy (ESGE) recommending endoscopic therapy and/or ESWL as first-line 
therapy in patients with chronic pancreatitis who have a PD obstruction in the head or body of the 
pancreas.3 In regards to size, the ESGE also recommends ESWL for stones > 5 mm in diameter and ERCP 
for stones < 5 mm in diameter, but clarifies that PPL be performed when ESWL is not available or for stones 
that are not adequately fragmented by ESWL.3 In the US, ESWL is primarily performed by urologists for 
treatment of kidney stones, and the lack of familiarity with chronic pancreatitis has led to a general 
reservation by urologists in performing ESWL for pancreatic duct stones.11 Furthermore, the difficulty in 
coordinating the schedules of anesthesia, urology, and gastroenterology together to perform ESWL for 
this disease has discouraged the use of the ESWL in the US.16 
Therefore, our long-term goal is to determine the optimal treatment regimen for chronic pancreatitis-
related pain associated with main pancreatic duct stones. Our overall objectives in this application, which 
is the next step toward attainment of our long-term goal, are to (i) determine whether PPL is superior to 
ESWL in removing main pancreatic duct stones, and (ii) ascertain the effectiveness of PPL or ESWL in 
improving pain and quality of life. Our central hypothesis is that PPL is superior to ESWL in removing 
difficult PD stones, thereby improving pain levels and quality of life in patients with chronic calcific 
pancreatitis. Our hypothesis has been formulated based on previous retrospective studies from our group 
demonstrating a higher stone clearance rate with PPL compared to published stone clearance rates for 
ESWL.6, 13, 14, 16, 17 The rationale for this project is that the determination of the superior lithotripsy method 
and its effect on pain and quality of life is likely to guide clinical decision-making in patients with PD stones 
whereby optimal strategies for the treatment of chronic pancreatitis can be developed. To attain the 
overall objective, the following two specific aims will be pursued: 
1. Perform a multicenter randomized clinical trial to compare the efficacy of per oral 
pancreatoscopy-guided lithotripsy with extracorporeal shock-wave lithotripsy in the removal 
of pancreatic duct stones. Based on preliminary data, our working hypothesis is that PPL is 
superior to ESWL in the clearance of PD stones. 
2. Compare the effect of per oral pancreatoscopy-guided lithotripsy with extracorporeal shock-
wave lithotripsy in reducing pain and improving quality of life in patients with chronic 
pancreatitis. Based on preliminary data, our working hypothesis is that stone clearance will 
reduce pain levels, decrease opiate use, and improve quality of life. 
At the completion of the proposed research, our expected outcomes are to have determined which 
lithotripsy method is clinically superior in PD stone removal. We also expect to demonstrate the effect of 
PD stone removal on pain and quality of life. These results are expected to have an important positive 
impact because they will provide a strong evidence-based support for endoscopic therapies to ultimately 

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treat chronic calcific pancreatitis more effectively. 
Basic Design of the Study 
This study is a multicenter randomized trial comparing per oral pancreatoscopy-guided lithotripsy (PPL) 
using either laser lithotripsy (LL) or electrohydraulic lithotripsy (EHL) with extracorporeal shock wave 
lithotripsy (ESWL) in removing main pancreatic duct (PD) stones from patients with chronic calcific 
pancreatitis. Specific aims for this trial include: 
• 
SA1: To determine whether PPL is more effective than ESWL in removing PD stones in terms 
of main pancreatic duct stone clearance rate in patients with chronic calcific pancreatitis. 
• 
SA2: Evaluate the effectiveness of main pancreatic duct stone removal in reducing pain and 
improving quality of life in patients with chronic calcific pancreatitis. 
 
SA2a: To determine whether a greater clearance of PD stones via PPL or ESWL 
will improve quality of life to a greater extent. 
 
SA2b: To determine whether a greater clearance of PD stones via PPL or ESWL 
will reduce pain and opiate requirements to a larger extent. 
The primary endpoint of this trial will be complete clearance of main PD stones in eligible patients. This 
study will be statistically powered to detect superiority of PPL over ESWL in this primary endpoint. Major 
secondary endpoints will include: 1) change in quality of life after PD stone removal; 2) change in pain 
levels after PD stone removal; 3) change in opiate use after PD stone removal; 4) comparison of total 
number of procedures in both arms, and 5) PD stone recurrence rate. 
Sample and Methodology 
We will enroll 150 subjects (Figure 1) with chronic pancreatitis who have symptomatic main PD stones 
identified by non-invasive imaging, endoscopic ultrasound or prior endoscopic retrograde 
pancreatography (ERP). 
Following baseline assessments and identification of main PD stones, patients will be randomly assigned to 
receive either PPL or ESWL as the primary lithotripsy method to fracture PD stones. Both these procedures 
represent potential next steps in the algorithm of managing PD stones.3 If partial clearance (removal of 
some, but not all stones) of PD stones is achieved as determined by the performing endoscopist, subjects 
can receive repeated PPL or ESWL sessions (for a maximum of 4 sessions total as is commonly practiced 
before referral for alternative therapy) until complete removal of stones is achieved.5 Failure to remove 
any main PD stones will be considered a failure of the treatment. Additionally, failure to achieve complete 
clearance within a maximum of 4 sessions of either PPL or ESWL will be considered a treatment failure, 
even if partial clearance is achieved. 
Cross-over and/or combination therapy will be allowed at the discretion of the endoscopist after 
treatment failure. As described in the statistical analysis, under the intention-to-treat (primary) analysis, 
should cross-over occur, the final outcome of complete stone clearance will be attributed to the initial 
therapy. Under the per-protocol (secondary) analysis, in the case of cross-over, the final outcome of 
complete stone clearance will be attributed to the combination of ESWL and PPL. Similarly, in terms of 
survey collection, should cross-over occur, the analysis of the survey results will be attributed to the 

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originally assigned intervention in the intention-to-treat (primary) analysis. In the per-protocol 
(secondary) analysis, the outcomes will be attributed to the combination of both interventions resulting 
in technical success. 
Patients who are randomized and subsequently found to have an exclusion criteria identified will continue 
follow-up per study protocol. 
Stone clearance will be determined by occlusion pancreatography showing the absence of main PD 
stones. Complete stone clearance will be defined as the absence of stones in the head or body of the main 
PD. Partial stone clearance will be defined as the removal of more than 50% but less than 100% of 
stone/stone fragments in the head or body of the main PD. 
Recurrence will be defined as the presence of stones following confirmed clearance in the final 
pancreatogram. To be considered as recurring, the stone must require intraductal lithotripsy for removal. 
Following complete PD stone removal, patients will be given a validated quality-of-life instrument, the 
PANQOLI18,  at 1, 3, 6, 12, 18, and 24 months post-treatment. Similarly, the visual analog scale will also be 
given at 1, 3, 6, 12, 18, and 24 months post-treatment. Lastly, daily opiate use will be recorded at 1, 3, 6, 
12, 18, and 24 months post-treatment. The 1, 3, 6, 12, 18, and 24-month assessments will have a ± 2 
weeks window to be completed. 
In order to ensure that subjects respond to the questionnaires as required, REDCap will be programmed 
to automatically send three reminders to the participants' email when the questionnaires are due. 
Furthermore, the study coordinator will make three separate attempts to contact non-responding 
patients within the designated timeframe. If a patient remains unresponsive, these instances will be 
documented as protocol deviations. 
Documentation on interventions for chronic pancreatitis occurring outside of scheduled appointments 
will be recorded a separate CRF (“non-scheduled chronic pancreatitis interventions”). This CRF will 
encompass any pancreatic interventions (other than POP x ESWL planned visits) taking place between the 
subject's consent form signature and their final follow-up. 
All patients will have a HgbA1c and fecal elastase drawn at baseline (within 12 months prior to treatment 
initiation) and at the 1-year mark from treatment completion. Laboratory tests will be drawn per standard 
of care, and tests results will be added to the REDCap database. 
 

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Figure 1: Study Flowsheet 
 
 
 
Subject Inclusion and Exclusion Criteria 
Inclusion Criteria: 
1. Subjects aged 18-89 
2. Subjects with abdominal pain secondary to chronic calcific pancreatitis and main pancreatic 
duct stones found on cross-sectional imaging, EUS, or ERP with upstream PD dilation 
3. Main PD stones in the head or body that are greater than 50% in size of the immediate 
downstream diameter of the pancreatic duct 
4. Stones ≥ 5 mm in diameter or impacted in the main PD on cross-sectional imaging or EUS 
 
Exclusion Criteria: 
1. Subjects who have previously received PPL or ESWL for PD stones within 12 months of 
enrollment 
2. Patients with PD stones isolated in the tail or side branches of the main duct 
3. Pancreatic tail stones comprising more than one-third of the stone burden within the main PD, 
if multiple locations of stones are noted within the main PD 
4. Nontraversable ansa loop with upstream stones 
5. Inability to place a transpapillary pancreatic duct stent during ERP 
6. Patients with prior pancreatic surgery or surgically altered gastroduodenal anatomy, such as 
Roux-en-Y surgery 

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7. Acquired pancreas divisum 
8. Significant cardiopulmonary co-morbidities precluding general anesthesia 
9. Patients with coagulation disorders that cannot be corrected to an INR below 2.0 
10. Patients with ongoing alcohol abuse and/or illicit drug use, except products containing THC 
11. Pregnancy 
12. Patients in active treatment for malignancy other than non-melanoma skin cancer or papillary 
thyroid cancer 
Study Steps 
Screening/Baseline Evaluation 
Potential eligible patients will undergo an initial visit in which eligibility will be confirmed and the trial 
protocol explained in detail. All willing and eligible patients providing informed consent will have baseline 
data obtained including detailed history of chronic pancreatitis (i.e. disease duration, etiology, drug use, 
and family history of pancreatic disease), endoscopy history, and current medication use. Baseline quality 
of life and pain levels will also be obtained. Laboratory tests: HbA1c and Fecal elastase will be drawn per 
standard of care within 12 months prior to enrollment, and tests results will be documented in the study. 
The National Institute of Alcohol Abuse and Alcoholism (NIAAA) defines binge drinking as a pattern of 
drinking alcohol that brings blood alcohol concentration (BAC) to 0.08 percent - or 0.08 grams of alcohol 
per deciliter - or higher. For a typical adult, this pattern corresponds to consuming 5 or more drinks (male), 
or 4 or more drinks (female), in about 2 hours.19 
Patients of childbearing potential will undergo a serum/urine pregnancy test based on each site practice, 
as per the standard of care. 
Consent 
Patients will be provided the necessary information regarding the study and consent will be obtained 
either in person and/or electronically through medical records depending on specific site IRB approval 
guidelines. Consent for the study will be obtained by a member of the study team either in person or 
electronically through medical records depending on specific site IRB approval guidelines. 
Randomization 
Randomization will occur after informed consent is obtained and prior to receiving lithotripsy. Once 
enrolled, the research coordinator will enter the patient into the REDCap database, at which 
randomization will occur via computer algorithm. 
Randomization will be performed using a 1:1 ratio. The investigator will then inform the patient which 
lithotripsy therapy will be subsequently performed. 
Treatment Regimens 
Per oral pancreatoscopy-guided lithotripsy 
Standard ERP will be performed to cannulate the PD, perform pancreatic sphincterotomy, and stricture 

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dilation as necessary. A pancreatoscope (Spyglass Digital System, Boston Scientific, Marlborough, MA) will 
then be inserted through the duodenoscope into the PD. For PPL, electrical pulses will be delivered 
through an aqueous medium by EHL or LL with the probe tip in contact with or 1-2mm away from the 
stone. 
For EHL, the Nortech bipolar biliary EHL probe (1.9 Fr, 0.66 mm) will be used and lithotripsy will start at 
medium power and can be increased to high power (maximum of 100 Joules). In terms of frequency, the 
maximum frequency allowed will be 30 pulses/second. There will be no limit to the number of EHL probes 
used during a session of lithotripsy, but the maximum time of lithotripsy allowed will be 1 hour. 
For LL, Holmium laser will be utilized with energy ranging from 1 to 10.5 Joules, a frequency of 8-14 Hz and 
a power from 5-25W. LL fibers will include 200, 272, and 365 µmeter fibers. Similar to EHL, a maximum of 
1 hour of intraductal lithotripsy will be allowed. Both forms of intraductal lithotripsy can be performed 
during the same treatment session. 
EHL and/or LL will be continued until stone fragments are ≤ 3 mm or a maximum of 1 hour of lithotripsy.  
Extracorporeal shock wave lithotripsy 
Stone localization will first be performed by obtaining high-quality plain films of the pancreatic area in left 
and right oblique positions using a two-dimensional radiologic targeting system. 
Depending on the stone localization, ESWL will then be performed with the patient in either slight left or 
right lateral decubitus with shock waves entering the body from the ventral side. The shockwaves will be 
focused first on the most downstream located stone within the main duct and then on other calculi 
moving from the head towards the body. If a stent has been inserted during preceding ERP then this may 
also serve as a guide to target main pancreatic duct stones by ESWL. 
ESWL will start at the lowest power level and will gradually be increased until 25% of the shocks have been 
delivered to help create vascular constriction to minimize the risk of hematoma. The middle 50% of the 
shocks will be equally distributed between the 1st 25% of shocks and the final 25% of shocks at the top 
level of power. The final 1000 shocks should be administered at the highest power level number. The 
range of shocks delivered will be limited to 4000 to 6000 shocks. The rate of shocks will range from 70-
90/minute. 
A KUB (kidney-urether-bladder)-right posterior oblique X-ray will be done within 7 days after the ESWL 
session to determine the level of fragmentation of the stones. The goal will be to continue ESWL until 
stone fragments are felt to be ≤ 3mm. 
Non-lithotripsy pancreatoscopy maneuvers will be permitted in the ESWL arm and not result in primary 
endpoint failure. 
Outcome Determination 
An occlusion pancreatogram following extraction of stone fragments will be obtained after the 
endoscopist/urologist has determined treatment completion. All patients will receive an ERP at the 
completion or either PPL or ESWL, with an occlusion pancreatogram performed to determine stone 

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clearance. An initial pancreatogram (or PD image from cross-sectional test – MRCP, MRI, CT scan, or EUS) 
with stone location and two representative final occlusion pancreatogram images will be uploaded to the 
REDCap database and will be reviewed by a blinded endoscopist to assess the level of stone clearance 
(complete or partial). 
Standard of Care/Research Procedure 
The current standard of care for the treatment of PD stones varies by region. In Europe, extracorporeal 
shock- wave lithotripsy (ESWL) is a primary method by which stones are fragmented. Once ESWL is 
performed, however, ERP is still performed to remove the stone fragments. In Europe, ESWL is frequently 
performed by gastroenterologists who can perform ERP as well. 
In the United States, however, ESWL is primarily performed by urologists for the treatment of kidney 
stones. Few gastroenterologists have direct access to ESWL and urologists remain hesitant to use ESWL for 
non-kidney stones. Therefore, in the United States, standard therapy has become ERP.4 In ERP, 
pancreatography is performed by cannulating the PD and then injecting radio-opaque iodine contract into 
the PD. Pancreatography allows for radiographic visualization of a stone and associated strictures; stone 
removal can be achieved by sweeping the PD with either a balloon or basket after performing a pancreatic 
sphincterotomy where the sphincter opening the PD is cut and coagulated. This is often followed by 
balloon or catheter dilation of any downstream pancreatic duct strictures. ERP is typically made more 
difficult by strictures downstream of the stones and the presence of numerous, large (>5mm in diameter) 
or hard stones. 
In this study, per-oral pancreatoscopy-guided lithotripsy (PPL) will be compared with ESWL. 
Pancreatoscopy, the placement of a small endoscope directly into the PD, allows for direct visualization 
of the PD and stones. This allows for intraductal lithotripsy to be performed while directly visualizing the 
stones. Briefly, EHL, one version of intraductal lithotripsy, creates high-frequency shock-wave pulses 
which generate energy that can result in the fragmentation of stones. LL, on the other hand, involves the 
focusing of laser light on the surface of a stone which can induce wave-mediated stone fragmentation. 
Both techniques can fragment stones into smaller pieces, which can then be swept out of the PD using 
standard techniques such as balloon or basket sweeping. 
Upon completion of the procedure, all patients will be observed in the post-anesthesia care unit for 1 
hour as is the current standard of care. Following the index ERP session and sphincterotomy, extended 
recovery in the hospital or discharge will be planned per institutional practice. If patients exhibit 
symptoms such as intractable abdominal pain or severe N/V, they will be admitted for overnight 
observation. All patients will receive a phone call within 48 hours of discharge as is standard practice to 
identify any short-term AE’s. 
Subject and Study Stopping Criteria 
Subjects may withdraw from the study at any time for any reason. Subjects can also be withdrawn from 
the study at any time at the discretion of the investigators for breach of study protocol or emergence of an 
exclusion criteria (i.e. pregnancy). 
The study can be stopped at any point should the Data Safety Monitoring Board (DSMB) request cessation 

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of the trial based on any compilation of adverse events or clear demonstration of superiority of one 
technique. Similarly, should the interim analysis reveal futility in that the study hypothesis is deemed 
unprovable within the constraints of the study, the study may be stopped. The study will also be stopped 
once the intended sample size goal is reached and 6-month follow-up has been obtained. Lastly, the study 
can be stopped should study costs exceed the allotted budget. 
Data Collection Tool 
A comprehensive system has been previously developed at this institution, and will support the data 
collection and reporting needs of this project which includes:  
(i) streamlining data collection from the participating centers, 
(ii) creating a secure database from which statistical analysis can be performed. Data will be stored at the 
University of Colorado instance of REDCap15, which resides on a local secure server. Data regarding stone 
clearance rates and adverse events will be entered by investigators at each center. Using an Application 
Programming Interface (API), data can be transferred to and from REDCap to SAS software (v.9.3, SAS 
Institute, Cary, NC) used to export data from REDCap to SAS to conduct analysis. SAS software interfaces 
seamlessly with REDCap-produced syntax files (i.e. SAS code) and SAS-ready CSV (comma separated 
variables) data files. Results of these analyses will be imported back into REDCap, using the API, for long-
term storage, reference, and further analysis. Access to these data will be controlled by a custom module 
and all users of the site will be required to log in. No protected health information will be collected or 
displayed and data stored in our HIPAA compliant serve environment to ensure privacy. 
Data Analysis Plan 
Statistical Analysis: Comparison of technical success rate, defined as the rate of complete clearance of PD 
stones, between PPL and ESWL will be performing using the chi-squared test or Fisher’s exact test. 
Secondary outcomes including adverse event (both overall and serious adverse event) rates, procedure 
length, and number of procedures will be compared using a chi- square test or Fisher’s exact test for 
categorical variables and the Student’s t test will for continuous variables. A p value <0.05 will be 
considered significant. In the primary analysis, all results will be analyzed under an intention-to-treat 
protocol. A per-protocol (secondary) analysis will also be performed where the technical success will be 
attributed to the combination of modalities resulting in achieving the primary outcome should cross-over 
occur. 
To identify predictors for technical success, a multivariable logistic regression will be performed 
incorporating variables that were associated (p<0.2) with technical success on univariate analysis. 
In terms of secondary outcomes, change in PANQOLI scores, VAS scores, and opiate daily doses will be 
compared between subjects in the PPL group and ESWL group. Additional outcomes to be measured 
include stone recurrences and number of chronic pancreatitis-related hospitalizations during the follow-up 
period. Should cross- over occur, under the primary (intention-to-treat) analysis, the outcomes will be 
attributed to the initially randomized intervention. In the secondary (per-protocol) analysis, the outcomes 
will be attributed to the combination of treatments resulting in technical success. A subgroup analysis will 
also be performed on patients who achieved only partial stone clearance (thus considered a treatment 

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failure) in the above-mentioned outcomes. Comparisons will be made using a chi-squared test or Fisher’s 
exact test for categorical variables and the Student’s t test for continuous variables. Paired t tests will be 
performed to evaluate individual changes within each arm. A p value <0.05 will be considered significant. 
Power analysis: A large meta-analysis by Moole et al found a complete stone clearance rate of 70% in 
patients who received ESWL in conjunction with ERCP.14 In contrast, the largest studies examining 
pancreatoscopy-guided lithotripsy methods have found complete stone clearance rates ranging from 83-
99%.6, 17 Using a conservative stone clearance rate of 90% for pancreatoscopy- guided lithotripsy, a sample 
size calculation was performed using a two-sided test with 80% power and significance (α) of 0.05. This 
demonstrated the need for 124 subjects total, with 62 in each arm. Accounting for an expected dropout 
rate of 20%, the sample size needed would be a total of 150, or 75 subjects in each arm. 
Data and safety monitoring plan 
A Data and Safety Monitoring Board (DSMB) will be established to monitor the data and safety of this 
project. A DSMB will be appointed by the study team and will include at a minimum: A senior faculty 
member clinician with substantial research experience within the Division of Gastroenterology and 
Hepatology at the University of Colorado who is not involved in the study, and will serve as the group 
leader, a statistician, and a senior gastroenterologist from a non- participating academic institution. The 
DSMB will meet every six months. DSMB meetings will be only open to designated DSMB staff and other 
individuals who have been approved to have access to unblinded data. Any recommendations for 
alteration or termination for part or all of the trial shall be based on consideration of the accumulating 
data in the context of totality of evidence. Specific statistical monitoring guidelines for safety and efficacy 
concerning the primary and secondary endpoints will be developed in cooperation with the DSMB. 
Definition of AEs, serious AEs, and unanticipated problems 
AEs are defined as any undesired, harmful, or pathological change in a patient as indicated by signs, 
symptoms, or laboratory changes that occur in association with the use of the trial interventions, whether 
considered intervention-related or not. This definition includes intercurrent illness or injuries, 
exacerbation of existing conditions, psychological events, psychosocial events, and AEs as a result of the 
study intervention. All endoscopic AEs will be defined and classified as recommended by the American 
Society for Gastrointestinal Endoscopy (ASGE).20  
The most common AEs for PPL are expected to include pancreatitis and bleeding. The most common 
infectious complications are expected to include cholangitis, cholecystitis, and less likely or rare 
duodenoscope-related infection transmissions and perforation. No differences in the types and 
proportion of AEs have been found in previous studies examining EHL and LL.10 
The risks of ESWL include post-ESWL pancreatitis, bleeding, infection, steinstrasse, sepsis, and rarely, 
perforation,  pancreatic duct leak and arrhythmias. An overall AE rate for ESWL is 6.7%.21 The most 
common adverse event associated with ESWL remains pancreatitis with a meta-analysis finding a rate of 
4.2%.14 Mild skin erythema and tenderness also typically occurs at the region of contact with the 
shockwaves and other adverse events such as bleeding and infection occur in approximately 1% of cases.3 
Similarly, the primary risk of PPL is pancreatitis which in a meta-analysis was found to occur in 8.7% of 
cases.15 Additional risks include incomplete fragmentation of the stone requiring alternative treatment, 

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stone migration, inability to access stones(s), no stones, need for further procedures, loss of pancreas 
and/or death. Machine malfunction may occur, necessitating rescheduling. In addition, the stones might 
not get removed completely. In comparison, surgery, an alternative treatment modality typically 
consisting of either a lateral pancreaticojejunostomy or a Frey procedure, has a higher rate of adverse 
events. In a randomized trial comparing surgery with endoscopy, the surgical treatment arm had a 27% 
adverse event rate with the main adverse events including anastomotic leakage (6.8%), bleeding (6.8%), 
incisional hernia (4.5%), pneumonia (4.5%), and severe delayed gastric emptying (4.5%).22 Additionally, as 
these procedures would typically be performed as part of the management of patients with PD stones at 
the study sites, there are no separate research risks from the risks of standard care. 
Worsening abdominal pain may occur after either of the procedures, with the potential need for 
prolonged observation. Abdominal pain may be related to ductal manipulation, stone mobility, or due to 
other adverse events.  
The definition of a serious AE is any AE that results in any of the following outcomes: 
1) death, 2) life-threatening, 3) persistent or significant disability/incapacity, or 4) requires or 
prolongs hospitalization. Serious AEs are expected to include perforation, air embolism, and 
cardiopulmonary AEs associated with the use of general anesthesia, which will be used in all 
procedures. 
Unexpected AEs will be defined as any AEs with specificity or severity which is not consistent with the 
current risk information in this investigational plan as formulated from prior studies investigating the trial 
interventions. 
Grading of severity of AEs will be done in accordance to the grading system proposed by the ASGE and the 
revised Atlanta classification.20, 23 For pancreatitis, grading will be done according to the revised Atlanta 
classification as follows: 
1) Mild – no organ dysfunction, 2) Moderate - transient organ failure <48 hours OR local or 
systemic AEs without persistent organ failure, and 3) Severe – persistent single or multi organ 
failure >48 hours OR present or persistent systemic inflammatory response syndrome (SIRS). 
All other AEs will be classified as follows: 
1) Mild – AE is usually transient, does not require any special treatment, and does not interfere 
with the patient’s daily activities, 2) Moderate – AE usually introduces a low level of 
inconvenience or concern to the patient and may interfere with daily activities, but are usually 
ameliorated with simple therapeutic maneuvers, and 3) Severe – AE interrupts a patient’s usual 
daily activity and generally requires systemic drug therapy or other intervention. 
Procedures for documentation of adverse events 
All AEs are to be reported using the centralized online data collection system. All AEs must be entered 
within 14 days of occurrence. A standardized reporting system will be available on the REDCap system, 
which will be accessible to all study members at each site. AE reporting can be done by either site PIs or 
research coordinators. 

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All serious AEs that occur from initiation of the study to 14 days post final intervention are to be reported 
immediately (within 24 hours) using the electronic data collection system. All serious AEs will then be 
immediately relayed to the PIs. The PIs will first review the AEs to: 1) ascertain the seriousness, 2) ascertain 
the relationship between AE and intervention, 3) verify that all data are complete, and 4) follow-up with 
the specific site for incomplete data and/or data clarification. The PIs will then submit the AEs to the DSMB, 
who will then review the AEs to confirm the findings of the PIs. 
All AEs from ESWL are ESWL-related. PPL is part of the ERCP procedure. Most AEs in this group will be 
related to the ERCP procedure itself. A potential rare AE specific to PPL (EHL or LL) is ductal perforation 
from the lithotripsy fiber and will be noted by the investigator. The investigator will determine the 
relationship of an AE specific to a lithotripsy device used to fragment the stones. 
Monitoring of Data 
The DSMB will be responsible for data and safety monitoring. All primary and secondary outcomes as well 
as data integrity and study progress along with all AEs will be reviewed by the DSMB. 
The DSMB will meet at least twice a year to review the data mentioned above. These meetings will every 
six months. 
An interim analysis will be performed at the halfway point of enrollment, which is expected to be at the 
75th patient. Should the interim analysis reveal an unexpected accumulation of AEs or a clear superiority 
of one lithotripsy method over the other, the DSMB may recommend stopping the study, which will be 
reported to the PIs, IRB and the funding agency. 
The DSMB will include at a minimum the following individuals: 
• 
Frank Scott: Gastroenterologist, University of Colorado 
• 
Jay Burton: Hepatologist, University of Colorado 
• 
Biostatistician: Non-study Statistician 
• 
Sunil Sheth: Gastroenterologist, Beth Israel Deaconess Medical Center 
Feasibility/Recruitment Plan/Materials 
The power analysis suggests that a total of 150 participants will need to be enrolled to achieve sufficient 
statistical power to compare the two lithotripsy methods. With a total of 8 recruitment sites, we anticipate 
complete enrollment within 5 years and with a follow-up of 12 months/patient post completion of 
treatment, the study is anticipated to be completed within 6 years. 
All recruitment will be done at each study site by the site-specific PI. As each study site is a referral site for 
patients with chronic pancreatitis who have PD stones, no advertising will be performed. All patients will 
be recruited based on screening done prior to regularly scheduled clinic or procedural visits. 
Training Plan 
The PIs will be responsible for training all study staff. The initial training meeting will occur at the 1st 
Investigators Meeting involving all PIs, co-investigators, and the study coordinator. The protocol will be 

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reviewed in its entirety and all standard procedures will be reviewed. Informed consent will also be 
reviewed during this session to ensure consistency across the study sites. All questions from the study staff 
will also be answered during this time. The protocol will then be reviewed at each site with the site-specific 
PIs and research assistants. 
Quarterly conference calls involving all PIs, study coordinator and research assistants will be held once 
enrollment begins to ensure that any questions the study group has are answered. In addition, all potential 
protocol changes will be discussed during these calls. Should an emergent protocol change be needed, an 
emergent conference call will be held to discuss the change and once agreed upon, the changes will be 
submitted to the respective Institutional Review Boards. 
 
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