Pancreatic Endotherapy for Refractory Chronic Pancreatitis
Phase: NA
Conditions: Pancreatic Duct Stone, Pancreatic Duct Stricture, Pancreatic Duct Dilatation
Sponsor: Oregon Health and Science University

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Pancreatic Endotherapy for Refractory Chronic PancreaTitis 
(PERCePT) 
 
STUDY CHAIR 
Gregory A. Cote, MD, MS 
 
 
SPONSOR 
Department of Defense 
Congressionally Directed Medical Research Programs (CDMRP) 
 
 

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Table of Contents 
1.0 
Objectives / Specific Aims ............................................................................................................ 4 
1.1. 
Aim #1. To determine the feasibility of a sham-controlled pancreatic endotherapy trial. ........... 4 
1.2. 
Aim #2. To define the optimal outcomes for a definitive clinical trial. ...................................... 4 
2.0 
Background ................................................................................................................................... 4 
2.1 
The fibrotic pancreas, pain, opioid dependence, and quality of life............................................ 4 
2.2 
Pancreatic duct hypertension is one mechanism for chronic pancreatitis-related pain ................ 5 
2.3 
Sham-controlled studies of endoscopy for painful chronic pancreatitis are lacking .................... 5 
2.4 
Endotherapy requires repeated interventions, possibly having a negative long-term impact ....... 6 
2.5 
Depression, opioid misuse, quality of life, and catastrophizing are important covariates in the 
treatment of pain associated with chronic pancreatitis ........................................................................... 6 
2.6 
Quality of life is significantly reduced among patients with chronic pancreatitis, primarily due 
to pain 7 
3.0 
Intervention to be studied .............................................................................................................. 7 
3.1 
Main pancreatic duct drainage. ................................................................................................. 7 
3.2 
Main pancreatic duct stone lithotripsy and extraction ................................................................ 8 
3.3 
Main pancreatic duct stricture dilation ...................................................................................... 8 
4.0 
Study Endpoints ............................................................................................................................ 8 
4.1 
Pilot primary outcome .............................................................................................................. 8 
4.2 
Pilot secondary outcomes ......................................................................................................... 8 
5.0 
Inclusion and Exclusion Criteria/ Study Population ....................................................................... 9 
5.1 
Inclusion Criteria ...................................................................................................................... 9 
5.2 
Exclusion Criteria ..................................................................................................................... 9 
6.0 
Number of Subjects ....................................................................................................................... 9 
7.0 
Setting ........................................................................................................................................... 9 
8.0 
Recruitment Methods ...................................................................................................................10 
9.0 
Consent Process ...........................................................................................................................10 
10.0 Study Design / Methods ...............................................................................................................10 
10.1 
Study procedures .....................................................................................................................10 
10.1.1 
Run-in period .....................................................................................................................10 
10.1.2 
Baseline and randomization procedures .............................................................................13 
10.1.3 
Follow-up visits, day 0 -90 .................................................................................................14 
10.1.4 
Follow-up visits, day 91-360 ..............................................................................................16 
11.0 Data Management ........................................................................................................................17 
11.1 
Data Monitoring Plan ..............................................................................................................17 
11.2 
Sample Size.. ...........................................................................................................................18 
11.3 
Data Management.. ..................................................................................................................18 
11.4 
Statistical Analysis.. ................................................................................................................18 

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11.5 
Data Security and Confidentiality. ...........................................................................................18 
11.6 
Quality Control.. ......................................................................................................................19 
11.7 
Web Based System.. ................................................................................................................19 
12.0 Provisions to Monitor the Data to Ensure the Safety of Subjects ...................................................19 
12.1 
DoD Independent Research Monitor. .......................................................................................19 
12.2 
PERCePT Data and Safety Monitoring Board Members ..........................................................19 
13.0 Withdrawal of Subjects ................................................................................................................19 
14.0 Risks to Subjects ..........................................................................................................................20 
14.1 
Loss of Confidentiality.. ..........................................................................................................20 
14.2 
Interviews & Questionnaires. ...................................................................................................20 
14.3 
Quantitative Sensory Testing.. .................................................................................................20 
14.4 
Endoscopic ultrasound (EUS).. ................................................................................................20 
14.5 
Randomization.........................................................................................................................20 
14.6 
Blinding. ..................................................................................................................................20 
14.7 
Sham.. .....................................................................................................................................20 
14.8 
ERCP. .....................................................................................................................................20 
14.9 
Endotherapy. ...........................................................................................................................21 
14.10 Stent Placement. ......................................................................................................................21 
15.0 Potential Benefits to Subjects or Others ........................................................................................21 
15.1 
Potential benefits to the study subjects. ....................................................................................21 
15.2 
Potential benefits to science and society.. .................................................................................21 
16.0 Sharing of Results with Subjects...................................................................................................21 
17.0 References ....................................................................................................................................22 
 

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1.0 
Objectives / Specific Aims 
 
The overarching hypothesis is that endoscopic treatment of main pancreatic duct obstruction due to 
chronic pancreatitis reduces pain and improves quality of life. There is a critical need to test this hypothesis, 
since ERCP is often performed in clinical practice despite limited data and potential negative short- and 
long-term consequences on the natural history of chronic pancreatitis.  
 
1.1. Aim #1. To determine the feasibility of a sham-controlled pancreatic endotherapy trial.   
The PERCePT study is a pilot, sham-controlled, randomized clinical trial to evaluate the feasibility 
of recruitment, retention, and blinding procedures, as well as to refine the enrollment criteria for a 
subsequent definitive clinical trial. Patients with painful chronic pancreatitis and main pancreatic 
duct obstruction will be randomized to endoscopic ultrasound (EUS) + sham versus EUS + ERCP 
with pancreatic endotherapy, the latter being defined by the use of extracorporeal or intraductal 
lithotripsy, stone extraction, stricture dilation, stent placement, or some combination. Pancreatic 
duct obstruction will be defined by the presence of a main pancreatic duct stone, stricture, or both, 
with consequential upstream dilation of the main pancreatic duct ≥ 6mm. After completion of the 
initial endoscopic intervention, patients will be assessed by individuals blinded to treatment 
allocation for 90 days. At this time, subjects will complete a comprehensive assessment including 
measures of pain, quality of life, sleep, mood, functioning, and medication use. All subjects will 
continue to be followed for 12 months after the randomization procedure to assess longer term 
outcomes. 
1.2. Aim #2. To define the optimal outcomes for a definitive clinical trial.   
The goals of pancreatic endotherapy are to reduce pain, improve pancreatic function, and thus 
improve quality of life and other patient-centered outcomes. The optimal outcome measures for a 
definitive clinical trial will be defined. Pain, pain-related disability, patient expectation of 
response, and quality of life will be measured at baseline, 90 days, 6 months, and 12 months 
following the randomization procedure. Changes in pain and disability and the relationship to 
quality of life and patient expectation (the nocebo effect)1 will be evaluated.  An essential 
component to defining outcomes related to pain is to identify what is important to the patient. The 
baseline case report forms and follow-up assessments will include querying subjects to prioritize 
outcomes of pancreatic endotherapy. 
 
2.0 
Background 
 
2.1 The fibrotic pancreas, pain, opioid dependence, and quality of life 
Pancreatic duct obstruction causing pancreatic duct hypertension is one of several mechanisms 
of pain, the most debilitating symptom for patients with chronic pancreatitis.2, 3 Smoking and 
alcohol are the principal etiologic factors for chronic pancreatitis, a fibroinflammatory disease 
that is overrepresented in men, soldiers, and veterans given the high prevalence of smoking and 
alcohol.4, 5 Due to the paucity of effective interventions for painful chronic pancreatitis, many 
patients require the use of opioids for long-term management; this often leads to opioid 
dependence, reductions in quality of life, and pain-related disability.6 Endoscopic retrograde 
cholangiopancreatography (ERCP) with treatment of main pancreatic duct obstruction is often 
used in the management of painful chronic pancreatitis, despite a paucity of clinical trials and no 
sham-controlled data to support its use. 

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The PERCePT study is a pilot, sham-controlled, randomized clinical trial evaluating the 
feasibility of pursing a definitive trial to examine the efficacy of a procedure (ERCP) and 
endoscopic devices used to treat pancreatic duct obstruction. 
 
2.2 Pancreatic duct hypertension is one mechanism for chronic pancreatitis-related pain 
By causing intraductal hypertension, pancreatic duct obstruction from stones (a.k.a., 
calcifications), stricture, or both is one of several pathophysiologic bases for pain due to chronic 
pancreatitis. This has been elucidated in animal models 7 and is the foundation for endoscopic and 
surgical interventions for painful chronic pancreatitis. Duct obstruction is typically defined by the 
presence of a main pancreatic duct stricture, stone, or both in association with upstream pancreatic 
duct dilation. Furthermore, pancreatic duct dilation is considered a phenotypic manifestation of 
increased pancreatic duct pressure, which is hypothesized to represent one mechanism for pain in 
chronic pancreatitis.8, 9 However, small studies suggest poor correlation between findings at 
ERCP, pain scores, and intraductal pressure.3, 10 
It is widely recognized that the etiology of pain is multifactorial, with pancreatic duct obstruction 
representing one of several mechanisms that include pancreatic ischemia, intrapancreatic nerve 
damage (manifested by inflammation, enlargement, fibrosis, or some combination), and impaired 
central nervous system modulation. Given the complex pathogenesis of chronic pancreatitis pain 
and variability in pain phenotypes 11, treatment of pancreatic duct obstruction (and thus, pancreatic 
duct hypertension) is logical but not unequivocally beneficial – three randomized trials comparing 
endoscopy with surgery or extracorporeal shock wave lithotripsy reported favorable outcomes in 
< 50% of the endoscopy population.12-14 Therefore, a sham-controlled trial of pancreatic 
endotherapy is needed. 
 
2.3 Sham-controlled studies of endoscopy for painful chronic pancreatitis are lacking 
The usual response to sham procedures in blinded interventional studies is closer to 35%.15-17 
Society guidelines 18 acknowledge that pain relief is achieved in 32-68% of patients, suggesting 
the possibility of a profound placebo effect and other mechanisms for pain relief in this population. 
Despite variability in patient response and potential for a marked placebo effect, there have been 
no sham-controlled studies evaluating pancreatic endotherapy for the relief of painful chronic 
pancreatitis.  Sham trials in interventional endoscopy are few and far between. The importance of 
the sham design is best illustrated by the Evaluating Predictors & Interventions in Sphincter of 
Oddi Dysfunction (EPISOD) trial, a sham controlled, randomized clinical trial of ERCP with 
endoscopic sphincterotomy for patients with abdominal pain attributed to sphincter of Oddi 
dysfunction.15 At enrollment, all subjects had high levels of pain-related disability, as defined by 
the Recurrent Abdominal Pain Intensity and Disability (RAPID) instrument. Among 73 subjects 
randomized to sham, 47% reported > 50% reduction in pain (as defined by RAPID) after 12 
months. When asked about their satisfaction at long-term follow-up (median 4.8 years) using the 
Patient Global Impression of Change (PGIC) instrument, 73% (of 22 followed long-term) of 
subjects randomized to sham reported much, or very much improvement; only 37% who had 
undergone intervention (endoscopic sphincterotomy) met this definition.   
The intricacies of the healing process are often minimized in favor of technical interventions.19 
This is exemplified by the Western approach to treating painful chronic pancreatitis: when the 
pancreatic duct appears obstructed, patients are often offered pancreatic endotherapy to relieve 
their pain. Since pain relief and other patient-centered outcomes such as pain-related disability 
and quality of life are influenced by numerous factors, it is possible that reported improvement to 
pancreatic endotherapy is not solely due to the technical management of main pancreatic duct 
obstruction. 
 

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2.4 
Endotherapy requires repeated interventions, possibly having a negative long-term 
impact 
Pancreatic endotherapy includes a spectrum of maneuvers performed during ERCP: 
pancreatic endoscopic sphincterotomy, lithotripsy and extraction of main pancreatic duct 
stones, and dilation with stenting of main pancreatic duct strictures. All of these maneuvers 
are completed using devices approved for use by the FDA, and are employed in clinical 
practice today. The short-term risk (up to 40%) of adverse events from pancreatic 
endotherapy include exacerbation of pain, post-procedure infection, pancreatitis, bleeding, 
and perforation.18 The effect of prior pancreatic endotherapy on subsequent surgical therapy 
is unknown but may be deleterious.20 Long-term adverse events include the development of 
symptomatic strictures secondary to pancreatic stents and post-sphincterotomy re-stenosis.21  
The risks of pancreatic endotherapy and the need for repeated endoscopic interventions to 
treat pancreatic duct obstruction illustrate the need to prove whether or not pancreatic 
endotherapy is effective. 
 
2.5 
Depression, opioid misuse, quality of life, and catastrophizing are important covariates 
in the treatment of pain associated with chronic pancreatitis  
Pain is a complex experience that has sensory-discriminatory, motivational-affective, and 
cognitive-evaluative dimensions. 22 Numerous psychosocial factors may influence, and are 
influenced by, pain experience including depression, sleep, anxiety, pain catastrophizing, 
quality of life, activity level, alcohol, and opioid use/misuse. In a pilot, quasi-experimental 
study, clinical variables potentially associated with risk for opioid misuse were assessed in 
individuals with chronic pancreatitis at the Medical University of South Carolina (MUSC) 
6. The study included 307 individuals with non-alcoholic chronic pancreatitis engaged in 
chronic opioid therapy for pain. Participants completed the Chronic Opioid Misuse Measure 
(COMM), Brief Pain Inventory (BPI), Short Form Health Survey (SF-12), Center for 
Epidemiological Studies 10-item Depression Scale (CESD), and a single item asking about 
current alcohol use. Mean scores on the CESD, COMM, BPI pain-on-average item, and the 
SF-12 physical and psychological quality of life factors (t-scores) were: 11.2±6.7, 8.5±7.3, 
4.8±2.8, 39.7±7.0, and 45±9.0, respectively. Descriptive analyses revealed that 55% met 
criteria for depression and 39% for opioid misuse. Regression analyses identified several 
factors associated with higher opioid misuse measure scores, including increased depressive 
symptoms (ß=.38, p<0.0001), increased pain at the time of the office visit (ß=.16, p=0.03), 
impairment of psychological quality of life (ß=-.27, p=0.001) and endorsement of alcohol 
use (ß=.16, p=0.03). These factors accounted for 37% of the variance in current opioid 
misuse scores. Thus, depression, quality of life, pain intensity, and alcohol use may be good 
candidate variables for prospective studies to determine clinical risk factors for opioid 
misuse among patients with acute recurrent pancreatitis and chronic pancreatitis. 
Additionally, another MUSC study confirmed that interprofessional care combining 
behavioral approaches to pain management, behavioral contingency management for opioid 
delivery, psychological, and psychotropic treatments for depression, anxiety, and addiction 
are associated with lower resource utilization.23 Finally, an MUSC study identified a 
correlation between opioid misuse and improvement in quality of life following total 
pancreatectomy for refractory chronic pancreatitis.24  
A second cross-sectional study was performed to determine if depressive symptoms were 
associated with variability in pain perception and quality of life (QOL) among patients 
(n=692) with nonalcohol-related chronic pancreatitis 25. The mean age of the sample was 
52.6 (SD = 14.7); 41% of the sample was male. Participants completed the SF-12, CESD, 
and a numeric rating scale measure of "pain on average" from the Brief Pain Inventory. 
Depressive symptoms were significantly related to participants' reports of increased pain and 

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decreased QOL. The mean CESD score was 10.6±6.5 and 52% scored above the cutoff for 
significant depressive symptomology. Patients scoring above the clinical cutoff on the 
depression screening measure rated their pain as significantly higher than those below the 
cutoff (P < 0.0001) and had significantly lower physical and mental QOL (P < 0.0001 for 
each). These findings suggest that among patients with nonalcoholic chronic pancreatitis, 
depressive symptoms are a common and important covariate in research assessing pain and 
QOL. 
Pain catastrophizing (i.e., cognitive characterizations of pain as awful, horrible and 
unbearable) is increasingly being recognized as an important factor in the experience of pain 
and pain exacerbation. Catastrophizing appears to augment pain by enhancing attention to 
painful stimuli and heightening limbic circuitry responses.26 Catastrophizing has been 
associated with depression as well as activity in areas of the brain associated with central 
sensitization which is often seen in patients with chronic pancreatitis. 27 This phenomenon 
affects both the cognitive (dorsolateral prefrontal cortex; DLPFC) and limbic aspects of pain 
processing, and can affect activity in cingulate cortex (ACC) and medial frontal cortex.26 
Therefore, pain catastrophizing is an important covariate when examining the effectiveness 
of clinical interventions for pain.  
 
2.6 
Quality of life is significantly reduced among patients with chronic pancreatitis, 
primarily due to pain 
Patients with chronic pancreatitis have lower quality of life, as quantified by significantly 
lower physical and mental component scores compared to healthy controls and even patients 
with acute recurrent pancreatitis.28, 29 The presence of constant abdominal pain and disability 
due to chronic pancreatitis-related symptoms are two of the most important factors 
associated with lower quality of life. Reductions in opioid utilization following total 
pancreatectomy are closely associated with improvements in physical and mental 
components of quality of life.30 Since interventions to improve pain would be expected to 
improve quality of life and disability, the primary outcome for this pilot study will focus on 
pain. Recognizing the complex interaction between pain, depression, quality of life, 
catastrophizing, and opioid misuse, among others, a secondary aim of this pilot study is to 
examine several potential outcome measures in anticipation of a definitive clinical trial to 
follow.  
 
3.0 
Intervention to be studied 
 
The intervention being tested in this pilot, sham controlled, clinical trial is a composite of maneuvers 
classified as pancreatic endoscopic therapy (i.e., “pancreatic endotherapy”). This term represents a 
combination of complementary maneuvers offered in clinical practice for 
the treatment of pancreatic duct obstruction. The components of pancreatic 
endoscopic therapy are detailed below: 
 
3.1 
Main pancreatic duct drainage. 
The majority of patients with main pancreatic duct stones, 
strictures, or both require the endoscopic placement of one 
or more pancreatic duct stents across the area of obstruction 
(if two or more are placed, they are deployed side-by-side 
so that the overall diameter is larger than one stent alone) 
(figure 1). These stents are FDA-approved for drainage of 
the pancreatic duct and widely used in clinical practice, so an Investigational Device 
Exemption is not required for this study.31 Pancreatic duct stents are comprised of 
Figure 1. Examples of pancreatic 
stents 

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polyethylene (Cook Zimmon and Cook Geenen, Cook Medical, Winston-Salem, NC, 
USA), polyethylene and polyurethane blend (Cook Geenan Sof-Flex and Cook Johlin 
Wedge, Cook Medical, Winston-Salem, NC, USA), or proprietary polymers (Boston 
Scientific Advanix Pancreatic Stent, Boston Scientific Corp., Marlborough, MA, USA and 
Freeman Pancreatic Flexi-Stent, Hobbs Medical, Inc, Stafford Springs, CT, USA). Since 
there are no data to suggest the superiority of one brand versus another, the choice of stent 
type and manufacturer is typically based on physician preference and facility purchasing 
agreements. For these reasons, a specific type of stent will not be required; however, stent 
characteristics (manufacturer, external and internal characteristics, length, and diameter) will 
be measured during the randomization and follow-up ERCP procedures, as applicable. 
 
3.2 
Main pancreatic duct stone lithotripsy and extraction 
For some patients with painful obstructive chronic pancreatitis, the etiology of pancreatic 
duct obstruction is in part due to the presence of a main pancreatic duct stone (a.k.a., 
calcification). Pancreatic stones often begin to form within pancreatic duct side branches but 
may evolve to occlude the main pancreatic duct. The majority of stones may be removed 
from the main pancreatic duct via direct stone extraction, intraductal lithotripsy, 
extracorporeal shock wave lithotripsy (ESWL), or some combination. The requisite 
technique(s) depend on several variables including physician expertise, location of stone 
(pancreatic head, genu, or body), and size of unaffected pancreatic duct. In order to 
maximize technical success in this pilot clinical trial, physicians will be allowed to perform 
any combination of these maneuvers to successfully remove main pancreatic duct stones 
during the index (randomization) ERCP. The performance of each maneuver will be 
measured through case report forms. This will minimize the likelihood that failure to meet 
one or more of the study outcome measures is due to technical failure of pancreatic 
endotherapy. 
 
3.3 
Main pancreatic duct stricture dilation 
Pancreatic duct obstruction may also occur in the setting of a fibrotic stricture in the main 
pancreatic duct. A main pancreatic duct stricture is defined by the presence of upstream main 
pancreatic duct dilation ≥ 6mm, and technical success in treating this process is defined by 
the ability to insert at least one pancreatic stent across the area of narrowing.18 Dilation of 
the stricture using a bougie or hydrostatic balloon catheter is often performed prior to stent 
placement, but treatment via dilation alone is not performed due to poor outcomes.18  
 
4.0 
Study Endpoints 
4.1 
Pilot primary outcome 
The primary efficacy outcome for this pilot study will be average daily pain from the 
electronic diaries during the 14-day period preceding the 90-day assessment, compared to 
the average daily pain reported during the 14-day run-in. Clinical improvement will be 
defined by the change in the average pain score between these two intervals, and without 
the need for increased opioids or additional interventions/procedures. A standardized 11-
point Numeric Rating Scale (NRS) will be used to capture average daily pain with the 
empirically-supported anchors of 0=No Pain and 10=Worst Pain Imaginable.32 
 
4.2 
Pilot secondary outcomes 
At 90-days, change from baseline in functional impairment due to pain (BPI), quality of 
life, opioid misuse, pain catastrophizing, depression, and central sensitization will be 
examined. 

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5.0 
Inclusion and Exclusion Criteria/ Study Population 
Patients referred to Oregon Health and Science University (OHSU) and Medical University of 
South Carolina (MUSC) for endoscopic treatment of pain related to chronic calcific pancreatitis 
will be considered for enrollment in the PERCePT trial.  
 
5.1 
Inclusion Criteria  
• Age ≥ 18 years  
• Main pancreatic duct obstruction, defined by the presence of one or both of 
the following features: 
• Main pancreatic duct calcification with upstream main duct dilation ≥ 
6mm. 
• Main pancreatic duct stricture, defined by the presence of main 
pancreatic duct narrowing with upstream main duct dilation ≥ 6mm. 
• Baseline average abdominal pain score ≥ 4 during the run-in period, based on 
Ecological Momentary Assessment 11-point Numeric Rating Scale  
• Ability to provide written, informed consent  
 
5.2 
Exclusion Criteria 
• Symptoms attributable to a pancreatic pseudocyst or walled off necrosis 
• Clinical suspicion of pancreatobiliary malignancy* 
• Low probability of follow-up to complete study objectives 
• Pregnancy or incarceration 
• Medical comorbidities that contraindicate the performance of ERCP 
• Previous pancreatic endotherapy 
* Pancreatobiliary malignancy will be ruled out immediately prior to randomization, during 
endoscopic ultrasound 
 
6.0 
Number of Subjects 
This study will randomize 30 subjects into a dual center, pilot, sham-controlled clinical trial of 
ERCP with pancreatic endotherapy for pain secondary to chronic pancreatitis with main pancreatic 
duct obstruction. We plan to enroll approximately 10 subjects at OHSU and 20 subjects at MUSC. 
 
7.0 
Setting 
Participant enrollment, screening, intervention, and follow up procedures will take place at the 
Medical University of South Carolina as well as Oregon Health and Science University, which are 
both  high volume ERCP centers with expertise in therapeutic endoscopy and pancreatitis care. 
Some follow up visits may be completed by phone.  
 

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8.0 
Recruitment Methods 
Patients will be recruited through the Medical University of South Carolina and Oregon State Health 
and Science University’s clinical practices and existing referral network. Potential subjects will be 
identified in the GI medicine and surgery clinics where they will be screened for eligibility. 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 chronic pancreatitis is higher in men (approximately 60:40), since heavy 
alcohol use and smoking are more common among men. Therefore, per our enrollment criteria, we 
anticipate our cohort will reflect the epidemiology of chronic pancreatitis and have more men than 
women. We do not plan to actively pursue one sex, as we want our cohort to reflect the disease 
population. Both the Medical University of South Carolina and Oregon Health and Science 
University treat patients across a diverse geographic and socioeconomic spectrum. The clinical 
practices reflects the local regions in terms of minority populations, and we will recruit patients 
meeting eligibility criteria without discrimination. Race, ethnicity, and gender will be tracked and 
monitored in the study database and in the study screening log, both of which are part of the online 
data and trial management system, to ensure that the distribution among enrolled subjects is not 
skewed from the distribution among eligible patients. This allows us to monitor for disparities which 
can then be investigated to determine if any intervention is necessary to prevent disproportionate 
enrollment. Pregnant women are excluded from this protocol because of potential risk to the fetus. 
Patients who do not have access to a mobile phone will also not be included in the study.  
 
9.0 
Consent Process 
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. The informed consent to participate in the research study will 
be obtained at the time of a planned clinical encounter. This will occur in the ambulatory clinics (GI surgery 
and Gastroenterology) at the Medical University of South Carolina and Oregon Health and Science 
University where the discussion regarding the study protocol is held in private between the investigator and 
subject with or without family members present (standard of care).  
Designated study investigator(s) will discuss the study, its purpose and study protocol with potential 
patients in detail. Potential subjects who are interested to take part in the study will be asked to sign the 
informed consent. Potential subjects will have adequate opportunity to review the informed consent and to 
ask any questions they may have about the research, risks, and benefits. No study procedures will be 
performed prior to obtaining a signed and dated informed consent from the patients. Recruitment and 
informed consent will be completed by physician investigators with the support of one or more research 
coordinators. 
 
10.0 
Study Design / Methods 
 
10.1 
Study procedures 
 
10.1.1 Run-in period 
A schedule of study procedures is detailed in Table 1. To summarize, potential subjects will 
be identified in GI medicine and surgery clinics where they will be screened for eligibility. 
If eligible and the subject completes the informed consent process, a 14-day run-in period 

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will commence. During this time, the subject will complete a daily diary using an Ecological 
Momentary Assessment tool developed for this pilot study. The diary will include the 11-
point Numeric Rating Scale for pain, number of hours of sleep the night prior, activity level 
(11-point scale), and details on opioid medication use in the past 24 hours. In addition, the 
subject will undergo Quantitative Sensory Testing (QST).  
Baseline Assessment. Once consent is obtained, eligible subjects will be enrolled and 
complete a baseline assessment, which will include several validated instruments measuring 
pain, pain quality, quality of life, psychological factors and comorbidities, sleep, opioid use, 
alcohol use, and pain-related disability (Table 2). Additionally, patients will undergo QST 
to assess thermal pain thresholds, tolerance and central sensitization via wind-up and 
conditioned pain modulation tasks. The baseline assessment is estimated to include an 
approximately 1-hour visit to complete the baseline measures and a separate 1-hour visit for 
the QST in the Behavioral Medicine laboratory.  
Quantitative Sensory Testing (QST). QST provides indices of baseline perception and 
changes in specific peripheral and central nociceptive and proprioceptive processing. Using 
QST we will assess: (1) mechanical pain threshold using the IITC Life Sciences Digital 
Aesthesiometer applied to the distal phalange of the digiti minimi of the left hand (increased 
at rate of 10grams/sec; pressure recorded in grams); (2) thermal pain tolerance using 5 trials 
of cutaneous heat stimuli via the ATS thermode of the Medoc TSA-II Neurosensory 
Analyzer; (3) thermal wind-up pain (3 trials) with the ATS thermode delivering 20 brief 
(0.75s) suprathreshold thermal pulses at the rate of 1 pulse per 1.5 secs thereby selectively 
stimulating C-fibers (during the 3 trials of 30sec of repeated heat stimulation, subjects will 
indicate their level of pain severity using a dynamic visual analogue scale); and (4) 
conditioned pain modulation (3 trials) using mechanical pain thresholds assessed via the IITC 
Life Sciences Digital Aesthesiometer applied to the right trapezus (increased at rate of 
10grams/sec; pressure recorded in grams) with and without simultaneous stimulation via the 
ATS thermode (tonic 30sec heat stimulus to the left volar forearm using participants’ 
individualized thermal pain threshold temperature). 
Ecological Momentary Assessment (EMA). Given the variability in pain patterns and 
potential for recall bias, all eligible patients will complete a 14-day run-in period where pain, 
psychological status, and use of analgesics will be measured prospectively. Ecological 
Momentary Assessment (EMA) will be employed via Electronic Daily Diaries administered 
by phone, SMS or using survey links sent to the patient’s cellphone or e-mail address. If a 
subject does not have access to a smartphone, they may be provided with a smartphone for 
the duration of the study (up through the 90-day follow-up assessment).  We will assess daily 
(via standard 11-point numeric rating scales (0-10); NRS) average pain, pain at its worst, 
pain unpleasantness, mood, anxiety, activity level, opioid cravings, and will assess amount 
of prescription opioid and other substance use. We have developed a SMS/MMS encrypted 
gateway which enables ecological momentary assessment of these variables. This 
communication system was selected due to its widespread availability on all major cell phone 
types and their carriers. Measures will be collected at random times during waking hours 
each day to minimize response bias associated with event related reporting.  
Medical management during the run-in period will include dose adjusting analgesic 
medication, if necessary. During the run-in period and prior to randomization, it is possible 
that subjects will improve clinically which that endotherapy is no longer appropriate. The 
decision to proceed with endotherapy will be based on usual clinical care, but primarily 
related to the persistence of abdominal pain with an average daily pain score ≥ 4 as per study 
enrollment criteria. However, we are reluctant to have additional pre-specified criteria since 

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the decision to proceed with procedural intervention is nuanced. These subjects will continue 
to be followed systematically as an observational cohort but not undergo the randomization 
procedures. If the subject continues to meet enrollment criteria after the 14-day run in period, 
the subject will proceed to the randomization procedures. The observational cohort will be 
capped at n=15 and will follow the same data collection schedule as the randomized cohort. 
 
 
 
 
Table 1. Summary of Study procedures* 
Visit 
Details 
Screening visit 
• 
Patient seen in pancreatobiliary clinic for painful chronic pancreatitis 
• 
Review eligibility criteria 
Informed consent 
• 
Obtain informed consent 
Run-in period (approximately -
14 to 0 days) 
• 
Subject provides daily diary for approximately 14 days (Ecological Momentary 
Assessment) 
Quantitative Sensory Testing  
• 
Complete Quantitative Sensory Testing prior to randomization procedure 
Randomization visit (day 0) 
• 
Confirm eligibility criteria 
• 
Finalize completion of baseline assessment instruments 
• 
Randomization procedures  
Randomization procedures (day 
0) 
• 
Complete EUS + sham or EUS + ERCP with pancreatic endotherapy 
• 
No randomization procedure if observational subject. 
Telephone contact (day 7) 
• 
Telephone contact to confirm no procedure-related adverse events 
Telephone contact (day 30) 
• 
Telephone contact to confirm no procedure-related adverse events 
Complete Daily Diary (days 0-
30 and 76-90) 
• 
Subject will complete daily diary for 30 days after randomization procedures 
(Ecological Momentary Assessment) 
• 
Subject will complete daily diary for the 14-day period leading up to their follow-up 
visit (days 76-90), which will be scheduled on day 90  
Follow-up visit (day 90) 
• 
Subject returns for in- person follow-up assessment (repeat baseline assessment 
instruments and quantitative sensory testing).  
o 
Observational subject may complete visit by telephone 
• 
Repeat ERCP with pancreatic endotherapy if applicable (if stents are in place and 
require removal or upsizing) 
• 
Perform ERCP if failure to improve, subject is unmasked and found to be in sham 
group, and subject wishes to proceed with pancreatic endotherapy 
• 
Complete primary outcome measures 
Follow-up visit (day 180) 
• 
Subject completes follow-up assessment (abbreviated version of the baseline 
assessment) 
• 
Repeat pancreatic endotherapy scheduled, if applicable 
• 
Referral for pancreatic surgery, if applicable 
Follow-up visit (day 270) 
• 
Subject completes  follow-up assessment (abbreviated version of the baseline 
assessment) 
• 
Repeat pancreatic endotherapy scheduled, if applicable 
• 
Referral for pancreatic surgery, if applicable 
Follow-up visit (day 360) 
• 
Subject completes follow-up assessment (abbreviated version of the baseline 
assessment) 
• 
Repeat pancreatic endotherapy scheduled, if applicable 
• 
Referral for pancreatic surgery, if applicable 
Study completion visit (day 
360) 
• 
Complete all study-related activities 
* All visits are research-related visits.  Please note that endoscopic ultrasound (EUS) and endoscopic retrograde 
cholangiopancreatography (ERCP) are not experimental procedures since they are used in clinical practice. Given the 
randomized nature of the study design, the costs for the randomization procedures will be covered by the grant.  All follow-
up procedures will be billed per usual clinical care. 

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10.1.2 Baseline and randomization procedures 
The subject will complete baseline instruments detailed in table 2. The subject will return 
on study day 0. Patients will be compensated $75 for their time completing the baseline 
assessments. Women of childbearing potential will be administered a urine pregnancy test. 
If the result is positive for pregnancy, the patient will be excluded from the study. After 
confirmation of meeting eligibility criteria, the subject will undergo the randomization 
procedures (endoscopic ultrasound + sham pancreatic endotherapy or endoscopic ultrasound 
+ ERCP with pancreatic endotherapy). 
All subjects will undergo anesthesia administered sedation and endoscopic ultrasound 
(EUS). The endoscopist will assess the pancreas for parenchymal and ductal features of 
chronic pancreatitis and confirm the absence of exclusion criteria (such as the presence of 
an occult pancreatobiliary malignancy). Following the completion of the EUS, assuming that 
eligibility criteria are still met, and while the subject remains under anesthesia, the subject 
will be randomized to ERCP with pancreatic endotherapy or EUS only (sham). If 
randomized to sham, the endoscopist will not perform ERCP. To maintain the blind, the 
patient and clinical team will stay in the endoscopic suite for at least 45 minutes after 
randomization. This is the average length of time the ERCP with endotherapy could take if 
randomized to this group. 
If randomized to ERCP with pancreatic endotherapy, the endoscopist will proceed with this 
intervention immediately following the completion of EUS and treatment allocation (during 
the same anesthesia). Pancreatic endotherapy may include any or all of the following 
maneuvers: pancreatic endoscopic sphincterotomy, stricture dilation using a bougie or 
hydrostatic balloon catheter, pancreatic stone extraction with or without mechanical or 
electrohydraulic lithotripsy, extracorporeal shock wave lithotripsy, and stent placement. 
Overall technical success will be defined by the ability to insert at least one pancreatic stent 
across the dominant main pancreatic duct obstruction. Technical success for pancreatic stone 
treatment will be defined by the ability to remove all fluoroscopically visible main pancreatic 
duct stones.  
At the discretion of the treating physician, patients may be given a medication called an 
indomethacin suppository to help prevent post-ERCP pancreatitis. Indomethacin is 
commonly used to prevent post-ERCP pancreatitis in clinical practice based on previous 
studies, but is not FDA approved for this specific purpose. 
Table 2. Baseline assessment in the PERCePT trial 
Potential covariate(s) 
Instrument(s) 
Explanation and estimated completion time 
Patient characteristics 
PERCePT study case 
report forms 
TIGAR-O 33 
• 
Data will be collected as applicable and available: history of 
acute pancreatitis episodes, date of chronic pancreatitis 
diagnosis, duct and parenchyma characteristics on prior 
imaging, anthropomorphic data, chronic pancreatitis risk 
factors (TIGAR-O)  
• 
5-minutes 
Harmful alcohol drinking 
Alcohol Use Disorders 
Test (AUDIT) 34 
• 
Screening instrument for hazardous and harmful alcohol 
drinking 
• 
2-minutes 
Current pain disability 
RAPID 35 
• 
Pain-related disability (90-day recall); developed, validated, 

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10.1.3 Follow-up visits, day 0 -90 
The subject will be contacted by telephone at day 7 and 30, and complete the Ecological 
Momentary Assessment during this 30-day period.  After the 30 day follow up phone call is 
complete, the participant will be compensated $50 for their time. Thereafter, follow-up will 
and used for the EPISOD study 
• 
3-minutes 
Average daily pain, mood, 
activity-level, sleep and 
analgesic medication use 
Ecological Momentary 
Assessment (EMA) 
• 
Ecological daily diaries designed to capture repeated measures 
of average daily pain using an 11-point Numeric Rating Scale 
• 
Repeated measures of activity level, sleep, and use of opioid 
medications 
• 
Assessed from day -14 to day 0 
Pain Severity and 
Functional Impairment 
Brief Pain Inventory 
(BPI) 
• 
Measures pain at its worst, least, average, and at time of 
evaluation 
• 
Measures patient perception of effectiveness of current pain 
medications 
• 
Measures functional impairment due to pain 
• 
7-minutes 
Pain Character 
PROMIS Pain Quality 
- Neuropathic and 
Nociceptive 
• 
Assessment of pain quality 
• 
5-minutes 
Pain Catastrophizing 
Pain Catastrophizing 
Scale (PCS) 
• 
Measurement of negative cognitive-set brought to bear during 
painful experiences 
• 
Predictor of functional impairment due to pain and pain-
related depression 
• 
5-minutes 
Quality of life 
PROMIS 29 Profile 
• 
Assessment of anxiety, depression, fatigue, pain interference, 
physical function, sleep disturbance, ability to participate in 
social roles and activities, and a single pain intensity item 
• 
5-minutes 
Somatization 
Brief Symptom 
Inventory – 18 (BSI-
18)** 
• 
Assessment of psychological distress and somatization 
• 
5-minutes 
Patient expectation of 
response 
Questions Before 
ERCP-Endotherapy 
• 
Quantitative measure of the degree to which a patient expects 
to improve after pancreatic endotherapy 
• 
1-minute 
Opioid utilization 
- Current Opioid 
Misuse Measure 
(COMM) 
- Baseline Opioid 
Medication For 
Abdominal Pain Form 
• 
Self-report measures of risk for aberrant medication-related 
behavior in patients prescribed opioids for chronic pain 
• 
3-minutes 
Laboratory Pain and 
Central Sensitization  
Quantitative Sensory 
Testing (QST) 
• 
Thermal and mechanical pain threshold, pain tolerance, as well 
as wind-up and conditioned modulation testing to assess 
central pain facilitation and inhibition 
• 
1-hour baseline visit 
**The study investigator or their staff will respond to any subjects presenting suicidal ideations by using standard psychiatric procedures 
for safety purposes. If the BSI -18 Question 17 is answered low (1-2), the Coordinator will refer the subject to a mental health specialist 
for follow up. If the risk is considered moderate to high (3-4), the Coordinator will page the PI or a clinician and seek guidance for 
possible admission to mental health services without leaving the subject alone. 

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be on an as-needed basis until the subject returns on day 90 for the first formal follow-up 
assessment (details in table 3). The discussion regarding next steps in treatment will occur 
between the subject, a blinded gastroenterologist, and a blinded pancreatobiliary surgeon. A 
multidisciplinary discussion between patient, endoscopist, and surgeon complies with 
society guidelines.  In the case of medical management, this will be directed by the blinded 
physicians. In the event of an emergency room or inpatient hospitalization due to abdominal 
pain or other symptoms potentially attributable to chronic pancreatitis, a blinded physician 
will determine whether repeat endoscopic or surgical intervention is warranted before the 
90-day outcome assessment. In the event that the patient is referred for repeat endoscopic or 
surgical intervention before reaching the 90-day outcome assessment, the Ecological 
Momentary Assessment tool will be reactivated in order to capture pain data for up to 14 
days leading up to and including the day of intervention, as feasible. Rather than assuming 
no change from baseline in pain scores for those that have a re intervention prior to day 90, 
we will capture the pain score prior to re intervention and use these data to calculate the 
change score for the primary analysis.  
 
 The day 90 follow-up assessment will include completion of selected instruments and a 
discussion with blinded physician investigators about their clinical course. It is not realistic 
to assign a threshold pain score above which further intervention should be offered, so it is 
expected that the blinded physicians and patient will decide whether an intervention is 
required to treat pain; this highlights the importance of the study’s sham design.  Potential 
scenarios are detailed in figure 2. Although not incorporated into this study’s pilot primary 
outcome, is it expected that a decision to proceed with an intervention to treat pain would be 
considered a “failure” of pancreatic endotherapy in a definitive clinical trial.  Each of the 
groups in figure 2 are explained in further detail below. The design of the hierarchical 
diagram is deliberate and intends to illustrate that management options for groups 3 and 4 
are the same. In addition, follow-up is in part dependent on the original treatment allocation. 
So, after all blinded assessments have been completed and a decision regarding intervention 
determined, an unblinded investigator will need to advise the subject regarding next steps. 
Participants will be compensated $75 after completing the 90-day follow up visit. If 
participants complete all visits, they will be compensated a total of $200.  
 
1. Sham group, no intervention advised. In this scenario, the subject is doing well enough 
that no intervention is advised. Since no procedures have been performed until this point, 
continued medical management is reasonable. The subject would be followed through day 
360 for relevant changes in clinical course and to assess secondary endpoints. 
2. Endotherapy group, no intervention advised. In this scenario, the subject is doing well 
enough that no intervention is advised. Since pancreatic endotherapy had been performed 
during the randomization procedure, the subject would be advised to undergo repeat 
pancreatic endotherapy to remove pancreatic duct stents. In some cases, the treating 
endoscopist may recommend replacing or upsizing stents in an effort to minimize stricture 
recurrence. This will be determined by the unblinded treating physician per standard of care. 
Follow-up procedures would be open-label, although it is possible that the subject remain 
blinded to their original treatment allocation.  
3. Sham group, intervention advised. In this scenario, the subject is doing poorly, and an 
intervention is advised. The blinded physicians will discuss three options with the patient: 
1) further medical management, including the initiation or titration of analgesics; 2) 
pancreatic endotherapy; 3) consideration of surgical interventions. 
4. Endotherapy group, intervention advised. In this scenario, the subject is doing poorly, 
and an intervention is advised. The blinded physician investigator will discuss three options 

Version 1.5; Oct-2022 
 
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with the patient: 1) further medical management, including the initiation or titration of 
analgesics; 2) pancreatic endotherapy; 3) consideration of surgical interventions. Since the 
subject had previously undergone pancreatic endotherapy, the unblinded physician 
investigator will need to be informed of the recommendation and proceed endoscopy to 
remove pancreatic duct stents if necessary and applicable. 
All procedures performed during the day 90 visit and thereafter will be open-label and are within the 
spectrum of routine clinical procedures. 
 
10.1.4 Follow-up visits, day 91-360 
Every effort will be made to preserve the integrity of the original treatment allocation, 
recognizing the need for a pragmatic approach to the follow up period. Although 90-day 
outcomes will be the focus of this pilot study, all subjects will be followed for 12 months 
after randomization at which point the same outcome measures will be assessed. These data 
will be used to examine changes in the 90-day and 12-month outcomes, recognizing that 
interventions performed after 90 days will be unblinded.  
The content of follow-up visits at days 180, 270, and 360 are detailed in table 3 and may be 
completed by telephone or in-person.  
Table 3. Follow-up assessments in the PERCePT trial 
Outcome measures 
Instrument(s) 
Follow-up visit 
Explanation and estimated completion time 
90 
180 
270 
360 
Clinical evaluation 
Blinded physician 
evaluation 
X 
 
 
 
• 
Assessment by a blinded gastroenterologist and 
pancreatobiliary surgeon 
Patient characteristics 
PERCePT study 
follow-up case 
report forms 
 
X 
X 
X 
X 
• 
Data will be collected as applicable and 
available: history of acute pancreatitis episodes, 
opioid utilization, interventions performed and 
hospital encounters during the interval follow-up 
period  
• 
5-minutes 
Harmful alcohol 
drinking 
Alcohol Use 
Disorders Test 
X 
X 
X 
X 
• 
Screening instrument for hazardous and harmful 
alcohol drinking 
No intervention advised
1. Sham group
Continue present 
management
2. Endotherapy group
Repeat ERCP per 
standard of care
Intervention advised
Further medical 
management
Pancreatic endotherapy
Pancreatic surgery 
evaluation
3. Sham group
4. Endotherapy group
Figure 2. Potential scenarios during the 90-day follow-up visit 

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11.0 
Data Management  
 
11.1 
Data Monitoring Plan 
The below applies to the PERCePT pilot trial and subsequent multicenter, definitive trial, as 
applicable. 
The purpose of clinical trial monitoring is to ensure that: 1) the rights and well-being of human 
subjects are protected; 2) trial data are accurate, complete, and verifiable from source documents; 
and, 3) the trial is conducted in compliance with the current approved protocol, with GCP, and 
applicable regulatory requirements.  In accordance with the FDA’s “Guidance for Industry 
Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring”, the study team will 
adopt a dynamic approach to data monitoring, which focuses on critical risks and utilizes centralized 
monitoring, and on-site site monitoring to increase data quality, maximize efficiency, reduce 
(AUDIT) 34 
• 
2-minutes 
Current pain disability 
RAPID 35 
X 
X 
• 
Pain-related disability (90-day recall); developed, 
validated, and used for the EPISOD study 
• 
3-minutes 
Average daily pain, 
mood, activity-level, 
sleep and analgesic 
medication use 
Ecological 
Momentary 
Assessment (EMA) 
X 
 
 
 
• 
Electronic daily diaries designed to capture 
repeated measures of pain, activity, sleep, and 
opioid use 
• 
Daily from days 0-30 and 76-90 
Pain Severity and 
Functional Impairment 
Brief Pain 
Inventory (BPI) 
X 
X 
X 
X 
• 
Measures pain at its worst, least, average, and at 
time of evaluation 
• 
Measures patient perception of effectiveness of 
current pain medications 
• 
Measures functional impairment due to pain 
• 
7-minutes 
Quality of life 
PROMIS 29 
Profile 
X 
X 
X 
X 
• 
Assessment of anxiety, depression, fatigue, pain 
interference, physical function, sleep disturbance, 
ability to participate in social roles and activities, 
and a single pain intensity item 
• 
5-minutes 
Laboratory Pain and 
Central Sensitization  
Quantitative 
Sensory Testing 
(QST) 
X 
 
 
 
• 
Thermal and mechanical pain threshold, pain 
tolerance, as well as wind-up and conditioned 
modulation testing to assess central pain 
facilitation and inhibition 
• 
1-hour follow-up visit 
Opioid Utilization 
Current Opioid 
Misuse Measure 
(COMM) 
X 
X 
X 
X 
• 
Self-report measures of risk for aberrant 
medication-related behavior in patients 
prescribed opioids for chronic pain 
• 
3-minutes 
Pain Catastrophizing 
Pain 
Catastrophizing 
Scale (PCS) 
X 
X 
X 
X 
• 
Measurement of negative cognitive-set brought to 
bear during painful experiences 
• 
Predictor of functional impairment due to pain 
and pain-related depression 
• 
5-minutes 
Patient Global 
Impression of Change 
PGIC 
X 
X 
X 
X 
• 
Patient’s assessment of efficacy from the index 
ERCP procedure 
• 
1 minute 

Version 1.5; Oct-2022 
 
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redundancy, and better utilize monitoring resources. The DCU which is serving as the statistical and 
data management center for the proposed trial are highly experienced in providing centralized and 
risk-based monitoring for clinical trials. As data are submitted by the enrolling site during the course 
of the study, the data manager carefully reviews the data for errors or omissions within or across 
forms.  Meanwhile, the study statistician carefully reviews the eCRF data in aggregate and across 
CRFs to identify errors and trends.  As errors are identified by the data manager and statistician, the 
data manager generates Data Clarification Requests (DCRs) to the site using the DCU’s clinical 
trials management system, referred to as WebDCU™.  Critical or systemic errors identified by 
central monitoring are shared with study team members so that swift and appropriate action can be 
taken including the development of a corrective action plan when needed. 
The DCU’s risk-based monitoring approach is based upon the premise that a certain level of random 
error in non-critical data is acceptable and that efforts should be focused on decreasing errors in data 
associated with the planned analysis and human subject protection.  The level of risk is affected by 
factors including study design, study endpoints, study population, experience of investigators, data 
collection methods, safety profile of an investigational product/intervention, stage of the study, and 
quantity of data.  Prior to the start of the study, the study team will identify the risks associated with 
the trial.  This monitoring plan is then developed to most effectively mitigate these critical risks, if 
the source of risk cannot be eliminated entirely.   
11.2 
Sample Size. A total of 30 subjects will be randomized (15 per arm) within a 21-month 
period. In a recent retrospective cohort study including patients undergoing first-time pancreatic 
endotherapy for chronic pancreatitis at the Medical University of South Carolina, the average 
number of new patients/year undergoing pancreatic endotherapy was 22, and > 30 in recent 
years. This is above our estimated enrollment rate for this pilot study. 
11.3 
Data Management. Paper files will be stored in locked filing cabinets in restricted access 
offices at OHSU and MUSC. All clinical data on enrolled subjects will be data entered by study 
personnel into a web-based clinical trials management system, WebDCU, which is managed by 
the Data Coordination Unit (DCU), Department of Public Health Sciences at MUSC. This user 
friendly, secure web-based database system, developed by the DCU, will be used for subject 
randomization, data entry, data validation, project progress monitoring, subject tracking, user 
customizable report generation and secure data transfer. Access to data will be restricted to study 
personnel. All study team members will receive a unique user account and ability to set up their 
own private password. The system has an audit trail to track all logins and enter/edit of study 
data.  
De-identified data from the study will be stored indefinitely. In the event of a screen failure of a 
consented subject, data collected during screening will be retained for separate analysis. 
11.4 
Statistical Analysis. The analysis will be conducted according to the intention-to-treat (ITT) 
principle wherein subjects will be analyzed according to the assigned treatment. Several 
exploratory analyses and descriptive statistics will be examined, including covariates. Secondary 
analyses of additional outcomes, including change in QOL scores, disability, and depression, 
will be approached in a similar manner and considered exploratory using confident intervals 
rather than p values.  
11.5 
Data Security and Confidentiality. During the course of the trial, user access to the files 
with subject identifiers, and the 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.  

Version 1.5; Oct-2022 
 
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11.6 
Quality Control. 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. The site will be 
monitored by the DCU and the site monitor 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. 
11.7 
Web Based System. Because the DCU uses a web-based system, source documents and 
CRFs will remain at the study site. This 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.  
12.0 
Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
12.1 
DoD Independent Research Monitor. The Research Monitor, the PERCePT Data and 
Safety Monitoring Board, is responsible to oversee the safety of the research and report 
observations and findings to the IRB. The Research Monitor will review all unanticipated 
problems involving risks to subjects or others associated with the protocol and provide an 
independent report of the event to the IRB. The Research Monitor may discuss the research 
protocol with the investigators; shall have authority to stop a research protocol in progress, 
remove individual human subjects from a research protocol, and take whatever steps are 
necessary to protect the safety and well-being of human subjects until the IRB can assess the 
monitor’s report; and shall have the responsibility to promptly report their observations and 
findings to the IRB and the HRPO.  
12.2 
PERCePT Data and Safety Monitoring Board Members 
12.2.1 Walter Park, MD (Chair)– Assistant Professor of Medicine, Stanford University 
School of Medicine 
12.2.2 Nicholas Zyromski, MD – Professor of Medicine, Indiana University School of 
Medicine 
12.2.3 Hyungjin Kim, Sc. D – Adjunct Professor of Biostatistics, University of Michigan 
School of Public Health 
13.0 
Withdrawal of Subjects 
• 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, 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.  
• If the 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 

Version 1.5; Oct-2022 
 
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follow-up to complete all questionnaires, or at a minimum will be willing to be contacted to provide 
information on quality of life.  
• Investigators and/or the sponsor may stop a subject’s participation in the study at any time if they decide 
it is in the subject’s best interest. They may also do this if the subject does not follow the investigator’s 
instructions.  
 
14.0 
Risks to Subjects 
14.1 Loss of Confidentiality. All studies carry some risk for the potential loss of confidentiality. 
Every effort will be made to protect your information. 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 coded format with 
the key maintained with the local site PI. Furthermore, study binders will be maintained in locked 
physical facilities and only accessible to authorized study team members to protect patient 
privacy.  
14.2 Interviews & Questionnaires. Some of the questions the researchers ask may be upsetting 
or may make patients feel uncomfortable answering. If the patient does not want to answer a 
question, they may skip it and go to the next question.  
14.3 Quantitative Sensory Testing. The procedure proposed in this study are widely used to 
research and clinical practice and have been shown to be safe. For thermal pain procedures, the 
stimulator will be set with a limit of 50ºC which is well below the threshold for causing any 
damage to the subject’s skin or nerve endings. However, it is not unusual to experience some 
tenderness, redness or inflammation in the heated skin area after completion of the thermal pain 
procedures. These symptoms subside within a few hours with no intervention. For mechanical 
stimulation procedures, the range of von Frey Hair weights (digital and analog) to be used for 
stimulation will be incapable of breaking the skin or doing any tissue damage.  
14.4 Endoscopic ultrasound (EUS). Risks of EUS include bleeding, heart or lung problems, 
infection, or inflammation at the intravenous (IV) site, perforation and adverse reaction to 
medication.  
14.5 Randomization. Subjects will be assigned to receive the EUS procedure only or the EUS + 
ERCP with endotherapy procedure by chance. One treatment group may prove to be less 
beneficial or have more risks than the other group. 
14.6 Blinding. To keep free from bias, the protocol has been carefully developed to minimize 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 provider through the Statistical and Data Coordination Center (SDCC).  
14.7 Sham. Subjects in the sham group will not receive ERCP with endotherapy. 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.  
14.8 ERCP. If randomized to ERCP plus endotherapy, the procedure will be performed 
immediately after EUS and under the same anesthetic. Subjects undergoing ERCP will be at risk 
for the ERCP specific complications which includes post-ERCP pancreatitis (5-10%).  

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14.9 Indomethacin. Indomethacin is used in clinical practice to prevent post-ERCP pancreatitis, 
but is not FDA approved for this indication. Long or medium-term use of non-steroidal anti-
inflammatory drugs (NSAIDs), such as indomethacin, is associated with several adverse events 
including peptic ulcer disease, kidney failure, heart attack, strong, and worsening of congestive 
heart failure or high blood pressure. The risk of these adverse is related to the duration of use. A 
single dose of indomethacin is extremely unlikely to cause the biochemical, hormonal, and 
physiological changes necessary to induce such events. 
14.10 Endotherapy. The risks of endotherapy involve bleeding around the site, infection, or 
obstruction caused by the fragments of material created by the endotherapy that may require 
more endotherapy to remove.  
14.11 Stent Placement. There is a chance that the stent placement could be placed within or migrate 
into the duct and cause pancreatitis, infection, or perforation. Migrated stents can be difficult to 
retrieve and may require an operation.  
 
15.0 
Potential Benefits to Subjects or Others 
15.1 Potential benefits to the study subjects. If ERCP with pancreatic endotherapy improves 
pain, quality of life, or other outcome measures of interest, then subjects randomized to the 
treatment arm (EUS + ERCP with pancreatic endotherapy) will have benefited from this 
intervention. If this hypothesis is refuted, then subjects randomized to EUS alone (EUS + sham) 
will have avoided a potentially harmful intervention (ERCP with pancreatic endotherapy).   
15.2 Potential benefits to science and society. The results of this study are expected to provide 
preliminary data required to plan a definitive clinical trial evaluating pancreatic endotherapy. 
Such a trial would be expected to have a direct and immediate impact on patient care irrespective 
of the final outcome. Currently, the decision to perform ERCP with pancreatic endotherapy is 
physician-specific and a topic of repeated controversy among experts. If the study proves that 
ERCP with pancreatic endotherapy improves pain (or other relevant outcomes), then this practice 
will be adopted more widely across the world. However, if the study refutes the hypothesis that 
ERCP with pancreatic endotherapy reduces pain, then the practice of performing ERCP with 
pancreatic endotherapy for painful chronic pancreatitis would be expected to diminish 
significantly.  
 
16.0 
Sharing of Results with Subjects 
The results of the initial randomization procedures will not be shared with the participants until completion 
of the study. However, if the subject’s doctor recommends additional procedures during the course of the 
study, the results of these procedures will be shared with the participant.  
 
 

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17.0 
References 
 
1. 
Petersen GL, Finnerup NB, Colloca L, et al. The magnitude of nocebo effects in pain: a meta-
analysis. Pain 2014;155:1426-34. 
2. 
Ebbehoj N, Borly L, Bulow J, et al. Evaluation of pancreatic tissue fluid pressure and pain in chronic 
pancreatitis. A longitudinal study. Scand J Gastroenterol 1990;25:462-6. 
3. 
Manes G, Buchler M, Pieramico O, et al. Is increased pancreatic pressure related to pain in chronic 
pancreatitis? Int J Pancreatol 1994;15:113-7. 
4. 
Brown DW. Smoking prevalence among US veterans. J Gen Intern Med 2010;25:147-9. 
5. 
Hoggatt KJ, Lehavot K, Krenek M, et al. Prevalence of substance misuse among US veterans in the 
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