A Patient-Driven Registry for Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis
Conditions: Chronic Pancreatitis
Sponsor: CorEvitas

 
 
 
 
PAtient-CenTric Chronic Pancreatitis Registry (PACT-CP)  
PROTOCOL 
 
 
Protocol ID: 
NES-EPI-100 
Study Type: 
Non-Interventional  
Version Number:  3.0 
Sponsor: 
Nestlé Health Science USA 
Version Date: 
13 April 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notice of Confidentiality 
This document contains confidential information belonging to HealthiVibe, a division of CorEvitas, LLC. 
Except as otherwise agreed to in writing, by accepting or reviewing this document, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) 
or use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, 
HealthiVibe must be promptly notified.  
 
 

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PROTOCOL SYNOPSIS 
Protocol ID  NES-EPI-100 
Sponsor 
Nestlé Health Science USA 
Study Title    PACT-CP 
 
Study Objective & Specific Aims 
The main objective of this study is to generate real-world evidence reflecting the experience of individuals 
with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis (CP). Efforts will be directed toward 
understanding the unmet need and therapeutic burden to identify the most critical factors that influence 
treatment choices/prescribing patterns, quality of life, and healthcare utilization outcomes in standard of 
care for individuals with EPI due to CP. This study has the following specific aims: 
1. Create a cohort of well-characterized patients with EPI due to CP for participation in retrospective and 
prospective research 
2. Collect clinical data to characterize both the EPI due to CP disease history and disease progression 
through a combination of retrospective and prospective collection of medical history, comorbidities, 
and treatment approaches aimed at increasing the level of understanding of a heterogeneous condition 
such as EPI 
3. Collect data on the differing clinical care practices for patients with EPI to better understand the impact 
of those patterns on outcomes (including quality of life, comorbidities, and treatments) 
4. Collect data on treatment compliance that may impact the EPI due to CP disease experience and/or 
outcome  
5. Collect baseline and longitudinal participant-reported outcome (PRO) data on abdominal pain, 
gastrointestinal (GI) symptoms, dietary habits, health-related quality of life, depression/anxiety, and 
PERT use and treatment satisfaction to evaluate the impact of EPI on individuals’ health and daily life 
6. Gather data on healthcare utilization to be combined with clinical data to generate evidence for the 
impact and burden of EPI due to CP in this cohort on the healthcare system. 
 
Study Design 
This is a prospective, non-interventional research study for individuals diagnosed with EPI due to CP under 
the care of a gastroenterologist. Target enrollment is approximately 400 individuals, to be recruited over a 
period of 24 months. The study duration from enrollment to closeout will be five (5) years. Approximately 
20 clinical gastroenterology practices in the United States will be contracted to participate. 
 
Eligibility Criteria 
To be eligible for the study, study participants must meet all the inclusion criteria and none of the exclusion 
criteria at the time of enrollment. 
Inclusion criteria  
To be eligible for enrollment, a study participant must meet the inclusion criteria below:  
1. At least 18 years of age (or age of majority) 
2. Willing to provide consent to participate  
3. Meet ONE (1) of the following at the time of enrollment: 
a. Diagnosis of chronic pancreatitis (CP)  
b. Diagnosis of recurrent acute pancreatitis (RAP)  

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4. Suspected or confirmed diagnosis of EPI made by a healthcare provider 
5. On pancreatic enzyme replacement therapy (PERT), either prior to the Enrollment Visit or newly 
prescribed at the time of the Enrollment Visit. 
Exclusion criteria 
To be eligible for enrollment into the registry, a study participant must not meet any of the criteria below:  
1. Currently participating in or planning to participate in a double-blind randomized trial and/or open-
label Phase 3b/4 on CP or EPI 
2. Diagnosed with any of the following conditions at the time of enrollment: 
a. Cystic fibrosis 
b. Fibrosing colonopathy 
c. A history of or current diagnosis of pancreatic cancer, main duct papillary mucinous neoplasms 
(IPMNs), and other pancreatic malignancies 
d. Allergy to pork or other porcine pancreatic enzyme products (PEPs)  
e. Any condition that would, in the investigator’s opinion, limit the individual’s ability to complete 
the study. 
 
Study Procedures  
Study data will be collected from Investigators at the time of routine clinical encounters, as well as from 
study participants remotely in between routine visits. 
Enrollment 
Study participants will be enrolled in the study if they meet eligibility criteria and after they have provided 
consent to participate. During the Enrollment Visit, the Investigator will confirm eligibility and will provide 
information on suspected/confirmed EPI diagnosis (date of diagnosis, date of onset of symptoms indicative 
of EPI, method of EPI diagnosis, if applicable), CP etiology, clinical manifestations of EPI (i.e., GI and 
nutritional manifestations), medical history (comorbidities, surgical and radiological procedures, endoscopic 
procedures, and laboratory abnormalities), and current treatment(s). Information collected from the study 
participant includes demographics, current work status, current insurance coverage, family disease history, 
weight/height, current over the counter (OTC) herbal/nutritional supplements, healthcare utilization, and 
participant-reported outcome assessments on abdominal pain, GI symptoms, health-related quality of life, 
depression/anxiety, and PERT use and treatment satisfaction.  
Follow-Up 
Follow-up data will be collected from the study participants remotely via electronic data capture (EDC) 
portal. Every 3 months, study participants will complete assessments on current work status, current 
insurance coverage, current weight, current OTC herbal/nutritional supplements, and abdominal pain, GI 
symptoms, and PERT use and treatment satisfaction. Every 6 months, in addition to the assessments 
completed every 3 months, study participants will also complete assessments on health-related quality of 
life, depression/anxiety, and healthcare utilization. 
The Investigator will provide updates during routine clinical encounters approximately every 6 months or at 
least 150 days from the last registry visits. Data will be collected on clinical manifestations of EPI, current 
treatment(s), and active assessment of adverse events/serious adverse events (AEs/SAEs) since last visit. “Early” 
follow-up visits will be conducted whenever a study participant is prescribed a new PERT product. The 
Investigator will not complete any assessments if the study participants do not return to the sites for their 
expected routine clinical encounter.  

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Study Participant Exit 
Study participants exit the study upon withdrawal from the study, lost to follow-up (LTFU), transfer of care 
to a different gastroenterologist, death, or any other reason resulting in a study participant’s exit. The 
Investigator will document the reason for the exit. 
 
 
Data Collection 
Study participants will be followed prospectively, and data from study participants will be collected at 3-
month intervals via EDC portal. Investigators will complete assessments approximately every 6 months at 
the time of routine clinical encounters. AEs will be collected as part of the study data collection forms. SAEs 
are to be reported within 24 hours (1 business day) of awareness, whether or not the site learns of the event 
at the time of a registry follow-up visit.   
 
 
 
Data Analysis 
Analyses will be guided by the specific aims of the registry. Complete details of all analyses will be described 
in a standalone Statistical Analysis Plan (SAP) with accompanying mock Tables, Figures and Listings (TFLs). 
Briefly, all data will be summarized descriptively. Study disposition of all participants will be summarized 
including dropouts (with reasons presented for those who drop out), and for lost to follow-up (at what point 
they are lost, and if they return). Multivariate modeling will be employed to analyze clinical data on EPI 
disease history and disease progression by analyzing patterns of medical history, comorbidities, and 
treatment approaches. Clinical care practices will be explored with their potential impact on quality of life, 
comorbidities, and treatments using the same multivariate modeling. Treatment compliance will be 
examined for each of the models, knowing that biases are introduced with participant recall. Prescribing 
practices will be descriptively presented (to include type of PERT, dose at initiation and escalation, 
recommendation on how to take PERT, and reason for switching to another PERT, if applicable). If trends are 
identified in prescribing patterns, these trends may be further explored. Healthcare utilization data will be 
assessed with key variables from the clinical dataset.  
Confounding will be assessed for predicting outcomes with the registry data. If any confounding is identified, 
statistical procedures may be employed as appropriate for that confounder and outcome. Given that 
groupings within a study population may exist, these potential grouping effects will be handled with use of 
ANOVA (analysis of variance) models. Data quality assessed in terms of missing data, out of range values, 
and completeness will be presented, as to allow for appropriate interpretation and extrapolation of the study 
results. 
 
 
 
 
 
 

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PROTOCOL SIGNATURE PAGE 
Investigator Agreement   
 
This agreement at the front of this document must be signed and dated by the Investigator. The 
original must be kept on file with the Investigator and a copy sent to HealthiVibe.  
By my signature below, I acknowledge that I have read the protocol and agree that it contains 
all necessary details for carrying out the research described therein. Furthermore, I agree to 
conduct this research in compliance with said Protocol, all applicable research regulations, and 
in compliance with my contractual obligations to HealthiVibe, a division of CorEvitas, LLC. 
___________________________________  
 
Investigator Full Name (print) 
___________________________________  
_______________  
Investigator Signature 
 
 
               Date Signed 
 
 
 
 
 
HealthiVibe Site ID Number 
 
 
 

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ABBREVIATIONS 
AE 
Adverse event 
AP 
Acute pancreatitis 
CP 
Chronic pancreatitis 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EPI 
Exocrine pancreatic insufficiency  
GI 
Gastrointestinal 
HADS 
Hospital Anxiety and Depression Scale 
HIPAA  
Health Insurance Portability and Accountability Act 
HRQOL 
Health-related quality of life 
ICF 
Informed consent form 
IRB 
Institutional review board 
LTFU 
Lost to follow-up 
OTC 
Over the counter 
PERT  
Pancreatic enzyme replacement therapy 
PRO 
Participant-reported outcome 
RAP 
Recurrent acute pancreatitis 
RMP 
Registry monitoring plan 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SF-12 
12-item Short Form Survey 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication – 9 items 
 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................................................ 2 
PROTOCOL SIGNATURE PAGE .................................................................................................................................. 5 
ABBREVIATIONS ......................................................................................................................................................... 6 
1. 
BACKGROUND ................................................................................................................................................... 9 
2. 
STUDY OBJECTIVES .......................................................................................................................................... 10 
3. 
STUDY DESIGN ................................................................................................................................................. 11 
3.1 
STUDY PLAN AND DURATION ......................................................................................................................... 11 
3.2 
STUDY DURATION ......................................................................................................................................... 11 
4. 
SITE SELECTION ................................................................................................................................................ 11 
4.1 
INVESTIGATOR QUALIFICATIONS ...................................................................................................................... 11 
4.2 
STUDY-SPECIFIC TRAINING FOR INVESTIGATORS AND SUPPORT STAFF ................................................................... 12 
5. 
STUDY POPULATION ....................................................................................................................................... 12 
5.1 
STUDY PARTICIPANT SELECTION CRITERIA ......................................................................................................... 12 
5.2 
INCLUSION CRITERIA ...................................................................................................................................... 12 
5.3 
EXCLUSION CRITERIA ...................................................................................................................................... 12 
6. 
STUDY PROCEDURES ....................................................................................................................................... 12 
6.1 
SCHEDULE OF ASSESSMENTS ............................................................................................................................ 12 
6.2 
ENROLLMENT ................................................................................................................................................ 13 
6.2.1 Informed Consent ................................................................................................................................... 13 
6.2.2 Clinical Data Points ................................................................................................................................ 14 
6.3 
FOLLOW-UP ................................................................................................................................................. 14 
6.3.1 Direct From Study Participant Follow-Up ............................................................................................... 14 
6.3.2 On-Site Follow-Up Visit .......................................................................................................................... 15 
6.3.3 EARLY Follow-Up Visit ........................................................................................................................... 15 
6.3.4 Clinical Data Points ................................................................................................................................ 15 
6.4 
STUDY PARTICIPANT EXIT ............................................................................................................................... 16 
7. 
STUDY EVALUATIONS AND MEASUREMENTS ................................................................................................ 16 
7.1 
DIAGNOSIS, ETIOLOGY, AND CLINICAL MANIFESTATIONS ................................................................................... 16 
7.2 
MEDICAL HISTORY AND AES ........................................................................................................................... 16 
7.3 
TREATMENTS ................................................................................................................................................. 18 
7.4 
STUDY PARTICIPANT DEMOGRAPHICS AND OTHER STUDY METRICS ..................................................................... 18 
7.5 
STUDY PARTICIPANT ASSESSMENTS ................................................................................................................... 18 
7.5.1 Abdominal Pain ...................................................................................................................................... 18 
7.5.2 Gastrointestinal Symptoms ...................................................................................................................... 19 
7.5.3 Dietary Habits ........................................................................................................................................ 19 
7.5.4 Health-Related Quality of Life ................................................................................................................ 19 
7.5.5 Anxiety/Depression ................................................................................................................................. 19 
7.5.6 PERT Use and Treatment Satisfaction ...................................................................................................... 19 
8. 
DATA COLLECTION AND MANAGEMENT ....................................................................................................... 20 
8.1 
ELECTRONIC DATA CAPTURE SYSTEM ............................................................................................................... 20 

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8.2 
INVESTIGATOR FORMS .................................................................................................................................... 20 
8.3 
STUDY PARTICIPANT FORMS ........................................................................................................................... 20 
8.4 
STUDY PARTICIPANT IDENTIFICATION AND PRIVACY ........................................................................................... 20 
8.5 
SOURCE DOCUMENTS/SOURCE DATA .............................................................................................................. 21 
8.6 
CORRECTIONS TO SOURCE DOCUMENTS .......................................................................................................... 21 
8.7 
CASE REPORT FORMS (ECRFS) ......................................................................................................................... 21 
8.8 
RECORD RETENTION ...................................................................................................................................... 21 
9. 
SAFETY REPORTING .......................................................................................................................................... 21 
9.1 
ADVERSE EVENTS ........................................................................................................................................... 21 
9.2 
SERIOUS ADVERSE EVENTS .............................................................................................................................. 22 
10. STUDY PARTICIPANT WITHDRAWAL .............................................................................................................. 22 
11. DATA ANALYSIS ................................................................................................................................................ 23 
12. QUALITY CONTROL AND QUALITY ASSURANCE .......................................................................................... 23 
12.1 
STUDY MONITORING ..................................................................................................................................... 24 
12.1.1 
Responsibilities of the Investigator ...................................................................................................... 24 
12.1.2 
Responsibilities of the Sponsor ............................................................................................................ 24 
12.2 
PROTOCOL DEVIATIONS ................................................................................................................................. 24 
13. ETHICAL AND REGULATORY STANDARDS ..................................................................................................... 25 
13.1 
ETHICAL PRINCIPLES ....................................................................................................................................... 25 
13.2 
INFORMED CONSENT ..................................................................................................................................... 25 
13.3 
INSTITUTIONAL REVIEW BOARD ....................................................................................................................... 25 
14. ADMINISTRATIVE EXPECTATIONS ................................................................................................................... 25 
14.1 
CONFIDENTIALITY .......................................................................................................................................... 25 
14.2 
DATA PROTECTION ........................................................................................................................................ 26 
14.3 
STUDY RESULTS ............................................................................................................................................. 26 
14.4 
REGISTRY TERMINATION OR COMPLETION ........................................................................................................ 26 
15. REFERENCES ...................................................................................................................................................... 27 
16. APPENDICES ...................................................................................................................................................... 29 
APPENDIX A – ELIGIBLE PERT ...................................................................................................................................... 29 
APPENDIX B – STUDY PARTICIPANT EXIT FORM .............................................................................................................. 30 
 
 
 

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1. BACKGROUND 
Exocrine pancreatic insufficiency (EPI) is a condition caused by reduced or inappropriate secretion or activity of 
pancreatic juice and its digestive enzymes, and pancreatic lipase in particular. EPI can result in clinical 
manifestations such as steatorrhea, weight loss, and biochemical alterations related to lipids and liposoluble 
micronutrients malabsorption and maldigestion (Perbtani & Forsmark, 2019). While overt maldigestion is 
associated with easily detectable symptoms and impact on quality of life (Johnson et al., 2017), long-term 
malnutrition can have significant detrimental consequences on overall health, as well as increased risk of mortality 
in patients with chronic pancreatitis (CP) due to cancer, infections, and cardiovascular events (de la Iglesia-Garcia 
et al., 2018). Thus, it is important that EPI is diagnosed early and treated appropriately to alleviate symptoms and 
reduce the risk of long-term complications associated with EPI; however, EPI symptoms and manifestations are not 
specific and are often shared with other common gastrointestinal (GI) conditions. This can lead to a lack of 
recognition in many individuals with EPI. Even in those who are correctly diagnosed, many are not treated with 
appropriate dosages of pancreatic enzyme replacement therapy. 
The prevalence of EPI in the general population is unknown. It is most often associated with diseases of the exocrine 
pancreas, being a common late-stage manifestation of CP. CP is a disorder characterized by ongoing pathological 
pancreatic inflammation, leading to fibrosis and eventually to the loss of both endocrine and exocrine function. 
EPI typically develops after 5 – 10 years of CP, requiring approximately 90% of the endogenous pancreatic enzyme 
secretion to be lost (C. E. Forsmark, 2013). The risk of EPI varies with the underlying etiology of CP, with the highest 
risk population being those with chronic alcohol use (Ammann et al., 1987). Smoking has an independent effect 
on the development of CP, and the probability of EPI increases when tobacco exposure is combined with alcohol 
(Luaces-Regueira et al., 2014). In addition, EPI can also occur following severe acute pancreatitis (AP) as a result 
of loss of pancreatic parenchyma and functional capacity due to significant amounts of pancreatic necrosis 
(Hollemans et al., 2018), or recurrent acute pancreatitis without the overt presence of CP at the time of evaluation. 
Other causes for EPI are pancreatic malignancies (Sikkens et al., 2014) and resective pancreatic surgeries such as 
pancreatic duodenectomy (Goess et al., 2016) and distal pancreatectomy (Okano et al., 2016). EPI is also observed 
in other conditions, such as cystic fibrosis (Singh & Schwarzenberg, 2017), diabetes (Mohapatra et al., 2016), 
inflammatory bowel disease (Maconi et al., 2008), and GI surgeries (Antonini et al., 2018; Huddy et al., 2013; 
Straatman et al., 2017).  
The diagnosis of EPI is best made by a combination of clinical history, ruling out other causes of malabsorption, 
cross sectional imaging of the pancreas, and diagnostic tests. The most practical approach involves diagnostic 
procedures that are noninvasive, inexpensive, and readily available. Such available lab tests are indirect measures 
of pancreatic function and include fecal elastase-1 (FE-1) test, fecal fat measurement, and fat-soluble vitamin 
measurements. These tests are generally less expensive and easier to perform compared to direct pancreatic 
functional tests. 
Treatment of EPI relies on pancreatic enzyme replacement therapy (PERT). Pancrelipase formulations available in 
the United States are enteric coated (brand names: CreonÒ, PancreazeÒ, PertzyeÒ, and ZenpepÒ) and non-enteric 
coated (brand name: ViokaseÒ). Enteric coating prevents the enzymes from being denatured by gastric acid and 
the coating dissolves in the duodenum. All available formulations are derived from porcine origin. Finding the 
ideal dosing of PERT for a particular patient can be challenging because the response to treatment is variable from 
patient to patient. In general, enteric coated formulations are preferred because of gastric acid protection. Multiple 
studies have estimated that at least 30,000 IU (or about 90,000 USP units) of lipase delivered to the intestine with 
each meal should eliminate steatorrhea (Forsmark et al., 2002; Imrie et al., 2010; Keller & Layer, 2005). This 
amount represents approximately 10% of normal pancreatic secretion (Shandro et al., 2018). The goal is not to 

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replace 100% of estimated pancreatic function since steatorrhea only develops in severe disease. Therefore, 
starting doses should be between 30–40,000 IU with every meal and 15–20,000 IU with snacks (Imrie et al., 2010; 
Keller & Layer, 2005; Shandro et al., 2018). Patients should be instructed to take ½ the total dose with the first bite 
of the meal and other ½ either during the meal or at the end of the meal. In clinical practice, the choice of 
formulation will also be determined by cost and insurance coverage of the individual patient. In addition to PERT, 
lifestyle changes are paramount in the management of EPI. All patients should be counseled to stop smoking and 
drinking alcohol. Diet changes such as a healthy balanced diet and more frequent, smaller meals can also alleviate 
symptoms.  
The benefits in treatment of EPI have led to practice guideline recommendations for the use of PERT in patients 
with CP, pancreatic cancer, and pancreatic surgery (Sabater et al., 2016). However, studies suggest that the 
majority of patients are either not treated or treated with inadequate dosages. In a European survey study of patients 
with EPI due to CP or pancreatic cancer, one-quarter of patients took three or fewer capsules a day and more than 
two-thirds of patients reported ongoing symptoms of steatorrhea (Sikkens et al., 2012b). Similarly, in a Dutch 
national survey of patients with CP and EPI, the median initiating daily dosage was suboptimal (four capsules daily, 
25,000 USP units of lipase each), and a majority of patients reported ongoing gastrointestinal symptoms of EPI 
including steatorrhea and weight loss (Sikkens et al., 2012a). More recently, in a US population-based analysis, 
6.5% of patients with CP received any testing for EPI, 30.4% received a prescription for PERT, and only 10% 
received a minimally effective dose (Forsmark et al., 2017a). Likewise, in a similar analysis of patients with 
pancreatic cancer, only 1.9% of patients had testing for EPI and 22% received a prescription for PERT, with only 
5.5% receiving an adequate dose (Forsmark et al., 2017b). Ultimately, these studies highlight that diagnostic testing 
is rarely performed, treatment with PERT is infrequent, and, if utilized, the dosage amounts are generally 
inadequate. 
In order to better study the disease journey and the effectiveness and safety of available therapies for EPI, databases 
and registries are needed. To date, however, there have only been a few observational studies conducted on EPI. 
These existing databases are limited as they lack measures that could advance the understanding of the disease, 
comorbidities, disease progression, risk and/or mitigating factors. In addition, these studies do not provide a 
comprehensive assessment of existing treatments. This observational study with geographical representation across 
the United States will be well positioned to address the above-mentioned issues by collecting a comprehensive set 
of real-world data around disease and treatment outcomes. 
2. STUDY OBJECTIVES 
The main objective of this study is to generate real-world evidence reflecting the experience of individuals with 
exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis (CP). Efforts will be directed toward 
understanding the unmet need and therapeutic burden to identify the most critical factors that influence treatment 
choices/prescribing patterns, quality of life, and healthcare utilization outcomes in standard of care for individuals 
with EPI due to CP. This study has the following specific aims: 
1. Create a cohort of well-characterized patients with EPI due to CP for participation in retrospective and 
prospective research 
2. Collect clinical data to characterize both the EPI due to CP disease history and disease progression through a 
combination of retrospective and prospective collection of medical history, comorbidities, and treatment 
approaches aimed at increasing the level of understanding of a heterogeneous condition such as EPI 
3. Collect data on the differing clinical care practices for patients with EPI to better understand the impact of 
those patterns on outcomes (including quality of life, comorbidities, and treatments) 

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4. Collect data on treatment compliance that may impact the EPI due to CP disease experience and/or outcome  
5. Collect baseline and longitudinal participant-reported outcome (PRO) data on abdominal pain, GI symptoms, 
dietary habits, health-related quality of life, depression/anxiety, and PERT use and treatment satisfaction to 
evaluate the impact of EPI on individuals’ health and daily life 
6. Gather data on healthcare utilization to be combined with clinical data to generate evidence for the impact 
and burden of EPI due to CP in this cohort on the healthcare system. 
3. STUDY DESIGN 
This is a prospective, non-interventional study for individuals with EPI due to CP who are under the care of a 
gastroenterologist. Longitudinal data will be collected from both study participants as well as from their clinical 
encounters with their treating gastroenterology providers using a structured and standardized data collection 
method. The scope of data collection (see Schedule of Assessments) from the study participants includes 
demographics, current work status, current insurance coverage, family disease history, weight/height, current over 
the counter (OTC) herbal/nutritional supplements, healthcare utilization, and PROs on abdominal pain, GI 
symptoms, dietary habits, health-related quality of life, depression/anxiety, and PERT use and treatment 
satisfaction. At the time of routine clinical encounters, Investigators complete assessments on medical history, 
information on suspected/confirmed EPI diagnosis, CP etiology, clinical manifestations of EPI (GI and nutritional 
manifestations), AEs, and current treatment(s).  
3.1 
Study Plan and Duration 
Target enrollment is approximately 400 study participants with suspected or confirmed EPI. Approximately 20 
clinical gastroenterology sites in the United States will be contracted to participate.  
3.2 
Study Duration 
This is a 5-year study with an anticipated first enrollment date of 01 April 2021. The total enrollment period will 
be 24 months in length and data collection and study close-out will take place 3 months prior to the anticipated 
study end date. The study duration from enrollment to study end is five (5) years.  
4. SITE SELECTION 
4.1 
Investigator Qualifications 
Investigators will be selected after review of required qualifications and available resources. Investigators will be 
selected based on a number of criteria (e.g., practice setting, practice geographical location, number of EPI patients 
seen per month, type of IRB, etc.) to ensure that a representative sample of sites will be included in the study. A 
qualified Investigator is entitled to provide health care under the laws of the state where the registry site is located 
and for the purposes of this study must also be a licensed board eligible or board-certified gastroenterologist, or an 
advanced practice provider (i.e., certified nurse practitioner, physician assistant, gastroenterology resident or 
fellow) working at a gastroenterology practice and in good standing with a professional medical association. The 
Investigator is responsible for validating all information in the defined study schedule. If the study is conducted by 
a team of individuals at a site, the Investigator will need to complete a delegation of authority log for the registry. 
Each qualified physician at a site is assigned a unique ID to use when collecting and providing data for the registry. 
The Investigator will be asked to complete an assessment on provider demographics (e.g., age, gender, years in 
practice, number of EPI patients per month) and other site metrics (e.g., specialty, practice setting, practice type, 
and geographical location).  

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4.2 
Study-Specific Training for Investigators and Support Staff 
Study-specific training must be completed by Investigators, Sub-Investigators, and all support staff at each 
participating registry site prior to the initiation of study participant enrollment and data collection. Required 
training presentations and assessments (if applicable) are provided by HealthiVibe via teleconference and/or 
videoconference sessions prior to enrollment. The registry site training will be documented in a training log, which 
will capture the site staff that completed the trainings along with confirmation that the training content was 
understood.  
5. STUDY POPULATION 
5.1 
Study Participant Selection Criteria 
To be eligible for the registry, study participants must meet all inclusion criteria and none of the exclusion criteria 
below. 
5.2 
Inclusion Criteria  
To be eligible for enrollment, a study participant must meet the inclusion criteria below:  
1. At least 18 years of age (or age of majority) 
2. Willing to provide consent to participate  
3. Meet ONE (1) of the following at the time of enrollment: 
a. Diagnosis of chronic pancreatitis (CP)  
b. Diagnosis of recurrent acute pancreatitis (RAP)  
4. Suspected or confirmed diagnosis of EPI made by a healthcare provider  
5. On PERT, either prior to the Enrollment Visit or newly prescribed at the time of the Enrollment Visit. 
5.3 
Exclusion Criteria 
To be eligible for enrollment into the registry, a study participant must not have any of the criteria below:  
1. Currently participating in or planning to participate in a double-blind randomized trial and/or open-label Phase 
3b/4 on CP or EPI 
2. Diagnosed with any of the following conditions at the time of enrollment: 
a. Cystic fibrosis 
b. Fibrosing colonopathy 
c. A history of or current diagnosis of pancreatic cancer, main duct papillary mucinous neoplasms 
(IPMNs), and other pancreatic malignancies 
d. Allergy to pork or other porcine pancreatic enzyme products (PEPs)  
e. Any condition that would, in the investigator’s opinion, limit the individual’s ability to complete the 
study.  
6. STUDY PROCEDURES 
6.1 
Schedule of Assessments 
The registry activities are summarized in the schedule of assessments outlined in Table 1. 

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Table 1. Schedule of Assessments 
 
Enrollment  
Day 0 
Follow-up direct from 
study participant 
 
± 7 days 
Follow-up  
on-site 
(Clinical 
encounter)  
 
Every 6 months* 
Study 
participant 
exit‡ 
 
May occur any 
time; max. data 
collection period 
is 5 years 
 
 
Every 3 
months 
Every 6 
months 
 
 
Study Participant Provided Data§ 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
Demographic information  
X 
 
 
 
 
Family disease history 
X 
 
 
 
 
Training for remote assessment completion 
X 
 
 
 
 
Height 
X 
 
 
 
 
Weight 
X 
X 
 
 
 
Current Insurance/work status 
X 
X 
 
 
 
Current OTC nutritional/herbal supplements 
X 
X 
 
 
 
Abdominal pain 
X 
X 
 
 
 
GI symptoms 
X 
X 
 
 
 
PERT use and treatment satisfaction 
X 
X 
 
 
 
Dietary habits 
X 
 
X 
 
 
Health-related quality of life 
X 
 
X 
 
 
Anxiety/depression 
X 
 
X 
 
 
Healthcare utilization 
X 
 
X 
 
 
Investigator Provided Data* 
 
 
 
 
 
Review/confirm participant eligibility 
X 
 
 
 
 
EPI diagnosis 
X 
 
 
 
 
CP etiology 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
EPI clinical manifestations 
X 
 
 
X 
 
AEs • 
 
 
 
X 
 
Current treatment(s) 
X 
 
 
X 
 
Reason for exit 
 
 
 
 
X 
 
§   Study participant provided data will be collected remotely via EDC portal.  
*   Investigator provided data will be provided during clinical encounters at the registry site. Every 180 days ±30 days with minimum 150 days 
between visits unless follow-up visit meets criteria for EARLY On-Site Follow-Up (see section 6.3.2) 
‡  Occurs if data collection period has ended or if study participant exits the study due to death, is LTFU, transfers to another gastroenterologist, 
withdraws from the study or being terminated by the Investigator. 
•    The Investigator will provide information about the occurrence and seriousness of AEs at Follow-up. In the event that an AE is serious, the 
Investigator will complete an SAE form. 
6.2 
Enrollment 
6.2.1 
Informed Consent 
Study participants will be enrolled when all of their questions about the study have been addressed, they have 
signed the informed consent form (ICF) and have met all of the inclusion criteria and none of the exclusion criteria 
(see Study Participant Selection Criteria). Informed consent will be obtained either via paper and/or electronic 
consent. 

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Once the participant’s consent is obtained, a unique study participant identifier will be assigned that will be used 
to collect the participant’s data throughout the study. 
6.2.2 
Clinical Data Points 
During the Enrollment visit, the following information will be collected from the study participant: 
 
• 
Demographics (i.e., age, gender, ethnicity, race, marital status, highest level of education, annual household 
income, residence setting, and zip code) 
• 
Current insurance coverage and current work status 
• 
Height/weight (current weight, highest weight ever, unintentional weight loss) 
• 
Family history of pancreatic disease, pancreatic cancer, pancreatic resection, celiac disease, and diabetes 
• 
Current OTC herbal/nutritional supplements 
• 
Abdominal pain, GI symptoms, dietary habits, health-related quality of life, depression/anxiety, PERT use and 
treatment satisfaction, and healthcare utilization. 
The following assessments will be collected during the clinical encounters with the Investigator: 
• 
EPI-related information including EPI diagnosis, date of onset of symptoms indicative of EPI, method of 
confirmed/suspected EPI diagnosis (i.e., abnormal fecal elastase FE-1 test, clinical steatorrhea, vitamin 
deficiency, weight loss, pancreatic function testing, and/or other), CP etiology following the Toxic-metabolic, 
Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis and Obstructive (TIGAR-O) v2.0 
classification (Whitcomb, 2019), and clinical manifestations of EPI (i.e., GI manifestations such as 
diarrhea/loose stool, steatorrhea, abdominal pain, bloating; nutritional manifestations such as unintentional 
weight loss/difficulty gaining weight, malnutrition, vitamin D and other vitamin/mineral deficiencies, and 
other)  
• 
Medical history (history of comorbidities and surgical/endoscopic procedures, laboratory abnormalities)   
• 
Current treatment(s) including medication (i.e., PERT and others) and other therapies, such as nutritional 
support, cognitive-behavioral therapy, as well as response to therapy. 
6.3 
Follow-Up 
At Follow-Up, data will be collected from the study participant through remote data collection and by the 
Investigator at on-site clinical encounters. Study procedures for Follow-Up will be described in the sections below.  
6.3.1 
Direct From Study Participant Follow-Up 
The study participant will complete assessments remotely via EDC portal, accessed via a mobile-friendly secure 
web URL every 3 months.  
Autogenerated reminders via email or text (depending on study participant preference) will be sent weekly starting 
3 weeks prior to the scheduled data collection date. If the study participant does not complete their assessments 
through the EDC portal within 7 days of the scheduled date, reminders will be sent to the study participant every 
other day. If the participant has not completed the assessments 21 days after the scheduled data collection date, 
the HealthiVibe Registry Manager will call the study participant to remind them to complete the assessments and/or 
find out about the reason for the delay. 

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6.3.2 
On-Site Follow-Up Visit 
Routine clinical encounters are performed approximately every 6 months or sooner if a study participant is 
prescribed another PERT (see Appendix A for eligible PERT). Each registry visit is anchored to the date of the 
previous on-site visit. There must be at least 150 days between each on-site visit unless the Early Follow-Up Visit 
criteria are met (see section EARLY Follow-Up Visit). Other routine clinical encounters may occur in between two 
registry visits, but the data collected in the Follow-Up forms should cover the time period since the last registry 
visit. If registry Follow-Up visits cannot occur approximately every 6 months, the site is encouraged to attempt to 
schedule a Follow-Up visit as soon as possible. 
6.3.3 
EARLY Follow-Up Visit 
An EARLY Follow-up is considered any visit that occurs within fewer than 150 days from the previous visit. As 
stated above, an on-site visit does not qualify as Follow-Up visit if the visit occurs within fewer than 150 days since 
the last visit, unless the study participant is prescribed another PERT (see Appendix A for eligible PERT). When the 
EARLY Follow-Up criteria are met, the next follow-up visit will be calculated from the date of the Early Follow-Up 
visit. 
6.3.4 
Clinical Data Points 
The following information will be collected from the study participants remotely via EDC portal every 3 months: 
• 
Weight (current) 
• 
Current insurance coverage and current work status 
• 
Current OTC herbal/nutritional supplements 
• 
Abdominal pain 
• 
GI symptoms 
• 
PERT use and treatment satisfaction 
 
To limit burden on study participants, the following data will be collected from via EDC portal every 6 months: 
• 
Dietary habits 
• 
Health-related quality of life 
• 
Anxiety/depression 
• 
Healthcare utilization 
 
The Investigator will provide the following information during the routine clinical encounters (approx. every 6 
months): 
• 
Clinical manifestations of EPI 
• 
Current treatment(s) since last visit including medication (PERT and others) and other therapies such as 
nutritional support, and cognitive-behavioral therapy, as well as response to therapy 
• 
Collection of AEs/SAEs occurring during the study (see Medical History and AEs and SAFETY REPORTING for 
more details). 

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6.4 
Study Participant Exit 
A study participant exits the study for one of the following reasons: 
• 
Death 
• 
The study participant withdraws from the study 
• 
The study participant is being terminated by the Investigator 
• 
The study participant transfers to a different gastroenterologist who is not a participating registry site  
• 
The study participant is lost to follow-up (LTFU) 
• 
The data collection period of the registry has ended 
A study participant is LTFU when, despite all reasonable efforts (phone calls, email, letters, etc.), contact with the 
study participant cannot be reestablished, if a study participant does not complete their assessments remotely for 
2 consecutive timepoints. This effort must be clearly documented by the HealthiVibe Registry Manager and 
information about the study participant’s vital status (living or deceased) should be documented when known. 
The Investigator will document the reason for the study participant’s exit using the Study Participant Exit form (see 
Appendix B). If the reason for exit is due to death, any associated AEs, and/or AEs occurring after the last follow-
up visit should be recorded and reported to HealthiVibe (see SAFETY REPORTING). The Investigator should 
carefully choose the option that best reflects the reason for exit at the time; the form should be completed within 
5 business days of site awareness of the study participant’s exit from the study.  
7. STUDY EVALUATIONS AND MEASUREMENTS 
7.1 
Diagnosis, Etiology, and Clinical Manifestations 
The Investigator will confirm eligibility criteria and provide detailed information on the history of EPI, date of the 
confirmed/suspected EPI diagnosis, method of confirmed/suspected EPI diagnosis (i.e., abnormal fecal elastase FE-
1 test, clinical steatorrhea, vitamin deficiency, weight loss, pancreatic function testing, and/or other), and the date 
of start of EPI symptoms that may precede a confirmed diagnosis of EPI.  
The Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis and Obstructive 
(TIGAR-O) v2.0 classification (Whitcomb, 2019) classification will be used to define the CP etiology.  
The Investigator will also report the clinical manifestations of EPI that have been observed in the study participant. 
These clinical manifestations include GI (i.e., diarrhea/loose stool, steatorrhea, abdominal pain, bloating, and 
flatulence) and nutritional manifestations (i.e., unintentional weight loss/difficulty gaining weight, malnutrition, 
vitamin/mineral deficiencies). 
7.2 
Medical History and AEs 
At Enrollment, the Investigator will provide information on the study participant’s medical history related to the 
following:  
• 
GI disorders 
• 
Cardiovascular disorders 
• 
Infections/inflammatory diseases 

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• 
Metabolic, endocrine, and bone health 
• 
Mental health 
• 
Social history 
• 
Malignancies 
• 
Surgical, radiological, and endoscopic procedures 
• 
Laboratory abnormalities, if available/ordered as part of routine clinical practice 
At the Follow-Up Visits, Investigators will provide information on any AEs/SAEs that may have occurred since last 
visit. For every AE that is reported, the following information will be collected:  
• 
Event term 
• 
Onset date 
• 
Relation to PERT 
• 
Event seriousness 
• 
Any other events meeting SAE definition 
• 
Outcome of SAE. 
For any reported SAE, the following information will be collected: 
• 
SAE event term 
• 
SAE onset date 
• 
SAE outcome (i.e., hospitalization, immediately life-threatening, death, persistent/significant disability, 
congenital abnormality or birth defect, treatment with intravenous antibiotics or anti-infectives, otherwise 
serious in the option of the Investigator) 
• 
SAE final outcome/status (i.e., resolved/fully recovered, recovered with sequalae, ongoing, death, 
condition worsening) 
• 
Brief description of the study participant with no personal identifying information 
• 
Intervention/treatment for the SAE (i.e., medication or nutritional supplement, device, surgery, 
behavioral/lifestyle, observation) 
• 
Details on medications used for the disease under study (i.e., drug name, dose, frequency, route, start date, 
date of last dose, event relation to the drug, continuation/discontinuation/changes of the drug) 
• 
List of any relevant tests, laboratory data/results, and history, including preexisting conditions 
• 
Brief description/narrative of the SAE 
• 
Status of the SAE report (i.e., confirmed event, SAE previously reported between registry visits/duplicate, 
not an event) 
 
At each Follow-up, Investigators will also complete a COVID-19 reporting form, which will collect the following 
information: 
• 
COVID-19 diagnosis 

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• 
COVID-19 symptoms (i.e., fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle 
or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or 
vomiting, diarrhea)  
• 
COVID-19 vaccination date(s) and manufacturer(s), if applicable 
• 
COVID-19 vaccine side effects (i.e., tiredness, headache, muscle pain, chills, fever, nausea), if applicable. 
7.3 
Treatments 
The Investigator will complete a questionnaire on treatments at Enrollment with focus on: 
• 
Medical therapies (PERT, pain medication, neuromodulators, antidiarrheals, vitamins and antioxidants, and 
other medication such as antidiabetics, proton pump inhibitors, and H2 blockers) 
• 
Dietician and other nutritional support 
• 
Cognitive behavioral therapy. 
At the On-Site Follow-Up Visits, the Investigator will provide any updates on treatment(s) since the last visit (5-
point scale; major symptom improvement to major worsening in symptoms). 
7.4 
Study Participant Demographics and Other Study Metrics 
At Enrollment, information collected on demographics includes age, gender, race/ethnicity, highest level of 
education, marital status, annual household income, and geographical location (zip code and residence setting). 
Other study metrics include height, current weight, and weight history (maximum weight ever, episodes of 
unintentional weight loss, difficulty gaining weight). Family history of pancreatic cancer, chronic pancreatitis, 
pancreatic surgery, cystic fibrosis, and diabetes (Type I, II, or IIIc) will also be collected. Additionally, current 
insurance coverage, current work status, current OTC herbal/nutritional supplements, and healthcare utilization 
metrics (i.e., number of healthcare provider/ER/tele health visits, hospitalizations and length of stay, and number 
of sick days, if employed in the past 6 months) will be documented at Enrollment and at Follow-Up. 
7.5 
Study Participant Assessments 
Study participants will complete a number of participant-reported assessments at Enrollment and Follow-Up. The 
information collected comprises the following domains: abdominal pain, GI symptoms, dietary habits, HRQOL, 
anxiety/depression, and PERT use and treatment satisfaction. Each of these domains is described in more detail 
below. 
7.5.1 
Abdominal Pain 
Multiple constructs will be measured for abdominal pain, which will be collected with single-item questions 
around the abdominal pain pattern (constant vs. episodic), episodic abdominal pain intensity (0 – 10 numerical 
rating scale), frequency (number of abdominal pain episodes last month), and episode duration over the past 
month. Additionally, the abdominal pain history (in months), abdominal pain triggers (high-fat meals, stress, 
alcohol, tobacco, activity, other), abdominal pain relief methods (bowel movement, OTC analgesic medication, 
rest, fasting/diet adjustment), and abdominal pain control over the past month will be collected. Study participants 
will also be asked whether the abdominal pain was severe enough to seek medical attention, and if so, when and 
what type of medical attention they received (primary care provider, specialist, emergency room, urgent care, 
hospitalization). In the event they were hospitalized, the length of stay will be collected as well.  

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7.5.2 
Gastrointestinal Symptoms 
Single-item questions will be used to evaluate the severity of bloating (none to very severe), flatulence (none to 
very severe), and nausea (none to very severe) over the past week. Stool frequency will be captured with the 
average number of stools per day over the past week. Stool urgency will be measured with the number of urgency 
episodes over the past week (none to multiple times per day). Steatorrhea will be measured with a single-item 
question on the stool appearance (i.e., stool that is oily, bad smelling, and/or floats/difficult to flush; never to all 
the time). The stool consistency over the past week will be defined using the Bristol Stool Form Scale (BSFS). The 
BSFS is used for classifying the form of stool into 7 categories scored from 1 to 7; (1) Separate hard lumps like nuts 
(difficult to pass); (2) Sausage-shaped but lumpy; (3) Like a sausage but with cracks on its surface; (4) Like a sausage 
or snake, smooth and soft; (5) Soft blobs with clear-cut edges (passed easily); (6) Fluffy pieces with ragged edges, 
a mushy stool; (7) Watery, no solid pieces, entirely liquid. Study participants choose one of the BSFS scores which 
has a nearest analog form with their stools at every defecation.  
7.5.3 
Dietary Habits 
Questions on dietary habits include the type of diet (vegetarian, mostly vegetarian, meat/poultry a few times/week 
or daily, vegan, gluten-free, low FODMAP, diabetic, other), number of meals/snacks per day, fat diet (high fat diet, 
average fat diet, low fat diet) and sweets intake (never to a few times per day). Study participants will also be asked 
if they have any dietary restrictions to avoid symptoms such as bloating, flatulence, abdominal pain, etc. (never to 
all the time).  
7.5.4 
Health-Related Quality of Life 
HRQOL will be measured using the 12-item Short Form Survey (SF-12). The SF-12 is a survey designed for use 
with individuals with chronic conditions. This 12-item scale can be used to assess the physical and mental health 
of respondents. 10 of the 12 questions are answered on a 5-point Likert scale and 2 are answered on a 3-point 
Likert scale. The questions are then scored and weighted into 2 subscales, physical health and mental health. 
Respondents can have a score that ranges from 0 – 100 with 100 being the best score and indicating high physical 
or mental health. A 3-point change in SF-12 score reflects a meaningful difference. 
7.5.5 
Anxiety/Depression 
Anxiety and depression levels will be measured with the Hospital Anxiety and Depression Scale (HADS). The 
HADS consists of 14 items divided into two 7-item subscales: Anxiety (HADS-A) and depression (HADS-D). 
Respondents rate each item on a 4-point scale from 0 (absence) to 3 (extreme presence). The total score is 42 (21 
per subscale). Scores are derived by summing responses for each of the two subscales or for the scale as a whole. 
Higher scores indicate greater levels of anxiety and depression.   
7.5.6 
PERT Use and Treatment Satisfaction 
Study participants will be asked whether PERTs have an impact on their symptoms (greatly improved symptoms to 
greatly worsened symptoms) and how they are taking the PERTs on a typical day (i.e., frequency, number of pills, 
and with/without meals and snacks). Treatment satisfaction related to PERTs will be measured with the Treatment 
Satisfaction Questionnaire for Medication – 9 items (TSQM-9). The TSQM-9 is a global satisfaction scale used to 
assess the overall level of participant's satisfaction or dissatisfaction with their medications. It comprises 9 items 
on 3 subscales: effectiveness, convenience and global satisfaction. The scores are computed by adding items for 
each domain, i.e., items 1 – 3 for effectiveness, items 4 – 6 for convenience and items 7 – 9 for global satisfaction 
(Bharmal et al., 2009). The lowest possible score (1 for each item and 3 for all 3 subscales) is subtracted from the 
composite score and divided by the greatest possible score range. The greatest range is (7-1) X 3 items = 18 for the 
effectiveness and convenience, and (5-1) x 3 items = 12 for global satisfaction. This provides a transformed score 

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between 0 and 1 that is then multiplied by 100; scores for the domains range from 0 (extremely dissatisfied) to 100 
(extremely satisfied), with higher scores indicating greater satisfaction. 
8. DATA COLLECTION AND MANAGEMENT  
8.1 
Electronic Data Capture System 
Data collected in this registry will be entered into a 21 CFR Part 11-ready web-based EDC system at the specified 
data collection timepoints.  
8.2 
Investigator Forms 
The Investigator or trained study site personnel will enter the data required by the registry directly into the EDC 
system. Instructions for proper completion of the electronic case report forms (eCRFs) and on how to use the EDC 
system will be provided to the site. An access code with login password will be provided to the Investigator 
following training. Any additional persons authorized to enter data into the eCRFs will be provided with a personal 
access code following training. The Investigator is responsible for ensuring that all sections of the eCRF are 
complete and correct and those entries can be verified against source data. At study closeout, the Investigator will 
be required to sign off on all eCRF before closure of the registry database.  
8.3 
Study Participant Forms 
The study participant will complete their assessments at the site during Enrollment and remotely via EDC portal, 
accessed via a mobile-friendly secure web URL for Follow-Up. 
Study personnel are prohibited from completing any part of the Study Participant forms on behalf of the study 
participant. However, study personnel are allowed to assist the study participant in the event of issues with the 
electronic device and can show the study participant where the data should be entered. If a study participant 
requests assistance during the visit, study personnel are permitted to facilitate completion of the form by 
transcribing the study participant’s verbal responses to the Study Participant Form. At Enrollment, study participants 
will undergo a training on how to complete their assessments remotely via EDC portal for Follow-Up. 
Site personnel are expected to review the study participants’ responses for completeness, and to follow-up on any 
information captured in the forms. Details regarding any AEs occurring in the study participant and reported in the 
Study Participant Form must also be transcribed to the Investigator Form.  
8.4 
Study Participant Identification and Privacy 
A registry study participant ID number (a unique, 6-character standard ID number) will be assigned to each study 
participant. To keep study participants’ information confidential, this ID number will be used for data collection 
throughout the study. The site is responsible for assigning study participant IDs according to study-specific 
numbering requirements.  
Each study participant’s data collected in the registry will be stored under the registry participant ID number. The 
collection of protected health information (PHI) will be kept to the minimum that is required for the conduct of the 
study. Data protection and privacy regulations will be observed in capturing, forwarding, processing, and storing 
study participant data. Study participants will be informed accordingly and will be asked to give their consent on 
data-handling procedures in accordance with national regulations.  

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8.5 
Source Documents/Source Data 
Source documents are original documents, data, and records (or certified copies of original records) of clinical 
findings and observations. Source documents are the records where clinical observations are first recorded (i.e., 
part of the medical record and the first point of entry). Some examples include hospital records, medical charts, 
and laboratory reports. 
Source documents can exist in a paper or electronic format and they contain the raw data that are required to 
reconstruct, evaluate, and validate the integrity of a research study. 
8.6 
Corrections to Source Documents 
Any corrections or changes made to source documents must be clearly attributable to the individual making the 
change and the date the change was made. An explanation should also accompany the change if it is not self-
evident. If paper source documents are used, any modifications to the record must not obscure the original entry.  
8.7 
Case Report Forms (eCRFs) 
eCRFs are forms designed to capture all required information for each registry participant. CRF data entry is done 
using the electronic EDC which constitutes the submission of registry data to HealthiVibe. 
Data in the eCRFs that are first recorded/captured elsewhere (such as on paper or in an electronic database) should 
always be consistent with and substantiated by the source documents. When data for the registry are first recorded 
in an electronic CRF, the CRF is also a source document. Each registry site will document which data are being 
transcribed to the EDC and which data are considered source. This information will be kept in their registry binder. 
8.8 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or HealthiVibe, the Investigator agrees to keep all 
required study records in compliance with HealthiVibe’s record retention policy. This includes but is not limited 
to the identity of all registry study participants, all source documents, and IRB approvals, as well as documentation 
of relevant study correspondence and change notifications (e.g., memos-to-file, reports, deviation forms, etc.). 
Study records can be stored electronically or converted to an electronic format as certified copies of the original 
paper documents.  
All study records and source data should be retained by the Investigator throughout the entire duration of his or 
her study participation and in compliance with local laws. Upon Sponsor termination of the registry or Investigator 
termination of their participation, all source data should be retained according to state laws for the minimum 
medical record retention periods for records held by medical doctors and hospitals. 
If the Investigator becomes unable for any reason to continue to retain study records for the required period (e.g., 
retirement, relocation), HealthiVibe should be prospectively notified. The study records must be transferred to a 
designee acceptable to HealthiVibe, such as another Investigator, another institution, or to an independent third 
party arranged by HealthiVibe. 
9. SAFETY REPORTING 
9.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a study participant administered a pharmaceutical 
product and which does not necessarily have to have a causal relationship with the treatment. AE data collection 

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begins after a study participant has completed an Enrollment Visit. During the Follow-Up on-site visits, the 
Investigator and/or designee is required to question the study participant regarding the occurrence of AEs since the 
previous registry visit. Pertinent details regarding any reported AEs are to be captured using the pertinent sections 
in the Investigator Follow-Up forms. 
Any AEs that are reported by the study participant, discovered as a result of general questioning by the Investigator, 
should be recorded in the Investigator Follow-Up Form at the next scheduled registry visit following the onset of 
the event.  
9.2 
Serious Adverse Events  
SAEs are defined as adverse events that result in any of the following outcomes: 
- 
Hospitalization (new or prolongation) 
- 
Death 
- 
Immediately life threatening (urgent intervention required to prevent outcome of death) 
- 
Persistent/significant disability or incapacity 
- 
Congenital abnormality or birth defect 
- 
Otherwise serious (important medical event) in the opinion of the Investigator (i.e., event that may 
jeopardize the study participant and require medical or surgical intervention/treatment to prevent one of 
the other outcomes listed above). 
SAEs are to be reported by sites in accordance with registry AE Reporting Guidelines as soon as possible after the 
site learns of the event (within 1 business day), via the electronic data capture system or approved backup 
mechanism (per the AE Reporting Guidelines). These events should also be captured by the Investigator at the next 
registry visit following the onset date of the event. Sites are required to request supporting documents (e.g., hospital 
records, laboratory results, etc.) for each SAE. These records should be submitted as soon as they become available 
to the site (between registry visits). The Investigator or qualified designee must remove all of the study participant’s 
personal identifiers from the supporting documents prior to submission to HealthiVibe.  
10. STUDY PARTICIPANT WITHDRAWAL  
Study participants have the right to withdraw their consent for participation in the registry at any time and for any 
reason without penalty or loss of benefits to which they would otherwise be entitled. They may withdraw by 
notifying the Investigator in writing, in person, or by telephone. When a study participant withdraws from the 
registry, the Investigator or the designee completes a Study Participant Exit Form and cites the reason(s) for 
withdrawal.  
If a study participant also withdraws their consent for the use of their personal information either partially or 
completely, the Investigator or designee must notify HealthiVibe. If the participant withdraws from the registry, 
and also withdraws consent for disclosure of future information, no further evaluations are performed, and no 
additional data are collected.  
Date of revocation is the date the study participant requested removal of contact info or withdrawal of consent. 
Because it is documented in the EDC system, it is of critical importance that registry personnel enter a study 
participant’s decision to revoke use of their personal information immediately upon awareness to ensure there is 
no lag between when a study participant communicates their request for withdrawal and when HealthiVibe 
receives that request. 

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11. DATA ANALYSIS  
Statistical analyses will be guided by the specific aims of the registry. Complete details of all analyses will be 
described in a standalone Statistical Analysis Plan (SAP) with accompanying mock Tables, Figures and Listings 
(TFLs).   
All data will be summarized descriptively. Continuous variables will be described through reporting of the mean 
(± standard deviation), median and range, while categorical data will be described through reporting of frequency 
and percent. The participant population will be characterized by demographics and baseline attributes. From this 
characterization, important subgroups of interest may be identified if sample sizes are sufficiently robust for 
additional exploratory analyses. All pre-planned, clinically important subgroups for analyses will be identified in 
the SAP. 
Study disposition of all participants will be summarized including dropouts (with reasons presented for those who 
drop out), and for lost to follow-up (at what point they are lost, and if they return). 
Multivariate modeling will be employed to study both the EPI due to CP disease history and disease progression 
by analyzing patterns of medical history, comorbidities, and treatment approaches. Variables in the modeling will 
also include clinical care practices and their impact on the modeling. 
Clinical care practices will be further explored with their potential impact on quality of life, comorbidities, and 
treatments using the same multivariate modeling. Treatment compliance will be examined for each of the models, 
knowing that biases are introduced with participant recall. Prescribing practices will be descriptively presented (to 
include type of PERT, dose at initiation and escalation, recommendation on how to take PERT, and reason for 
switching to another PERT, if applicable). If trends are identified in prescribing patterns, these trends may be further 
explored. 
Healthcare utilization data will be assessed with key variables from the clinical dataset. Impact and burden of EPI 
due to CP will be assessed for impact on the healthcare system (the number of ER visits, healthcare provider visits, 
number of hospitalizations, length of hospital stay, and number of sick days taken). Associations will be presented 
descriptively, and if the data are robust, inferential statistics will be presented using rates and 95% confidence 
intervals. 
Confounding will be assessed for predicting outcomes with the registry data. For example, selective prescribing 
(confounding by indication) will be reviewed to verify if those with more severe disease or those who have failed 
other treatments are more likely to receive experimental or newer treatments than those with less severe disease 
or less access to new treatments due to socioeconomic, geographic locations, or other identified factors collected 
in the registry. Other potential confounders of the data may be identified and will be further outlined in the SAP.  
If any confounding is identified, statistical procedures such as stratified analysis, multivariable analysis, and/or 
sensitivity analysis may be employed as appropriate for that confounder and outcome.  Given that groupings within 
a study population may exist (e.g., patients seen by a single site/practice/physician may themselves predict health 
outcomes of interest, these potential grouping effects will be handled with use of ANOVA (analysis of variance) 
models. 
Data quality assessed in terms of missing data, out of range values, and completeness will be presented, as to allow 
for appropriate interpretation and extrapolation of the study results. 
All analyses will be conducted in SAS version 9.1.3 or higher. 
12. QUALITY CONTROL AND QUALITY ASSURANCE 

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During study conduct, HealthiVibe will monitor and audit registry data and investigative sites to ensure the 
protocol, data collection requirements, and applicable research regulations are complied with. The monitors may 
review source documents to confirm that the data in the registry database are accurate and verifiable. The 
Investigator must allow HealthiVibe monitors and appropriate regulatory authorities direct access to source 
documents to perform this verification. These personnel, bound by study participant privacy laws, must maintain 
the confidentiality of all personal identity or personal medical information (according to confidentiality and 
personal data protection rules). 
The study site may also be subject to review by the IRB, and/or to quality assurance audits performed by 
HealthiVibe, or companies working with or on behalf of HealthiVibe and/or to inspection by appropriate regulatory 
authorities. 
12.1 Study Monitoring 
12.1.1 Responsibilities of the Investigator 
The Investigator is required to ensure compliance with all procedures required by this protocol and with all data 
collection requirements defined by the Sponsor. The Investigator agrees to participate in a site initiation visit and 
to participate in the required training. The Investigator also agrees to provide reliable data and all information 
requested by the registry protocol via the most current data collection requirements and any resulting requests for 
data clarifications in an accurate and timely manner in compliance with the procedures defined by HealthiVibe. 
The Investigator will also need to provide appropriate training to study participants on how to use the EDC portal 
for remote data collection at Follow-Up.  
The Investigator must also ensure that authorized HealthiVibe representatives are given direct access upon request 
and sufficient notice to examine, analyze, and verify any source documents that are important to the evaluation 
and integrity of the registry study. 
12.1.2 Responsibilities of the Sponsor 
On behalf of the Sponsor, HealthiVibe is responsible for taking all reasonable steps to ensure the proper conduct 
of the registry protocol with regards to research ethics, compliance, and the standardization, integrity, and validity 
of the data collected. Thus, the main duty of the monitoring team and other authorized HealthiVibe representatives 
is to help the Investigator and Sponsor maintain a high level of ethical, scientific, technical, and regulatory quality 
in all aspects of the registry in accordance with data collection and quality assurance standards for non-
interventional, observational registries. 
At regular intervals as defined by the registry monitoring plan (RMP), Investigative sites are contacted by 
HealthiVibe representatives to participate in monitoring visits. These visits are primarily carried out remotely via 
email, phone, or a virtual meeting space, but may occur on location at a registry site.  
Representatives may request to discuss study progress and performance, review compliance with registry 
evaluation and data collection requirements, verify registry data via source document verification, as well as 
investigate any emergent data quality issues detected from an aggregate review of data quality indicators. 
12.2 Protocol Deviations   
Because HealthiVibe registries support human research, HealthiVibe must have written procedures for sites that 
ensure prompt reporting of deviations. Protocol deviations for non-interventional, observational research are 
defined as those that may affect the rights or privacy of human subjects or the scientific integrity of the registry’s 
objectives. If a protocol deviation occurs which meets this definition, the registry site will need to complete a 
protocol deviation form which will be sent to HealthiVibe. 

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13. ETHICAL AND REGULATORY STANDARDS 
13.1 Ethical Principles  
HealthiVibe is responsible for ensuring that the study will be conducted in accordance with applicable legal and 
regulatory requirements, as well as the Guidelines for Good Clinical Practice (International Conference on 
Harmonization 1996), the Declaration of Helsinki (World Medical Association 2008), and the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA), where applicable. 
The Investigator is responsible for ensuring that the registry is conducted in accordance with the protocol and all 
applicable local, state, and federal laws and regulations and is responsible for protecting the rights, privacy, and 
welfare of study participants participating in the registry under his or her care. 
In compliance with HealthiVibe public disclosure commitments, this non-interventional study will be recorded in 
the public registry website clinicaltrials.gov. The registry will contain basic information about the study sufficient 
to inform interested study participants (and their healthcare practitioners) on how to enroll in the registry. 
13.2 Informed Consent 
The Investigator or designee must ensure that each study participant is fully informed about the nature and 
objectives of the registry and possible risks associated with participation, in language and terms the study 
participant is able to understand. The Investigator or designee will obtain documentation of informed consent from 
each study participant before any registry evaluation is performed.  
The Investigator will retain the original of each study participant's signed ICF. If the study participant is legally 
blind and/or illiterate, an impartial witness must be present for the consent process and this individual must also 
sign and personally date the informed consent form. 
13.3 Institutional Review Board 
It is the responsibility of the Investigator to have prospective approval of the study protocol, protocol amendments, 
informed consent forms, study participant data collection forms, and other relevant documents (e.g., recruitment 
advertisements, assessment completion reminders) from the Institutional Review Board (IRB). All correspondence 
with the IRB should be retained in the site regulatory file. Copies of local IRB approvals should be forwarded to 
HealthiVibe. Amendments to any documents may not be initiated prior to Sponsor, HealthiVibe, and IRB approval. 
14. ADMINISTRATIVE EXPECTATIONS   
14.1 Confidentiality 
All information disclosed or provided by the Sponsor (or any company/institution acting on their behalf), or 
produced during the registry, including, but not limited to, the registry protocol, the data collection forms, and 
informed consent, is confidential. The Investigator and any person under his/her authority agree to undertake to 
keep confidential and not to disclose the information to any third party without the prior written approval of the 
Sponsor. 
However, the submission of this registry protocol and other necessary documentation to the IRB is expressly 
permitted, the IRB members having the same obligation of confidentiality. 
The Sub-Investigators shall be bound by the same obligation as the Investigator. The Investigator shall inform the 
Investigator and Sub-Investigators of the confidential nature of the registry. 

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Furthermore, all Investigators and HealthiVibe agree to adhere to the principles of personal data confidentiality in 
relation to the study participants, Investigators, and all other collaborators involved in the study. 
14.2 Data Protection 
The study participant's personal information shall be treated in compliance with all applicable health information 
privacy laws and regulations. When archiving or processing study participant personal information, HealthiVibe 
shall take all appropriate measures to safeguard and prevent access to this data by any unauthorized third party.  
The same privacy laws and regulations apply to the study participant’s clinical data identified by a study participant 
ID that are stored in the EDC. HealthiVibe shall take all the appropriate measures to ensure that this database is 
protected and secured from unauthorized disclosure during processing or archiving of clinical database records.  
In accordance with applicable research and health information privacy laws, clinical data and personal 
information collected for this registry are maintained in separate databases for an undefined time period.  
HealthiVibe also collects demographic data on Investigators and any person involved in the registry which may 
be included in a database. Again, HealthiVibe shall take all the appropriate privacy measures to ensure that this 
information is protected and secured from unauthorized or inadvertent disclosure.  
14.3 Study Results 
At least thirty (30) days prior to submission for Publication, Investigator shall submit to Nestlé for review and 
comment any proposed oral or written Publication ("Review Period"). Investigator will consider any such comments 
in good faith but is under no obligation to incorporate Nestlé’s suggestions. The Review Period for abstracts or 
poster presentations shall be thirty (30) days. If during the Review Period, Nestlé notifies Investigator in writing 
that: (i) it desires patent applications to be filed on any inventions disclosed or contained in the disclosures, 
Investigator will defer Publication for a period not to exceed sixty (60) days, to permit Nestlé to file any desired 
patent applications; and (ii) if the Publication contains Confidential Information as defined in Section 14.1 and 
Nestlé requests Investigator in writing to delete such Confidential Information, the Investigator agrees to delete 
such Confidential Information only to the extent such deletion does not preclude the complete and accurate 
presentation and interpretation of the Study results. Upon request by Nestlé, Investigator shall include an 
appropriate reference to Nestlé and the Study. 
14.4 Registry Termination or Completion 
The Sponsor reserves the right to terminate the registry at any time. Both the Sponsor and HealthiVibe have the 
right to terminate the Investigator’s participation in the study according to the registry study agreements. 

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15. REFERENCES 
Ammann, R. W., Buehler, H., Muench, R., Freiburghaus, A. W., & Siegenthaler, W. (1987). Differences in the 
natural history of idiopathic (nonalcoholic) and alcoholic chronic pancreatitis. A comparative long-term study 
of 287 patients. Pancreas, 2(4), 368–377. 
Antonini, F., Crippa, S., Falconi, M., Macarri, G., & Pezzilli, R. (2018). Pancreatic enzyme replacement therapy 
after gastric resection: an update. Digestive and Liver Disease, 50(1), 1–5. 
Bharmal, M., Payne, K., Atkinson, M. J., Desrosiers, M.-P., Morisky, D. E., & Gemmen, E. (2009). Validation of an 
abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) among patients on 
antihypertensive medications. Health and Quality of Life Outcomes, 7(1), 1–10. 
de la Iglesia-Garcia, D., Vallejo-Senra, N., Iglesias-Garcia, J., López-López, A., Nieto, L., & Domínguez-Muñoz, J. 
E. (2018). Increased risk of mortality associated with pancreatic exocrine insufficiency in patients with chronic 
pancreatitis. Journal of Clinical Gastroenterology, 52(8), e63–e72. 
Forsmark, C. E. (2013). Management of Chronic Pancreatitis. Gastroenterology, 144(6), 1282-1291.e3. 
https://doi.org/10.1053/j.gastro.2013.02.008 
Forsmark, C, Feldman, M., Friedman, L. S., & Brandt, L. J. (2002). Sleisenger and Fordtran’s gastrointestinal and 
liver disease. Philadelphia: WB Saunders Co. 
Forsmark, Chris, Tang, G., Xu, H., & Yadav, D. (2017a). Oral Pancreatic Enzyme Replacement Therapy (PERT) in 
Chronic Pancreatitis (CP) is Infrequent and Often Suboptimal: A National Level Analysis. Gastroenterology, 
152(5), S677. https://doi.org/10.1016/S0016-5085(17)32382-X 
Forsmark, Chris, Tang, G., Xu, H., & Yadav, D. (2017b). Oral Pancreatic Enzyme Replacement Therapy (PERT) in 
Chronic Pancreatitis (CP) is Infrequent and Often Suboptimal: A National Level Analysis. Gastroenterology, 
152(5), S677. https://doi.org/10.1016/S0016-5085(17)32382-X 
Goess, R., Ceyhan, G. O., & Friess, H. (2016). Pancreatic exocrine insufficiency after pancreatic surgery. 
Panminerva Medica, 58(2), 151. 
Hollemans, R. A., Hallensleben, N. D. L., Mager, D. J., Kelder, J. C., Besselink, M. G., Bruno, M. J., Verdonk, R. 
C., van Santvoort, H. C., & Group, D. P. S. (2018). Pancreatic exocrine insufficiency following acute 
pancreatitis: Systematic review and study level meta-analysis. Pancreatology, 18(3), 253–262. 
Huddy, J. R., Macharg, F. M. S., Lawn, A. M., & Preston, S. R. (2013). Exocrine pancreatic insufficiency following 
esophagectomy. Diseases of the Esophagus, 26(6), 594–597. 
Imrie, C. W., Connett, G., Hall, R. I., & Charnley, R. M. (2010). Enzyme supplementation in cystic fibrosis, chronic 
pancreatitis, pancreatic and periampullary cancer. Alimentary Pharmacology & Therapeutics, 32, 1–25. 
Johnson, C. D., Arbuckle, R., Bonner, N., Connett, G., Dominguez-Munoz, E., Levy, P., Staab, D., Williamson, N., 
& Lerch, M. M. (2017). Qualitative assessment of the symptoms and impact of pancreatic exocrine 
insufficiency (PEI) to inform the development of a patient-reported outcome (PRO) instrument. The Patient-
Patient-Centered Outcomes Research, 10(5), 615–628. 
Keller, J., & Layer, P. (2005). Human pancreatic exocrine response to nutrients in health and disease. Gut, 54(suppl 
6), 1–28. 
Luaces-Regueira, M., Iglesias-García, J., Lindkvist, B., Castiñeira-Alvariño, M., Nieto-García, L., Lariño-Noia, J., & 
Domínguez-Muñoz, J. E. (2014). Smoking as a risk factor for complications in chronic pancreatitis. Pancreas, 
43(2), 275–280. 
Maconi, G., Dominici, R., Molteni, M., Ardizzone, S., Bosani, M., Ferrara, E., Gallus, S., Panteghini, M., & Porro, 
G. B. (2008). Prevalence of pancreatic insufficiency in inflammatory bowel diseases. Assessment by fecal 
elastase-1. Digestive Diseases and Sciences, 53(1), 262–270. 
Mohapatra, S., Majumder, S., Smyrk, T. C., Zhang, L., Matveyenko, A., Kudva, Y. C., & Chari, S. T. (2016). Diabetes 
mellitus is associated with an exocrine pancreatopathy: conclusions from a review of literature. Pancreas, 

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45(8), 1104. 
Okano, K., Murakami, Y., Nakagawa, N., Uemura, K., Sudo, T., Hashimoto, Y., Kondo, N., Takahashi, S., & Sueda, 
T. (2016). Remnant pancreatic parenchymal volume predicts postoperative pancreatic exocrine insufficiency 
after pancreatectomy. Surgery, 159(3), 885–892. 
Perbtani, Y., & Forsmark, C. E. (2019). Update on the diagnosis and management of exocrine pancreatic 
insufficiency. F1000Research, 8(3), 1991. https://doi.org/10.12688/f1000research.20779.1 
Sabater, L., Ausania, F., Bakker, O. J., Boadas, J., Domínguez-Muñoz, J. E., Falconi, M., Fernández-Cruz, L., 
Frulloni, L., González-Sánchez, V., & Lariño-Noia, J. (2016). Evidence-based guidelines for the management 
of exocrine pancreatic insufficiency after pancreatic surgery. Annals of Surgery, 264(6), 949–958. 
Shandro, B. M., Nagarajah, R., & Poullis, A. (2018). Challenges in the management of pancreatic exocrine 
insufficiency. World Journal of Gastrointestinal Pharmacology and Therapeutics, 9(5), 39. 
Sikkens, E. C. M., Cahen, D. L., de Wit, J., Looman, C. W. N., van Eijck, C., & Bruno, M. J. (2014). A prospective 
assessment of the natural course of the exocrine pancreatic function in patients with a pancreatic head tumor. 
Journal of Clinical Gastroenterology, 48(5), e43–e46. 
Sikkens, E. C. M., Cahen, D. L., van Eijck, C., Kuipers, E. J., & Bruno, M. J. (2012a). Patients with exocrine 
insufficiency due to chronic pancreatitis are undertreated: a Dutch national survey. Pancreatology, 12(1), 71–
73. 
Sikkens, E. C. M., Cahen, D. L., van Eijck, C., Kuipers, E. J., & Bruno, M. J. (2012b). The daily practice of pancreatic 
enzyme replacement therapy after pancreatic surgery: a northern European survey. Journal of Gastrointestinal 
Surgery, 16(8), 1487–1492. 
Singh, V. K., & Schwarzenberg, S. J. (2017). Pancreatic insufficiency in cystic fibrosis. Journal of Cystic Fibrosis, 
16, S70–S78. 
Straatman, J., Wiegel, J., Van Der Wielen, N., Jansma, E. P., Cuesta, M. A., & Van Der Peet, D. L. (2017). Systematic 
review of exocrine pancreatic insufficiency after gastrectomy for cancer. Digestive Surgery, 34(5), 364–370. 
Whitcomb, D. C. (2019). Pancreatitis: TIGAR-O version 2 risk/etiology checklist with topic reviews, updates, and 
use primers. Clinical and Translational Gastroenterology, 10(6). 
 
 
 

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16. Appendices 
Appendix A – Eligible PERT 
Drug Type 
Non-Proprietary Name 
Brand Name 
Pancreatic Enzyme Replacement Therapy 
Pancrelipase 
ZenpepÒ 
 
Pancrelipase 
CreonÒ 
 
Pancrelipase 
PancreazeÒ 
 
Pancrelipase  
PertzyeÒ 
 
Pancrelipase 
ViokaseÒ 
 
 
 
 
 

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Appendix B – Study Participant Exit Form 
What is the reason for the study participant’s exit? 
£ Study participant withdrew from the study 
£ Study participant was terminated by the Investigator 
£ Please specify reason: [ADD FREE TEXT] 
£ Study participant is lost to follow up 
£ Study participant transferred care to another gastroenterologist 
£ Data collection period of the registry has ended