Diagnosing Pancreatic-Based Malabsorption in Patients With Chronic Pancreatitis
Phase: PHASE2
Conditions: Chronic Pancreatitis
Sponsor: Children's Hospital of Philadelphia

 
  
 
 
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Diagnosing Pancreatic-Based Malabsorption in 
Patients with Chronic Pancreatitis 
 
AbbVie Inc. 
May 5, 2017 
 
Lead Investigator/ Study Physician 
Virginia A. Stallings, MD 
3535 Market Street Rm 1558 
Philadelphia, PA 19104 
Phone 215-590-1664 
email: stallingsv@email.chop.edu  
 
 
Principal Investigator  
Babette Zemel, PhD 
3535 Market Street Rm 1558 
Philadelphia, PA 19104 
Phone 215-590-1669 
email: zemel@email.chop.edu  
 
  
 
 
 
 
 
 
 
 
 

 
  
 
 
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TABLE OF CONTENTS 
Table of Contents............................................................................................................ ii 
Abbreviations and Definitions of Terms ......................................................................... iii 
Abstract ......................................................................................................................... iv 
Protocol Synopsis ........................................................................................................... 1 
1 
BACKGROUND INFORMATION AND RATIONALE ................................................................................... 6 
2 
STUDY OBJECTIVES ................................................................................................................................ 9 
3 
INVESTIGATIONAL PLAN ...................................................................................................................... 10 
4 
STUDY PROCEDURES ........................................................................................................................... 12 
5 
STUDY EVALUATIONS AND MEASUREMENTS ...................................................................................... 19 
6 
STATISTICAL CONSIDERATIONS ........................................................................................................... 23 
7 
STUDY MEDICATION ............................................................................................................................ 27 
8 
SAFETY MANAGEMENT…………………………………………………………………………………………………………………….28 
9 
STUDY ADMINISTRATION  ................................................................................................................... 30 
10 
PUBLICATION ...................................................................................................................................... 34 
11 
REFERENCES ........................................................................................................................................ 35 
 
 
 
 

 
  
 
 
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ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
 
Adverse event 
BC 
 
Bomb calorimetry 
BMI 
 
Body mass index 
CF 
 
Cystic fibrosis 
CFA 
 
Coefficient of fat absorption 
CP 
 
Chronic pancreatitis 
Creon36TM 
 
Creon (pancrelipase) Delayed-Release Capsules: 36,000 USP 
units of lipase 
CTRC 
 
Clinical Translational Research Center 
DXA 
 
Dual energy x-ray absorptiometry 
FFM 
 
Fat free mass 
FM 
 
Fat mass 
HA 
 
Heptadecanoin 
MBT 
 
Malabsorption blood test 
NDS  
 
Nutrition Data System 
PA 
 
Pentadecanoic acid 
PHI  
 
Personal health information 
PIVKA  
 
Proteins induced by vitamin K antagonism or absence 
PROMIS 
 
Patient reported outcomes 
QOL 
 
Quality of life 
SAE  
 
Serious adverse event 
THA 
 
Triheptadecanoic acid 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
  
 
 
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ABSTRACT 
Context: Reduced exocrine pancreatic function or pancreatic insufficiency (RPF/PI) contributes to 
poor clinical outcome in a number of diseases and conditions.  The incidence, mechanism and 
substantial adverse clinical outcomes of PI are well known in patients with cystic fibrosis (CF), and 
the life sustaining role of pancreatic enzyme medication in CF care is well established1-3.  Much less 
is known about the incidence and impact of RPF/PI in patients with chronic pancreatitis (CP).  
Reliable non-invasive screening or diagnostic tests with acceptable patient burden are not available 
for RPF/PI. 
Objectives: The objective of this study is to evaluate the malabsorption blood test (MBT), stool 
coefficient of fat absorption (CFA) and stool bomb calorimetry (BC) methods as potential screening 
or diagnostic tests for RPF/PI. A further objective is to determine the test responses before and 
after pancreatic enzyme medication administration (Creon36TM) in the patients with CP. We will 
also explore the association of specific genotypes with fat malabsorption in the context of CP. 
Study Design:  This is a cohort study of subjects with CP who will be evaluated before and after 
pancreatic enzyme medication (Creon36TM) administration.  A cohort of healthy subjects will serve 
as a comparison group and will be evaluated only once. 
Setting/Participants: This outpatient study will be conducted at CHOP. Twenty four subjects with CP 
and evidence of being at-risk for malabsorption, age 30-75 years, and 24 healthy comparisons, age 
30-70 years, with no known chronic disease that would affect dietary or fat absorption will be 
enrolled. 
Study Interventions and Measures:  Subjects with CP will receive Creon36TM, a pancreatic enzyme 
medication, and fat and energy absorption will be evaluated using three methods: MBT, CFA, and 
BC before and after administration of Creon36TM .  Many patients with CP are at risk for RPF/PI yet 
they rarely undergo diagnostic testing.  Pancreatic enzyme medication will likely improve clinical 
outcomes and quality of life in some of those with RPF/PI. A cohort of healthy volunteers will be 
evaluated with the three methods to provide essential comparison data to optimize the 
understanding and interpretation of the findings from the three methods and the RPF/PI cohort 
with CP. There will be no intervention for the healthy cohort.  

 
  
 
 
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PROTOCOL SYNOPSIS 
Study Title 
Diagnosing Pancreatic-Based Malabsorption in Patients with Chronic 
Pancreatitis 
Funder 
AbbVie Inc.  
Clinical Phase 
Phase II – This is an open-label intervention therapeutic exploratory study 
Study Rationale 
Reduced exocrine pancreatic function or pancreatic insufficiency (RPF/PI) 
contributes to poor clinical outcome in a number of diseases and conditions.  
The incidence, mechanism and substantial adverse clinical outcomes of PI are 
well known in patients with cystic fibrosis (CF), and the life sustaining role of 
pancreatic enzyme medication in CF care is well established1-3.  Much less is 
known about the incidence and impact of RPF/PI in patients with chronic 
pancreatitis (CP).  Reliable non-invasive screening or diagnostic tests with 
acceptable patient burden are not available for RPF/PI.  We propose a study to 
evaluate the malabsorption blood test (MBT), stool coefficient of fat absorption 
(CFA) and stool bomb calorimetry (BC) methods as potential screening or 
diagnostic tests for RPF/PI. In subjects with CP, we also propose to administer 
pancreatic enzyme medication (Creon36TM) to determine the test responses 
before and after pancreatic enzyme medication administration in these 
patients.  Many patients with CP are at risk for RPF/PI yet they rarely undergo 
diagnostic testing. Pancreatic enzyme medication will likely improve clinical 
outcomes and quality of life in some of those with RPF/PI. A cohort of healthy 
volunteers will be evaluated with the three methods to provide essential 
comparison data to optimize the understanding and interpretation of the 
findings from the three methods and the RPF/PI cohort with CP. 
Study Objective(s) 
Primary  
Utilizing the MBT, CFA and BC methods to identify RPF/PI in subjects with CP, 
our primary hypotheses are:  
H1: Subjects diagnosed with CP and not receiving pancreatic enzyme 
medication will have RPF/PI as indicated by the reduced MBT, CFA and BC fat 
and energy absorption pattern compared to healthy participants.   
H2: Subjects with CP with reduced RPF/PI by the MBT, CFA and BC fat and 
energy absorption pattern will have improved fat absorption after pancreatic 
enzyme medication (Creon36TM) as indicated by the MBT, CFA and BC increased 
fat and energy absorption pattern.   
Secondary 
The secondary objective of this proposal is to utilize these data to optimize the 
MBT design and application by reducing the time and blood samples required.  
H3:  The MBT will be optimized to identify RPF/PI with 3-4 blood samples (vs 9 
current samples) over 4-5-hours (vs current 8-hours).  

 
  
 
 
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We will explore the utility of the MBT compared to the CFA and BC (both 
require the burdensome 72-hour total stool and dietary intake collection) in 
identifying differences in fat absorption between subjects with CP and healthy 
comparisons and within the CP cohort, with and without pancreatic enzyme 
medication. We will also collect saliva for genetic testing, in order explore the 
association of specific genotypes with fat malabsorption in the context of CP. 
Test Article 
Creon36TM, a pancreatic enzyme preparation 
Study Design 
 
We propose to characterize pancreatic-based fat malabsorption in subjects 
with chronic pancreatitis (CP) compared to a healthy comparison group. 
Furthermore, we propose a longitudinal study design to assess pancreatic-
based fat absorption before and after pancreatic enzyme medication in 
subjects with CP.  

 
  
 
 
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Inclusion and 
Exclusion: 
INCLUSION CRITERIA 
Chronic Pancreatitis Cohort 
 
Chronic pancreatitis diagnosis by gastroenterologist.  Participants with CP 
will be characterized based on the TIGAR-O (toxic, genetic, autoimmune, 
recurrent, obstructive) etiology system, on pancreatic morphology 
(Cambridge criteria) when available, and on physiological state (exocrine 
and endocrine function) as recommended by the recent American 
Pancreatic Association Practice Guidelines4.   
   Age 30-75 years old 
   Evidence of at-risk for malabsorption including: 1) history of use of and 
response to pancreatic enzyme medication; 2) history of unintentional 
weight loss; 3) history of increased stools per week or fatty stools; and/or 
4) other clinical signs or symptoms suggestive of fat malabsorption  
 
In usual state of health for past two weeks including no change in 
medications 
 
Able to consume a moderate fat diet for stool evaluations 
 
Able to participate in the study for about four weeks with two study visits 
Healthy Cohort 
  Age 30-70 years old 
 
No known chronic disease that would affect dietary intake or fat absorption 
 
In usual state of health for past two weeks, with stable medications, diet 
and weight 
 
BMI from 14-35 
 
Able to consume a moderate fat diet for stool evaluations 
 
Able to participate in the study for about one week with one study visit 
EXCLUSION CRITERIA 
Chronic Pancreatitis Cohort 
 
Evidence of normal fat absorption in medical record 
 
Medications that alter fat absorption (i.e. orlistat, other weight loss 
medications, ursodeoxycholic acid) 
 
Allergy to pork products 
 
History of intestinal blockage or fibrosing colonopathy 
 
 Current diagnosis of gout and treatment with allopurinol medical therapy   
Pregnancy or breast feeding 
Healthy Cohort 
 
Evidence of fat malabsorption 
 
Medications that alter fat absorption (i.e. orlistat, other weight loss 
medications, ursodeoxycholic acid) 
 
Pregnancy or breast feeding 
Number Of Subjects  24 subjects with CP 
24 healthy subjects  

 
  
 
 
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Study Location 
All study visits will occur at outpatient research offices at the Clinical and 
Translational Research Center of the Children’s Hospital of Philadelphia (CHOP), 
a pediatric health care center. 
Study Duration 
CP subject participation will last about four weeks 
Healthy subject participation will last about one week  
Study Phases  
Screening: screening for eligibility and obtaining consent  
Visit 1: First study visit at CHOP for CP (pancreatic enzyme medication -naive) 
and Healthy subjects 
 Visit 2: One to four weeks after end of stool collection for first visit, a follow-up 
visit at CHOP for CP subjects only after three-day pancreatic enzyme 
medication treatment 
Efficacy Evaluations The efficacy of pancreatic enzyme medication administration (Creon36TM) will 
be evaluated in subjects with CP using MBT, CFA% and BC outcomes 
Pharmacokinetic 
Evaluations 
N/A 
Safety Evaluations 
Safety will be monitored by adverse events reporting. The frequencies of AEs 
by type, body system, severity and relationship to study supplement will be 
summarized. SAEs (if any) will be described in detail. 
Statistical And 
Analytic Plan 
The goal of the primary aims is to 1) describe pancreatic-based fat 
malabsorption in subjects with CP using MBT, SFA% and BC outcomes 
compared to healthy subjects, and 2) compare these outcomes before and 
after pancreatic enzyme medication administration in subjects with chronic 
pancreatitis.  Descriptive statistics for MBT, CFA% and BC outcomes (mean, 
standard deviation, median, range, 95% CI) will be calculated for the CP cohort 
and for the healthy comparison group, and differences between CP and healthy 
groups assessed with unpaired t tests.  For the MBT outcomes, a moment-
based pharmacokinetic (PK) analysis will be performed based on non-
compartmental methodology using WinNonLin version 9.1 (Pharsight, Cary, 
NC). Baseline (C0) and maximum (Cmax) plasma concentrations are calculated, 
and area under the curve from time zero to eight hours (AUC) is calculated 
using the linear trapezoid method. PK parameters can then be compared 
between treatment groups using a paired t-test or Wilcoxon signed rank test as 
appropriate. Alternately, population PK analyses for repeated-measures 
endpoints can be conducted via nonlinear mixed-effects modeling. Descriptive 
statistics for MBT, CFA% and BC outcomes (mean, standard deviation, median, 
range, 95% CI) will also be calculated for the CP cohort with and without 
pancreatic enzyme medication administration, and the significance of changes 
over time assessed with paired t tests. A mixed effects modeling approach will 
be employed to examine the correlation of subject characteristics (age, BMI, 
sex, disease status, etc.) to PA and HA exposure metrics derived from the non-
compartmental analysis to assess change over time in MBT response to 
pancreatic enzyme medication administration in subjects with CP. 

 
  
 
 
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Pharmacokinetic modelling will be employed to identify the three to four blood 
samples over the first four to five hours of the MBT that provide the most 
informative and most reproducible estimate of the full 8-hour MBT (nine blood 
samples) in the CP and healthy cohorts. The goal is a shorter sampling scheme 
for the MBT to optimize its use as a clinical diagnostic test.  In exploratory 
analyses, we will compare the methods for detection of fat malabsorption as 
measured by CFA% and BC with fat absorption as measured by MBT for the 
subjects with CP compared to healthy individuals and also within the CP cohort 
before and after pancreatic enzyme medication use. A correlation analysis will 
be conducted to evaluate the performance of the MBT relative to that of the 
CFA%. HA and PA Cmax, AUC, and HA/PA ratios will be plotted against CFA% or BC 
caloric loss to explore the relationship between the two tests. Any relationships 
observed in the plots will be further explored using correlation analysis and 
appropriate regression analysis as dictated by the observations. If a reasonable 
model can be developed to describe the response of MBT, CFA% and BC 
response to pancreatic enzyme medication treatment within the CP cohort, 
additional simulation studies will be performed to further examine the 
performance characteristics of both tests. 
MONITORING PLAN 
The Principal Investigator (PI) (Dr. Zemel) is ultimately responsible for 
monitoring data integrity and patient safety and for overall study oversight. The 
study will be monitored weekly by the PI and Lead Investigator (LI)/ Study 
Physician (Dr. Stallings). The study protocol will be carried out in accordance 
with OHRP guidelines and requirements. SAEs that are unanticipated, serious, 
and possibly related to the study will be managed by the PI and LI/ Study 
Physician in consultation with the participant’s adult gastroenterology 
physician team (Dr. Chandrasekhara (Perelman Center for Advanced 
Medicine/HUP, [Penn Medicine/HUP]) or Dr. Rajala (Penn Medicine/ 
Philadelphia Veterans Affairs Medical Center [Penn Medicine/VA Hospital]) 
who will be immediately notified and will assume acute care management. Dr. 
Stallings will also consult with Dr. Mamula (CHOP/GI) who will be notified if an 
unexpected acute event occurs during a study visit at CHOP. In the case of AEs 
and SAEs arising in healthy subjects, the event will be managed by the PI and 
Dr. Stallings (the LI/ Study Physician) in consultation with the primary care 
physician identified by the participant upon enrollment in the study, who will 
be immediately notified. SAEs will also be reported to the study sponsor, IRB, 
CTRC, and all members of the research team in accordance with requirements. 
Anticipated SAEs or those unrelated to the study will be reported to the same 
individuals/entities in accordance with requirements. There will be ongoing 
collection of data on adverse events and compliance to the treatment protocol 
throughout the study by research staff and which will be reviewed weekly by 
the PI and the LI/ Study Physician (Dr. Stallings).    
 
 
 

 
  
 
 
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SCHEDULE OF STUDY PROCEDURES & STUDY TIMELINE 
Table 1 
Cohort with CP 
Comparison 
Group 
Assessment 
Visit 1  
Without 
Creon36TM 
Visit 2 
With 
Creon36TM 
Visit 1 
Study Intervention: Administration of Creon36TM 
 
√ 
 
Primary outcome 
 
 
 
   Malabsorption Blood Test (MBT) (PA, HA, HA/PA   
     absorption, pharmacokinetics) 
√ 
√ 
√ 
Secondary Outcomes 
 
 
 
   72 hour Stool Fat: coefficient of fat absorption (CFA) 
√ 
√ 
√ 
   Fecal Bomb Calorimetry (BC) 
√ 
√ 
√ 
   Fecal Elastase 1 
√ 
 
 
   Serum Fat Soluble Vitamins (A,D,E,K), Pre-albumin  
√ 
√ 
√ 
   Fatty Acid panel 
√ 
√ 
 
   Serum Zinc and Selenium  
√ 
√ 
√ 
Genetics 
 
 
 
   DNA Sequencing (PRSS1, CTRC, CFTR, SPINK1) and others 
√ 
 
 
Diet 
 
 
 
   3-Day Weighed Food Record 
√ 
√ 
√ 
Safety 
 
 
 
   Serum Comprehensive Metabolic Panel (CMP) 
√ 
√ 
 
   Complete Blood Count (CBC) w/ Differential 
√ 
√ 
 
   Adverse Event Monitoring 
√ 
√ 
√ 
Other 
 
 
 
   Anthropometry: Height, Weight, Skinfolds, Circumferences 
√ 
√ 
√ 
   Whole body DXA: body composition 
√ 
 
 
   Home Environment Questionnaire 
√ 
  
√ 
   Health History and Medications  
√ 
 
√ 
   Quality of Life  (MOS SF-36) and PROMIS survey 
√ 
 
√ 
 
Table 2. Study Timeline 
 
 
1 BACKGROUND INFORMATION AND RATIONALE 
1.1 
Introduction 
Reduced exocrine pancreatic function or pancreatic insufficiency (RPF/PI) contributes to poor 
clinical outcome in a number of diseases and conditions.  The incidence, mechanism and substantial 
 
Month of study
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15
16 Total
Start-up
X
X
X
Healthy Controls
Healthy Controls
Baseline
 
2
3
3
3
3
3
3
2
2
24
Baseline
CP group
 
CP
 
Baseline
 
2
3
3
2
2
2
2
3
3
2
24
Baseline
Follow Up
 
2
3
3
2
2
2
2
3
3
2
24
Follow Up
 
 
 
Visit Total
 
6
9
9
7
7
7
7
8
8
4
 
 
72
Total 
Analysis
 
 
 
 
 
 
X
X
X
X
X
X
Closeout
X
X
 
19
5
19
5
60
12
Year 1  (2016)
Year 2  (2017)
Year 1
Year 2
22
2

 
  
 
 
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adverse clinical outcomes of PI are well known in patients with cystic fibrosis (CF), and the life 
sustaining role of pancreatic enzyme medication in CF care is well established1-3.  Much less is 
known about the incidence and impact of RPF/PI in patients with chronic pancreatitis (CP).  Reliable 
non-invasive screening or diagnostic tests with acceptable patient burden are not available for 
RPF/PI.  We propose a study to evaluate the malabsorption blood test (MBT), stool coefficient of fat 
absorption (CFA) and stool bomb calorimetry (BC) methods as potential screening or diagnostic 
tests for RPF/PI and to determine the test responses to pancreatic enzyme medication compared to 
responses with pancreatic enzyme medication-naive status in patients with CP.  Many patients with 
CP are at risk for RPF/PI yet they rarely undergo diagnostic testing.  Pancreatic enzyme medication 
will likely improve clinical outcomes and quality of life in those with RPF/PI. A cohort of healthy 
volunteers will be evaluated with the three methods to provide essential comparison data to 
optimize the understanding and interpretation of the findings from the three methods and the 
RPF/PI cohort with CP.  All subjects will be seen at the Children’s Hospital of Philadelphia’s 
outpatient Clinical Translational Research Center.  
1.2 
Name and Description of Investigational Product or Intervention 
CREON (pancrelipase) Delayed-Release Capsules 36,000 USP units of lipase (Creon36TM), a 
pancreatic enzyme preparation, is a drug that requires prescription for use.  It is approved for use, 
including the current indication and dosage, by the FDA.   
1.3 
Findings from Non-Clinical and Clinical Studies 
N/A – This is an FDA approved drug 
1.4 
Selection of Drugs and Dosages 
Subjects with CP will take Creon36TM for nine days, and the daily dose selected is 72,000 lipase units 
per meal (two capsules) and 36,000 units per snack (one capsule), with each Creon capsule 
containing 36,000 lipase units. Subjects will take Creon36TM for three days prior to Visit 2, the day 
of Visit 2 and then for five days after the visit until they have completed stool collections.  The 
pancreatic enzyme medication dose range for adults with CP is not well standardized.  The dose 
chosen for these short term studies are in the higher range recommended for initial treatment5, 6.    
1.5 
Relevant Literature 
CP is a disease of chronic pancreatic inflammation that is progressive with scarring and irreversible 
tissue damage resulting in loss of endocrine and exocrine function.  Patients often have chronic 
abdominal and back pain, nausea and vomiting, weight loss, steatorrhea and increased number of 
bowel movements as the disease progresses.  Diabetes may occur later in the course. Symptom 
severity is described as mild, moderate or severe and can change over time in individuals.  
Incidence is estimated to be from about 4.4 to 11.9 per 100,000 people per year7-14 and is more 
common in men.  The prevalence of CP is estimated to be from about 37 to 42 per 100,000 people9, 
11.  The approach to diagnostic testing and clinical care is not standardized, in part because there is 
no standard approach to diagnosis, diagnostic criteria vary, and many diagnostic approaches are 
costly and invasive4.  Related to this protocol, there is little information on nutrition status and 
disease outcomes, and no clinical standards for screening or treatment of nutrition-related 
complications of CP.  This proposal focuses on the specific issue of progressive loss of exocrine 
pancreatic function to the point of clinically meaningful malabsorption of dietary fat, and 

 
  
 
 
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concomitant loss of calories, fat soluble vitamins, minerals, and linoleic acid which are all essential 
nutrients for adult health.  There is a large body of literature related to the diagnosis and treatment 
of CP, including some reports related to nutritional risks of malabsorption with CP. For example 
there have been a number of clinical trials using CFA to describe fat malabsorption in subjects with 
CP and confirmed pancreatic insufficiency and have demonstrated significant improvement in fat 
absorption from before to after pancreatic enzyme medication administration15-21. Ramesh et al15 
found an increase in CFA% from 66.7±14.0 before pancreatic enzyme medication to 88.9±5.2% 
after pancreatic enzyme medication (a change of 22.7±12.2%) in Indian adults with CP.  Also in 
adults from India participating in a placebo-controlled trial, Thorat et al16 saw CFA% increase from 
66.5±14.1 to 86.1±7.5% in those taking pancreatic enzyme medication compared to an increase 
from 67.0±14.0 to 72.9±11.5% for placebo, a treatment  effect of 13.7% (95% CI: 9.1, 18.2) after 
one week of pancreatic enzyme medication. Others have detected similar improvements in 
absorption in pancreatic enzyme medication trials in people with CP living in the US and in Eastern 
Europe17, 18.  Additional selected references from the past four years are noted here4, 22-43. 
Gene-environment interactions play a major role for the risk, development, and progression of 
pancreatic disease including both acute and chronic pancreatitis.44  Major pancreatic risk factor 
genes have been identified (PRSS1, CTRC, CTFR, SPINK1),44-47 and others have been implicated 
(CaSR, CEL, CPA1, PRSS2-3, SBDS, UBR1 and CLDN2).44, 45 The association of specific genotypes with 
fat malabsorption in the context of CP remains to be fully explored.   
Patients with CP are rarely evaluated for RPF/PI because there are no non-invasive, clinically 
available, affordable, acceptable and reliable diagnostic tests.  Historically, the CFA is considered 
the gold standard for RPF/PI diagnosis.  However, CFA is almost never used in clinical care in large 
part due to patient burden related to 72-hr stool and diet collections.  The CFA method requires the 
patient consume a moderate fat diet, accurately document all food intake and collect all stool for 
72-hours.  A dietitian analyzes the record using software that calculates the daily and three day 
average fat intake (g/day).  The multiple stool sample containers are shipped to one of a few 
laboratories that homogenizes and measures stool fat content (g/day).   CFA% is calculated by the 
clinician once both diet and stool results are available. Lastly, reference ranges for healthy 
individuals evaluated with modern techniques for stool and dietary collections, and fat extraction 
and measurement are unavailable. 
The MBT uses the general approach of the commonly utilized glucose tolerance test, with 
consumption of a beverage containing the nutrient of interest (fatty acid, rather than glucose) 
followed by  the determination of the timing and amount of the fatty acids in blood samples.  The 
MBT consists of administering two odd-chain length fatty acids: pentadecanoic acid (PA), a free 
fatty acid that does not require pancreatic lipase for absorption; and triheptadecanoic acid (THA), a 
triglyceride that requires pancreatic lipase for hydrolysis to three heptadecanoic (HA) fatty acids. 
These two fatty acids were selected for the MBT for the following reasons: 1) they are found in 
small amounts only in dairy foods; 2) the vast majority of individuals have very low serum 
concentrations of PA and HA; 3) they are safe even in larger doses than typically found in the diet; 
and 4) they are easily identified in the serum by well-established laboratory methods and 
absorption pharmacokinetics that can be readily described.  Following the ingestion of the MBT 
fatty acids, the pharmacokinetics of the fat absorption for both PA and HA is assessed over an 8-
hour period and the relative absorption of HA/PA is determined. A moment-based pharmacokinetic 
(PK) analysis is performed based on non-compartmental methodology using WinNonLin version 9.1 
(Pharsight, Cary, NC). Baseline (C0) and maximum (Cmax) plasma concentrations are calculated, and 
area under the curve from time zero to eight hours (AUC) is calculated using the linear trapezoid 

 
  
 
 
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method. PK parameters are then compared between treatment groups using a paired t-test or 
Wilcoxon signed rank test as appropriate. To describe HA exposure relative to that of PA, the ratio 
of the HA to PA Cmax (Cmax HA/PA) and AUC (AUC HA/PA) is calculated for each subject after molar 
transformation and dose-normalization of exposure metrics.  Also, population PK analyses for 
repeated-measures endpoints is  conducted via nonlinear mixed-effects modeling with a qualified 
installation of the nonlinear mixed-effects modeling (NONMEM) software, Version VII, Level 2.0 
(ICON Development Solutions, Hanover, MD)48. Using this method, population PK modeling is 
conducted by simultaneously fitting structural PK models to both PA and HA concentrations. 
We have shown that the MBT detects pancreatic-based fat malabsorption in healthy subjects using 
a lipase inhibitor medication (Orlistat)49 and in subjects with CF and PI compared to healthy 
individuals and while on or off pancreatic enzyme medication treatment49, 50.  Furthermore, the 
MBT can detect changes in fat absorption in subjects with CF and PI based upon the time of 
pancreatic enzyme administration related to food ingestion50. 
In this proposed study, we will use the MBT, CFA and BC methods to detect fat malabsorption in 
subjects with CP compared to healthy subjects, and the utility of the tests in detecting changes in 
fat absorption before and after pancreatic enzyme medication. The CFA is the “gold standard” for 
documenting fat malabsorption in research and in the regulatory environment.  Currently CFA is the 
only method accepted by the FDA for evaluation of treatment of RPF/PI.  Furthermore, a shorter 
sampling scheme for the MBT will be explored to optimize its potential use in clinical research.  
With these data from n = 48 participants  including healthy comparisons and participants with 
varying severity of RPF/PI, pharmacokinetic methods will be employed to explore the possibility to 
reduce the time required and number of blood samples needed for the MBT to provide reliable 
classification of RPF/PI vs non-RPF/PI. 
It is very likely that some patients with CP have RPF/PI and currently are not diagnosed or treated 
with pancreatic enzyme medication. There is no well accepted (non-invasive, acceptable patient 
burden, reasonably informative, and cost effective) approach to support clinical research or clinical 
care, nor are there established general clinical indicators or nutritional status risk factors to guide 
care of patients. Clinicians may avoid serious consideration of the possibility of exocrine pancreatic 
deterioration or just empirically try pancreatic enzyme medication. Improved care of patients with 
CP will be supported by additional well designed clinical research to evaluate approaches to 
diagnosis and establish risk factor profiles. The proposed study will contribute evidence to support 
future patient care in CP and physician education about RPF/PI and malnutrition in this group. 
1.6 Compliance Statement 
This study will be conducted in full accordance of all applicable Children’s Hospital of Philadelphia 
Research Policies and Procedures and all applicable Federal and state laws and regulations 
including 45 CFR 46.  All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain consent, and 
will report unanticipated problems involving risks to subjects or others in accordance with The 
Children’s Hospital of Philadelphia IRB Policies and Procedures and all federal requirements. 
Collection, recording, and reporting of data will be accurate and will ensure the privacy, health, and 
welfare of research subjects during and after the study. 

 
  
 
 
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2 STUDY OBJECTIVES 
2.1 
Primary Aims 
2.1.1.   Our first primary aim is to compare fat and energy absorption from the diet in subjects with 
CP and healthy subjects utilizing the MBT, CFA and BC methods to characterize fat and energy 
absorption patterns.  
2.1.2.   Our second primary aim is to determine if, in subjects with CP, fat and energy absorption 
will improve after pancreatic enzyme medication utilizing the MBT, CFA and BC methods to 
characterize the fat and energy absorption patterns.   
2.2 
Secondary Aims 
2.2.1. The secondary aim of this proposal is to utilize these data to optimize the MBT design and 
application by reducing the time and blood samples required.  
2.2.2. We will also explore the utility of the MBT compared to the CFA and BC (both require the 
burdensome 72-hour total stool and dietary intake collection) in identifying differences in fat 
absorption between subjects with CP and healthy individuals and within the CP cohort, with and 
without pancreatic enzyme medication.  
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
3.1.1 Screening Phase 
Potential subjects will be screened using the protocol inclusion and exclusion criteria.  Subjects will 
be recruited from regional academic hospitals and gastroenterology, and pancreatology 
subspecialty centers.  Primary recruitment centers will include: 1) University of Pennsylvania 
Medical Center Hospital; 2) Pennsylvania Hospital; 3) Presbyterian Hospital; and 4) Philadelphia 
Veterans Administration Medical Center.  Other likely collaborators and recruitment centers may 
include: 1) GI Centers at the Jefferson Medical Center; 2) Main Line Medical Center (Lankenau and 
Bryn Mawr Hospitals); and 3) other regional centers.  These outside institutions will be involved 
with recruitment of subjects only and will otherwise not be engaged in the research.  We will 
recruit the healthy subjects from the greater Philadelphia region using general adult practices, 
flyers, and recommendations from subjects with CP regarding healthy family and friends interested 
in participating. The CHOP Recruitment Enhancement Core (REC) will be utilized to recruit healthy 
adult subjects. The Recruitment Enhancement Core provides assistance with recruitment plan 
development and may assist in identifying and contacting potential participants using the Clinical 
Recruiting Unit (CRU), the CHOP Recruitment Registry and internal communication resources. Our 
research team anticipates no difficulty in enrolling well-qualified participants with the proposed 
sample size and staff (see Table 2. Study Timeline).  Informed consent will be obtained prior to any 
study related procedures being performed, and this will include the discontinuation of pancreatic 
enzyme medication for those participants who are taking this medication at the time of enrollment 
in the study.  

 
  
 
 
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3.1.2 Study Treatment Phase   
All study visits will occur at outpatient research offices of the Clinical and Translational Research 
Center at The Children’s Hospital of Philadelphia (CHOP), a pediatric health care center. Eligible 
subjects will be enrolled into the study and come to CHOP for the study visits. Refer to Table 1 for 
list of assessments and the study timeline for the pace of recruitment.  
3.1.3    Open-label treatment with Creon36TM 
Subjects with CP only will receive Creon36TM intervention and return to CHOP for Visit 2, about one 
to two weeks after their Visit 1. Refer to Table 1 for list of assessments and the study timeline for 
the visit schedule.  
3.2 
Allocation to Treatment Groups and Blinding 
This is an open-label intervention therapeutic exploratory study, and not a randomized controlled 
trial.     
3.3 
Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
The study duration per subject will be up to four weeks for the subjects with CP.  The study 
duration for healthy subjects will be up to one week. 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at one investigative site in the United States, the Children’s Hospital of 
Philadelphia. Recruitment will occur across regional centers as described above. 
Recruitment will stop when 24 subjects with CP and 24 healthy comparison subjects are enrolled. It 
is expected that 24 subjects in each group will be enrolled to produce 22 evaluable subjects in each 
group.  
3.4 
Study Population 
3.4.1 Inclusion Criteria 
Chronic Pancreatitis Cohort 
 
Chronic pancreatitis diagnosis by gastroenterologist.  Participants with CP will be 
characterized based on the TIGAR-O (toxic, genetic, autoimmune, recurrent, 
obstructive) etiology system, on pancreatic morphology (Cambridge criteria) when 
available, and on physiological state (exocrine and endocrine function) as 
recommended by the recent American Pancreatic Association Practice Guidelines4.   
 
Age 30-75 years old 
 
Evidence of at-risk for malabsorption including: 1) history of use of and response to 
pancreatic enzyme medication; 2) history of unintentional weight loss; 3) history of 
increased stools per week or fatty stools; and/or 4) other clinical signs or symptoms 
suggestive of fat malabsorption  
 
In usual state of health for past two weeks including no change in medications 

 
  
 
 
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 
Able to consume a moderate fat diet for stool evaluations 
 
Able to participate in the study for about four weeks with two study visits 
Healthy Cohort 
 
Age 30-70 years old 
 
No known chronic disease that would affect dietary intake or fat absorption 
 
In usual state of health for past two weeks, with stable medications, diet and 
weight 
 
BMI from 14-35 
 
Able to consume a moderate fat diet for stool evaluations 
 
Able to participate in the study for about one week with one study visit 
 
3.4.2 Exclusion Criteria 
Chronic Pancreatitis Cohort 
 
Evidence of normal fat absorption in medical record 
 
Medications that alter fat absorption (i.e. orlistat, other weight loss medications, 
ursodeoxycholic acid) 
 
Allergy to pork products 
 
History of intestinal blockage or fibrosing colonopathy 
 
 Current diagnosis of gout and treatment with allopurinol medical therapy   
Pregnancy or breast feeding 
Healthy Cohort 
 
Evidence of fat malabsorption 
 
Medications that alter fat absorption (i.e. orlistat, other weight loss medications, 
ursodeoxycholic acid) 
 
Pregnancy or breast feeding 
4 STUDY PROCEDURES 
4.1 
Screening  
Subjects will be screened with support from the clinical sites using the protocol inclusion and 
exclusion criteria. Clinic staff will inform eligible individuals of the existence of this study and ask for 
permission from these individuals to share their contact information with the CHOP study staff. 
Either verbal or in person screening can occur. In the instance of screening over the phone, verbal 
subject permission will be obtained. In the instance of in person screening, study staff will obtain a 
signature from the subject. For both instances, screening consent will occur prior to obtaining any 
information from study subjects.   
All subjects will be enrolled in their usual state of good health defined as no hospitalizations, 
emergency room or unscheduled acute illness clinic visits, and with activity levels and food intake 
considered typical by the subject for two weeks prior to Visit 1.  
Healthy subjects will be identified from the greater Philadelphia region using referrals of friends 
and family of the subjects with CP.  The subjects with CP will first ask for potential healthy subjects’ 

 
  
 
 
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permission to release their contact information to the CHOP study team.  Healthy subjects will also 
be identified using general adult practices, CHOP staff interested in participating in a research 
study, and through the CHOP Recruitment Enhancement Core (REC). The Recruitment 
Enhancement Core provides assistance with recruitment plan development and may assist in 
identifying and contacting potential participants using the Clinical Recruiting Unit (CRU), the CHOP 
Recruitment Registry and internal communication resources. Verbal subject permission will be 
obtained prior to obtaining any health information from these subjects to determine eligibility.      
4.2 
Study Treatment Phase  
Subjects with CP will have two visits in this study.  Visit 1 will be without pancreatic enzyme 
medication and Visit 2 will occur after they receive Creon36TM as their pancreatic enzyme 
medication therapy.   Healthy subjects will have one visit only in this study.  Both Visit 1 and 2 are 
identical with the exception of the several questionnaires (home environment, health history, 
quality of life) and fecal elastase assessment which are only collected once (refer to study 
procedures in Table 1). Collection of the saliva sample for genetic testing will only occur once, 
during Visit 1. 
Visit for Consent and HIPAA Authorization for release of medical record information 
 
Informed Consent will be obtained at a visit to precede Day 1 of protocol before 
any study procedures take place. If subjects are taking pancreatic enzyme 
medication and will need to discontinue medication 3 days prior to Visit 1, the visit 
for informed consent will occur prior to the beginning of any discontinuation of the 
medication. HIPAA Authorization forms from the subjects’ institutions will be 
obtained and will be signed in person or obtained by mail/fax/email.   
 
Instructions in preparation for study procedures will be given in person at this 
consent visit. 
There are two protocols for Visit 1.  The first protocol is for subjects with CP who are naïve to 
pancreatic enzyme medication, that is, they have not received pancreatic enzyme medication prior 
to Visit 1. The second protocol for Visit 1 is for subjects with CP who are currently taking pancreatic 
enzyme medication and will require a pancreatic enzyme medication washout period, that is, they 
will not take pancreatic enzyme medication for three days prior to Visit 1 (a “pancreatic enzyme 
medication washout” period).  Subjects with CP will be prescribed Creon36TM as their pancreatic 
enzyme medication therapy and will receive this therapy for Visit 2.  Visit 2 will be the same for all 
subjects with CP.   
Healthy subjects will have Visit 1 only. 
Visit 1: Protocol for All Healthy Subjects and for Subjects with CP who have not Received 
Pancreatic Enzyme Medication Prior to Visit 1 
 
Day 1 
 
 
Regular lunch/dinner except for no intake of dairy products 
 
No alcohol intake 
 
Normal daily activity 

 
  
 
 
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 
Fast overnight starting at 8 pm 
 
Day 2 – CHOP Visit to CTRC Outpatient Lab and NGL 
 
 
Urine pregnancy test for pre-menopausal females  
 
Insert heplock catheter 
 
Baseline blood draw for MBT, Fat soluble vitamins (A, D, E, K), pre-albumin, serum 
zinc and selenium (Both Cohorts). 
 
Baseline blood draw for CMP, CBC and fatty acid panel (CP Cohort only) 
 
Saliva collection for DNA sequencing (CP Cohort only)  
 
Administer MBT study meal (breakfast) 
 
MBT – hourly blood sample for 8 hours 
 
After hour 6 a low fat study lunch 
 
Anthropometry (height, weight, skinfolds, circumferences) 
 
Whole body DXA (CP cohort only) 
 
Spot stool sample will be collected for Fecal Elastase I (CP Cohort only) 
 
Questionnaires: Home Environment (Visit 1), Health History and medications, 
Quality of life questionnaire (MOS SF-36), PROMIS, Adherence, Adverse Events 
(Visit 2) 
 
Instructions will be given for collection and shipping for: stool collection (72-hour 
fecal fat analysis and bomb calorimetry), 3-day weighed food records, and adverse 
events diary 
 
Prescribe Creon36TM and dispense to subjects with CP (CP Cohort only) 
 
Day 3 - Home 
 
 
Maintain adverse events diary 
 
Day 4 - Home 
 
 
Moderate fat diet 
 
3-day weighed food record  begins  
 
Food record – Day 1 
 
Maintain adverse events diary 
 
Day 5 - Home 
 
 
Moderate fat diet 
 
Food record – Day 2 
 
Stool collection begins (72-hour fecal fat and bomb calorimetry), store frozen until 
brought to CHOP. 
 
72-hour stool – Day 1 
 
Maintain adverse events diary 
 
Day 6 - Home 

 
  
 
 
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 
Moderate fat diet 
 
Food record – Day 3 
 
72-hour stool – Day 2 
 
Maintain adverse events diary 
 
Day 7 - Home 
 
 
Moderate fat diet 
 
72-hour stool – Day 3 
 
Maintain adverse events diary 
Visit 1: Protocol for Subjects with CP who are Receiving Pancreatic Enzyme Medication 
Prior to Visit 1 and require a Washout Period 
Participants discontinuing pancreatic enzyme medication will be without this medication 
for the nine days encompassing Visit 1.  
 
Days 1 & 2 
 
 
Discontinue pancreatic enzyme medication (Washout)  
Day 3 
 
 
Discontinue pancreatic enzyme medication (Washout)  
 
Regular lunch/dinner except for no dairy intake 
 
No alcohol intake 
 
Normal daily activity 
 
Fast overnight starting at 8pm 
 
Day 4 – CHOP Visit to CTRC Outpatient Lab and NGL 
 
 
Urine pregnancy test for pre-menopausal females  
 
Insert heplock catheter 
 
Baseline blood draw for MBT, Fat soluble vitamins (A, D, E, K), pre-albumin, serum 
zinc and selenium (both cohorts) 
 
Baseline blood draw for CMP, CBC, and fatty acid panel (CP Cohort only) 
 
Saliva collection for DNA sequencing (CP Cohort only)  
 
Administer MBT study meal (breakfast) 
 
MBT – hourly blood sample for 8 hours 
 
After hour 6 a low fat study lunch 
 
Anthropometry (height, weight, skinfolds, circumferences) 
 
Whole body DXA (CP Cohort only) 
 
Spot stool sample will be collected for Fecal Elastase I (CP Cohort only) 

 
  
 
 
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 
Questionnaires: Home Environment (Visit 1), Health History and medications, 
Quality of life questionnaire (MOS SF-36), PROMIS Survey, Adherence, Adverse 
Events (Visit 2) 
 
Instructions will be given for collection and shipping for: stool collection (72-hour 
fecal fat analysis and bomb calorimetry), 3-day weighed food records, and adverse 
events diary 
 
Prescribe Creon36TM and dispense to subjects with CP (CP Cohort only) 
 
Day 5 - Home 
 
 
Maintain adverse events diary 
 
Day 6 - Home 
 
 
Moderate fat diet 
 
3-day weighed food record begins  
 
Food record – Day 1 
 
Maintain adverse events diary 
 
Day 7 - Home 
 
 
Moderate fat diet 
 
Food record – Day 2 
 
Stool collection begins (72-hour and bomb calorimetry), store frozen until brought 
to CHOP. 
 
72-hour stool – Day 1 
 
Maintain adverse events diary 
 
Day 8 - Home 
 
 
Moderate fat diet 
 
Food record – Day 3 
 
72-hour stool – Day 2 
 
Maintain adverse events diary 
 
Day 9 - Home 
 
 
Moderate fat diet 
 
72-hour stool – Day 3 
 
Maintain adverse events diary 

 
  
 
 
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4.3 
Open-Label Treatment with Creon36TM  
Subjects with CP only will receive open-label treatment with Ceon36TM as their pancreatic enzyme 
medication therapy and will receive this therapy for nine days encompassing Visit 2.  Visit 2 will be 
the same for all subjects with CP.   
Visit 2: Pancreatic Enzyme Medication Treatment Protocol for Subjects with CP Only  
 
Days 1 & 2 
 
 
Pancreatic enzyme medication treatment (two Creon36TM with meals, and one 
Creon36TM with snacks)  
Day 3 
 
 
Pancreatic enzyme medication treatment (two Creon36TM with meals, and one 
Creon36TM with snacks)  
 
Regular lunch/dinner except for no dairy intake 
 
No alcohol intake 
 
Normal daily activity 
 
Fast overnight starting at 8pm 
 
Day 4 – CHOP Visit to CTRC Outpatient Lab and NGL 
 
 
Pancreatic enzyme medication treatment (two Creon36TM with meals, and one 
Creon36TM with snacks)  
 
Insert heplock catheter 
 
Baseline blood draw for MBT, Fat soluble vitamins (A, D, E, K), pre-albumin, serum 
zinc and selenium, CMP, CBC and fatty acid panel   
 
Saliva sample for genetic testing 
 
Administer MBT study meal (breakfast) 
 
MBT – hourly blood sample for 8 hours 
 
After hour 6 a low fat study lunch 
 
Anthropometry (height, weight, skinfolds, circumferences) 
 
Adherence to pancreatic enzyme medication and Adverse Events Questionnaires 
 
Instructions will be given for collection and shipping for: stool collection (72-hour 
fecal fat analysis and bomb calorimetry), 3-day weighed food records, and adverse 
events diary 
 
Day 5 - Home 
 
 
Pancreatic enzyme medication treatment (two Creon36TM with meals, and one 
Creon36TM with snacks)  

 
  
 
 
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 
Resume usual diet 
 
Maintain adverse events diary 
 
Day 6 - Home 
 
 
Pancreatic enzyme medication treatment (two Creon36TM with meals, and one 
Creon36TM with snacks)  
 
3-day weighed food records begins 
 
Food record – Day 1 
 
Maintain adverse events diary 
 
Day 7 - Home 
 
 
Pancreatic enzyme medication treatment (two Creon36TM with meals, and 1one 
Creon36TM with snacks)  
 
Food record – Day 2 
 
Stool collection (72-hour and bomb calorimetry), store frozen until brought to 
CHOP. 
 
72-hour stool – Day 1 
 
Maintain adverse events diary 
 
Day 8 - Home 
 
 
Pancreatic enzyme medication treatment (two Creon36TM with meals, and one 
Creon36TM with snacks)  
 
Food record – Day 3 
 
72-hour stool – Day 2 
 
Maintain adverse events diary 
 
Day 9 - Home 
 
 
Pancreatic enzyme medication treatment (two Creon36TM with meals, and one 
Creon36TM with snacks)  
 
72-hour stool – Day 3 
 
maintain adverse events diary 
4.4 
Unscheduled Visits 
Due to the complexity of the study, no unscheduled visits will be permitted. 
4.5 
Subject Completion/Withdrawal 
For subjects with CP who were naïve to pancreatic enzyme medication at the start of the study, at 
the end of participation in the study (all collections are complete for Visit 2) Creon36TM will be 
discontinued and they will and resume their usual care without pancreatic enzyme medication.  For 
subjects with CP who were receiving pancreatic enzyme medication prior to the start of the study, 

 
  
 
 
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at the end of participation in the study (all collections are complete for Visit 2), Creon36TM will be 
discontinued and they will resume their usual care and will resume the pancreatic enzyme product 
and dose they were receiving before the study began.  
Subjects may withdraw from the study at any time without prejudice to their care.  They may also 
be discontinued from the study at the discretion of the Investigator for lack of adherence to study 
treatment or visit schedules, or adverse events. The Investigator or the Sponsor may also withdraw 
subjects who violate the study plan, or to protect the subject for reasons of safety or for 
administrative reasons.  It will be documented whether or not each subject completes the clinical 
study. If the Investigator becomes aware of any serious, related adverse events after the subject 
completes or withdraws from the study, they will be recorded in the source documents and on the 
CRF.  
5 STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
Variables that will be abstracted from the medical chart (paper or electronic): 
 
Date of birth - Age 30-75 years old 
 
Sex 
 
CP diagnosis:  Participants with CP will be characterized based on the TIGAR-O (toxic, 
genetic, autoimmune, recurrent, obstructive) etiology system, on pancreatic morphology 
(Cambridge criteria) when available, and on physiological state (exocrine and endocrine 
function) as recommended by the recent American Pancreatic Association Practice 
Guidelines4.   
 
History of unintentional weight loss or history of increased stools per week 
 
Other clinical signs or symptoms suggestive of fat malabsorption  
 
History of pancreatic enzyme use 
 
History of allergy to pork, Current diagnosis of gout and treatment with allopurinol medical 
therapy, or intestinal blockage or fibrosing colonopathy  
 
All medications, particularly medications that alter fat absorption (weight loss medications 
or ursodeoxycholic acid) 
5.1.2 Laboratory Evaluations 
Serum 25-dihydroxyvitamin D and pre-albumin (vitamin A) will be assessed at CHOP laboratories.  
Serum retinol and α-tocopherol [vitamin E] will be assayed at Craft Laboratories. PIVKA II (Sarah 
Booth, Tuft’s University, Medford, MA) and/or undercarboxylated osteocalcin % (UCOC %) will be 
assessed for vitamin K status (Caren Gundberg, Yale University, New Haven, CT). Zinc and selenium 
will be assessed at CHOP Laboratories using standard techniques.  This will provide additional 
evidence for vitamin, mineral and essential fatty acid status resulting from pancreatic disease that 
may be improved with pancreatic enzyme medication in subjects with RPF/PI indicated by the MBT, 
CFA% and BC response.  For subjects with CP, safety measures include results from serum 
comprehensive metabolic panel (CMP) and complete blood count with differential (CBC) performed 
at CHOP Laboratories using standard techniques.  The CMP will provide serum albumin, total 
protein, bilirubin and liver enzymes to provide additional liver and nutritional status information for 

 
  
 
 
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the CP cohort. Also linoleic acid (essential fatty acid panel) will be assessed at ARUP Laboratories 
for the CP cohort only.  All individuals from institutions outside of CHOP will receive only coded, not 
readily identifiable, samples for analyses and are not otherwise engaged in human subjects’ 
research. 
5.1.2.1 Pregnancy Testing 
A urine pregnancy test will be performed for pre-menopausal female subjects.  
5.1.3 Other Evaluations and Measures 
Genetic Testing: Saliva will be collected for DNA sequencing of all exons and intronic junctions of all 
major pancreatitis risk factor genes, including PSSR1, CTRC, CFTR and SPINK1,44-47 in the CP group 
only.    Results for additional genes that have been reported as CP disease associated will also be 
sequenced (CaSR, CEL, CPA1, PRSS2-3, SBDS, UBR1, and two SNPs near CLDN2). (Ariel Precision 
Medicine, Pittsburgh, PA).  Saliva samples are stable long term (>2y) and can be stored at room 
temperature to ship in batches. 
 
Fecal Elastase-1:  Pancreatic function will be assessed for the CP group by fecal elastase-1 to 
determine the level of pancreatic enzyme activity in the stool51, 52 (Joli Diagnostics, Williamsville, 
NY). Subjects will be provided with the stool collection kit and proper instructions and supplies, and 
samples will be collected during the day of the visit if possible, or at home and returned. The stool 
sample will be stored at -20oC, and analyzed with a monoclonal enzyme-linked immunosorbent 
assay (ARUP Laboratory, Salt Lake City, UT). 
Anthropometric Assessment: Weight, height, and BMI will be assessed. Measures of body 
composition will also be conducted for relative muscle and fat. All anthropometric techniques will 
follow those described by Lohman et al53. Weight (0.1 kg) will be measured on a digital electronic 
scale (Seca, Munich, Germany) and stature (0.1 cm) on a stadiometer (Holtain, Crymych, UK). 
Skinfold thickness will be measured (0.1 mm) at the triceps, biceps, subscapular, and supra-iliac 
sites with a skinfold caliper (Holtain, Crymych, UK) to assess subcutaneous fat stores. Mid upper 
arm circumference measured with a non-stretchable fiberglass tape (0.1 cm) (McCoy, Maryland 
Heights, MO). Upper arm muscle and fat area Z scores will be generated54, 55.   
Body Composition: Total body composition, total FFM and FM and percent body fat (%FAT), will be 
assessed by the skinfolds using prediction equations adapted for children, adolescents, and adults56, 
57. Body composition will also be assessed by dual energy x-ray absorptiometry  
(DXA) whole body scans (Delphi A, Hologic, Inc., Bedford, MA) for subjects with CP only at Visit 1. 
DXA uses very low-dose x-ray exposures (3 mrem) and measurements are rapid, making this a 
suitable technique for use in children. Standard positioning and clothing techniques are used. 
Quality control scans are performed daily using a simulated L1-L4 lumbar spine made of 
hydroxyapatite encased in epoxy resin, and a whole body composition phantom. A difference of 
>1.5% from the standard will be deemed out-of-range requiring servicing by the manufacturer. 
Whole body will be assessed by DXA at both Visit 1 and Visit 2. The scans will be analyzed to 
generate traditional DXA measures: whole body Area, BMC and areal-BMD (gm/cm2). In our 
institution, the in vitro CV is less than 0.6% and the in vivo coefficient of variation in adults is less 
than 1%.  A urine pregnancy test will be performed on female subjects who are pre-menopausal 
prior to the scan. Pregnant subjects will not be scanned and will leave the study.   

 
  
 
 
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Dietary Intake:  Three-day weighed food records will be obtained and calories, macro- and micro-
nutrient content calculated. Subjects will be provided with scales, spoons and all supplies necessary 
for the collection of the dietary data and will be conducted with assistance from the CTRC staff and 
Bionutrition Unit58, 59. Dietary intake will be analyzed using Nutrition Data System for Research 
software version 2012 developed by the National Coordinating Center (NCC, University of 
Minnesota. Minneapolis, MN)60.   
Disease Classification: Participants with CP will be characterized based on the TIGAR-O (toxic, 
genetic, autoimmune, recurrent, obstructive) etiology system, on pancreatic morphology 
(Cambridge criteria) when available, and on physiological state (exocrine and endocrine function) as 
recommended by the recent American Pancreatic Association Practice Guidelines4. 
Home Environment and Health Questionnaire: The questionnaire will be administered via interview 
by the research staff, and will consist of two sections. The Health History section has general 
questions about the subject’s health history including documentation of medical history, recent 
hospital admissions and illnesses, medication, history of pancreatic enzyme supplementation, and 
nutrient supplement use. A  Home Environment section describes aspects of environment, such as 
education and income level, whether on Medicaid/Medicare and household size to describe the 
demographic characteristics. In addition to subjects’ contact information (name, address, phone 
numbers); contact information from two additional contacts will be collected to maintain contact 
with the subject in the event that the subject cannot be contacted at their primary residence. 
Quality of Life Questionnaires: In order to assess the health-related quality of life (QOL), validated 
questionnaires will be administered to all subjects at Visit 1. For all subjects, the Medical Outcomes 
Study 36-Item Short-Form Health Survey (MOS SF-36), a standardized, validated healthy survey will 
be administered.  The MOS SF-36 covers physical functioning, bodily pain, general health 
perception, vitality, social functioning, emotional and mental health domains32, 61-65.  
Patient Reported Outcomes (PROMIS):  We will assess patient reported outcomes at every study 
visit using the following NIH developed PROMIS short forms: pain, fatigue, depressive symptoms, 
physical function – mobility, physical function – upper extremity, and peer relationships.  
Adherence: Adherence to pancreatic enzyme medication for subjects with CP will be assessed at 
study Visit 2 and by phone calls. This time will also be used to trouble-shoot any barriers to 
adherence, and also to collect information on adverse events experienced during the course of the 
study.   
Adverse Events Diary: Subjects will be asked about all adverse events at both Visit 1 and Visit 2, and 
asked to rate by intensity (mild, moderate, severe). Serious adverse events will be reported as per 
various policies in a timely manner to CHOP IRB, and CTRC. 
5.2   Efficacy  
5.2.2. Diagnostic tests, Scales, Measures 
Malabsorption Blood Test (MBT): The MBT primary outcomes consist of parameters from 
pharmacokinetic analyses.  The MBT consists of a simultaneous oral dose of pentadecanoic acid 
(PA), a free fatty acid, and triheptadecanoic acid (THA), a triglyceride with three heptadecanoic (HA) 
saturated fatty acids requiring hydrolysis by pancreatic lipase before HA can be intestinally 
absorbed (Patent # US 7402405 B2, July 22, 2008). The MBT with the PA and THA is delivered in a 
breakfast test meal after a 12-hour fast and 24 hours without dairy foods. Serum concentration 

 
  
 
 
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levels of PA and HA are assessed by gas-liquid chromatography (GC), from serum samples drawn 
prior to MBT and then hourly for eight hours. The MBT test meal is prepared immediately before 
consumption, with 5.0g of PA and 5.5g of THA blended into a test meal composed of 64g vanilla 
Scandishake (Axcan Scandipharm, Birmingham, AL), 6oz silk light chocolate soy milk, and 10ml 
microlipids (www.nestle-nutrition.com). The 8oz MBT test meal contains ~550 calories, 32 g fat, 
and 52% of calories from fat. The test meal was designed to be similar to a high fat dinner meal. 
Prior to administration of the MBT test meal, an indwelling catheter is placed for baseline (0 Hour) 
and subsequent blood draws at Hour 1, 2, 3, 4, 5, 6, 7 and 8 post ingestion for quantification of 
serum PA and HA. The MBT test meal is consumed within five minutes of the baseline blood draw. 
After the Hour 6 blood draw, subjects consume a 1000 kcal, low fat (12 g) lunch meal, and two 
blood samples will follow this meal (Hours 7 and 8). During the eight-hour protocol period, subjects 
are offered non-caloric and non-caffeinated beverages ad libitum. The 72-hour home stool 
collection will begin two days after the MBT visit, and the corresponding 3-day weighed food record 
will begin the day prior to the first day of the 72-hour stool collection.  
 
Table3. Protocol for each MBT visit 
Protocol 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Enzyme-naïve: 
MBT #1 
CP 
Healthy 
Comparisons 
- Fast from 
8pm 
- No dairy 
- No alcohol 
- Normal 
activity 
- MBT at 8am 
- Lunch at 2pm 
- 9 hourly blood 
draws 
Home 
Return to usual 
diet 
- Diet record 
 (day 1) 
- Diet record 
(day 2) 
- 72-hour stool 
(day 1) 
- Diet 
record 
(day 3) 
- 72-hour 
stool 
(day 2) 
- 72-hour 
stool 
(day 3) 
 
 
Enzyme-naïve 
with washout: 
MBT #1 
CP 
Wash-out 
No Enzymes 
Wash-out 
No Enzymes 
Wash-out 
No Enzymes 
- Fast from 8pm 
- No dairy 
- No alcohol 
- Normal activity 
- MBT at 8am 
- Lunch at 2pm 
- 9 hourly 
blood draws 
Home 
Return to usual 
diet 
- Diet 
record 
(day 1) 
- Diet 
record 
(day 2) 
- 72-hour 
stool 
(day 1) 
- Diet 
record 
(day 3) 
- 72-
hour 
stool 
(day 2) 
- 72-
hour 
stool 
(day 3) 
Pancreatic 
Enzyme 
Medication: 
MBT#2 
CP 
Enzyme 
treatment 
Enzyme 
treatment 
Enzyme 
treatment 
- Fast from 8pm 
- No dairy 
- No alcohol 
- Normal activity 
- MBT at 8am 
- Lunch at 2pm 
- 9 hourly 
blood draws 
Home 
Return to usual 
diet 
- Diet 
record 
(day 1) 
- Diet 
record 
(day 2) 
- 72-hour 
stool 
(day 1) 
- Diet 
record 
(day 3) 
- 72-
hour 
stool 
(day 2) 
- 72-
hour 
stool 
(day 3) 
 Each subject in CP cohort will have two MBT, the first on a pancreatic enzyme medication -naïve 
protocol and the second after three days of pancreatic enzyme medication treatment. If subjects 
are receiving pancreatic enzyme medication at study enrollment, after consultation with their 
medical team, they will be asked to discontinue pancreatic enzyme medication for three days prior 
to the first MBT, the day of the MBT and the five days following the MBT until the end of the 72-
hour stool collection.  Thus, the total number of days of data collection for the enzyme-naïve MBT 
protocol will be seven for subjects not receiving pancreatic enzyme medication at Visit 1, and nine 
for those requiring a washout period from pancreatic enzyme medication (see Table 3). For the 
MBT that will be administered with pancreatic enzyme medication, subjects will take pancreatic 
enzyme medication for three days prior to the MBT. Each day, the pancreatic enzyme medication 
dose will be 72,000 lipase units per meal and 36,000 units per snack using Creon 36,000 units per 
capsule. They will take two Creon36TM (72,000 lipase units) with the MBT on the morning of the test 
meal. Pancreatic enzyme medication dose range for adults with RPF/PI is not well standardized.  

 
  
 
 
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The dose chosen for these short term studies are in the higher range recommended for initial 
treatment5, 6.  Subjects will then continue to take pancreatic enzyme medication at home for the 
next five days until the 72-hour stool collection is completed.  The total number of days for the 
pancreatic enzyme medication MBT protocol is nine (see Table 3).  For the healthy individuals, the 
MBT protocol will last one week since they will be pancreatic enzyme medication -naïve.  
Plasma samples will be analyzed by a GC method at Wake Forest University (Winston-Salem, NC).  
Total lipids are extracted from 200µL of plasma following the method of Bligh and Dyer66. Following 
methylation of the fatty acids in the total lipid extract, fatty acid methyl esters are extracted into 
isooctane and 1µL was injected into the GC column for analysis using a Hewlett Packard 5890 series 
II gas chromatograph with a programmable cool on-column capillary inlet, flame ionization detector 
(FID), and HP7673 auto sampler/injector.  Chromatographic data collection and analysis is via a 
serial connection to a computer running ChromPerfect Spirit™ chromatography data system 
(Justice Laboratory Software, Denville, NJ).  The column used is a CP-Sil 88 for FAME, 100m (L) x 
0.25mm (ID) x 0.25µm (film thickness) (Agilent Technologies, Inc., Santa Clara, CA) with a 1m (L) x 
0.53mm (ID) deactivated precolumn.  Calibration curves are based on injections of methyl 
tridecanoate, methyl PA, and methyl HA injections.  Inter-assay variability (%CV) for the 
measurement of PA in samples with low, medium and high concentrations (1.30, 2.99, and 6.70 
mg/dL) was 2.9%, 2.6%, and 3.1%, respectively.  Inter-assay variability for the measurement of HA 
(0.56, 1.29, 3.05 mg/dL) in the same samples is 2.6%, 4.0%, and 3.9%, respectively. 
     The primary outcomes for the MBT include PA and HA pharmacokinetic analyses including 
comparison of absorption curves, Cmax and AUC, and percent absorption of plasma PA and HA 
concentrations and also the HA/PA ratio 1) between CP and the healthy reference group, and 2) 
with pancreatic enzyme medication exposure compared with pancreatic enzyme medication -naive 
status in the CP cohort. 
Utilizing the relative absorption of HA to PA, the MBT has been shown to respond to changes in fat 
absorption in healthy adult subjects using a lipase inhibitor and in subjects with CF and PI while on 
and off pancreatic enzyme therapy49, and is also sensitive to enzyme dose titration50. 
Coefficient of Fat Absorption (CFA):  The CFA primary outcome, the coefficient of fat absorption 
(CFA%) will be determined by the 72-hour stool collections at Visits 1 and 2 and a 3-day weighed 
food record collection while consuming a moderate fat (about 80+ g/day) diet. These stool 
collections will be performed at home and returned to CHOP. Subjects will be given a home 
collection kit and detailed instructions.  Specimens will be stored frozen until analysis of total fat 
content by a gravimetric method (Mayo Medical Laboratories, Rochester, MN). Total dietary intake 
of fat during the 3-day period will be assessed from the 3-day weighed food records which will 
coincide with the 72-hour stool collection, and the CFA% will be calculated67.  The CFA% will be 
compared 1) between the CP cohort and the healthy reference group, and 2) with pancreatic 
enzyme medication exposure compared with pancreatic enzyme medication-naive status in the CP 
cohort. 
 
Bomb calorimetry (BC):  The BC primary outcome for BC is the assessment of energy loss in the 
stool from the 72-hr stool collection (NIDDK sponsored research unit, Phoenix Indian Medical 
Center, Phoenix, AZ) using bomb calorimetry68-70. Samples will be shipped frozen and the heat of 
combustion (energy) will be measured in a bomb calorimeter, with energy liberated quantified in 
kcal/g stool. The energy loss from the stool will be compared 1) between the CP cohort and the 

 
  
 
 
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healthy comparison group, and 2) with pancreatic enzyme medication exposure compared with 
pancreatic enzyme medication -naive status in the CP cohort. 
5.3 Safety Evaluation 
Safety will be monitored by adverse events reporting. The frequencies of AEs by type, body system, 
severity and relationship to study supplement will be summarized. SAEs (if any) will be described in 
detail. 
6 STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary aim is to utilize the MBT, CFA and BC methods to characterize the fat and energy 
absorption patterns to compare fat and energy absorption from the diet in subjects with CP and 
healthy subjects.  We will also determine if fat and energy absorption will improve after pancreatic 
enzyme medication administration in subjects with CP utilizing the MBT, CFA and BC methods to 
characterize the fat and energy absorption patterns.   
6.2 Secondary Endpoint 
The secondary aim is to utilize the data from the MBT, CFA and BC outcomes to optimize the MBT 
design and application by reducing the time and blood samples required.   We will also explore the 
utility of the MBT compared to the CFA and BC (both require the burdensome 72-hour total stool 
and dietary intake collection) in identifying differences in fat absorption between subjects with CP 
and healthy individuals and within the CP cohort, with and without pancreatic enzyme medication. 
We will also explore the association of specific genotypes with fat malabsorption in the context of 
CP. 
6.3 
Statistical Methods 
Analysis will begin with descriptive analyses of the study sample using means, standard deviations, 
medians, and ranges for continuous variables, and frequency distributions for categorical variables. 
Descriptive statistics and exploratory graphing such as frequencies, means, standard deviations, 
box plots, and scatter plots will be used to assess the normality of the data in terms of the presence 
of skew and/or outliers.  
6.3.1 Efficacy Analysis 
Statistical Analysis:  H1 and H2: Descriptive statistics for MBT, CFA% and BC outcomes (mean, 
standard deviation, median, range, 95% CI) will be calculated for the CP cohort and for the healthy 
comparison group, and differences between CP and healthy groups assessed with unpaired t tests.  
For the MBT outcomes, a moment-based pharmacokinetic (PK) analysis will be performed based on 
non-compartmental methodology using WinNonLin version 9.1 (Pharsight, Cary, NC). Baseline (C0) 
and maximum (Cmax) plasma concentrations are calculated, and area under the curve from time 
zero to eight hours (AUC) is calculated using the linear trapezoid method. PK parameters can then 
be compared between treatment groups using a paired t-test or Wilcoxon signed rank test as 
appropriate. To describe HA exposure relative to that of PA, the ratio of the HA to PA Cmax (Cmax 
HA/PA) and AUC (AUC HA/PA) is calculated for each subject after molar transformation and dose-
normalization of exposure metrics49.  Alternately, population PK analyses for repeated-measures 
endpoints can be conducted via nonlinear mixed-effects modeling with a qualified installation of 
the nonlinear mixed-effects modeling (NONMEM) software, Version VII, Level 2.0 (ICON 

 
  
 
 
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Development Solutions, Hanover, MD)48. Using this method, population PK modeling is conducted 
by simultaneously fitting structural PK models to both PA and HA concentrations50.   
        Descriptive statistics for MBT, CFA% and BC outcomes (mean, standard deviation, median, 
range, 95% CI) will also be calculated for the CP cohort with and without pancreatic enzyme 
medication administration, and the significance of changes over time assessed with paired t tests. 
HA and PA concentrations will be transformed to molar quantities and the ratios for HA to PA Cmax 
and AUC and the associated 95% confidence interval will be calculated. A mixed effects modeling 
approach will be employed to examine the correlation of subject characteristics (age, BMI, sex, 
disease status, etc.) to PA and HA exposure metrics derived from the non-compartmental analysis 
to assess change over time in MBT response to pancreatic enzyme medication administration in 
subjects with CP. Metrics to be tested will be CFA%, PA and HA Cmax, AUC, HA/PA Cmax and AUC ratio 
and the %HA response compared to the healthy reference group. A value of p<0.05 will be 
considered statistically significant. 
          H3: Pharmacokinetic modelling will be employed to identify the three to four blood samples 
over the first four to five hours of the MBT that provide the best and most reproducible estimate of 
the full eight-hour MBT (nine blood samples) in the CP cohort and healthy comparisons. The goal is 
a shorter sampling scheme for the MBT to optimize its use as a clinical diagnostic test.    
          In exploratory analyses, we will compare the estimates of percent fat absorption from the 
MBT with both the CFA% from the 72-hour fecal fat and diet analysis and the BC results (energy loss 
in the stool). We will compare the methods for detection of fat malabsorption as measured by 
CFA% and BC with fat absorption as measured by MBT for the subjects with CP compared to 
healthy individuals and also within the CP cohort before and after pancreatic enzyme medication 
use. A correlation analysis will be conducted to evaluate the performance of the MBT relative to that 
of the CFA%. HA and PA Cmax, AUC, and HA/PA ratios will be plotted against CFA% or BC caloric loss to 
explore the relationship between the two tests. Any relationships observed in the plots will be 
further explored using correlation analysis and appropriate regression analysis as dictated by the 
observations. If a reasonable model can be developed to describe the response of MBT, CFA% and BC 
response to pancreatic enzyme medication treatment within the CP cohort, additional simulation 
studies will be performed to further examine the performance characteristics of both tests. 
6.3.1 Safety Analysis 
Safety will be monitored by adverse events reporting. The frequencies of AEs by type, body system, 
severity and relationship to study supplement will be summarized. SAEs (if any) will be described in 
detail. 
6.4 
   Sample Size and Power 
Sample Size Considerations: The primary hypotheses of this study: 1) the MBT, CFA and BC methods 
will detect differences in fat absorption between healthy subjects and subjects with CP when they 
are pancreatic enzyme medication -naive; and 2) the MBT, CFA and BC methods will detect changes 
in fat absorption with pancreatic enzyme medication administration in the CP cohort. For the MBT 
method, the sample size selected for the CP cohort (n=24) and the healthy comparisons (n=24) is 
based upon our previous experience in CF with detecting differences in Cmax and AUC for HA and 
the HA/PA ratio49, and in detecting the percent change in HA absorption (from pharmacokinetic 
modeling) compared to healthy subjects50.  For the CP vs. healthy comparison, 22 subjects in each 
group will have 80% power to detect a difference in means of 0.60 (the difference in Cmax (in AUC) 

 
  
 
 
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IRB 16-013001_ 05052017 
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HA/PA ratio between health group mean of 1.62 (1.30) and CP group mean of 1.02 (0.70)), which is 
37% decrease in Cmax and 46% decrease in AUC from health group to CP group, assuming that the 
common SD is 0.68 using a t-test with α =0.05.  
   For the CFA% outcome, our experience has been in CF and PI, with average CFA% of 81±14% in 
one study67 and 83±10% in another71 when subjects were on pancreatic enzyme medication. In 
comparison, in healthy subjects, CFA% is typically ≥93%.  From the literature for CP, a number of 
clinical trials have used CFA% to describe fat malabsorption in subjects with CP and confirmed 
pancreatic insufficiency before and after administration of pancreatic enzyme medication.  Ramesh 
et al15 found an increase in CFA% from 66.7±14.0 before pancreatic enzyme medication to 
88.9±5.2% after pancreatic enzyme medication (change of 22.7±12.2%) in adults with CP from 
India.  Also in adults from India participating in a placebo-controlled trial, Thorat et al16 saw CFA% 
increase from 66.5±14.1 to 86.1±7.5% in those taking pancreatic enzyme medication compared to 
an increase from 67.0±14.0 to 72.9±11.5% for placebo, a treatment  effect of 13.7% (95% CI: 9.1, 
18.2) after one week of pancreatic enzyme medication. From this combined experience with 
variability of the CFA% in both CF and CP, 21 subjects in each group will have 80% power to detect a 
difference in means of 10% (the difference in CFA% between health group mean of 95% and CP 
group mean of 85%) assuming that the common SD is 11% using a t-test with α =0.05.  
For the BC method, there is limited information for typical variability in calories lost in stool in 
either healthy subjects or those with malabsorption diagnoses. Using 72-hour stool assessments, 
Wierdsma et al70 has recently reported average daily energy loss of 213±66 kcal in 23 healthy 
adults.  This loss was less in those >50 years old (197±49 kcal).  If we assume that approximately 
200 kcal/day are lost in the stool of healthy subjects, 21 subjects in each group will have 80% power 
to detect a difference in means of 50 kcal (the difference in BC between health group mean of 200 
and CP group mean of 250 kcal lost in stool) assuming that the common SD is 56 using a t-test with 
α =0.05.  
     For the paired comparisons within the CP cohort before and after pancreatic enzyme medication 
use, 22 subjects will have 80% power to detect a difference in means of 0.44 (Cmax HA/PA ratio 
changes from 1.02 to 1.46 or AUC HA/PA ratio of 1.7 to 1.14), assuming a SD of differences of 0.68, 
using a paired t-test with α =0.05 two-sided significance level.  We have demonstrated that 
differences of this magnitude in MBT outcomes (exposure metrics) indicating the degree of fat 
absorption between groups and with varying treatment regimens, are significant when samples of 
16 subjects or less have been compared. We acknowledge that PA and HA absorption is moderately 
variable within subjects with CF and PI49, 50. Between-observation variability was estimated to be 
45.3% and 31.9% for PA and HA, respectively50.  For CFA%, from the literature on CP, the change in 
CFA% for subjects with CP and confirmed PI before and after pancreatic enzyme medication 
administration has ranged from 8 to 23% with the SD of that change ranging from 12 to 18%, but 
averaging at 14%. For CFA%, 22 subjects will have 80% power to detect a difference in means of 9% 
(increase in CFA% from 85 to 94% after pancreatic enzyme medication administration), assuming a 
SD of differences of 14%, using a paired t-test with α =0.05 two-sided significance level. For BC, 22 
subjects will have 80% power to detect a difference in means of 36 (decrease from 250 to 214 
kcal/day in the stool), assuming a SD of differences of 56, using a paired t-test with α =0.05 two-
sided significance level. 
     We expect no more than 10% attrition in this study given a relatively short time period between 
first and second protocol visits. By enrolling 24 subjects in each group (CP and healthy), we can 

 
  
 
 
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account for attrition and also allow for the possibility of greater variability in the MBT, CFA% and BC 
outcomes within the CP cohort for which we have had no previous experience.  
6.5 Interim Analysis 
No interim analysis is planned.  
7 STUDY MEDICATION  
7.1 Description 
CREON (pancrelipase) Delayed-Release Capsules 36,000 USP units of lipase (Creon36TM), a 
pancreatic enzyme preparation, is a drug that requires prescription for use.  It is approved for use, 
including the current indication and dosage, by the FDA.   
7.1.1 Packaging 
Creon36TM capsules containing 36,000 lipase units (LU) each will be provided (AbbVie, Inc.) to 
subjects with chronic pancreatitis. An 11 day supply of Creon36TM (one bottle or 100 capsules for 
approximately nine capsules/day) will be provided for nine days of use (81 capsules).  Subjects will 
return unused capsules to the study team at the end of the study, and will be provided with mailing 
envelopes for this purpose.  
7.1.2 Labeling 
Storage will be at CHOP North Campus in room temperature (below 77 F) and dry conditions 
(humidity less than 70%).  This facility is temperature controlled and continuously monitored.  
7.1.3 Dosing 
Participants will take two Creon36TM capsules (72,000 lipase units[LU]) at each meal for three meals 
a day, and one Creon36TM capsule (36,000 LU) with each snack up to three snacks a day for a total 
of nine capsules/day or 324,000 LU/day.     
7.1.4 Treatment Compliance and Adherence 
Adherence will be systematically assessed using the following methods: 1) One bottle of 100 
capsules, enough for eleven days (approximately nine capsules/day) of Creon36TM will be 
prescribed for the subjects with CP at Visit 1 by Dr. Stallings, the Lead Investigator/ Study Physician 
investigator with experience in cystic fibrosis care and use of pancreatic enzyme medication, and 
dispensed to the subjects by the study team under Dr. Stallings’ supervision.  Participants will be 
asked to begin taking the Creon36TM capsules three days prior to their Visit 2 study visit to CHOP.  
2) Subjects will be asked to complete an Adherence Survey, a semi-structured interview to 
document adherence to taking the Creon36TM over the nine days at Visit 2. We will maintain regular 
contact with participants via telephone and/or text message to ensure the subject has an adequate 
supply of Creon36TM and to obtain a cursory assessment of barriers to adherence so that we can 
develop individualized strategies to overcome these barriers. 3) Subjects will be provided with 
calendars on day 0 as a scheduling aid for study visits and a reminder to adhere to taking 
Creon36TM. 4) Subjects will return unused Creon36TM capsules at the end of the study to the study 
team in a mailing envelope provided.   

 
  
 
 
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7.1.5 Drug Accountability 
Records of Creon36TM receipt and disposition will be maintained by the study team. Records of 
receipts, and dispensing records will be examined during the course of the study.  The purpose of 
these records is to ensure regulatory authorities that the Creon36TM will not be distributed to any 
person who is not a study subject under the terms and conditions set forth in this protocol. 
Creon36TM will be prescribed for the subjects with CP by Dr. Stallings, the Lead Investigator/ Study 
Physician , with experience in cystic fibrosis care and use of pancreatic enzyme medication, and 
dispensed to the subjects by the study team under Dr. Stallings’ supervision, and may not be used 
for any purpose other than that described in this protocol. At study completion, all left over 
Creon36TM will be returned to the study team and this will be used as one estimate of adherence. 
Once the dataset is closed, leftover Creon36TM will be destroyed by the PI. 
8 SAFETY MANAGEMENT 
8.1 
Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
8.2 
Adverse Event Reporting 
Since the study procedures are not greater than minimal risk, SAEs are not expected. If any 
unanticipated problems related to the research involving risks to subjects or others happen during 
the course of this study (including SAEs) these will be reported to the IRB in accordance with CHOP 
IRB SOP 408: Unanticipated Problems Involving Risks to Subjects. AEs that are not serious but that 
are notable and could involve risks to subjects will be summarized in narrative or other format and 
submitted to the IRB at the time of continuing review.  
8.3 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has participated in the 
research protocol. The occurrence does not necessarily have to have a causal relationship with the 
research activities. An AE can therefore be any unfavorable or unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the research activities. 
All AEs (including serious AEs) will be noted in the study records and on the case report form with a 
full description including the nature, date and time of onset, determination of non-serious versus 
serious, intensity (mild, moderate, severe), duration, causality, and outcome of the event. 
8.4 
Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse experience occurring that results in any of the following outcomes:  
 
death 
 
a life-threatening event (at risk of death at the time of the event)  
 
requires inpatient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 
 
a congenital anomaly/birth defect in the offspring of a subject   

 
  
 
 
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IRB 16-013001_ 05052017 
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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
8.4.1 Relationship of SAE to investigation or other intervention 
The relationship of each SAE to the study activities will be characterized using one of the following 
terms in accordance with CHOP IRB Guidelines: definitely, probably, possibly, unlikely or unrelated.  
8.5 
IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all on-site unanticipated, serious Adverse Events 
that are related to the research activity. Other unanticipated problems related to the research 
involving risk to subjects or others will also be reported promptly. Written reports will be filed using 
the eIRB system and in accordance with the timeline below. External SAEs that are both 
unexpected and related to the study activities will be reported promptly after the investigator 
receives the report.  
Type of Unanticipated Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life Threatening 
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems Related to 
Research 
7 days 
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important AEs may 
be reported at time of continuing 
review 
8.5.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes 
the investigator’s assessment of the event, a follow-up report including all relevant new or 
reassessed information (e.g., concomitant medication, medical history) should be submitted to the 
IRB. The investigator is responsible for ensuring that all SAE are followed until either resolved or 
stable.  
8.6 
Investigator Reporting of a Serious Adverse Event to Sponsor 
Reporting will be consistent with regulatory and sponsor requirements. All serious adverse events 
experienced by a study subject receiving Creon36TM will be reported to the AbbVie, Inc. within 24 
hours of learning of the event regardless of the relationship of the event to Creon36TM, the AbbVie 
product.  The PI shall make available to AbbVie promptly such records as may be necessary and 
pertinent to investigate any such event, if specifically requested by AbbVie. Medical Emergencies 
For medical emergencies, we will follow the CHOP procedures for medical emergencies that may 
occur for adult visitors to CHOP. 

 
  
 
 
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9 STUDY ADMINISTRATION 
9.1 
Treatment Assignment Methods 
This is an open-label intervention therapeutic exploratory study.  All subjects with CP will be 
administered Creon36TM. Healthy subjects will receive no intervention.  This is not a randomized 
controlled trial. 
9.2 
Data Collection and Management 
We will establish a database to store study data using standard software (e.g. RedCap). The 
database will be designed to perform automatic computations, such as exact age based upon birth 
date and date of exam, and averaging anthropometric measures, which are recorded in triplicate. 
Reports containing the number of subjects enrolled and data entered for each subject are 
generated and reviewed each month by the PI.  The PI, or study staff, will review all data collection 
forms on an ongoing basis for data completeness and accuracy as well as protocol compliance. 
Following data entry, all primary and secondary endpoint data will be verified against original 
source documents.  Data verification will be performed by someone other than the individual 
originally collecting and entering the data.  
All subjects will be assigned a unique identification number that will be used to insure strict 
confidentiality. The databases are secured with password protection to insure confidentiality and 
security. The informatics manager receives only coded information which is entered into the 
database under those identification numbers. Electronic communication with outside 
collaborators involves only coded, not readily identifiable, information.  A master list containing 
PHI and subject ID number will be kept separate from the data forms and the database that will 
only have a study ID number. The master list will be on a separate computer (password protected).  
Copies of the master list with PHI will also be stored on the CHOP secured server.  All source 
documents including case report forms, laboratory results, and subject study binders will be kept 
in secured locations.  The file cabinets and the study-specific room will be locked with access to 
study personnel only, and the outer hallway is also locked with limited access to CHOP research 
personnel. 
Routine backup to the main study database, files created for analyses, and analysis programs will 
be completed. The main study database will be archived on a daily basis and stored on a CHOP 
secured server. The Informatics Core of the CTRC will create case report forms, set up the 
database in RedCap, and provide oversight for data entry and quality assurance for this study. 
9.3 
Confidentiality 
Medical history information will be obtained at baseline.  All of the materials collected are for 
research purposes only, and data will be kept in strict confidence. No information will be given to 
anyone without permission from the subject. This will be stated in the consent form.  
Confidentiality is assured by use of identification codes. All data, whether generated in the 
laboratory or at the bedside, will be identified with an identification code unique to the subject.  
To maintain confidentiality, private health information will be collected, accessed and stored in 
accordance with Institutional policies and HIPAA guidelines, including the use of multilevel 
password protection and enforcement of system user privileges on the database. To minimize the 
risk of disclosure, all direct identifiers will be removed as soon as possible and codes will be 
substituted for personal identifiers. PHI collected for this study will be kept up to five years after 

 
  
 
 
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final publication. Records of individuals are stored with ID numbers and a code with no discernible 
personal identifiers. Code lists and data files will be stored in separate, secure locations. Data will 
be accessed and stored on password-protected computers. To maintain confidentiality, codes will 
be used in the database, presentations and publications. The Investigator and other site personnel 
will not use such data and records for any purpose other than conducting the study. 
9.4 
Regulatory and Ethical Considerations 
9.4.1 Data and Safety Monitoring Plan 
The Principal Investigator (PI) (Dr. Zemel) is ultimately responsible for monitoring data integrity and 
patient safety and for overall study oversight. The study will be monitored weekly by the PI and the 
Lead Investigator (LI)/ Study Physician (Dr. Stallings). The study protocol will be carried out in 
accordance with OHRP and NIH guidelines and requirements. For participants with CP, AEs and 
SAEs that are unanticipated, serious, and possibly related to the study will be managed by the PI 
and Dr. Stallings (LI) LI/ Study Physician   in consultation with the participant’s adult 
gastroenterology physician team (Dr. Chandrasekhara (Perelman Center for Advanced 
Medicine/HUP [Penn Medicine/HUP]) or Dr. Rajala (Penn Medicine/ Philadelphia Veterans Affairs 
Medical Center [Penn Medicine/VA Hospital]) who will be immediately notified and will assume 
acute care management. Dr. Stallings will also consult with Dr. Mamula (CHOP/GI) who will be 
notified if an unexpected acute event occurs during a study visit at CHOP.  For healthy participants, 
unexpected AEs and SAEs will be managed by the PI and Dr.Stallings (LI/ Study Physician) in 
consultation with the primary care physician identified by the participant upon enrollment in the 
study, who will be immediately notified.  SAEs will also be reported to the IRB, CTRC, all members 
of the research team, the clinical care team, and sponsor in accordance with requirements. There 
will be ongoing collection of data on adverse events and compliance to the treatment protocol 
throughout the study by research staff and which will be reviewed weekly by the PI  and LI / Study 
Physician (Dr. Stallings). 
9.4.2 Risk Assessment 
The most common side effects associated with taking the pancreatic enzyme Creon36TM in clinical 
trials were abdominal pain, hyperglycemia, hypoglycemia, frequent abnormal bowel movements, 
flatulence, vomiting, dizziness, sore throat and cough.  Irritation of the inside of the mouth may 
occur if Creon36TM is not swallowed completely. Increase in blood uric acid levels (hyperuricemia), 
and severe allergic reactions (pork allergy) including trouble with breathing, skin rashes or swollen 
lips, although rare, may occur. Although it has never been reported, it is possible for a person to 
get a viral infection from taking pancreatic enzyme products that come from pigs.  Fibrosing 
colonopathy and colonic strictures is a rare, serious adverse reaction associated with chronic high-
dose pancreatic enzyme use over a prolonged period of time with enzyme doses in excess of 6,000 
LU/kg body weight per meal or 10,000 LU/kg/day in patients with cystic fibrosis. The dose of 
Creon36TM prescribed for this study is a maximum of 324,000 LU/day.  For an adult weighing 60 kg, 
this dose is 5,400 LU/kg/day or about half this amount. For an adult weight 40 kg, this daily dose is 
8,100 LU/kg/day, still well below.  An adult would have to weigh <33 kg (73 lbs.) to match or 
exceed the 10,000/kg/day dose that is considered excessive.  
There are risks associated with discontinuing pancreatic enzyme medication for people with 
pancreatic insufficiency or reduced pancreatic function resulting in fat malabsorption.  These 
include feelings of indigestion, stomach cramping after meals, gas, foul smelling, floating stools, 

 
  
 
 
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light-colored, orange or yellow stools, frequent or loose stools, or weight loss. Some participants 
in the study may be at increased risk for these symptoms. 
 
The participants receiving pancreatic enzyme medication prior to enrolling in the study 
who will discontinue use prior to the first study visit (Visit 1) may be at risk for signs and 
symptoms of fat malabsorption (described above) for nine days of the study. These nine 
days include the three days prior to study Visit 1 (washout period), the day of Visit 1 to 
CHOP, and the five days of specimen collection after Visit 1. These participants will 
resume their pancreatic enzyme product and dose for the period of time between the end 
of the nine days encompassing Visit 1 and the start of the three days prior to Visit 2 when 
they will switch to Creon 36TM.  Therefore, they will not be at increased risk for the signs 
and symptoms of fat malabsorption during the time between visits or during the nine 
days encompassing Visit 2 as they will be taking pancreatic enzyme medication 
throughout this period.  When the study is completed, these participants will discontinue 
Creon36TM and resume their usual care and resume their usual pancreatic enzyme product 
and dose. 
 
 
The participants who are naïve to pancreatic enzyme medication prior to entering the 
study, will take Creon36TM for the nine days encompassing Visit 2 of the study, that is, 
three days prior to the protocol visit to CHOP, the day of the visit, and then five days after 
the visit until all specimen collections have been completed.  If these participants have 
undiagnosed reduced pancreatic function and reduced fat absorption, they may have 
increased risk for the signs and symptoms of fat malabsorption upon discontinuation of 
Creon36TM at the end of the study. If their pancreatic function and fat absorption is 
normal, withdrawal from Creon36™ at the end of the study will not increase their risk for 
these symptoms. 
 The procedures in this study involve the potential risks related to the drawing of blood.  The risks 
of drawing blood are rare, and minimal. There is a small risk of pain, infection and local irritation 
associated with insertion of an intravenous heplock catheter. However, this is considered a 
minimal risk and skilled research staff will insert the intravenous catheter. Each subject with CP 
will have approximately 100cc (approximately 6-7 Tbsp.) of blood drawn at each study visit.  Each 
healthy subject will have approximately 88cc (approximately 5-6 Tbsp.) of blood drawn at their 
visit.   
There is minimal risk associated with the low radiation exposure from the DXA scan. Radiation 
exposure is estimated to be no more than 3.0 μSv (depending on age and size) per visit, well below 
everyday background exposure (approximately 8.2 μSv). DXA instruments are regularly monitored 
for safety, and only experienced pediatric research personnel will conduct these tests.        
There is minimal risk associated with collection of saliva for genetic testing. Potential risks related 
to genetic analyses can be to individuals or groups. These harms include stigmatization and 
insurability. To reduce this risk, no samples will be stored or used for future research. Information 
about this study will not be recorded in subjects’ medical record. The genetic tests are being 
performed in a CLIA-certified lab, therefore results will be returned to subjects upon request. These 
results will not be included in the medical record.  Any results that are clinically significant will be 
returned to the subject and included in their medical record. The likelihood of this happening is 
low.  
 

 
  
 
 
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Anthropometric measurements and pregnancy testing pose minimal risk to the subjects. There is 
minimal risk associated with sharing dietary intake, demographic information, health history and 
medical information.   
Collection and storage of stool is associated with a small risk of fecal contamination. However, for 
safety and convenience, subjects will be provided with proper stool collection instructions and 
supplies (gloves, disposable collection containers, storage freezer container). 
Private health information will be collected, accessed and stored according to HIPAA guidelines, 
including the use of multilevel password protection and enforcement of system user privileges on 
the database. To minimize the risk of disclosure, all direct identifiers will be removed as soon as 
possible and codes will be substituted for personal identifiers. Records of individuals are stored 
with ID numbers and a code with no discernible personal identifiers. Code lists and data files will 
be stored in separate, secure locations. Data will be accessed and stored on password-protected 
computers. To maintain confidentiality, codes will be used in the database, presentations and 
publications.  
9.4.3 Potential Benefits of Study Participation 
We cannot ensure a direct benefit to the subjects as a result of participating in this study. 
Participants may benefit from knowing that they will contribute to a clinical research study that is 
important to the health of people with CP in the U.S. and around the world. 
9.4.4 Risk-Benefit Assessment 
The research we propose is justified, considering that the risk associated with participation is 
minimal compared to the potential and anticipated benefits. The benefits of participation clearly 
outweigh the risks, in view of the potential positive benefits of the study to the larger population 
of people living with CP. 
9.5 
Recruitment Strategy 
It is expected that all subjects will be recruited by word of mouth and at the recommendation of 
the subjects’ CP Care Team. Healthy subjects will be recruited using general adult practices, flyers, 
use of the CHOP Recruitment Enhancement Core (REC), and recommendations from subjects with 
CP of healthy family and friends interested in participating. 
9.6 
Informed Consent and HIPAA Authorization 
Once a subject has expressed interest in participating a CHOP-based research team member will 
contact the subject via telephone and continue the introduction of the study to subjects. Verbal 
consent and HIPAA authorization for phone screening will be obtained prior to the collection of 
health information to determine eligibility. If screening occurs in person in the clinical care setting, 
participants will sign the screening consent prior to the collection of any health information to 
determine eligibility. A HIPAA Authorization form from the subjects’ institutions for obtaining non-
CHOP medical records, will be signed in person or obtained by mail/fax/email. All members of the 
team will be available (in person, by phone or email) to discuss the details and answer any study 
related questions as they arise. Once interest and eligibility are determined, procedures to set up 
enrollment will begin.  At entry into the study, all subjects will be asked to review the study consent 
form.  The Project Coordinator or other member of the clinical research team will meet with the 
subject to confirm the subject understands the study, and to answer any questions that the subject 
might have.  A physician-level study team member will be available in person, by phone or by email 

 
  
 
 
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to answer any questions of issues that may arise.  After all study-related questions are answered 
and subjects have had time to consider their decision, the Project Coordinator or member of the 
clinical research team will obtain fully informed, written consent from the adult subjects.  The 
consent will be signed in the presence of a team member. Subjects will be given a printed copy of 
the signed, informed consent.    
9.6.1 Waiver of Documentation of Consent/ Alteration of HIPAA Authorization 
A waiver of documentation of consent will be sought for the verbal screening component of the 
study when potential participants are approached by phone. The rights and welfare of the subject 
will not be adversely affected because during the verbal consent process it is explained to the 
subject that we are recording their health information to determine eligibility for the study. The 
research could not practicably be carried out without this waiver as it is not practicable to approach 
and screen all potential participants in person. An alteration of HIPAA authorization will be sought 
for the screening component of the study. The use and disclosure of protected health information 
for the purposes of screening for eligibility involves no more than minimal risk to the privacy of 
participants, as the identifiers will be protected from improper use and disclosure, identifiers will 
be destroyed at the earliest opportunity consistent with the conduct of the study, and protected 
health information will not be reused or disclosed to any other person or entity, except as required 
by law for authorized oversight of the research project.  The research could not practicably be 
conducted without access to and use of the protected health information collected during 
screening to determine eligibility.   
 Study staff stress during the verbal consent that the screening is voluntary, but necessary if they 
wish to participate, and that they can decline and stop the process at any point. Screening may also 
take place in person in which case the participant will sign the screening consent prior to the 
collection of health information to determine eligibility, and a waiver of documentation of consent 
will not apply. A written informed consent will be obtained prior to study entry and before any 
study procedures are performed, and this will include the discontinuation of pancreatic enzyme 
medication for those participants who are taking this medication at the time of enrollment in the 
study. 
9.7 
Payment to Subjects 
9.7.1 Payments to subject   
All participants are adults (30-75 yr.) and will be compensated $200 for each visit for time and 
effort associated with each study visit: Visit 1 Visit 2.  Subjects with CP will receive a total of $400 
($200 for each visit), while healthy subjects will receive $200 (one visit only).  Subjects living outside 
of the Philadelphia area will receive reimbursement for travel expenses (mileage, tolls, e.g.). 
10 PUBLICATION 
The research data obtained through the study outlined in this protocol will be shared with the 
research community, both through oral presentation at scientific meetings, and in written form, as 
published manuscripts.  Reported factual material (primary data on which summary statistics and 
tables are based), commonly accepted in the scientific community as necessary to document and 
support research findings, will be provided in a timely fashion upon request by members of the 
scientific community to the principal investigator for a period of three years following acceptance 
for publication. The CHOP investigator will have access to the complete study data.  
 

 
  
 
 
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