Clinical trial NCT03097029
Conditions: Short Bowel Syndrome
Keywords: pancreatic enzymes
Sponsor: Children's Hospital of Philadelphia
Start date: 2017-03-24; Completion date: 2019-02-01
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Patients with short bowel syndrome have a high mortality rate that is mainly attributed to complications from central lines and long-term intravenous (IV) nutrition. There are few medical therapies to date that improve gut absorption in patients with short bowel syndrome. The primary objective of this study is to evaluate if absorption from the GI tract improves in subjects with short bowel syndrome following therapy with pancreatic enzymes.

Detailed description:
This is an interventional study of subjects with short bowel syndrome to determine if enteral absorption improves following therapy with pancreatic enzymes. The study will assess enteral absorption and nutritional status at baseline through a series of stool tests, blood tests, and anthropometric measurements. Following approximately ten days of therapy with pancreatic enzymes, the study will reassess enteral absorption.

Arms: arm 1: All subjects in this study will have exposure to therapy with pancreatic enzymes for a period of about ten days.
Interventions: intervention 1: Pancreatic Enzyme
Intervention descriptions: intervention 1: All subjects will take pancreatic enzymes at a dose appropriate for their weight. Pancreatic enzymes are used to help digest fat and other nutrients.

Protocol documents:
Prot_SAP_000.pdf: 
 
  
 
 
IRB  
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Use of Pancreatic Enzymes in Short Bowel Syndrome 
 
 
November 6, 2019 
 
Principal Investigator 
Nina N. Sainath, MD 
3401 Civic Center Boulevard 
Division of Gastroenterology, Hepatology, and Nutrition 
Philadelphia, PA 19104 
Phone 617-680-8701 
email: sainathn@email.chop.edu 
 
  
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
Table of Contents .................................................................................................................i 
Abbreviations and Definitions of Terms ............................................................................. iii 
Abstract .............................................................................................................................. iv 


 
  
 
 
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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 ...................................................................................... 33 
6 
STATISTICAL CONSIDERATIONS ........................................................................................................... 23 
7 
STUDY MEDICATION............................................................................................................................ 41 
8 
SAFETY MANAGEMENT…………………………………………………………………………………………………………………….28 
9 
STUDY ADMINISTRATION  ................................................................................................................... 45 
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 
CFA 
 
Coefficient of fat absorption 
CCK 
 
Cholecystokinin  
CNA 
 
Coefficient of nitrogen absorption  
CreonTM 
 
Creon (pancrelipase) Delayed-Release Capsules  
CTRC 
 
Clinical Translational Research Center 
DXA 
 
Dual energy x-ray absorptiometry 
FFM 
 
Fat free mass 
FM 
 
Fat mass 
GH 
 
Growth hormone 
GLP-2 
 
Glucagon-like-peptide 2 
HA 
 
Heptadecanoic acid 
IGFBP-3 
 
Insulin-like growth factor binding protein 3 
IGF-1 
 
Insulin-like growth factor 1 
MBT 
 
Malabsorption blood test 
NDS  
 
Nutrition Data System 
PA 
 
Pentadecanoic acid 
PHI  
 
Personal health information 
PIVKA  
 
Proteins induced by vitamin K antagonism or absence 
QOL 
 
Quality of life 
SAE  
 
Serious adverse event 
SBS 
 
Short bowel syndrome  
THA 
 
Triheptadecanoic acid 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
  
 
 
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ABSTRACT 
Context: Patients with short bowel syndrome (SBS) have a high mortality rate that is mainly 
attributed to complications from central venous access and parenteral nutrition1. The primary goal 
in clinical management of patients with SBS is to wean off of parenteral nutrition and establish 
enteral autonomy. This goal can be difficult to achieve due to the significant malabsorption that 
occurs in SBS. There are few medical therapies that improve absorption in patients with SBS. The 
impact of pancreatic enzymes on enteral absorption has not been evaluated in this patient 
population. SBS is a life threatening illness in which it is essential to maximize absorption in order to 
minimize morbidity and mortality.  
Objectives: The objective of this study is to evaluate if enteral absorption improves in subjects with 
SBS following therapy with pancreatic enzymes. Enteral absorption will primarily be assessed using 
stool coefficient of fat absorption (CFA). Secondary objectives of the study include measurement of 
coefficient of nitrogen absorption (CNA) and stool bomb calorimetry (BC) before and after 
pancreatic enzyme administration. A subset of subjects will also have enteral absorption measured 
using the malabsorption blood test (MBT) before and after pancreatic enzyme administration.   
Study Design:  This is an interventional study of subjects with SBS who will be evaluated before and 
after pancreatic enzyme administration. A subset of subjects will have the MBT performed before 
and after pancreatic enzyme administration as a measure of enteral fat absorption.  
Setting/Participants: This outpatient study will be conducted at CHOP. Approximately, sixteen 
subjects with SBS between the ages of 4.0 and 17.9 years and ten adult subjects with SBS between 
the ages of 18 and 75 years will be enrolled. Only adult subjects have the option to be part of the 
subset that has the MBT.  
Study Interventions and Measures:  Subjects with SBS will be evaluated both on and off Creon™, a 
pancreatic enzyme medication. Enteral absorption will be measured before and after pancreatic 
enzyme administration. Enteral absorption will be measured using three methods: CFA, CNA, and 
BC.  A subset of adult subjects will also have the MBT before and after pancreatic enzyme 
administration. Subjects with SBS have significant malabsorption and have several proposed 
mechanisms of functional pancreatic insufficiency. The longterm goal is to determine if pancreatic 
enzymes improve enteral absorption in patients with SBS, it may allow parenteral nutrition to be 
weaned and improve both their morbidity and mortality.  
 


 
  
 
 
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PROTOCOL SYNOPSIS 
Study Title 
The Use of Pancreatic Enzymes in Short Bowel Syndrome  
Funder 
AbbVie Inc.  
Clinical Phase 
Phase II – This is an open-label intervention therapeutic exploratory study 
Study Rationale 
Patients with short bowel syndrome (SBS) have a high mortality rate that is 
mainly attributed to complications from central venous access and parenteral 
nutrition1. In 2012, Squires et al1 published the largest retrospective review to 
date that described outcomes for patients with SBS at fourteen centers in the 
United States. The study showed that over a 5-year period, the mortality rate 
was 27%. Central venous access and parenteral nutrition also expose patients 
to an increased risk of several morbidities, including gallstones, cholestatic liver 
disease, glucose instability, deep vein thromboses, bone disease, and emboli. 
The ultimate goal in clinical management of patients with SBS is to wean off of 
parenteral nutrition and establish enteral autonomy. This goal can be difficult 
to achieve due to the significant malabsorption that occurs in SBS. Madsen et 
al2 studied a cohort of subjects with short bowel syndrome, high stool output, 
and high fecal energy losses and demonstrated that they had  a low coefficient 
of fat absorption of about 48%. This study demonstrates how significant 
malabsorption can be in patients with SBS and therefore highlights the 
challenge that clinicians face in attempting to minimize parenteral nutrition 
use. There are few medical therapies that improve absorption in patients with 
SBS. To date, teduglutide, a glucagon-like-peptide 2 (GLP-2) analog, is the only 
medication that has been clinically shown to improve intestinal adaptation and 
allow parenteral nutrition to be weaned in adults3. This drug shows great 
promise, but there are several concerns, such as increased risk of cancer and a 
loss of response with drug withdrawal.   
Pancreatic enzymes have been successful in improving enteral absorption in 
several patient populations, most notably in cystic fibrosis4,5. The impact of 
pancreatic enzymes on enteral absorption has not been evaluated in patients 
with SBS and will be the main focus of this study. Maximizing absorption to 
reduce parenteral nutrition needs in this patient population will be essential in 
reducing morbidity and mortality.  
The main objective of this study is to demonstrate if therapy with pancreatic 
enzymes will improve enteral fat absorption in patients with SBS. We 
hypothesize that patients with SBS are functionally pancreatic insufficient as a 
result of their intestinal resection for the following reasons: 1) decreased 
cholecystokinin (CCK) secretion and impaired enteroendocrine hormone 
secretion, 2) rapid intestinal transit, 3) high intestinal intraluminal volume, and 
4) gastric acid hypersecretion.  
Exploratory aspects of the study also address the changes that nutrient 
absorption will have on intestinal adaptation and enteroendocrine hormone 
signaling. In our study, we will measure several hormone and enteroendocrine 


 
  
 
 
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hormone concentrations at baseline and following administration of pancreatic 
enzymes both as evidence for proper digestion and as markers of intestinal 
adaptation.  
SBS is a life threatening disease process with a paucity of noninvasive therapies 
that directly improve enteral absorption and improve patient outcome. If 
pancreatic enzyme medication is found to improve enteral absorption, this 
study will increase the clinical use of pancreatic enzymes in patients with SBS. 
This study will also provide further information on the mechanisms of 
malabsorption in patients with SBS, which could facilitate identification of other 
therapeutic targets to improve enteral absorption. It will provide the 
framework for larger studies to improve enteral absorption in patients with 
SBS.  
Study Objective(s) 
Primary: 
The primary objective of this study will be to determine if enteral absorption 
improves in subjects with SBS following therapy with pancreatic enzymes. 
Patients with SBS have significant fat malabsorption for several reasons2. Lipid 
malabsorption in SBS occurs due to bowel resection, diluted pancreatic 
enzymes, altered enteroendocrine hormone signaling, acid hypersecretion, and 
rapid intestinal transit6. Pancreatic enzymes play a major role in enteral fat 
absorption.  We propose that administering pancreatic enzymes to subjects 
with SBS will improve absorption of enteral nutrition.  
The primary hypothesis of this study is:   
H1: Pancreatic enzyme medication will improve enteral fat absorption in 
subjects with SBS, which will be indicated by an improved stool coefficient of 
fat absorption (CFA).  
Secondary:  
A secondary hypothesis of this study will aim to further characterize the 
effect that pancreatic enzyme medication will have on global nutrient 
absorption.  
H2: Coefficient of nitrogen absorption (CNA) and bomb calorimetry (BC) will 
detect changes in enteral protein absorption and stool energy losses, 
respectively, before and after therapy with pancreatic enzymes.  
We will address the unique difficulty of measuring enteral fat absorption in 
subjects with SBS. Fat absorption in a subset of subjects will be measured using 
the MBT. CCK concentration will also be measured in this subset as an 
additional area of exploration, as CCK plays a pivotal role in pancreatic enzyme 
secretion6. Additionally, we will explore the effect that improved nutrient 
absorption will have on intestinal adaptation by measuring changes in markers 
of intestinal mass and hormone levels.  


 
  
 
 
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H3: The MBT will detect changes in enteral fat absorption before and after 
therapy with pancreatic enzyme medication on a subset of subjects. It will also 
help characterize the degree of pancreatic insufficiency in subjects. Baseline 
serum CCK concentration and serum CCK concentration following pancreatic 
enzyme therapy will also be determined in this subset.  
H4: By promoting lipid digestion and release of free fatty acids, pancreatic 
enzymes will promote intestinal adaptation by stimulating endocrine signaling. 
Specifically, GLP-2, insulin-like growth factor 1 (IGF-1), insulin-like growth factor 
binding protein 3 (IGFBP-3), and growth hormone (GH) concentrations will be 
measured from blood samples before and after treatment with pancreatic 
enzymes. Plasma citrulline will also be measured as a marker of intestinal mass 
before and after treatment with pancreatic enzymes.  
Test Article 
CreonTM, a pancreatic enzyme preparation 
Study Design 
 
This study will characterize enteral absorption, including enteral fat absorption, 
in subjects with SBS. We propose a longitudinal study design to assess enteral 
absorption before and after pancreatic enzyme medication in subjects with 
SBS.   


 
  
 
 
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Inclusion and 
Exclusion: 
INCLUSION CRITERIA 
General Inclusion Criteria 
• 
History of a small bowel resection  
o If small bowel resection occurred under 18 years of age, subjects 
must have dependence on parenteral nutrition for at least three 
months following small bowel resection 
o If small bowel resection occurred at 18 years of age or older, 
subjects must have 200 centimeters or less of residual bowel length 
and must have more than 3 bowel movements per day following 
small bowel resection  
• 
Age 4 years to 75 years  
• 
Usual state of health for the past two weeks with no medication changes 
• 
Able to participate in a study for about four weeks with 2-4 study visits 
• 
Able to take pancreatic enzyme medication orally 
MBT/CCK Subset Inclusion Criteria 
• 
Age 18 years to 75 years  
 
All available details of estimated bowel length and presence or absence of an 
ileocecal valve will be taken into account, but there are no inclusion restrictions 
based on this information.  
 
EXCLUSION CRITERIA 
General Exclusion Criteria  
• 
Significant disease other than SBS affecting the gastrointestinal tract that 
impacts absorption or digestion  
• 
Motility disorders that affect the upper gastrointestinal tract (i.e. chronic 
pseudo-obstruction, severe gastroparesis) or motility disorders that are 
poorly controlled 
• 
Unable to discontinue medications that directly alter fat absorption (i.e. 
bile acid sequestering agents, orlistat, weight loss medications, 
ursodeoxycholic acid) for one week prior to the first blood draw for the 
study until completion of stool collection following study visit 2 based on 
the preference of the subject or primary gastroenterologist. Permission 
must be obtained from the primary gastroenterologist before discontinuing 
medications in this category.  
• 
Cholestatic liver disease defined as a serum conjugated bilirubin greater 
than 1.0 mg/dL), chronic renal failure requiring dialysis or listed for kidney 
transplant, or gout   
• 
History of a pork allergy 
• 
Candidate for intestinal transplantation and listed as status 1 
• 
Women who are pregnant or lactating  


 
  
 
 
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• 
History of fibrosing colonopathy  
MBT/CCK Subset Exclusion Criteria  
• 
History of a soy or safflower oil allergy 
 
Number Of 
Subjects  
Non-MBT/CCK Subset: 16 subjects with SBS between the ages of 4 years and 
17.9 years 
MBT/CCK Subset: 10 subjects with SBS between the ages of 18 years and 75 
years, subjects will have the option not to perform the MBT  
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 
Subject participation will last about 3-4 weeks.   
Study Phases  
Study Visit 0: Informed consent, full 24 hour dietary recall if written consent 
obtained, blood draw if consent obtained and subject weighs less than 55 
pounds, subjects may complete informed consent by telephone. If informed 
consent is obtained via telephone, then a signed informed consent form will be 
obtained either prior any study procedures, which includes a 24 hour dietary 
recall. 
Study Visit #1: First study visit at CHOP. Subjects on pancreatic enzymes at 
baseline will have a three day washout period. Subjects who are not on 
pancreatic enzymes at baseline will not require a washout period. On the day of 
the study visit, all subjects will have laboratories drawn and anthropometrics. 
Those subjects in the MBT/CCK cohort will have a first MBT performed. 
Subjects who sign the informed consent form at visit 1 will complete a full 24 
hour dietary recall instead of study visit 0. All subjects will be given instructions 
on how to complete a 3-day diet record and a 72-hour stool collection.  
Study Visit #2: Following the initial diet record and stool collection, subjects can 
start pancreatic enzyme medication at study doses. Study visit #2 will be 
scheduled for day 5 of pancreatic enzyme medication. On the day of study visit 
#2, subjects will have laboratories drawn. Those subjects in the MBT/CCK 
cohort will have a second MBT performed. All subjects will complete a second 
3-day diet record and a 72-hour stool collection at home. Following this, 
pancreatic enzyme medication will be discontinued and those subjects who 
were on pancreatic enzyme prior to the study will resume their regular dosing.  
Study Visit #3: All subjects will provide their second 3-day dietary record and 
72-hour stool collection. This visit will be used to ensure subject well-being and 
to monitor for adverse events. Subjects may complete this visit by telephone 
and mail stool samples to CHOP.  
Efficacy Evaluations The efficacy of pancreatic enzyme medication administration (CreonTM) will be 
evaluated in subjects with SBS using CFA as the primary outcome. CNA and BC 
will be measured as secondary outcomes. Some subjects in the MBT/CCK 
cohort will also have the MBT as an outcome of the change in enteral fat 
absorption before and after pancreatic enzyme medication administration.  


 
  
 
 
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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 aim of the study is to compare the outcome CFA before 
and after pancreatic enzyme medication administration in subjects with SBS. 
The secondary outcomes of CNA and BC will also be compared in subjects with 
SBS before and after pancreatic enzyme medication administration. Descriptive 
statistics for CFA, CNA, and BC outcomes (mean, standard deviation, median, 
range, 95% CI) will be calculated for the SBS cohort before and after pancreatic 
enzyme medication administration with paired t-tests or Wilcoxon sign rank 
tests depending on skewness of data.  
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 metrics7.  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 Development Solutions, Hanover, MD8. 
Using this method, population PK modeling is conducted by simultaneously 
fitting structural PK models to both PA and HA concentrations9.   
Descriptive statistics (mean, standard deviation, median, range, 95% CI) will 
also be employed to assess outcomes related to intestinal hormone signaling 
that controls pancreatic enzyme secretion and intestinal adaptation in H4 
(glucagon-like peptide 2, insulin-like growth factor 1, insulin-like growth factor 
binding protein 3, and growth hormone concentrations).  All variables will be 
tested for normality and nonparametric tests used as appropriate.  The change 
in status for these variables before and after pancreatic enzyme medication 
administration will be explored with paired t-tests and Wilcoxon sign rank tests 
depending on skewness. 


 
  
 
 
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MONITORING PLAN 
The Principal Investigator, Dr. Nina Sainath, is ultimately responsible for 
monitoring data integrity, patient safety, and overall study oversight. The study 
will be monitored weekly by the PI and 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, Dr. Sainath, as well as her mentor (Dr. Stallings). For subjects with SBS 
primarily managed at CHOP, members of the Intestinal Rehabilitation Program 
(Dr. Christina Bales) will be consulted immediately for all SAEs. For subjects 
with SBS primarily managed at Penn Medicine/HUP, their primary 
gastroenterologist and co-investigator, Dr. Octavia Pickett-Blakely, will be 
consulted immediately and will assume medical care. SAEs will 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 the PI, Dr. 
Sainath, which will be reviewed weekly by Dr. Stallings.  
 
 
 


 
  
 
 
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SCHEDULE OF STUDY PROCEDURES & STUDY TIMELINE 
Table 1. Summary of Study Visits #1 and #2 and Methods  
 
All 
subjects 
MBT/CCK Subset 
Non-MBT/CCK 
Subset 
All 
subjects 
Assessment 
Visit 0 
Visit 1 
Visit 2 
Visit 1 
Visit 2 
Visit 3 
Obtain informed consent  
● 
 
 
 
 
 
Study Intervention: Administration of CreonTM 
 
 
● 
 
● 
 
Primary Outcome 
 
 
 
 
 
 
Coefficient of Fat Absorption (stool) 
 
● 
● 
● 
● 
 
Secondary Outcomes 
 
 
 
 
 
 
Coefficient of Nitrogen Absorption (stool) 
 
● 
● 
● 
● 
 
Fecal Bomb Calorimetry (stool) 
 
● 
● 
● 
● 
 
Malabsorption Blood Test (MBT) (PA, HA, HA/PA absorption, 
pharmacokinetics) 
 
●# 
●# 
 
 
 
Serum prealbumin 
 
● 
● 
● 
● 
 
Intestinal Adaptation: serum citrulline, IGF-1, IGF BP3, GLP 2, 
GH, stool pH, gastric pH 
 
● 
● 
● 
● 
 
Serum CCK 
 
●# 
●# 
 
 
 
Fecal elastase 
 
● 
 
● 
 
 
Diet 
 
 
 
 
 
 
24-hour dietary recall 
● 
●** 
 
 
 
 
3-day Weighed Food Record 
 
● 
● 
● 
● 
 
Safety 
 
 
 
 
 
 
Complete Blood Count with Differential 
 
● 
● 
● 
● 
 
Serum Basic Metabolic Panel  
 
● 
● 
● 
● 
 
Serum Hepatic Function Panel 
 
● 
● 
● 
● 
 
Adverse Event Monitoring  
 
● 
● 
● 
 
 ● 
● 
Other 
 
 
 
 
 
 
Anthropometry: height, weight, DXA, skinfolds, 
circumferences 
 
● 
 
● 
 
 
Nutrition Labs: serum vitamins A, E, K; 25-OH vitamin D; zinc; 
selenium; fatty acid profile 
●* 
● 
 
● 
 
 
Health History and Medications 
 
● 
 
● 
 
 
Home Environment Questionnaire  
 
● 
 
● 
 
 
Pancreatic enzyme medication adherence  
 
 
● 
 
● 
● 
Quality of life (MOS SF-36 for adults, PedsQL for subjects < 18 
years)  
 
● 
 
● 
  
 
* Nutrition labs will only be drawn at study visit 0 in subjects who weigh less than 25 kilograms 
** Subjects who sign the informed consent form at the start of study visit 1 will have a 24 hour 
dietary recall performed at study visit 1 instead of study visit 0 
# Subjects in the MBT/CCk cohort will have the option not to have the MBT and serum CCK 
 
 
 


 
  
 
 
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Table 2. Study Timeline 
Table 3. Protocol for MBT/CCK subset# 
Protocol 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
MBT #1 
Wash-out  
No PE* 
Wash-out 
No PE 
Wash-out 
No PE 
- Fast from 
8 pm 
- No dairy 
- No 
alcohol 
- Normal 
activity 
STUDY 
VISIT #1 
MBT at 8 
am 
- Lunch at 
2 pm 
- 9 hourly 
blood 
draws 
LABS 
ANTHROS  
 Home 
- Return to 
usual diet 
Diet 
record 
(day 1) 
- Diet record 
(day 2) 
- 72-hour 
stool 
collection 
(day 1) 
- Diet record 
(day 3) 
- 72-hour stool 
collection (day 
2) 
- 72-hour 
stool 
collection 
(day 3) 
- PE can be 
started 
following 
stool 
collection 
-- 
MBT #2 
 
PE 
treatment 
PE 
treatment 
PE 
treatment 
PE 
treatment 
- Fast from 
8 pm 
- No dairy 
- No 
alcohol 
- Normal 
activity 
PE 
treatment 
STUDY 
VISIT #2 
MBT at 8 
am 
- Lunch at 
2 pm 
- 9 hourly 
blood 
draws 
LABS 
PE 
treatment 
Home 
- Return 
to usual 
diet 
PE 
treatment 
Diet record 
(day 1) 
PE treatment 
- Diet record 
(day 2) 
- 72-hour stool 
collection (day 
1) 
PE 
treatment 
- Diet 
record (day 
3) 
- 72-hour 
stool 
collection 
(day 2) 
PE treatment 
- 72-hour 
stool 
collection 
(day 3) 
- PE can be 
discontinued 
following 
stool 
collection 
* PE = pancreatic enzymes 
# subjects in the MBT/CCK subset who elect not to have the MBT will follow the non-MBT/CCK 
protocol 
  
Year 1 (2016-2017) 
 
  
 May 
 
June  
 
July 
Aug 
 
Sept 
 Oct 
 
Nov 
 
Dec 
 
Jan 
 
Feb 
 
March 
Total  
Start-up 
x 
  
  
   
  
  
  
  
  
  
  
MBT/CCK Subset 
  
  
  
  
  
  
  
  
  
  
  
  
Baseline 
  
1 
0 
1 
3 
3 
2 
 
  
  
  
10 
Follow-up 
  
0 
1 
1 
3 
3 
2 
 
  
  
  
10 
Non-MBT/CCK Subset 
  
  
  
  
  
  
  
  
  
  
  
  
Baseline 
  
0 
0 
5 
4 
4 
3 
 
  
  
  
16 
Follow-up 
  
0 
0 
5 
4 
4 
3 
 
  
  
  
16 
  
  
  
  
  
  
  
  
  
  
  
  
  
Total Visits 
  
1 
1 
12 
14 
14 
10 
 
  
  
  
52 
  
  
  
  
  
  
  
  
  
  
  
  
  
Data Analysis  
  
  
  
  
  
  
  
  
x 
x 
x 
  
Close out /Writing  
  
  
  
  
  
  
  
  
x 
x 
x 
  


 
  
 
 
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Table 4. Protocol for NON -MBT/CCK subset 
Protocol 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Phase 1 
Wash-out  
No PE 
Wash-out 
No PE 
Wash-out 
No PE 
 
STUDY 
VISIT #1 
LABS 
ANTHROS 
Home 
- Normal 
diet 
Diet 
record 
(day 1) 
- Diet 
record 
(day 2) 
- 72-hour 
stool 
collection 
(day 1) 
- Diet record 
(day 3) 
- 72-hour stool 
collection (day 
2) 
- 72-hour stool 
collection (day 
3) 
- PE can be 
started 
following stool 
collection 
-- 
Phase 2  
PE 
treatment 
PE 
treatment 
PE 
treatment 
PE 
treatment 
 
PE 
treatment 
STUDY 
VISIT #2 
LABS 
 
PE 
treatment 
Home 
- normal 
diet 
PE 
treatment 
Diet 
record 
(day 1) 
PE treatment 
- Diet record 
(day 2) 
- 72-hour stool 
collection (day 
1) 
PE treatment 
- Diet record 
(day 3) 
- 72-hour stool 
collection (day 
2) 
PE treatment 
- 72-hour stool 
collection (day 3) 
- PE can be 
discontinued 
following stool 
collection 
 
1 BACKGROUND INFORMATION AND RATIONALE 
1.1 
Introduction 
Short bowel syndrome (SBS) occurs when there is a history of prior bowel resection and the 
residual functional intestinal mass is insufficient to allow for adequate absorption of fluid, 
electrolytes, nutrients, and micronutrients provided by an age appropriate diet. There are several 
etiologies of SBS, which differ between pediatric and adult populations. In adults, the most 
common causes of SBS include mesenteric ischemia, Crohn disease, malignancy, radiation enteritis, 
surgical complications, and trauma6. In pediatric patients, SBS is most commonly due to necrotizing 
enterocolitis and congenital anomalies, such as intestinal atresia, gastroschisis, and malrotation10.  
Patients with SBS have a high mortality rate that is mainly attributed to complications from central 
venous access and parenteral nutrition1. In 2012, Squires et al1 published the largest retrospective 
review to date that described outcomes for patients with SBS at fourteen centers in the United 
States. The study showed that over a 5-year period, the mortality rate was 27%. Central venous 
access and parenteral nutrition also expose patients to an increased risk of several morbidities, 
including gallstones, cholestatic liver disease, glucose instability, deep vein thromboses, bone 
disease, and emboli. The ultimate goal in clinical management of patients with SBS is to wean off of 
parenteral nutrition and establish enteral autonomy. This goal can be difficult to achieve due to the 
significant malabsorption that occurs in SBS. Madsen et al2 studied a cohort of subjects with short 
bowel syndrome, high stool output, and high fecal energy losses and demonstrated that they had  a 
low coefficient of fat absorption of about 48%. This study demonstrates how significant 
malabsorption can be in patients with SBS and therefore highlights the challenge that clinicians face 
in attempting to minimize parenteral nutrition use.  
There are few medical therapies that improve absorption in patients with SBS. To date, teduglutide, 
a glucagon-like-peptide 2 (GLP-2) analog, is the only medication that has been clinically shown to 
improve intestinal adaptation and allow parenteral nutrition to be weaned in adults3. This drug 
shows great promise, but there are several concerns, such as increased risk of cancer and a loss of 
response with drug withdrawal.   


 
  
 
 
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Pancreatic enzymes have been successful in improving enteral absorption in several patient 
populations, most notably in cystic fibrosis4,5. The impact of pancreatic enzymes on enteral 
absorption has not been evaluated in patients with SBS and will be the main focus of this study.  
Our primary objective is to demonstrate that treating patients with SBS with pancreatic enzymes 
will improve enteral fat absorption. However, exploratory aspects of the study also address the 
changes that nutrient absorption will have on intestinal adaptation and enteroendocrine hormone 
signaling.  
SBS is a life threatening disease process with a paucity of noninvasive therapies that directly 
improve enteral absorption and improve patient outcome. Maximizing absorption to reduce 
parenteral nutrition needs in this patient population will be essential in reducing morbidity and 
mortality. This study will also provide further information on the mechanisms of malabsorption in 
patients with SBS, which could facilitate identification of other therapeutic targets to improve 
enteral absorption. It will provide the framework for larger studies to improve enteral absorption in 
patients with SBS.  
1.2 
Name and Description of Investigational Product or Intervention 
Creon™ (pancrelipase) Delayed-Release Capsules), a pancreatic enzyme preparation, is a drug that 
requires prescription for use.  It is approved for exocrine pancreatic insufficiency due to cystic 
fibrosis, chronic pancreatitis, or other conditions. In the study, we will use Creon 6 TM, 6,000 USP 
units of lipase; Creon12 TM, 12,000 USP units of lipase; Creon24 TM, 24,000 USP units of lipase; and 
Creon36 TM, 36,000 USP units of lipase.  
1.3 
Findings from Non-Clinical and Clinical Studies 
Creon™ is FDA approved for use in exocrine pancreatic insufficiency due to cystic fibrosis and other 
etiologies. It has been used anecdotally in patients with SBS and is cited as therapy for patients with 
SBS by experts in the field11. The effect of pancreatic enzymes on enteral absorption in SBS has 
never been formally studied.  
1.4 
Selection of Drugs and Dosages 
This is a proof of concept study and the use of pancreatic enzymes in short bowel syndrome has not 
been studied before. As a result, our preference would be to use the highest doses of pancreatic 
enzyme that are deemed safe for our subjects in order to assess if absorption can be improved.    
We have based pancreatic enzyme dosing on typical dosing used by the senior dietitian and a 
senior physician at the Cystic Fibrosis Center at the Children’s Hospital of Philadelphia (CHOP) and 
as recommended by the most recent consensus statement on pancreatic enzyme dosing in cystic 
fibrosis12. The recommended dosing for meals ranges from 500 – 2500 lipase units/kg/meal. The CF 
Center at CHOP uses a maximum dose of 2500 lipase units/kg/meal and 1250 lipase units/kg/snack. 
We will aim to administer about 1500 – 2500 lipase units/kg/meal and 750 – 1250 lipase 
units/kg/snack in this study (see Table 5 below). Exact dosing will depend on the subject’s 
complicated enteral feeding regimen. Pancreatic enzyme dosing will be weight based and we will 
not exceed 10,000 lipase units/kg/day for each patient12,13.  
We anticipate that several subjects in this study will have a complicated enteral feeding regimen 
that may be comprised of one or more of the following options: 1) bolus gastrostomy tube feeds, 2) 


 
  
 
 
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continuous overnight gastrostomy tube feeds, and 3) continuous gastrostomy tube feeds for 18 -24 
hours of the day. Please see Table 5 below for a summary of goal pancreatic enzyme dosing for 
each of these enteral feeding regimens. Subjects should be able to take pancreatic enzyme 
medication orally in order to be included in the study even if they rely on a gastrostomy tube or 
jejunostomy tube.  
Table 5. Goal Pancreatic Enzyme Dosing* 
 
Pancreatic Enzyme Dosing 
Meal 
1,500 – 2,500 lipase units/kg/meal 
Snack 
750 – 1,250 lipase units/kg/snack 
Bolus enteral feeds 
(typically 1 hour infusion) 
1,500 – 2,500 lipase units/kg/meal administered with each 
bolus+ 
Overnight enteral feeds 
(typically 8-12 hours) 
1,500 – 2,500 lipase units/kg/meal administered at the 
start and end of the feed 
Continuous enteral feeds  
(typically 20-24 hours) 
• 
1,500 – 2,500 lipase units/kg/meal administered at 
the start and end of the feed 
• 
While awake and during continuous feed, enzymes 
dosed every 4 hours based on grams of fat in formula 
(not to exceed 4,000 lipase units/grams of fat/day) 
* Will not exceed maximum daily enzyme dosing of 10,0000 lipase units/kg/day 
+ The dose of enzymes with each bolus depends on the enteral feeding regimen, grams of fat, and the volume 
and number of boluses 
Bolus feeds: The dose of enzymes that each subject receives prior to each bolus will depend on the 
volume and total number of boluses received per day. We will attempt to cover each bolus with a 
maximum dose of 1500 – 2500 lipase units/kg/meal, but this may be reduced if boluses are smaller 
in volume or occur frequently.  
Overnight feeds: This group includes subjects on overnight enteral feeds for 8-12 hours. These 
subjects will receive one meal dose of Creon™ (1500 - 2500 lipase units/kg) prior to feeds and one 
meal dose of Creon™ at the end of feeds, consistent with our current practice at CHOP. 
Continuous feeds: This group includes those subjects on continuous enteral feeds for 20-24 hours 
of the day. For these subjects, we will dose enzymes every 4 hours while awake based on grams of 
fat in the formula and based on recommended dosing per grams of fat. Overnight, they will receive 
one meal dose of Creon™ (1500 – 2500 lipase units/kg) before and after the overnight feed.  
We will not exceed 10,000 lipase units/kg/day or 4000 lipase units/grams of fat/day for any 
subject13. Each subject will receive pancreatic enzyme medication for a total of ten days. They will 
start Creon™ 4 days prior to study visit #2, they day of study visit #2, and then for five days after the 
visit until they have completed the second stool collection.  


 
  
 
 
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1.5 
Relevant Literature 
Pancreatic enzymes have been used in patients with SBS and it is cited as a possible therapy for use 
in SBS11. The main objective of this study is to demonstrate that therapy with pancreatic enzymes 
will improve enteral fat absorption in patients with SBS. We hypothesize that patients with SBS are 
functionally pancreatic insufficient as a result of their intestinal resection for the following reasons: 
1) decreased cholecystokinin (CCK) secretion and impaired enteroendocrine hormone secretion, 2) 
rapid intestinal transit, 3) high intestinal intraluminal volume, and 4) gastric acid hypersecretion.  
Cholecystokinin (CCK) is a hormone released by enteroendocrine cells in the small bowel. CCK is 
responsible for stimulating pancreatic and gallbladder secretions and inhibiting gastric emptying6. 
These functions together promote absorption. It has been shown that patients with SBS have a 
decreased CCK response following a meal when compared to healthy controls14. This impaired 
response may occur because bowel resection directly results in the loss of cells that secrete CCK. It 
also may occur due to the impaired secretion of other enteroendocrine hormones that affect CCK 
secretion. Decreased CCK production would result in decreased secretion of pancreatic enzymes 
into the intestinal lumen and thus functional pancreatic insufficiency.  
A second proposed mechanism for functional pancreatic insufficiency in SBS is related to the rapid 
intestinal transit that occurs in this population. The distal small bowel is responsible for the 
secretion of several enteroendocrine hormones, including peptide YY and GLP-26. In a small study 
on patients with SBS, Nightingale et al15 showed that patients who lack a distal small bowel and 
colon had more rapid intestinal transit compared to a healthy control population. This same study 
also showed that peptide YY hormone secretion was impaired following a meal in these same 
subjects compared to healthy subjects. This study suggests that resection of the distal small bowel 
and colon impairs peptide YY secretion, which results in accelerated intestinal transit. It is often 
thought that peptide YY and other hormones secreted by the distal small bowel and colon act as an 
‘intestinal break’, slowing down movement of the intestine in order to promote absorption6,15. Loss 
of this ‘intestinal break’ due to bowel resection is therefore thought to lead to faster movement of 
food through the intestine. Rapid intestinal transit impairs digestion and absorption, as it does not 
allow luminal contents adequate time to interface with digestive enzymes and the surface mucosa 
of the bowel. Thus, exogenous pancreatic enzymes can more readily promote micelle formation in 
the proximal bowel for prompt lipid absorption. 
A third proposed mechanism for functional pancreatic insufficiency in SBS is due to the dilution of 
pancreatic enzymes in the intestinal lumen. The notion of diluted pancreatic enzymes is supported 
by the clinical observation that when fecal elastase levels are checked as a measure of pancreatic 
function in patients with SBS, levels are often low due to dilution in watery stool. Though the 
pancreas may still secrete enzymes into the duodenum, they are likely to be diluted by the high 
volume of intestinal contents and therefore be less effective. This increased intraluminal volume is 
not only due to malabsorption, but also due to a high enteral caloric intake. Patients with SBS often 
receive a higher amount of enteral calories than required by healthy patients of a similar age. 
Finally, gastric acid hypersecretion may contribute to functional pancreatic insufficiency in patients 
with SBS.  Gastric acid hypersecretion, specifically, tends to occur for months following intestinal 
resection. It is thought to be due to altered enteroendocrine hormone signaling following resection 
and a loss of inhibition of gastrin that leads to increased gastric acid production6,16,17. The effect of 
gastric acid hypersecretion is two-fold in that it increases the volume of contents in the intestinal 


 
  
 
 
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lumen, which serves to dilute pancreatic enzymes present in the lumen. It also drives the luminal 
pH in the small bowel down, which results in suboptimal activity of pancreatic enzymes6,16,17. 
Our primary objective is to demonstrate that treating patients with SBS with pancreatic enzymes 
will improve enteral fat absorption. We will look to determine if administration of pancreatic 
enzymes in these subjects with SBS results in a change in CFA, as well as other markers of 
absorption, including stool bomb calorimetry and coefficient of nitrogen absorption (CNA).  
An exploratory aspect of this study includes the use of the malabsorption blood test (MBT) as a 
measure of enteral absorption. Clinically, it is challenging to measure absorption in patients with 
SBS and this is typically estimated by monitoring height, weight, and serum micronutrient levels. 
This study will be one of the first to perform multiple measures of absorption on patients with short 
bowel syndrome. Currently, the gold standard for gut absorption is the CFA. The MBT will be 
utilized on a subset of subjects in this study as an additional measure of enteral fat absorption, but 
also to characterize the degree of pancreatic insufficiency in subjects. In this test, subjects consume 
a high fat shake that contains pentadecanoic acid (PA), a free fatty acid, and triheptadecanoic acid 
(THA), a triglyceride. Baseline serum levels of PA and THA are measured and then serial serum 
levels are checked following consumption of the shake allowing calculations to determine enteral 
fat absorption to be made. The MBT is unique in that it measures absorption of both a triglyceride 
and a free fatty acid. Improved pancreatic function should result in improvement of triglyceride 
absorption specifically, as absorption of free fatty acids does not depend upon lipase.  
Exploratory aspects of the study also address the changes that nutrient absorption will have on 
intestinal adaptation and enteroendocrine hormone signaling. Intestinal adaptation refers to the 
process of improving and maximizing the absorptive capacity of the residual intestine in patients 
with SBS. It is clear that intestinal resection alters enteroendocrine hormone signaling6,18.  
Alterations in enteroendocrine hormone signaling impact both intestinal absorption and transit. As 
mentioned, repletion of one intestinal hormone, GLP-2, does improve absorptive capacity of the 
small intestine3. 
Endocrine hormones, such as CCK, stimulate proper digestion of triglyceride for fat absorption, but 
then free fatty acids also mediate downstream endocrine signaling.  It is clear that the type of 
macronutrient, as well as the phase of digestion are both important contributors in the stimulation 
of enteroendocrine cells19. For example, an undigested lipid does little to stimulate 
enteroendocrine hormone secretion, whereas free fatty acids and monoacylglycerols bind to 
specific receptors to stimulate hormone secretion, such as GLP-2. Patients with SBS have impaired 
secretion of GLP-2, which is associated with poor intestinal growth and absorption6. Removal of 
bowel also results in resection of enteroendocrine cells, which explains part of the change in 
hormonal signaling. One study20 demonstrated that rats with a significant bowel resection 
demonstrated improved small bowel growth and adaptation with exposure to GLP-2 and enteral 
nutrition together compared to enteral nutrition alone, GLP-2 alone, or parenteral nutrition.  Thus, 
not only do enteric hormones allow for proper digestion and absorption, but proper digestion also 
stimulates intestinal growth.  This study also highlights that the delivery of nutrients into the bowel 
plays a crucial role in hormone signaling.  
Several markers of intestinal adaption exist. Insulin-like growth factor 1 (IGF-1) is thought to play a 
key role in intestinal growth, specifically in that it likely serves downstream of the action of GLP-
220,21. Though it is produced primarily by the liver, IGF-1 is also thought to be produced locally in the 
intestine. Data on growth hormone and IGF-1 in humans has been conflicting, though a study by 


 
  
 
 
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Goulet et al21 demonstrated improved absorption and decreased dependence on parenteral 
nutrition following treatment with growth hormone.  These patients had increased plasma levels of 
citrulline, a measure of total intestinal mass, as well as increased serum IGF-1 and insulin-like 
growth factor binding protein 3 (IGFBP-3) concentrations in association with growth hormone (GH) 
therapy.   
In our proposed study, we will explore how improved nutrient absorption alters intestinal 
adaptation and enteric hormone secretion. We will measure baseline GLP-2, IGF-1, IGFBP-3, GH, 
and citrulline serum levels. Following administration of pancreatic enzymes, we will assess if 
improved digestion of nutrients promotes intestinal adaptation by stimulation of enteroendocrine 
cells. This would be reflected in an increase in serum levels of GLP-2, IGF-1, IGFBP-3, GH, and 
citrulline following exposure to pancreatic enzyme medication.  
As outlined above, rapid intestinal transit, high intestinal luminal volume that may dilute pancreatic 
enzymes, acid hypersecretion, and altered enteroendocrine hormone secretion all serve as likely 
causes of functional pancreatic insufficiency in patients with short bowel syndrome. In the 
proposed study, we will measure fat absorption in subjects with SBS at baseline and following 
exposure to pancreatic enzyme medication. If treatment with pancreatic enzymes results in 
improved enteral absorption, it could allow parenteral nutrition to be decreased. This may 
substantially improve morbidity and mortality in patients with SBS. Furthermore, pancreatic 
enzymes are a noninvasive intervention with a good safety profile in other disease processes. It 
would be easy to incorporate their use into the clinical care of patients with SBS if there was 
evidence that pancreatic enzymes improve enteral absorption.   
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. 
2 STUDY OBJECTIVES 
2.1 
Primary Aim 
2.1.1.   The primary aim of this study is to determine if pancreatic enzymes improve enteral fat 
absorption in subjects with SBS. Enteral fat absorption will be measured as CFA. For each subject, 
CFA will be compared before and after administration of pancreatic enzyme medication.  
2.2 
Secondary Aims 
2.2.1. The secondary aim of this proposal is to assess the effect that administration of pancreatic 
enzymes will have on global absorption. Specifically, CNA and stool BC will be measured to detect 
changes in enteral protein absorption and stool energy losses, respectively, before and after 
administration of pancreatic enzymes.  


 
  
 
 
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We hope to address the unique difficulty of measuring enteral fat absorption in subjects with SBS. 
Fat absorption in a subset of subjects will be measured using the MBT. CCK concentration will also 
be measured in this subset as an additional area of exploration, as CCK plays a pivotal role in 
pancreatic enzyme secretion6. Additionally, we hope to explore the effect that improved nutrient 
absorption will have on intestinal adaptation by measuring markers of intestinal mass and hormone 
levels.  
2.2.2. We will explore the ability of the MBT to detect changes in enteral fat absorption before and 
after administration of pancreatic enzymes in a subset of patients. This test will also help 
characterize the degree of pancreatic insufficiency in subjects. Baseline serum CCK concentration 
and serum CCK concentration following pancreatic enzyme therapy will also be determined in this 
subset. 
2.2.3 A final aim will explore if improved lipid digestion and release of free fatty acids due to 
pancreatic enzymes will promote intestinal adaptation by stimulating endocrine signaling. 
Specifically, GLP-2, IGF-1, IGFBP-3, and GH concentrations will be measured from blood samples 
before and after administration of pancreatic enzymes. Plasma citrulline will also be measured as a 
marker of intestinal adaptation before and after administration of pancreatic enzymes.  
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 subspecialty centers. Primary 
recruitment centers will include regional academic hospitals and gastroenterology subspecialty 
centers.  Primary recruitment centers will include: 1) The Children’s Hospital of Philadelphia and 2) 
University of Pennsylvania Medical Center Hospital. Primary recruitment centers may include: 1) 
Pennsylvania Hospital; 2) Presbyterian Hospital; and 3) Philadelphia Veterans Administration 
Medical Center.  Other likely collaborators and recruitment centers may include: 1) St. 
Christopher’s Hospital for Children and 2) other regional centers.  These outside institutions will be 
involved with recruitment of subjects only and will otherwise not be engaged in the research. Our 
research team anticipates no difficulty in enrolling well-qualified participants with the proposed 
sample size (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.   
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 2-4 study visits. Refer to Table 1 for 
list of assessments and the study timeline (Table 2) for the pace of recruitment.  


 
  
 
 
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3.1.3    Open-label treatment with Creon™ 
All subjects will receive Creon™ intervention that starts 4 days prior to Study Visit #2. Study visit #2 
will be about 2 weeks after Study visit #1. Please refer to Table 1 for list of assessments and the 
study timeline (Table 2) 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 for all subjects will be up to four weeks.  
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at two investigative site in the United States, the Children’s Hospital of 
Philadelphia and the University of Pennsylvania. Recruitment will occur across regional centers as 
described above. All study visits will occur at The Children’s Hospital of Philadelphia. 
Recruitment will stop when 16 subjects with SBS between the ages of 4 and 17.9 years are enrolled 
and when 10 subjects with SBS between the ages of 18 years and 75 years are enrolled. It is 
expected that 26 subjects will be enrolled to produce at least 22 evaluable subjects.  
3.4 
Study Population 
3.4.1 Inclusion Criteria 
General Inclusion Criteria for all Subjects 
• 
History of a prior small bowel resection  
o If small bowel resection occurred under 18 years of age, subjects must have 
dependence on parenteral nutrition for at least three months following 
small bowel resection 
o If small bowel resection occurred at 18 years of age or older, subjects must 
have 200 centimeters or less of residual bowel length and must have more 
than 3 bowel movements per day following small bowel resection  
• 
Age 4 years to 75 years  
• 
Usual state of health for the past two weeks with no medication changes 
• 
Able to participate in a study for about four weeks with four study visits 
• 
Able to take pancreatic enzyme medication orally  
 
MBT/CCK Subset Inclusion Criteria 
• 
Age 18 years to 75 years  
 


 
  
 
 
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All available details of estimated bowel length will be taken into account, but there are no inclusion 
restrictions based on this information.  
 
3.4.2 Exclusion Criteria 
General Exclusion Criteria for all Subjects 
• 
Significant disease other than SBS affecting the gastrointestinal tract that impacts 
absorption or digestion  
• 
Motility disorders that affect the upper gastrointestinal tract (i.e. chronic pseudo-
obstruction, severe gastroparesis) or motility disorders that are poorly controlled 
• 
Unable to discontinue medications that directly alter fat absorption (i.e. bile acid 
sequestering agents, orlistat, weight loss medications, ursodeoxycholic acid) for 
one week prior to the first blood draw for the study until completion of stool 
collection following study visit 2 based on the preference of the subject or the 
primary gastroenterologist. Permission must be obtained from the primary 
gastroenterologist before discontinuing medications in this category.  
• 
Cholestatic liver disease defined as a serum conjugated bilirubin greater than 1.0 
mg/dL), chronic renal failure requiring dialysis or listed for kidney transplant, or 
gout  
• 
History of a pork allergy 
• 
Candidate for intestinal transplant and listed as status 1 
• 
Women who are pregnant or lactating  
• 
History of fibrosing colonopathy  
 
MBT/CCK Subset Exclusion Criteria  
• 
History of a soy or safflower oil allergy 
 
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. The 
Recruitment Enhancement Core at CHOP will provide assistance with recruitment plan 
development and also identify individuals with a diagnosis of short bowel syndrome and contact 
potential participants. We will also use the Penn Analytics Data Center to identify patients with a 
diagnosis of short bowel syndrome. Once identified, we will contact their provider to inform 
individuals of the existence of the study either in person, by telephone, or via letter and to obtain 
permission 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. Screening will be performed by medical record review and administration of a 


 
  
 
 
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questionnaire with details on medical history. Questionnaires can be completed both in-person or 
over the telephone. Subjects will be asked to contact the lead investigator, Dr. Sainath, if their 
enteral feeding regimen changes between screening and Study Visit #1.  
All subjects will be enrolled in their usual state of 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 Study Visit #1.   
4.2 
Study Treatment Phase  
Subjects will have 2-4 visits in this study that will all occur at The Children’s Hospital of Philadelphia.  
Study visit 0 will be to obtain informed consent and laboratories may be drawn (see description 
below). Study Visit #1 will be without pancreatic enzyme medication and Study Visit #2 will occur 
after they receive CreonTM as their pancreatic enzyme medication therapy. Study visit #3 will be off 
of study doses of pancreatic enzyme medication, though subjects on pancreatic enzymes at 
baseline may resume their regular dose. Study visit #3 will be to assess subject well-being, 
medication adherence, and to drop off stool collected and dietary records.  
Study Visit #1 includes anthropometrics and baseline laboratories. A spot stool sample will be 
collected to determine stool pH. Subjects in the MBT/CCK cohort will have the MBT performed as 
well and a serum CCK concentration as part of their laboratories. Study Visit #2 includes repeat 
laboratories, which will not include micronutrient levels. A spot stool sample will be collected to 
determine stool pH. Subjects in the MBT/CCK cohort will again have the MBT performed and a 
serum CCK concentration drawn. (refer to study procedures in Table 1).  
Study Visit 0: Visit for Consent and HIPAA Authorization for release of medical record information 
• 
Informed Consent will be obtained at study visit 0. Subjects will have the option to 
complete this study visit via telephone.  If subjects are taking pancreatic enzyme 
medication and will need to discontinue medication 3 days prior to Study Visit #1, a 
signed, informed consent form will be obtained in person or by mail, fax, or email 
prior to the beginning of any discontinuation of the medication. If subjects are 
taking a medication that directly alters fat absorption and will need to discontinue 
medication one week prior to Study Visit #1, a signed, informed consent form will 
be obtained prior to the beginning of any discontinuation of the medication. 
Medications that alter fat absorption will not be discontinued without the 
permission of the primary gastroenterologist. We will obtain a signed, informed 
consent form for all subjects in the MBT/CCK cohort prior to initiation of fasting or 
dietary changes for study visit 1. 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 study 
visit 0. If this visit is conducted via telephone, instructions will be given via at that 
time.  
• 
At study visit 0, a 24 hour dietary recall will be completed once written consent is 
obtained in order to allow for detailed calculations of pancreatic enzyme 
medication dosing. If informed consent is obtained via telephone, a signed, 
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recall.  If signed, informed consent is obtained at study visit 1, completion of a 24 
hour dietary recall will occur at study visit 1.  
• 
At study visit 0, once consent has been obtained, subjects less than 25 kilograms 
will have laboratories drawn to check micronutrient levels. Subjects who weigh less 
than 25 kilograms must come to CHOP for study visit 0, but will have the option of 
completing informed consent via telephone. The informed consent form will be 
signed prior to having laboratories drawn at study visit 0.  
There are four protocols for Study Visit #1.  The first protocol is for subjects with SBS who are naïve 
to pancreatic enzyme medication, that is, they have not received pancreatic enzyme medication 
prior to Study Visit #1. The second protocol for Study Visit #1 is for subjects with SBS 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 
Study Visit #1 (a “pancreatic enzyme medication washout” period).  The third protocol is for 
subjects who are part of the MBT/CCK cohort who will have the MBT during Study Visit #1 and who 
are naïve to pancreatic enzyme medication. The fourth protocol is for subjects who are part of the 
MBT/CCK cohort and will have the MBT during Study Visit #1 and who also require a pancreatic 
enzyme medication washout. All subjects will be prescribed CreonTM as their pancreatic enzyme 
medication therapy and will receive this therapy for Study Visit #2. Please note that subjects eligible 
for the MBT/CCK subset will have the option to decline the MBT. If this occurs, these subjects will 
follow the same protocol as those in the non-MBT/CCK subset.  
Study Visit #1: Protocol for non-MBT/CCK Subjects who have not Received Pancreatic 
Enzyme Medication Prior to Study Visit #1 
 
Day 1-7 - Home 
 
• 
Those subjects who are on a medication that directly alters fat absorption will 
discontinue this medication after permission is obtained from their primary 
gastroenterologist. Study team must have a signed, informed consent form prior to 
discontinuation of medication.   
• 
Subject’s normal diet 
 
Day 8 – CHOP Visit to CTRC Outpatient Lab and NGL 
 
• 
Sign informed consent form if study visit 0 conducted via telephone for those 
subjects who do not have to discontinue medication or have labs at study visit 0 
• 
24-hour dietary recall for those subjects who sign the informed consent form at 
study visit 1 
• 
Urine pregnancy test for pre-menopausal females  
• 
Subject’s normal diet  
• 
Baseline blood draw: Fat soluble vitamins (A, D, E, K)*, pre-albumin, serum zinc*, 
selenium*, fatty acid profile*, citrulline, IGF-1, IGF BP3, GLP-2, GH, CBC, CMP, 
hepatic function panel 
• 
Anthropometry (height, weight, skinfolds, circumferences) 
• 
Whole body DXA  


 
  
 
 
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• 
Spot stool sample will be collected for stool pH and fecal elastase. Subjects who are 
unable to produce a sample at the visit will collect and freeze a stool sample at 
home on one occasion on Day 8, 9, or 10.  
• 
If subject has a G tube, spot gastric pH will be checked  
• 
Questionnaires: Health History and medications, Home Environment, Quality of Life 
(MOS SF-36 or PedsQL) 
• 
Instructions will be given for collection and shipping for: stool collection (72-hour 
fecal fat and nitrogen analysis and bomb calorimetry), 3-day weighed food records, 
and adverse events diary 
• 
Prescribe CreonTM and dispense to subjects  
 
Day 9 - Home 
 
• 
Maintain adverse events diary 
• 
Subject’s normal diet  
 
Day 10 - Home 
 
• 
Subject’s normal diet  
• 
3-day weighed food record  begins  
• 
Food record – Day 1 
• 
Maintain adverse events diary 
 
Day 11 - Home 
 
• 
Subject’s normal diet  
• 
Food record – Day 2 
• 
Stool collection begins (72-hour fecal fat, 72-hour fecal nitrogen, and bomb 
calorimetry), store frozen until brought to CHOP. 
• 
72-hour stool – Day 1 
• 
Maintain adverse events diary 
 
Day 12 - Home 
 
• 
Subject’s normal diet  
• 
Food record – Day 3 
• 
72-hour stool – Day 2  
• 
Maintain adverse events diary 
 
Day 13 - Home 
 
• 
Subject’s normal diet  
• 
72-hour stool – Day 3 
• 
Maintain adverse events diary 


 
  
 
 
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• These laboratories will be drawn at study visit 0 if the subject weighs less than 25 kg 


 
  
 
 
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Study Visit #1: Protocol for non-MBT/CCK Subjects who are Receiving Pancreatic Enzyme 
Medication Prior to Study Visit # 1 and require a Washout Period 
Participants discontinuing pancreatic enzyme medication will be without this medication 
for the nine days encompassing Visit 1.  
 
Day 1-4 - Home 
 
• 
Those subjects who are on a medication that directly alters fat absorption will 
discontinue this medication after permission is obtained from their primary 
gastroenterologist. Study team must have a signed, informed consent form prior to 
discontinuation of medication.    
• 
Subject’s normal diet  
 
Days 5, 6, &  7 
 
• 
Discontinue pancreatic enzyme medication (Washout) Subject’s normal diet  
 
Day 8 – CHOP Visit to CTRC Outpatient Lab and NGL 
 
• 
Sign informed consent form if study visit 0 conducted via telephone for those 
subjects who do not have to discontinue medication or have labs at study visit 0 
• 
24-hour dietary recall for those subjects who sign the informed consent form at 
study visit 1 
• 
Urine pregnancy test for pre-menopausal females  
• 
Subject’s normal diet  
• 
Baseline blood draw: Fat soluble vitamins (A, D, E, K)*, pre-albumin, serum zinc*, 
selenium*, fatty acid profile*, citrulline, IGF-1, IGF BP3, GLP-2, GH, CBC, CMP, 
hepatic function panel 
• 
Anthropometry (height, weight, skinfolds, circumferences) 
• 
Whole body DXA  
• 
Spot stool sample will be collected for stool pH and fecal elastase. Subjects who are 
unable to produce a sample at the visit will collect and freeze a stool sample at 
home on one occasion on Day 8, 9, or 10. 
• 
If subject has a G tube, spot gastric pH will be checked  
• 
Questionnaires: Health History and medications, Home Environment, Quality of Life 
(MOS SF-36 or PedsQL) 
• 
Instructions will be given for collection and shipping for: stool collection (72-hour 
fecal fat and nitrogen analysis and bomb calorimetry), 3-day weighed food records, 
and adverse events diary 
• 
Prescribe CreonTM and dispense to subjects   
 
Day 9 - Home 
 
• 
Subject’s normal diet 


 
  
 
 
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• 
Maintain adverse events diary  
 
Day 10 - Home 
 
• 
Subject’s normal diet 
• 
3-day weighed food record begins  
• 
Food record – Day 1 
• 
Maintain adverse events diary 
 
Day 11 - Home 
 
• 
Subject’s normal diet  
• 
Food record – Day 2 
• 
Stool collection begins (72-hour fecal fat, 72-hour fecal nitrogen, and bomb 
calorimetry), store frozen until brought to CHOP. 
• 
72-hour stool – Day 1 
• 
Maintain adverse events diary 
 
Day 12 - Home 
 
• 
Subject’s normal diet 
• 
Food record – Day 3 
• 
72-hour stool – Day 2 
• 
Maintain adverse events diary 
 
Day 13 - Home 
 
• 
Subject’s normal diet 
• 
72-hour stool – Day 3 
• 
Maintain adverse events diary 
* These laboratories will be drawn at study visit 0 if the subject weighs less than 25 kg 
Study Visit # 1: Protocol for MBT/CCK Subjects who have not Received Pancreatic Enzyme 
Medication Prior to Study Visit #1 
 
Day 1-6 - Home 
 
• 
Those subjects who are on a medication that directly alters fat absorption will 
discontinue this medication after permission is obtained from their primary 
gastroenterologist. Study team must have a signed, informed consent form prior to 
discontinuation of medication.     
• 
Subject’s normal diet  
 
Day 7 – Home  


 
  
 
 
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• 
Subject’s normal diet except for no dairy intake 
• 
No alcohol intake 
• 
Normal daily activity 
• 
Fast overnight starting at 8pm 
 Day 8 –  CHOP Visit to CTRC Outpatient Lab and NGL 
 
• 
Urine pregnancy test for pre-menopausal females  
• 
Insert heplock catheter 
• 
Baseline blood draw: baseline MBT draw, Fat soluble vitamins (A, D, E, K), pre-
albumin, serum zinc, selenium, fatty acid profile, citrulline, IGF-1, IGF BP3, GH, CBC, 
CMP, hepatic function panel, baseline CCK, baseline GLP-2 
• 
Administer MBT study meal (breakfast) 
• 
MBT – hourly blood sample for 8 hours 
• 
Blood sample for CCK concentration at 1 hour 
• 
Blood sample for GLP-2 concentration at 1 hour and 2 hours  
• 
After hour 6, a low fat study lunch 
• 
Anthropometry (height, weight, skinfolds, circumferences) 
• 
Whole body DXA 
• 
Spot stool sample will be collected for stool pH and fecal elastase. Subjects who are 
unable to produce a sample at the visit will collect and freeze a stool sample at 
home on one occasion on Day 8, 9, or 10. 
• 
If subject has a G tube, spot gastric pH will be checked  
• 
Questionnaires: Health History and medications, Home Environment, Quality of Life 
(MOS SF-36 or PedsQL) 
• 
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 CreonTM and dispense to subjects 
 
Day 9 – Home 
 
• 
Subject’s normal diet  
• 
Maintain adverse events diary  
 
Day 10 - Home 
 
• 
Subject’s normal Diet  
• 
Maintain adverse events diary 
• 
3-day weighed food record begins  
• 
Food record – Day 1 
 
 
Day 11 - Home 
 


 
  
 
 
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• 
Subject’s normal Diet   
• 
Food record – Day 2 
• 
Stool collection begins (72-hour fecal fat, 72-hour fecal nitrogen, and bomb 
calorimetry), store frozen until brought to CHOP. 
• 
72-hour stool – Day 1 
• 
Maintain adverse events diary 
 
Day 12 - Home 
 
• 
Subject’s normal diet 
• 
Food record – Day 3 
• 
72-hour stool – Day 2 
• 
Maintain adverse events diary 
 
Day 13 - Home 
 
• 
Subject’s normal diet 
• 
72-hour stool – Day 3 
• 
Maintain adverse events diary 
Study Visit #1: Protocol for MBT/CCK Subjects who are Receiving Pancreatic Enzyme 
Medication Prior to Study Visit # 1 and require a Washout Period 
 
Participants discontinuing pancreatic enzyme medication will be without this medication 
for the nine days encompassing Study Visit # 1.  
 
Day 1-4 - Home 
 
• 
Those subjects who are on a medication that directly alters fat absorption will 
discontinue this medication after permission is obtained from their primary 
gastroenterologist. Study team must have a signed, informed consent form prior to 
discontinuation of medication.      
• 
Subject’s normal diet  
 
Days 5 & 6 
 
Discontinue pancreatic enzyme medication (Washout) 
Day 7 
 
• 
Discontinue pancreatic enzyme medication (Washout)  
• 
Regular lunch/dinner except for no dairy intake 
• 
No alcohol intake 
• 
Normal daily activityFast overnight starting at 8pm 
 


 
  
 
 
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Day 8 – CHOP Visit to CTRC Outpatient Lab and NGL 
 
• 
Urine pregnancy test for pre-menopausal females  
• 
Insert heplock catheter 
• 
Baseline blood draw: baseline MBT draw, Fat soluble vitamins (A, D, E, K), pre-
albumin, serum zinc, selenium, fatty acid profile, citrulline, IGF-1, IGF BP3, GH, CBC, 
CMP, hepatic function panel, baseline CCK, baseline GLP-2 
• 
Administer MBT study meal (breakfast) 
• 
MBT – hourly blood sample for 8 hours 
• 
Blood sample for CCK concentration at 1 hour 
• 
Blood sample for GLP-2 concentration at 1 hour and 2 hours  
• 
After hour 6, a low fat study lunch 
• 
Anthropometry (height, weight, skinfolds, circumferences) 
• 
Whole body DXA 
• 
Spot stool sample will be collected for stool pH and fecal elastase. Subjects who are 
unable to produce a sample at the visit will collect and freeze a stool sample at 
home on one occasion on Day 8, 9, or 10. 
• 
If subject has a G tube, spot gastric pH will be checked  
• 
Questionnaires: Health History and medications, Home Environment, Quality of Life 
(MOS SF-36 or PedsQL) 
• 
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 CreonTM and dispense to subjects 
 
Day 9 - Home 
 
• 
Subject’s normal diet 
• 
Maintain adverse events diary 
 
Day 10 - Home 
 
• 
Subject’s normal diet 
• 
3-day weighed food record begins  
• 
Food record – Day 1 
• 
Maintain adverse events diary 
 
Day 11 - Home 
 
• 
Subject’s normal diet 
• 
Food record – Day 2 
• 
Stool collection begins (72-hour fecal fat, 72-hour fecal nitrogen, and bomb 
calorimetry), store frozen until brought to CHOP. 
• 
72-hour stool – Day 1 
• 
Maintain adverse events diary 


 
  
 
 
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Day 12 - Home 
 
• 
Subject’s normal diet 
• 
Food record – Day 3 
• 
72-hour stool – Day 2 
• 
Maintain adverse events diary 
 
Day 13 - Home 
 
• 
Subject’s normal diet 
• 
72-hour stool – Day 3 
• 
Maintain adverse events diary 
4.3 
Subjects who are on medications that directly alter fat absorption prior to the study 
Subjects who were on a medication that directly alters fat absorption will have stopped the 
medication 7 days prior to study visit #1. This will only occur with the permission of their primary 
gastroenterologist. Subjects must sign an informed consent form in person or send it via email, fax, 
or mail prior to discontinuation of medication. They will remain off the medication through the end 
of treatment with pancreatic enzyme medication. Once they complete the second stool collection 
and treatment with pancreatic enzyme medication as outlined below, they can resume this 
medication.  
4.4 
Open-Label Treatment with CreonTM  
Subjects will receive open-label treatment with CreonTM as their pancreatic enzyme medication 
therapy and will receive this therapy for nine days encompassing Study Visit #2.   There are two 
protocols for Study Visit #2. The first protocol is for subjects in the non-MBT/CCK cohort and the 
second protocol is for subjects in the MBT/CCK cohort. Please note that subjects who are eligible 
for the MBT/CCK subset and decline the MBT will follow the same protocol as the non-MBT/CCK 
subset.  
Study Visit #2: Pancreatic Enzyme Medication Treatment Protocol for Subjects in the non-
MBT/CCK Subset 
 
Days 1 -4 
 
• 
Pancreatic enzyme medication treatment 
• 
Subject’s normal diet 
 
Day 5 – CHOP Visit to CTRC Outpatient Lab and NGL 
 
• 
Subject’s normal diet 
• 
Pancreatic enzyme medication treatment   


 
  
 
 
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• 
Blood draw: pre-albumin, citrulline, IGF-1, IGF BP3, GLP-2, GH, CBC, CMP, hepatic 
function panel 
• 
Spot stool sample will be collected for stool pH 
• 
If subject has a G tube, spot gastric pH will be checked  
• 
Adherence to pancreatic enzyme medication and Adverse Events Questionnaires 
• 
Instructions will be given for collection and shipping for: stool collection (72-hour 
fecal fat, 72-hour fecal nitrogen, and bomb calorimetry), 3-day weighed food 
records, and adverse events diary 
 
Day 6 - Home 
 
• 
Pancreatic enzyme medication treatment 
• 
Subject’s normal diet 
• 
Maintain adverse events diary 
 
Day 7 - Home 
 
• 
Pancreatic enzyme medication treatment 
• 
Subject’s normal diet 
• 
3-day weighed food records begins 
• 
Food record – Day 1 
• 
Maintain adverse events diary 
 
Day 8 - Home 
 
• 
Pancreatic enzyme medication treatment 
• 
Subject’s normal diet 
• 
Food record – Day 2 
• 
Stool collection (72-hour fecal fat, 72-hour fecal nitrogen, and bomb calorimetry), 
store frozen until brought to CHOP. 
• 
72-hour stool – Day 1 
• 
Maintain adverse events diary 
 
Day 9 - Home 
 
• 
Pancreatic enzyme medication treatment 
• 
Subject’s normal diet 
• 
Food record – Day 3 
• 
72-hour stool – Day 2 
• 
Maintain adverse events diary 
 
Day 10 - Home 
 
• 
Pancreatic enzyme medication treatment 


 
  
 
 
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• 
Subject’s normal diet 
• 
72-hour stool – Day 3 
• 
Maintain adverse events diary 
 
Day 11 - Home 
 
• 
Subjects who had discontinued a medication that directly alters fat absorption for 
this study can resume this medication as it was prescribed by their primary 
physician 
 
 
Study Visit #2: Pancreatic Enzyme Medication Treatment Protocol for Subjects in the 
MBT/CCK Subset 
 
Days 1, 2, & 3 
 
• 
Pancreatic enzyme medication treatment  
• 
Subject’s normal diet  
Day 4 
 
• 
Pancreatic enzyme medication treatment 
• 
Subject’s normal diet except for no dairy intake 
• 
No alcohol intake 
• 
Normal daily activity 
• 
Fast overnight starting at 8pm 
 
Day 5 – CHOP Visit to CTRC Outpatient Lab and NGL 
 
• 
Pancreatic enzyme medication treatment  
• 
Insert heplock catheter 
• 
Blood draw: baseline blood draw for MBT, pre-albumin, citrulline, IGF-1, IGF BP3, 
GH, CBC, CMP, hepatic function panel, baseline CCK, baseline GLP-2 
• 
Administer MBT study meal (breakfast) 
• 
MBT – hourly blood sample for 8 hours 
• 
Blood sample for CCK concentration at 1 hour 
• 
Blood sample for GLP-2 concentration at 1 hour and 2 hours  
• 
After hour 6 a low fat study lunch 
• 
Adherence to pancreatic enzyme medication and Adverse Events Questionnaires 
• 
Instructions will be given for collection and shipping for: stool collection (72-hour 
fecal fat, 72-hour fecal nitrogen, and bomb calorimetry), 3-day weighed food 
records, and adverse events diary 
• 
Spot stool sample will be collected for stool pH 
• 
If subject has a G tube, spot gastric pH will be checked  
 


 
  
 
 
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Day 6 - Home 
 
• 
Pancreatic enzyme medication treatment  
• 
Subject’s normal diet 
• 
Maintain adverse events diary 
 
Day 7 - Home 
 
• 
Pancreatic enzyme medication treatment 
• 
Subject’s normal diet 
• 
3-day weighed food records begins 
• 
Food record – Day 1 
• 
Maintain adverse events diary 
 
Day 8 - Home 
 
• 
Pancreatic enzyme medication treatment 
• 
Subject’s normal diet 
• 
Food record – Day 2 
• 
Stool collection (72-hour fecal fat, 72-hour fecal nitrogen, and bomb calorimetry), 
store frozen until brought to CHOP 
• 
72-hour stool – Day 1 
• 
Maintain adverse events diary 
 
Day 9 - Home 
 
• 
Pancreatic enzyme medication treatment 
• 
Subject’s normal diet 
• 
Food record – Day 3 
• 
72-hour stool – Day 2 
• 
Maintain adverse events diary 
 
Day 10 - Home 
 
• 
Pancreatic enzyme medication treatment 
• 
Subject’s normal diet 
• 
72-hour stool – Day 3 
• 
Maintain adverse events diary 
 
Day 11 - Home 
 
• 
Subjects who had discontinued a medication that directly alters fat absorption for 
this study can resume this medication as it was prescribed by their primary 
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Study Visit #3: Follow-Up Visit for All Subjects  
Subjects will have the option to complete this visit via telephone. Questions on adverse 
events and medication adherence will be asked via telephone. Stool collection and diet 
records can be mailed or dropped off.  
 
Days 1 
 
• 
Adverse events monitoring 
• 
Final medication adherence questionnaire 
• 
Drop of final 72-hour stool collection and 3-day diet record 
 
4.5 
Unscheduled Visits 
Due to the complexity of the study, no unscheduled visits will be permitted. 
4.6 
Subject Completion/Withdrawal 
For subjects 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 Study Visit #2) CreonTM will be 
discontinued and they will and resume their usual care without pancreatic enzyme medication.  For 
subjects who were receiving pancreatic enzyme medication prior to the start of the study, at the 
end of participation in the study (all collections are complete for Study Visit #2), CreonTM 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 Investigators for lack of adherence to study 
treatment or visit schedules, or adverse events. The Investigators 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. All subjects withdrawn from the study will receive a follow up phone call weekly for one 
month. 
We expect investigator-based subject withdrawal to be rare. Subjects who experience an 
unexpected increase in ostomy or stool output during or following a baseline study will require 
additional monitoring of serum electrolytes and stools or ostomy output as needed. Those subjects 
who require changes to their parenteral nutrition for greater than three days or initiation of 
intravenous hydration and electrolyte repletion for greater than three days will not have a repeat 
MBT. These subjects will not require withdrawal from the study if both they and their primary care 
team for SBS agree to continued participation. Once electrolytes are stable, they will continue the 
study.  
If a subject withdraws from the study for any cause, baseline data will be used for analysis.  


 
  
 
 
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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): 
• 
History of a prior small bowel resection  
o If small bowel resection occurred under 18 years of age, subjects must have 
dependence on parenteral nutrition for at least three months following small 
bowel resection 
o If small bowel resection occurred at 18 years of age or older, subjects must have 
200 centimeters or less of residual bowel length and must have more than 3 bowel 
movements per day following small bowel resection  
• 
Date of birth - Age 4 years to 75 years 
• 
Sex 
• 
SBS diagnosis: estimated length of residual bowel, number and purpose of operations, 
presence or absence of ileocecal valve  
• 
Most recent enteral nutrition and parenteral nutrition regimen 
• 
Medical comorbidities that affect the gastrointestinal tract and impact absorption or 
digestion  
• 
Current diagnosis of a motility disorder (i.e. chronic pseudo-obstruction, severe 
gastroparesis) 
• 
Current diagnosis of cholestatic liver disease defined as a serum conjugated bilirubin 
greater than 1.0 mg/dL 
• 
Current listing status for intestinal transplant  
• 
History of pancreatic enzyme use 
• 
History of a pork, soy, or safflower oil allergy 
• 
History of gout, chronic renal failure requiring dialysis or listed for kidney transplant, or 
fibrosing colonopathy  
• 
All medications, particularly medications that alter fat absorption (weight loss medications, 
bile acid sequestering agents, or ursodeoxycholic acid)  
• 
All allergies 
• 
History of use of pancreatic enzymes 
• 
Hospitalizations in the past 2 weeks 
• 
Emergency room visits or unscheduled sick visits in the last month 
5.1.2 Laboratory Evaluations 
Serum 25-dihydroxyvitamin D and pre-albumin will be assessed at CHOP 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). Prealbumin, 
zinc, serum retinol (vitamin A), α tocopherol (vitamin E), and selenium will be assessed at CHOP 
Laboratories using standard techniques. A fatty acid profile will be assessed by Mayo Medical 
Laboratories (Rochester, MN). This will provide data on baseline malabsorption and nutritional 


 
  
 
 
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status resulting from short bowel syndrome that may be improved with pancreatic enzyme 
medication in subjects. Safety measures include results from serum basic metabolic panel (BMP), 
hepatic function panel, and complete blood count with differential (CBC) performed at CHOP 
Laboratories using standard techniques.  The hepatic function panel will provide serum albumin, 
total protein, bilirubin, and liver enzymes to provide additional liver and nutritional status 
information. Serum citrulline, IGF-1, IGF BP3, GLP-2, GH, and CCK levels (MBT/CCK subset only) will 
be assessed by the CTRC Core Laboratory at CHOP. 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 who are 9 years of age 
or older.  
5.1.3 Other Evaluations and Measures 
Dietary intake: A twenty-four hour dietary recall will be obtained after written, informed consent is 
obtained. This may be completed at study visit 0 or study visit 1. Information on parenteral 
nutrition and enteral nutrition will be obtained.  
Three day weighed food records will be obtained at baseline and while on PERT. Calories, 
macronutrient content, and micronutrient content will be calculated based on dietary records. All 
subjects will be provided with scales, spoons, and other supplies needed for accurate collection of 
dietary data. Analysis of the dietary records will be conducted with the assistance of the CTRC staff 
and Bionutrition Unit. In particular, dietary intake will be analyzed using Nutrition Data System 
(NDS) for Research software version 2012 developed by the National Coordinating Center (NCC, 
University of Minnesota, Minneapolis, MN) 
Anthropometric Assessment: Height and weight will be measured for each subject and BMI will be 
calculated. For subjects under 20 years of age, height, weight, and BMI Z scores will be calculated 
using growth charts from the Centers for Disease Control and Prevention (CDC)22. Anthropometric 
techniques will be measured using the methodologies described by Lohman et al23. Weight (0.1 kg) 
will be measured on a digital electronic scale (Seca, Munich, Germany) and height (0.1 cm) will be 
measured using a stadiometer (Holtain, Crymych, UK). In order to assess subcutaneous fat stores, 
skinfold thickness of the triceps, biceps, subscapular, and suprailiac areas will be measured (0.1 
mm) with a skinfold caliper. Total body composition, total free fat mass (FFM) and fat mass (FM) 
and percent body fat (%FAT), will be assessed by the skinfolds using prediction equations adapted 
for children, adolescents, and adults50, 51. Mid upper arm circumference will be measured with a 
fiberglass tape (0.1 cm). Upper arm muscle Z scores and fat area Z scores will be determined for 
each subject. All anthropometric assessments will be performed once at the study visit #1.  
Body Composition: Body composition will be assessed with dual-energy x-ray absorptiometry (DXA) 
(Delphi A, Hologic, Inc., Bedford, MA) for subjects only at study 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. We will attempt to obtain a DXA scan in subjects of all ages. 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. The scans will be analyzed to generate traditional DXA measures: whole body 


 
  
 
 
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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.   
 
Gastric and Stool pH: Stool pH will be measured at study visit #1 and #2 as a screen for gastric acid 
hypersecretion. Gastric pH will be measured study visit #1 and #2 if subjects have a gastrostomy 
tube or a nasogastric tube. This will be performed by the CTRC Core Laboratory at CHOP.   
 
Fecal elastase: Pancreatic function will be assessed by fecal elastase-1 at study visit #1 only to 
determine the level of pancreatic enzyme activity in the stool24 (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. If subjects are unable to produce a 
stool sample at study visit #1, they will be given supplies to collect a stool sample at home within 
two days following the visit. This stool sample will be frozen and returned on the day of study visit 
#2. The stool sample will be stored at -20oC, and analyzed with a monoclonal enzyme-linked 
immunosorbent assay (ARUP Laboratory, Salt Lake City, UT). 
Home Environment and Health Questionnaire: The questionnaire will be administered via interview 
by the research staff at Study Visit #1, 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, parenteral nutrition, 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 Study Visit #1. For all subjects 18 years of age 
and older, the Medical Outcomes Study 36-Item Short-Form Health Survey (MOS SF-36), a 
standardized, validated health survey will be administered. The MOS SF-36 covers physical 
functioning, bodily pain, general health perception, vitality, social functioning, emotional and 
mental health domain25. For subjects between 4 and 17.9 years of age, the Pediatric Quality of Life 
Inventory (PedsQLTM) is a validated health survey that will be administered. For subjects who are 4 
years old, a parent or legal guardian only will complete a proxy-report. For subjects between the 
ages of 5 and 17.9, both the subject and the parent or legal guardian will complete a survey. The 
PedsQLTM addresses physical, emotional, social, and school functioning26.  
Adherence: Adherence to pancreatic enzyme medication for subjects will be assessed at Study Visit 
#2 and #3 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 Study Visit #1, Study Visit 
#2, and Study Visit #3 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. 


 
  
 
 
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5.2   Efficacy  
5.2.2. Diagnostic tests, Scales, Measures 
Coefficient of fat absorption (CFA): The coefficient of fat absorption (CFA %) will be calculated 
based on a 72 hour stool and a 3-day weighed diet record collection performed after both Study 
Visit #1 and #2. Collection of stool will begin 24 hours after dietary records are started. All subjects 
will remain on their normal diet during stool collection. This includes the normal meals, snacks, and 
tube feeds that they typically receive. All subjects will receive a home collection kit and detailed 
instructions on stool collection. Stool collections will be performed at home and returned to CHOP 
upon completion. Subjects who are in diapers can either use plastic wrap to line the diaper or a 
urine collection bag secured around the anus for stool collection. They will then transfer stool from 
the plastic wrap or the collection bag to a stool collection container. All materials, including hand 
gloves, will be provided to ensure safe and accurate stool collection. All stool will be frozen until the 
time of analysis. Total fat content of the stool will be determined by a gravimetric method (Mayo 
Medical Laboratories, Rochester, MN). Total dietary intake of fat will be determined from the 3-day 
weighed food records. CFA % will be calculated based on determining the grams of fat consumed 
and the grams of fat excreted27. CFA % will be compared for each subject before and after 
administration of pancreatic enzymes.   
Coefficient of nitrogen absorption (CNA): The coefficient of nitrogen absorption (CNA %) will be 
calculated based on a 72 hour stool and a 3-day weighed diet record collection performed both at 
Study Visit #1 and #2. Collection of stool will begin 24 hours after dietary records are started. All 
subjects will remain on their normal diet during stool collection. This includes the normal meals, 
snacks, and tube feeds that they typically receive. Subjects will receive materials and instructions 
for proper stool collection. All samples will be collected at home and returned to CHOP. Stool will 
be frozen until the time of analysis. Total nitrogen content of stool will be determined by a 
gravimetric method (Mayo Medical Laboratories, Rochester, MN). Total dietary intake of nitrogen 
will be determined from a 3-day weighed food record. CNA % will be calculated based on grams of 
nitrogen consumed and grams of nitrogen excreted27. CNA % will serve as a measure of protein 
absorption. CNA % will be compared for each subject before and after administration of pancreatic 
enzymes.  
Bomb calorimetry (BC): Bomb calorimetry is a measure of energy loss in stool. This will be 
determined based on a 72-hour stool collection (Covance Labs, Madison, WI) performed on each 
subject before and after administration of pancreatic enzymes. All subjects will remain on their 
normal diet during stool collection. This includes the normal meals, snacks, and tube feeds that 
they typically receive. All samples will be collected at home, returned to CHOP, and frozen until the 
time of analysis. BC measures the heat of combustion of a reaction and in particular, measures the 
energy given off by a stool sample that is burned28. As a result, it provides a measure of fecal 
energy loss in kcal/g stool. The energy loss from stool will be compared in each subject before and 
after administration of pancreatic enzymes.   
Malabsorption blood test (MBT): This test will be performed on the MBT/CCK cohort only. These 
subjects will have the option to decline the MBT. The MBT is a measure of intestinal fat absorption 
and pharmacokinetic analyses yields primary outcomes from this test. The MBT involves 
consumption of an 8 ounce (oz) test meal that contains about 580 calories, 32.4 g of fat, and 50% 
calories from fat. Specifically, the fats contained in the test meal are pentadecanoic acid (PA), a free 
fatty acid, and triheptadecanoic acid (THA), a triglyceride with three molecules of heptadecanoic 


 
  
 
 
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saturated fatty acids bound to glycerol. THA requires hydrolysis by pancreatic lipase in the intestinal 
lumen prior to intestinal absorption. The MBT test meal is administered after the subject has fasted 
for 12 hours and eliminated dairy from the diet for 24 hours. The meal is prepared just prior to 
consumption and is composed of 64 g vanilla Scandishake (Axcan, Scandipharm, Birmingham, AL), 6 
oz Silk light vanilla soy milk, 0.5 ounces of Hershey’s chocolate syrup, 10 milliliters microlipid 
(www.nestle-nutrition.com), PA, and THA. An indwelling catheter is placed in the subject prior to 
consumption of the meal. Blood is drawn at baseline (0 hour) and then following ingestion of the 
test meal at Hour 1, 2, 3, 4, 5, 6, 7, and 8. The meal should be consumed within 5 minutes following 
the baseline blood draw. From the samples of blood, serum PA and heptadecanoic acid (HA) levels 
are assessed by gas-liquid chromatography (GC). After the blood draw at Hour 6, subjects are 
provided a 1000 kcal, low fat (12 g) lunch meal. They are also able to consume zero-calorie and 
caffeine-free beverages without limit during the MBT.  
Subjects in the MBT group who elect to have the MBT will have a MBT at baseline and again 
following administration of pancreatic enzymes. If subjects are on pancreatic enzymes prior to 
study enrollment, after consultation with their medical team, they will be asked to discontinue 
pancreatic enzymes three days before their study visit #1 until the end of the first 72 hour stool 
collection. For the second MBT that will be performed on pancreatic enzymes, subjects will take 
enzymes for 4 days and the MBT will be scheduled on day 5. Following this, they will continue to 
take pancreatic enzymes until the second 72-hour stool collection is complete. Please see Table 3 
for details of the MBT protocol. Subjects in the non-MBT group will not have a MBT performed.  
Plasma samples to measure PHA and TA levels will be analyzed by GC. Using methods from Bligh 
and Dyer, total lipids are extracted from 200 µl of plasma7,29. Fatty acids are methylated in the lipid 
extract and fatty acid methyl esters are then extracted into isooctaine. 1 µl of sample is then 
injected into a 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 that runs ChromPerfect Spirit™ chromatography data system (Justice Laboratory 
Software, Denville, NJ). The column used is a CP-Sil 88 for FAME, 100 m (L) x 0.25 mm (ID) x 0.25 µm 
(film thickness) (Agilent Technologies, Inc., Santa Clara, CA) with a 1 m (L) x 0.53 mm (ID) 
deactivated precolumn. Calibration curves are generated based on injections of methyl PA, methyl 
HA, and methyl tridecanoate 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) has been shown 
to be 2.9%, 2.6%, and 3.1%, respectively7. Inter-assay variability for the measurement of HA (0.56. 
1.29, and 3.05 mg/dL) in the samples has been shown to be 2.6%, 4.0%, and 3.9%, respectively7.  
Primary outcomes for the MBT include pharmacokinetic analyses of PA and HA, which includes 
comparison of the absorption curves, maximum plasma concentration (Cmax), area under the curve, 
percent absorption of plasma PA and HA concentrations, and the HA/PA ratio between each subject 
in the MBT cohort before and after administration of pancreatic enzymes.    
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. 


 
  
 
 
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6 STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary aim of this study is to determine if pancreatic enzymes improve enteral fat absorption 
in subjects with SBS. Enteral fat absorption will be measured as CFA. For each subject, CFA will be 
compared before and after administration of pancreatic enzyme medication.  
6.2 
Secondary Endpoint  
The secondary aim of this proposal is to assess the effect that administration of pancreatic 
enzymes will have on global absorption. Specifically, CNA and stool BC will be measured to detect 
changes in enteral protein absorption and stool energy losses, respectively, before and after 
administration of pancreatic enzymes.  
An additional secondary aim includes that we will explore the ability of the MBT to detect changes 
in enteral fat absorption before and after administration of pancreatic enzymes in a subset of 
patients. This test will also help characterize the degree of pancreatic insufficiency in subjects.  
A final secondary aim will explore if improved lipid digestion and release of free fatty acids due to 
pancreatic enzymes will promote intestinal adaptation by stimulating endocrine signaling. 
Specifically, GLP-2, IGF-1, IGFBP-3, and GH concentrations will be measured from blood samples 
before and after administration of pancreatic enzymes. CCK will also be measured in the MBT/CCK 
Cohort only before and after administration of pancreatic enyzmes. Plasma citrulline will also be 
measured as a marker of intestinal adaptation before and after administration of pancreatic 
enzymes.  
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, H2, and H3: Descriptive statistics for CFA, CNA, and BC outcomes (mean, 
standard deviation, median, range, 95% CI) will be calculated for the SBS cohort before and after 
PERT administration with paired t-tests or Wilcoxon sign rank tests depending on skewness of data. 
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 metrics7.  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, MD8. Using this method, population PK modeling is conducted by 
simultaneously fitting structural PK models to both PA and HA concentrations9.   
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 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. 
Descriptive statistics (mean, standard deviation, median, range, 95% CI) will also be employed to 
assess outcomes related to intestinal hormone signaling that controls pancreatic enzyme secretion 
and intestinal adaptation in H4 (glucagon-like peptide 2, insulin-like growth factor 1, insulin-like 
growth factor binding protein 3, and growth hormone concentrations).  All variables will be tested 
for normality and nonparametric tests used as appropriate.  The change in status for these 
variables before and after PERT administration will be explored with paired t-tests and Wilcoxon 
sign rank tests depending on skewness. 
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 hypothesis (H1) of this study is: 1) the CFA will detect 
changes in fat absorption with PERT administration in subjects with SBS.  The sample size selected 
for the SBS cohort (n=26) is based upon our previous experience in cystic fibrosis (CF) and chronic 
pancreatitis (CP) in detecting changes over time before and after administration of PERT.  Although 
few studies of fecal fat loss in subjects with SBS have been conducted, losses of about 48% of fat 
intake in the stool have been reported2. For the CFA outcome, our experience has been in CF and 
pancreatic insufficiency (PI), with average CFA of 81±14% in one study30 and 83±10% in another31 
when subjects were on PERT. In comparison, healthy subjects have CFA ≥93%.  From the literature 
for CP, a number of clinical trials have used CFA to describe fat malabsorption in subjects with CP 
and confirmed PI before and after administration of PERT. Ramesh et al32 found an increase in CFA 
from 66.7±14.0% before PERT to 88.9±5.2% after PERT (change of 22.7±12.2%) in adults with CP 
from India. Thorat et al33, in a randomized controlled trial in India, saw CFA increase from 66.5±14.1 
to 86.1±7.5% in those taking PERT 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 1 week of PERT. Drawing from the 
literature on CP in the absence of information for SBS, the change in CFA for subjects with CP and 
confirmed PI before and after PERT administration has ranged from 8 to 23% with the SD of that 
change ranging from 12 to 18%, but averaging at 14%. 22 subjects will have 80% power to detect a 
difference in means of 9% (increase in CFA% from 85 to 94% after PERT administration), assuming a 
SD of differences of 14%, using a paired t-test with α =0.05 two-sided significance level. 


 
  
 
 
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A secondary hypothesis (H2) in the study is: 2) the CNA and BC will detect changes in enteral 
protein absorption and stool energy losses, respectively, with PERT administration in subjects with 
SBS. There is limited data on CNA in SBS. One study2 found that subjects with SBS had a CNA of 
about 47%. From the literature on CF, Trapnell et al5 reported an increase in CNA from 49.9 ± 1.9% 
to 85.1 ± 1.9% after administration of PERT. Borowitz et al4 reported a similar increase in both CFA 
and CNA following PERT, with CNA specifically increasing from as low as 57% to 74.6% following 
administration of PERT. Ramesh et al32 studied adults patients with CP and demonstrated that PERT 
resulted in a significant increase in CNA from 79 ± 8.9% to 85.5. ± 3.8% (change of 6.5 ± 7.9%). 
Similar to CFA, for CNA, 22 subjects will have 80% power to detect a difference in means of 9% 
(increase in CNA% from 85 to 94% after PERT administration), assuming a SD of differences of 14%, 
using a paired t-test with α =0.05 two-sided significance level. 
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. It has been reported that patients 
with SBS can have fecal energy losses as high as 1609 ± 561 kcal/day2. Using 72-hour stool 
assessments, Wierdsma et al28 has recently reported an average daily energy loss of 213±66 kcal in 
23 healthy adults.  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 a healthy group mean of 200 and a 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 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 20% attrition in this study given a relatively short time period between 
study visit #1 and study visit #2. By enrolling 26 subjects with SBS, we can account for attrition and 
also allow for the possibility of greater variability in the CFA, CNA, and BC outcomes within the SBS 
cohort for which we have had no previous experience.    
Assessment of fat malabsorption using the MBT method (H3) will be conducted on a subset of 10 
subjects and is exploratory. We have previous experience in CF and PI with detecting differences in 
the pharmacokinetic parameters Cmax and AUC for HA and the HA/PA ratio7, and in detecting the 
percent change in HA absorption (from pharmacokinetic modeling) compared to healthy subjects9, 
and in detecting changes in subjects with CF before and after pancreatic enzyme adminsitration7,9.  
We have demonstrated differences in the magnitude of MBT outcomes (exposure metrics) 
indicating the degree of fat absorption in these subjects with varying treatment regimens of 
approximately 0.5 in both Cmax and AUC HA/PA ratios with a standard deviation of ~0.7.  Differences 
of this magnitude were significant with samples of 16 subjects or less. Given the small sample size 
of this subset of subjects with SBS (n=10) and the known moderate variability within subjects in PA 
and HA with CF and PI7,9, the use of the MBT method to detect fat malabsorption in SBS is 
considered an exploratory aim, and will inform future studies once effect sizes in the MBT 
outcomes are determined.  
6.5 Interim Analysis 
An interim analysis is now planned to help inform decisions on the number of subjects needed to 
adequately power the study.  


 
  
 
 
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7 STUDY MEDICATION  
7.1 Description 
CREON (pancrelipase) Delayed-Release Capsules (CreonTM), a pancreatic enzyme preparation, is a 
drug that requires prescription for use.  It is approved for use for exocrine pancreatic insufficiency 
due to various etiologies at the current dose.   
7.1.1 Packaging 
Creon36TM capsules containing 36,000 lipase units (LU) each, Creon24TM capsules containing 24,000 
lipase units (LU) each, Creon12TM capsules containing 12,000 lipase units (LU) each, and Creon6TM 
capsules containing 6,000 lipase units (LU) each  will be provided (AbbVie, Inc.) to subjects with SBS. 
A 12 day supply of CreonTM will be provided for ten days of use.  The exact daily dose for each 
subject will depend on their specific enteral nutrition regimen. 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 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 
This is a proof of concept study and the use of pancreatic enzymes in short bowel syndrome has not 
been studied before. As a result, our preference would be to use the highest doses of pancreatic 
enzyme that are deemed safe for our subjects in order to assess if absorption can be improved.    
We have based pancreatic enzyme dosing on typical dosing used by the senior dietitian and a 
senior physician at the Cystic Fibrosis Center at the Children’s Hospital of Philadelphia (CHOP) and 
as recommended by the most recent consensus statement on pancreatic enzyme dosing in cystic 
fibrosis12. The recommended dosing for meals ranges from 500 – 2500 lipase units/kg/meal. The CF 
Center at CHOP uses a maximum dose of 2500 lipase units/kg/meal and 1250 lipase units/kg/snack. 
We will aim to administer about 1500 – 2500 lipase units/kg/meal and 750 – 1250 lipase 
units/kg/snack in this study (see Table 5 below). Exact dosing will depend on the subject’s 
complicated enteral feeding regimen. Pancreatic enzyme dosing will be weight based and we will 
not exceed 10,000 lipase units/kg/day for each subject12,13.  
We anticipate that several subjects in this study will have a complicated enteral feeding regimen 
that may be comprised of one or more of the following options: 1) bolus gastrostomy tube feeds, 2) 
continuous overnight gastrostomy tube feeds, and 3) continuous gastrostomy tube feeds for 18 -24 
hours of the day. Please see Table 5 below for a summary of goal pancreatic enzyme dosing for 
each of these enteral feeding regimens. Subjects should be able to take pancreatic enzyme 
medication orally in order to be included in the study even if they rely on a gastrostomy tube or 
jejunostomy tube.  
 
 


 
  
 
 
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Table 5. Goal Pancreatic Enzyme Dosing* 
 
Pancreatic Enzyme Dosing 
Meal 
1,500 – 2,500 lipase units/kg/meal 
Snack 
750 – 1,250 lipase units/kg/snack 
Bolus enteral feeds 
(typically 1 hour infusion) 
1,500 – 2,500 lipase units/kg/meal administered with each 
bolus+ 
Overnight enteral feeds 
(typically 8-12 hours) 
1,500 – 2,500 lipase units/kg/meal administered at the 
start and end of the feed 
Continuous enteral feeds  
(typically 20-24 hours) 
• 
1,500 – 2,500 lipase units/kg/meal administered at 
the start and end of the feed 
• 
While awake and during continuous feed, enzymes 
dosed every 4 hours based on grams of fat in formula 
(not to exceed 4,000 lipase units/grams of fat/day) 
* Will not exceed maximum daily enzyme dosing of 10,0000 lipase units/kg/day 
+ The dose of enzymes with each bolus depends on the enteral feeding regimen, grams of fat, and the volume 
and number of boluses 
Bolus feeds: The dose of enzymes that each subject receives prior to each bolus will depend on the 
volume and total number of boluses received per day. We will attempt to cover each bolus with a 
maximum dose of 1500 – 2500 lipase units/kg/meal, but this may be reduced if boluses are smaller 
in volume or occur frequently.  
Overnight feeds: This group includes subjects on overnight enteral feeds for 8-12 hours. These 
subjects will receive one meal dose of Creon™ (1500 - 2500 lipase units/kg) prior to feeds and one 
meal dose of Creon™ at the end of feeds, consistent with our current practice at CHOP. 
Continuous feeds: This group includes those subjects on continuous enteral feeds for 20-24 hours 
of the day. For these subjects, we will dose enzymes every 4 hours while awake based on grams of 
fat in the formula and based on recommended dosing per grams of fat. Overnight, they will receive 
one meal dose of Creon™ (1500 – 2500 lipase units/kg) before and after the overnight feed.  
We will not exceed 10,000 lipase units/kg/day or 4000 lipase units/grams of fat/day for any 
subject13. Each subject will receive pancreatic enzyme medication for a total of ten days. They will 
start Creon™ 4 days prior to study visit #2, they day of study visit #2, and then for five days after the 
visit until they have completed the second stool collection.  
7.1.4 Treatment Compliance and Adherence 
Adherence will be systematically assessed using the following methods: 1) A supply of CreonTM that 
is sufficient for 12 days will be prescribed for all subjects at Study Visit #1 by Dr. Nina Sainath, the 
Lead Investigator and will be dispensed to the subjects by Dr. Sainath. All subjects will be asked to 
begin taking CreonTM capsules four days prior to their scheduled visit to CHOP for Study Visit #2. 2) 
Subjects will be asked to complete an Adherence Survey, a semi-structured interview to document 
adherence to taking the CreonTM over ten days at Study Visit #2 and Study Visit #3. Adherence at 


 
  
 
 
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Study Visit #3 may be assessed by telephone or in person. We will maintain regular contact with 
subjects via telephone, text message, or email to ensure that each subject has an adequate supply 
of CreonTM 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 CreonTM. 4) Subjects 
will return unused CreonTM capsules at the end of the study to the study team in a mailing envelope 
provided.   
7.1.5 Drug Accountability 
Records of CreonTM receipt and disposition for each dose used in the study 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 CreonTM will 
not be distributed to any person who is not a study subject under the terms and conditions set 
forth in this protocol. CreonTM will be prescribed for all subjects in the study by Dr. Sainath, the 
Lead Investigator, and dispensed to the subjects by Dr. Sainath. CreonTM may not be used for any 
purpose other than that described in this protocol. At study completion, all left over CreonTM will be 
returned to the study team and this will be used as one estimate of adherence. Once the dataset is 
closed, leftover CreonTM will be destroyed by the Lead Investigator.  
 
 


 
  
 
 
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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   
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 


 
  
 
 
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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 CreonTM will be reported to the AbbVie, Inc. within 24 
hours of learning of the event regardless of the relationship of the event to CreonTM, the AbbVie 
product.  The PI and the Lead Investigator shall make available to AbbVie promptly such records as 
may be necessary and pertinent to investigate any such event, if specifically requested by AbbVie. 
For medical emergencies, we will follow the CHOP procedures for medical emergencies that may 
occur for adult visitors to CHOP. 
9 STUDY ADMINISTRATION 
9.1 
Treatment Assignment Methods 
This is an open-label intervention therapeutic exploratory study.  All subjects will receive CreonTM. 
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 and the Lead Investigator.  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 


 
  
 
 
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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 
private health information (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 
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 study will be monitored weekly by the Principal Investigator, Dr. Sainath, as well as by Dr. 
Stallings. The study protocol will be carried out in accordance with OHRP and NIH guidelines and 
requirements. SAEs that are unanticipated, serious, and possibly related to the study will be 
managed by the Principal Investigator (Dr. Sainath), as well as by Dr. Stallings. For subjects with SBS 
primarily managed at CHOP, members of the Intestinal Rehabilitation Program (Dr. Christina Bales ) 
will be consulted immediately for all SAEs. For subjects with SBS primarily managed at Penn 
Medicine/HUP, their primary gastroenterologist, Dr. Octavia Pickett-Blakely, will be consulted 
immediately and will assume medical care. SAEs will be reported to the study sponsor, IRB, CTRC, 


 
  
 
 
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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 the PI, Dr. Sainath, which will be reviewed weekly by 
Dr. Stallings.  
9.4.2 Risk Assessment 
The most common side effects associated with taking the pancreatic enzyme CreonTM 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 CreonTM is not swallowed completely. Additionally, subjects in diapers are at risk of diaper 
dermatitis due to CreonTM if diapers are not changed frequently and a heavy barrier cream is not 
utilized. 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. Doses of CreonTM prescribed for this study will 
not exceed 10,000 LU/kg/day or 4000 LU/grams of fat/day for any subject.  
There are risks associated with discontinuing pancreatic enzyme medication for subjects with SBS 
who have noted clinical improvement on pancreatic enzymes.  These include feelings of 
indigestion, stomach cramping after meals, gas, foul smelling, floating stools, 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 (Study 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 
Study Visit #1 to CHOP, and the five days of specimen collection after Study 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 Study Visit #1 and the start of the three 
days prior to Study Visit #2 when they will switch to CreonTM at doses prescribed based on 
the study protocol.  Therefore, they will not be at increased risk for the signs and 
symptoms of fat malabsorption during the time between visits or during the ten days 
encompassing Study Visit #2 as they will be taking pancreatic enzyme medication 
throughout this period.  When the study is completed, these participants will discontinue 
CreonTM 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 CreonTM for the ten days encompassing Study Visit #2 of the study, that is, 
four 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 


 
  
 
 
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CreonTM at the end of the study. If their pancreatic function and fat absorption is normal, 
withdrawal from Creon™ at the end of the study will not increase their risk for these 
symptoms. 
Approximately ten adult subjects with SBS will have the option to have the MBT at both Study Visit 
#1 and Study Visit #2. During this test, a high fat supplement will be administered enterally. 
Subjects with poor absorption are therefore at risk of developing indigestion, abdominal pain or 
cramping, increased flatus, and frequent or loose stools. Ostomy output and stool output may 
increase and if estimated to be greater than 50 milliliters/kilogram/day, subjects may require 
serum electrolyte monitoring. If dehydration or severe electrolyte abnormalities occur, mainly 
acidosis (serum bicarbonate level less than 20 mmol/L) or hypokalemia (serum potassium less than 
3.5 mmol/L), subjects will be hospitalized. Subjects who are primarily followed at The Children's 
Hospital of Philadelphia by Dr. Christina Bales, subjects less than 18 years, or subjects followed by 
pediatric gastroenterologists will be admitted to CHOP for monitoring, hydration, and electrolyte 
repletion. Subjects who are primarily followed at adult institutions will be discussed with Dr. 
Octavia Pickett-Blakely. Dr. Pickett-Blakely will assume their care and they will be hospitalized at 
the Hospital of the University of Pennsylvania.  
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. In subjects who have 
central venous access and are under 18 years of age, we will give their parents/legal guardians the 
option of having blood drawn from their central line instead of a venipuncture. Skilled research 
staff will take all necessary precautions to avoid risk of infection. Each subject with SBS in the 
MBT/CCK subset will have approximately 136cc (approximately 9 tablespoons) of blood drawn at 
study visit #1 and about 111 cc (approximately 7-8 tablespoons) of blood drawn at study visit #2. 
Subjects in the non-MBT/CCK subset who weigh 25 kilograms or more will have approximately 50 
cc (approximately 3-4 tablespoons) of blood drawn at study visit #1 and approximately 25 cc 
(approximately 1-2 tablespoons) of blood drawn at study visit #2. Subjects in the non-MBT/CCK 
subset who weigh less than 25 kilograms will have approximately 26 cc (approximately 1-2 
tablespoons) of blood drawn at study visit 0 and approximately 25 cc (approximately 1-2 
tablespoons) of blood drawn at both study visit #1 and study visit #2. 
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.        
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 


 
  
 
 
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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 SBS 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 SBS. 
9.5 
Recruitment Strategy 
It is expected that subjects will be recruited by word of mouth and at the recommendation of the 
subjects’ SBS Care Team. The Recruitment Enhancement Core at CHOP will provide assistance with 
identifying individuals with a diagnosis of short bowel syndrome and contacting potential 
participants. Interested individuals can contact the study team. We will also use the Penn Analytics 
Data Center to identify and contact patients with a diagnosis of short bowel syndrome. Once 
identified, we will contact their provider to inform individuals of the existence of the study and to 
obtain permission to share their contact information with the CHOP study staff. 
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. Assent will not be obtained for pediatric subjects between 7 and 17.9 years on 
the screening consent form. 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.  Dr. Sainath or other member of the clinical research team will meet 
with the subject or discuss via telephone 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 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, Dr. Sainath or a member of the 
clinical research team will obtain fully informed, consent from the adult subjects or from the 
parents/legal guardians of pediatric subjects. If informed consent is obtained via telephone, then a 
signed informed consent form will be obtained either prior to having laboratories drawn at study 
visit 0 for those subjects who weigh less than 25 kilograms, prior to discontinuation of any 
medications as part of the study protocol, prior to obtaining a 24-hour dietary recall by telephone, 


 
  
 
 
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at the start of study visit 1 prior to any other study procedures scheduled that day, or prior to any 
dietary changes or fasting in preparation for study visit 1. If informed consent is obtained via 
telephone, a copy of the consent form will be provided to the subject or parent/guardian via email, 
fax, or mail prior to the informed consent process. In order for the consent process to be 
completed by phone, Dr. Sainath or a member of the clinical research team must speak to both 
parents/guardians if the subject is under 18 years and must also speak to the subject if the subject 
is 7 years or older. This may require multiple phone calls or a conference call. Informed consent for 
non-English speaking subjects will only be completed in person with an interpreter. Dr. Sainath or a 
member of the clinical research team will obtain assent for pediatric subjects between the ages of 7 
year and 17.9 years. Adult subjects will be given a printed copy of the signed, informed consent and 
the legal guardians of pediatric subjects less than 18 years 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. A waiver of assent of pediatric subjects between the 
ages of 7 and 17.9 years will be sought for the screening component of the study, as pediatric 
subjects may not be available when parents or legal guardians of potential participants are 
approached by phone. 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. Verbal consent/HIPAA authorization may be obtained for screening. A written 
informed consent will be obtained prior to main study entry. This will occur at study visit 0 either in 
person or by telephone. Subjects or their legal guardian will sign an informed consent form prior to 
having laboratories drawn at study visit 0 for those subjects who weigh less than 25 kilograms, prior 
to discontinuation of any medication as part of the study protocol, prior to completing a 24-hour 
dietary recall by telephone, prior to study procedures at study visit 1, or prior to dietary changes or 
fasting in preparation for study visit 1. Discontinuation of pancreatic enzyme medication for those 


 
  
 
 
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participants who are taking this medication at the time of enrollment in the study will not occur 
prior to obtaining written, informed consent 
9.7 
Payment to Subjects 
9.7.1 Payments to subject   
All participants who are part of the MBT/CCK cohort and have the MBT performed at Study Visit #1 
and Study Visit # 2 will be compensated $200 for Study Visit #1 and $175 for Study Visit #2 for time 
and effort associated with each study visit: Visit 1 Visit 2. All subjects will be compensated $25 for 
Study Visit #3 for time and effort associated with this last study visit. Subjects who complete study 
visit #3 by phone will receive payment once their stool samples are received either in person or by 
mail. Subjects in the MBT/CCK cohort will receive a total of $400 ($200 for Study Visit #1, $175 for 
Study Visit #2, and $25 for Study Visit #3) 
Pediatric subjects who are part of the non-MBT/CCK cohort and who are between the ages of 9 and 
17.9 years will be directly compensated for their efforts.  Parents or legal guardians of subjects in 
the non-MBT/CCK cohort and who are between the ages of 4 and 8.9 years will be compensated for 
their child’s participation. Adult subjects who are eligible for the MBT/CCK cohort and decline the 
MBT will follow the non-MBT/CCK protocol and will be compensated the same amount as non-
MBT/CCK subjects who are between the ages of 9 and 17.9 years. All participants who are part of 
the non-MBT/CCK cohort will be compensated $100 for Study Visit #1 and $75 for Study Visit #2 for 
time and effort associated with each study visit: Visit 1 Visit 2. All participants will be compensated 
$25 for Study Visit #3 for time and effort associated with this last study visit. Subjects who 
complete study visit #3 by phone will receive payment once their stool samples are received either 
in person or by mail. Subjects in the non-MBT/CCK cohort or their parent/legal guardian will receive 
a total of $200 ($100 for Study Visit #1, $75 for Study Visit #2, and $25 for Study Visit #3).  
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 lead investigator and 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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