Proton Pump Inhibitors (PPI) and Fat Absorption in Subjects With Cystic Fibrosis (CF) and Exocrine Pancreatic Insufficiency (EPI)
Phase: PHASE2
Conditions: Pancreatic Insufficiency, Cystic Fibrosis
Sponsor: Children's Hospital of Philadelphia

 
17-014666 
 
12/19/2023 
Title: 
Proton Pump Inhibitors and Fat Absorption in Subjects with Cystic 
Fibrosis and Pancreatic Insufficiency  
Short Title 
PPI and Fat Absorption in CF and EPI 
Regulatory Sponsor: 
 
eIRB Number 
17-014666 
Protocol Date: 
12/11/2019   
 
Sponsor 
Chiesi USA, Inc. 
1255 Crescent Green, Suite 250 
Cary, NC, 27518 
Principal Investigator 
Virginia A. Stallings, MD 
2716 South Street, Room 14473 
Philadelphia, PA, 19146 
Phone: 267.425.1633 
email: stallingsv@email.chop.edu 
 

  
 
 
 
 
 
 
 
ii 
TABLE OF CONTENTS 
Table of Contents ............................................................................................................. ii 
Abbreviations and Definitions of Terms .......................................................................... iv 
Abstract ........................................................................................................................... v 
Protocol Synopsis ............................................................................................................ vi 
1 
BACKGROUND INFORMATION AND RATIONALE ..................................................................................... 1 
1.1 
INTRODUCTION ........................................................................................................................................ 1 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ........................................ 1 
1.3 
SELECTION OF DRUGS AND DOSAGES ....................................................................................................... 1 
1.4 
RELEVANT LITERATURE AND DATA .......................................................................................................... 1 
1.5 
COMPLIANCE STATEMENT ........................................................................................................................ 3 
2 
STUDY OBJECTIVES ................................................................................................................................. 3 
2.1 
PRIMARY OBJECTIVE (OR AIM) ................................................................................................................ 4 
2.2 
SECONDARY OBJECTIVES (OR AIM) .......................................................................................................... 4 
3 
INVESTIGATIONAL PLAN ........................................................................................................................ 4 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ...................................................................................................... 4 
3.1.1 
Screening Phase .............................................................................................................................. 4 
3.1.2 
Study Treatment Phase (start of the study intervention) ................................................................ 5 
3.1.3 
Second Treatment Phase ................................................................................................................ 5 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING ............................................................................ 5 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ........................................................................ 5 
3.3.1 
Duration of Study Participation ...................................................................................................... 5 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected .................................................. 5 
3.4 
STUDY POPULATION ................................................................................................................................. 6 
3.4.1 
Inclusion Criteria ............................................................................................................................. 6 
3.4.2 
Exclusion Criteria ............................................................................................................................. 6 
4 
STUDY PROCEDURES .............................................................................................................................. 7 
4.1 
SCREENING/CONSENT VISIT (VISIT 1) ....................................................................................................... 7 
4.2 
STUDY TREATMENT PHASE ....................................................................................................................... 7 
4.2.2 
Visit 2 .............................................................................................................................................. 8 
4.2.3 
Visit 3 ............................................................................................................................................ 10 
4.3 
UNSCHEDULED VISITS ............................................................................................................................ 11 
4.4 
CONCOMITANT MEDICATION ................................................................................................................. 11 
4.5 
SUBJECT COMPLETION/WITHDRAWAL ................................................................................................... 11 
5 
STUDY EVALUATIONS AND MEASUREMENTS ....................................................................................... 12 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ..................................................... 12 
5.1.1 
Medical Record Review ................................................................................................................. 12 
5.1.2 
Laboratory Evaluations ............................................................................................................... 122 
5.1.3 
Other Evaluations, Measures ...................................................................................................... 133 
5.2 
EFFICACY EVALUATIONS ........................................................................................................................ 13 
5.2.1 
Diagnostic Tests, Scales, Measures, etc. ....................................................................................... 14 
5.3 
SAFETY EVALUATION ............................................................................................................................. 15 
6 
STATISTICAL CONSIDERATIONS ............................................................................................................ 16 

 
 
 
 
 
 
 
 
iii 
6.1 
PRIMARY ENDPOINT .............................................................................................................................. 16 
6.2 
SECONDARY ENDPOINTS ........................................................................................................................ 16 
6.3 
STATISTICAL METHODS .......................................................................................................................... 16 
6.3.1 
Baseline Data ................................................................................................................................ 16 
6.3.2 
Efficacy Analysis ............................................................................................................................ 16 
6.3.3 
Safety Analysis .............................................................................................................................. 17 
6.4 
SAMPLE SIZE AND POWER ...................................................................................................................... 17 
6.5 
INTERIM ANALYSIS ................................................................................................................................. 19 
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) .............................................. 19 
7.1 
DESCRIPTION .......................................................................................................................................... 19 
7.1.1 
Packaging ..................................................................................................................................... 19 
7.1.2 
Labeling ......................................................................................................................................... 19 
7.1.3 
Dosing ........................................................................................................................................... 19 
7.1.4 
Treatment Compliance and Adherence ......................................................................................... 19 
7.1.5 
Drug Accountability ...................................................................................................................... 20 
8 
SAFETY MANAGEMENT ........................................................................................................................ 20 
8.1 
CLINICAL ADVERSE EVENTS ................................................................................................................... 20 
8.2 
ADVERSE EVENT REPORTING ................................................................................................................. 20 
8.3 
DEFINITION OF AN ADVERSE EVENT ....................................................................................................... 20 
8.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ................................................................................ 21 
8.4.1 
Relationship of SAE to study drug or other intervention ............................................................... 21 
8.5 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS .......................................... 21 
8.5.1 
Follow-up report ........................................................................................................................... 22 
8.6 
INVESTIGATOR REPORTING OF A SERIOUS ADVERSE EVENT TO SPONSOR .............................................. 22 
8.7 
MEDICAL EMERGENCIES ......................................................................................................................... 22 
9 
STUDY ADMINISTRATION ..................................................................................................................... 23 
9.1 
TREATMENT ASSIGNMENT METHODS ..................................................................................................... 23 
9.1.1 
Randomization .............................................................................................................................. 23 
9.1.2 
Blinding ......................................................................................................................................... 23 
9.1.3 
Unblinding ..................................................................................................................................... 23 
9.2 
DATA COLLECTION AND MANAGEMENT ................................................................................................ 23 
9.3 
CONFIDENTIALITY .................................................................................................................................. 24 
9.4 
REGULATORY AND ETHICAL CONSIDERATIONS ...................................................................................... 24 
9.4.1 
Data and Safety Monitoring Plan ................................................................................................. 24 
9.4.2 
Risk Assessment ............................................................................................................................ 25 
9.4.3 
Potential Benefits of Trial Participation ........................................................................................ 26 
9.4.4 
Risk-Benefit Assessment ............................................................................................................... 26 
9.5 
RECRUITMENT STRATEGY ....................................................................................................................... 26 
9.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ................................................................ 27 
9.6.1 
Waiver of Documentation of Consent/Assent and Alteration of HIPAA Authorization ............ Error! 
Bookmark not defined. 
9.7 
PAYMENT TO SUBJECTS/FAMILIES ........................................................................................................... 27 
9.7.1 
Reimbursement for travel, parking and meals .............................................................................. 28 
9.7.2 
Payments to parent for time and inconvenience (i.e. compensation) .......................................... 28 
9.7.3 
Payments to subject for time, effort and inconvenience (i.e. compensation) ............................... 28 
9.7.4 
Gifts ............................................................................................................................................... 28 
10 
PUBLICATION ..................................................................................................................................... 28 

  
 
 
 
 
 
 
 
iv 
11 
REFERENCES ....................................................................................................................................... 28 
12 
Appendix ........................................................................................................................................... 34 
 
 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
 
Adverse event 
BMI 
 
Body mass index 
CF 
 
Cystic fibrosis 
CFA 
 
Coefficient of fat absorption 
CFQ-R 
 
Cystic Fibrosis Questionnaire - Revised 
CHOP 
 
Children’s Hospital of Philadelphia 
CHPS 
 
Center for Human Phenomic Science 
DXA 
 
Dual energy x-ray absorptiometry 
EPI 
 
Exocrine pancreatic insufficiency 
FFM 
 
Fat free mass 
FM 
 
Fat mass 
H2RA 
 
Histamine receptor antagonist 
HA 
 
Heptadecanoic acid 
IRB 
 
Institutional Review Board 
LI 
 
Lead investigator 
MBT 
 
Malabsorption blood test 
NDS  
 
Nutrition Data System 
PA 
 
Pentadecanoic acid 
PERT 
 
Pancreatic enzyme replacement therapy 
PHI  
 
Personal health information 
PI 
 
Principle investigator 
PPI 
 
Proton pump inhibitor 
PROMIS 
 
Patient-Reported Outcomes Measurement Information 
System 
REDCap 
 
Research Electronic Data Capture 
QOL 
 
Quality of life 
SAE  
 
Serious adverse event 
THA 
 
Triheptadecanoic acid 

  
 
 
 
 
 
 
 
v 
ABSTRACT 
Context: Fat malabsorption contributes to poor nutritional status in people with cystic 
fibrosis (CF) and exocrine pancreatic insufficiency (EPI). Prescribing gastric acid-reducing 
agents such as proton pump inhibitors (PPIs) and histamine receptor antagonists (H2RAs) 
as an adjunct to pancreatic enzyme replacement therapy (PERT) to improve PERT efficacy 
and dietary fat absorption has become accepted clinical practice in CF, despite limited 
evidence to support the practice. Establishing the efficacy and true health benefit of acid 
suppression for nutritional status and outcomes in CF is particularly important in light of 
potential health risks and cost associated with long-term or even lifetime use of these 
medications. 
Objectives: We aim to characterize changes in fat malabsorption using the coefficient of fat 
absorption (CFA) as the primary endpoint in subjects who are on and off acid suppression 
with a PPI in addition to PERT. Additionally, the SmartPill® (MedTronic), will be used to 
evaluate duodenal pH while on and off acid suppression and the malabsorption blood test 
(MBT) will be used to characterize changes in fat absorption. Associations will be explored 
between changes in nutritional status (weight, height, BMI), clinical GI symptoms, and 
quality of life in subjects treated with PPI vs. placebo. We hypothesize that omeprazole will 
significantly improve dietary fat absorption compared to placebo in subjects with CF and 
EPI as indicated by CFA; concurrently, omeprazole will increase duodenal pH as indicated 
by the SmartPill® and improve triglyceride absorption as measured by the MBT. 
Malabsorption Blood Test (MBT) Quality Improvement Project  
The objective of the MBT Quality Improvement project is to determine which laboratory 
our research group will use for future MBT analysis.  
Study Design: Randomized, double-blind, placebo-controlled crossover trial. 
Setting/Participants: Twenty-four subjects ages 12 and older with cystic fibrosis and 
exocrine pancreatic insufficiency who are in a general state of good health (FEV≥40) will be 
recruited from local cystic fibrosis centers.  
Study Interventions and Measures: Subjects will be randomized to receive 28-day 
treatment with either omeprazole or placebo while maintaining a moderate-to-high fat 
diet and their standard PERT regimen. At the end of the supplementation period, fat 
absorption and duodenal pH will be measured, as will anthropometrics and quality of life 
measures. Subjects will then undergo a 14-day washout period and cross over to the other 
treatment arm for an additional 28 days. Evaluations will be repeated at the end of this 
arm. The primary endpoint is improved dietary fat absorption as indicated by CFA %. 
 

  
 
 
 
 
 
 
 
vi 
PROTOCOL SYNOPSIS 
Study Title 
Proton Pump Inhibitors and Fat Absorption in Subjects with Cystic 
Fibrosis and Pancreatic Insufficiency 
Funder 
Chiesi USA, Inc. 
Clinical Phase 
Phase IV 
Study Rationale 
Fat malabsorption contributes to poor nutritional status in people with 
cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI). Gastric 
acid-reducing agents such as proton pump inhibitors (PPI) are prescribed 
as adjunct medications to pancreatic enzyme replacement therapy (PERT) 
to improve dietary fat absorption through a mechanism that reduces 
gastrointestinal acidity. There is insufficient evidence that this approach 
improves duodenal pH, nutritional outcomes, or fecal fat loss as 
measured by the coefficient of fat absorption (CFA) in patients with CF. 
We propose a randomized placebo-controlled double-blinded trial with a 
crossover design to determine the efficacy of the commonly-prescribed 
PPI, omeprazole, as an adjunct to PERT to improve dietary fat absorption 
in 24 adolescent (≥12 years) and adult subjects with CF and EPI. After a 
14-day washout period, subjects (12 in each group) will be randomized to 
receive 28-day treatment with either omeprazole or placebo while 
maintaining a moderate-to-high fat diet and standard PERT regimen. 
Upon completion of the first arm of the study, subjects will again undergo 
a 14-day washout period and cross over to the other treatment arm for 
an additional 28 days. Dietary fat absorption will be determined using the 
stool CFA as the primary outcome. The other outcomes include change in 
duodenal pH (SmartPill® wireless capsule) and improved fat absorption as 
indicated by the malabsorption blood test (MBT). By changing the 
gastroduodenal pH, omeprazole may improve fat absorption compared 
to placebo.  
Study Objective(s) 
Primary Hypothesis: 
• 
Omeprazole, a commonly-prescribed PPI, in combination with 
pancreatic enzyme replacement therapy (PERT) will significantly 
improve dietary fat absorption compared to placebo in subjects with 
CF and EPI as indicated by CFA.  
• 
MBT Quality Improvement Project  
The primary objective of this Quality Improvement project is to enroll 
two adults to have an MBT. The results will be used to determine 
which laboratory the research group will use for future processing 
and analysis of the MBT samples. 
Secondary Hypotheses: 
• 
In a subset of subjects (≥18 years), PPI in combination with PERT will 
increase duodenal pH compared to placebo as indicated by the 
SmartPill®. 

 
 
 
 
 
 
 
 
 
 
vii 
• 
PPI in combination with PERT will increase dietary fat absorption 
compared with placebo as indicated by the MBT. 
• 
Improvement in dietary fat absorption will be associated with 
improvements in quality of life and nutritional status measures. 
Test Article(s) 
(If Applicable) 
Omeprazole, a commonly-prescribed proton pump inhibitor, used 
with the patient’s current pancreatic enzyme replacement therapy 
Study Design 
 
This is a randomized placebo-controlled double-blinded trial with a 
crossover design to determine the efficacy of omeprazole as an 
adjunct to PERT to improve dietary fat absorption in 24 adolescent 
(≥12 years) and adult subjects with CF and EPI. 
Subject Population 
Key criteria for Inclusion 
and Exclusion: 
Inclusion Criteria 
1. Cystic fibrosis and pancreatic insufficiency  
(Fecal elastase <200 ug/g stool) 
2. Age ≥12 years 
3. In usual state of good health 
4. Willingness to participate in a four-month study with three 
visits 
• 
MBT Quality Improvement Project 
o Two Healthy Adults  
Exclusion Criteria 
5. FEV1 <40% predicted 
6. Pregnancy or breast feeding 
7. Other illness affecting growth or nutritional status 
8. Unwillingness to continue their clinically established PERT 
dose for the duration of the study 
9. Use of other medication that affects dietary fat absorption 
10. Allergy to soy products 
11. Allergy to safflower products (microlipids) 
12. For subjects ≥18 years, celiac disease or allergy to gluten 
 
MBT Quality Improvement Project  
• Pregnancy or breast feeding  
• Use of other medication that affects dietary fat 
absorption 
• Allergy to soy products 
Number Of Subjects  
24 subjects 

 
 
 
 
 
 
 
 
 
 
viii 
Study Duration 
Duration from consent to completion of the study for each subject 
is approximately 100 days.  
The entire study is expected to last two years.  
Study Phases  
Screening (Visit 1): Screening for eligibility and obtaining consent. Once 
consented, PPI dose will standardized and subjects will be randomized. 
Standardization of diet and PERT that will continue throughout the study  
Intervention: Subjects are given either placebo or omeprazole to take for 
28 days. 
Visit 2: Outcomes are measured after the 28 days of treatment or 
placebo; subjects then cross over to other treatment arm. 
Visit 3: Outcomes are again measured after another 28 days of treatment 
or placebo. Once 72-hour stool collection is completed, subjects 
complete the study and return to normal medication regimen. 
Efficacy Evaluations 
The efficacy of PPI as adjunct to PERT will be evaluated using the gold 
standard CFA, as well as the MBT and the SmartPill®. 
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 
Comparison of outcomes by randomization group at each time point: 
Descriptive statistics for CFA%, duodenal pH and MBT outcomes (mean, 
standard deviation, median, range, 95% CI) will be calculated and for the 
total group comparing on and off omeprazole treatment using pair t-tests 
or Wilcoxon sign rank tests as appropriate. Differences between 
randomization groups at each time point and differences in the change 
over time with treatment will be assessed with unpaired t tests or Mann 
Whitney U rank sum tests as appropriate. 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 for the total group comparing on and 
off omeprazole using paired t-tests or Wilcoxon sign rank tests as 
appropriate, and between randomization groups at each time point using 
an unpaired t-test or Mann Whitney U rank sum test as appropriate. A 
mixed effects modeling approach will be employed to examine the 
correlation of subject characteristics (age, BMI, sex, disease status, etc) to 
CFA%, duodenal pH and to PA and HA exposure metrics derived from the 
non-compartmental analysis to assess change over time in MBT response 
to PERT administration in subjects with CP. Metrics to be tested will be 
CFA%, PA and HA Cmax, AUC, HA/PA Cmax and AUC ratio and the %HA 

  
 
 
 
 
 
 
 
ix 
response comparing subjects when on or off omeprazole treatment and 
also comparing randomization groups at each time point. A value of 
p<0.05 will be considered statistically significant. 
MBT Quality Improvement Project  
The primary endpoint of this quality improvement project is to determine 
which laboratory will be used for future processing and analysis of MBT 
samples. After the MBT is completed on two healthy volunteers, the 
samples will be sent to each laboratory.  
 We will visually assess the measurements obtained from the two 
subjects (10 data points each) and 3 laboratories by generating profile 
plots (i.e., 3 plots for each subject from three laboratories) for each 
outcome, the PA and HA fatty acid concentrations at baseline and then 
each hour for nine hours post consumption of MBT meal. We may use 
the Bland-Altman analysis for repeated measurements to account for the 
correlation among the measurements taken from the two subjects to 
examine the agreement between each pair of laboratories (labs 1 & 2, 
labs 1 & 3 and labs 2 & 3 compared).  We summarize the lack of 
agreement by calculating the bias (estimated by the mean difference 
between two laboratories) and standard deviation of the differences. We 
can estimate the standard deviation of the difference using the mixed-
effects models accounting for correlations among the observations within 
subjects. We will report the intraclass correlation coefficient from the 
mixed-effects models. We will plot the difference against mean plot for 
measures obtained from each pair of two different laboratories (Bland-
Altman plot) to examine any possible relationship between the 
measurement error and true value. 
DATA AND SAFETY 
MONITORING PLAN 
The Principal Investigator (PI) (Dr. Stallings) is ultimately responsible for 
monitoring data integrity and patient safety and for overall study 
oversight. The study will be monitored weekly by the PI. 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 in consultation with the 
participant’s cystic fibrosis physician team, who will be immediately 
notified and will assume acute care management. In the case of AEs and 
SAEs arising in healthy subjects, the event will be managed by the PI in 
consultation with the primary care physician identified by the participant 
upon enrollment in the study, who will be immediately notified. SAEs will 
also be reported to the study sponsor, IRB, CHPS, and all members of the 
research team in accordance with requirements. Anticipated SAEs or 
those unrelated to the study will be reported to the same 
individuals/entities in accordance with requirements. There will be 
ongoing collection of data on adverse events and compliance to the 
treatment protocol throughout the study by research staff and which will 
be reviewed weekly by the PI.   
MBT Quality Improvement Project  

  
 
 
 
 
 
 
 
x 
The Principal Investigator (PI) (Dr. Stallings) is ultimately responsible for 
monitoring the data integrity as well as the patient safety for this 
methods research development project. She will oversee all 
communication and scheduling prior to the MBT, participate in the 
consent process, and oversee all data analysis and collection.  
Since the PI will be participating in this project and since other employees 
who report directly to the PI will be participating, we acknowledge that 
there is the risk of coercion. We want to make it clear that all participants 
were on this study prior to this amendment and are knowledgeable of 
the procedures and risks associated with the MBT. 

 
xi  
 
 
 
 
 
 
 
Table 1: Schedule of Study Procedures 
Study Phase 
Visit 1 
(Screening and Consent) 
Visit 2 
(Assessment 1) 
Visit 3 
(Assessment 2) 
Assessment 
Demographics 
X 
 
 
Prior/Concomitant Medications 
X 
 
 
Randomization  
X 
 
 
Dispense Study Drug 
X 
X 
 
Fecal elastase (if necessary) 
X 
 
 
Urine pregnancy test 
X 
 
 
Outcome Measures 
Coefficient of fat absorption 
 
X 
X 
pH via SmartPill® (≥18y, n=12) 
 
X 
X 
Malabsorption blood test 
 
X 
X 
Serum vitamins A and E, essential fatty acids 
 
X 
X 
Serum magnesium 
 
X 
X 
Nutritional status 
Height, weight, BMI 
X 
X 
X 
Circumferences / skinfolds 
 
X 
X 
Sexual maturity self-assessment (<18 y, n=12) 
X 
 
 
Diet 
Diet pattern history 
X 
 
 
Three-day weighed food record 
 
X 
X 
Questionnaires 
Health history  
X 
X 
X 
CF Quality of Life (CFQ-R) 
 
X 
X 
Patient Reported Outcomes (PROMIS) 
 
X 
X 
Demographics 
X 
 
 
GI Symptom Questionnaire (PROMIS) 
X 
X 
X 
Adherence to Treatment, Enzymes 
 
X 
X 

 
xii  
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
 
 
 
Table 2: Study Timeline 
 
 
Table 2: Timeline  
 
Feb
Mar
Apr
May
Jun
Jul
Aug
Sept
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sept
Oct
Nov
Dec
Jan
Total
Start-up
X
X
X
X
X
Visit 1: Consent
1
1
1
1
2
2
2
2
2
2
2
2
2
2
 
 
 
 
24
Visit 2: Assessment 1 
 
1
1
1
1
2
2
2
2
2
2
2
2
2
2
 
 
 
24
Visit 3: Assessment 2
 
1
1
1
1
2
2
2
2
2
2
2
2
2
2
 
 
24
 
 
 
 
  
Visit Total
1
2
2
3
4
5
5
6
6
6
6
6
6
6
4
2
2
 
 
 
 
72
Sample and Data Analysis
 
 
 
 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Closeout
 
 
 
X
X
Year 1  (2018-19)
Year 2  (2019-20)

 
  
 
 
 
1 
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 
Introduction 
Fat malabsorption contributes to poor nutritional status in people with cystic fibrosis (CF) 
and exocrine pancreatic insufficiency (EPI). Prescribing gastric acid-reducing agents such as 
proton pump inhibitors (PPIs) and histamine receptor antagonists (H2RAs) as an adjunct to 
pancreatic enzyme replacement therapy (PERT) to improve PERT efficacy and dietary fat 
absorption has become accepted clinical practice in CF, despite limited evidence to support 
the practice1. Results from previous trials are conflicting. The most recent Cochrane review 
concluded that acid suppression in addition to PERT may improve fat absorption and 
gastrointestinal symptoms, but there was no benefit of improved clinical and nutritional 
status or lung function2. Beyond a small subgroup analysis, no study has specifically 
examined the relationship between duodenal pH and fat absorption in patients with CF 
who are prescribed acid suppression in addition to PERT. In addition, absorption of 
triglycerides specifically has not been evaluated in this context. The malabsorption blood 
test (MBT) is a novel method comparing absorption of a triglyceride and a free fatty acid 
that has potential to provide an accurate and specific method for patients and research 
subjects with pancreatic-based fat malabsorption diagnoses. We have demonstrated the 
ability of the MBT to detect a reduction in fat absorption in healthy subjects receiving a 
lipase inhibitor and in subjects with CF and EPI not administered their routine PERT 
compared to when they were administered PERT; additionally, it detects differences 
between subjects with CF and EPI compared to healthy subjects, as well as differences in 
fat absorption depending upon the timing of administration of PERT around meals3, 4. 
Establishing the efficacy and true health benefit of acid suppression for nutritional status 
and outcomes in CF is particularly important in light of potential health risks and cost 
associated with long-term or even lifetime use of these medications. 
1.2 
Name and Description of Investigational Product or Intervention 
Omeprazole is a proton-pump inhibitor that can be obtained over the counter or by 
prescription to reduce gastroduodenal acidity, and its efficacy when used concurrently with 
pancreatic enzyme replacement therapy is the primary outcome of this study. 
1.3 
Selection of Drugs and Dosages 
Omeprazole is available in multiple dosage forms. For this study, the 20mg dosage form will 
be used. This is the generally recommended daily, over-the-counter dose.  
1.4 
Relevant Literature and Data 
There is limited evidence from randomized placebo-controlled trials that PPI or H2 blockers 
used in combination with PERT are associated with improvement in fat absorption and in 
gastrointestinal symptoms2. Heijerman and colleagues, in a small randomized controlled 
trial with a crossover design, found a reduction of 4.8% in fecal fat excretion in 11 subjects 
receiving 14 days of omeprazole compared to when they received 14 days of placebo 

 
  
 
 
 
2 
(18.1% vs. 22.9%, respectively)6. In another study using a similar crossover design, the 
same authors found a reduction in fecal fat excretion of 8.9%, from 19.6% after 14-day 
placebo treatment to 10.7% after 14-day omeprazole treatment in 9 subjects on high dose 
pancreatic enzyme therapy7. Proesmans et al, using a randomized crossover design in a 
study of 15 children with CF and confirmed steatorrhea, found a reduction 7.5 g of fecal fat 
(from 13.0 to 5.5 g) and an increase in CFA of 7% (from 87 to 94%) after one month of 
omeprazole use8. In other clinical trials of H2RAs and PERT, CFA% improved from 77.1 to 
83.6% in a study of 10 children with CF receiving PERT only compared to PERT plus 
cimetidine over 14-day periods9, and from 74.4% to 87.3% in 10 CF children receiving PERT 
only and PERT plus famotidine over 6-month periods10. Boyle et al11 found significant 
reduction in fecal weight and fecal fat and Chalmers et al12 found reduced fecal fat content 
with cimetidine use.  
In contrast, several other investigations found no significant reduction in fecal fat or fecal 
weight13 or no significant improvement in fat absorption14 with either PPI or H2RA 
medications vs. placebo used in conjunction with PERT. From a series of Cochrane 
Reviews2, 15-17 of clinical trials to determine the efficacy of drugs to improve outcomes in 
CF, including the most recent review by Ng and Moore2, have concluded that while there is 
limited evidence these drugs may improve fat absorption and gastrointestinal symptoms, 
there is no conclusive benefit of improved clinical, nutritional, or lung status in CF.   
Historically, the CFA is considered the gold standard for fat malabsorption diagnosis. 
However, CFA is rarely used in clinical care in large part due to patient burden related to 
72-hr stool and diet collections. The CFA method requires the patient consume a relatively 
high fat diet, accurately document all food intake, and collect all stool for 72 hours. A 
dietitian analyzes the record using software that calculates the daily and three day average 
fat intake (g/day). The multiple stool sample containers are shipped to one of a few 
laboratories that homogenizes the collection and measures stool fat content (g/day). CFA% 
is calculated once both diet and stool fat content results are available.  
The impairment of chloride and water transport with cystic fibrosis transmembrane 
regulator (CFTR) dysfunction results in the thickened mucus that characterizes CF. The 
CFTR also conducts the bicarbonate ion, and the secretion of bicarbonate from salivary, 
esophageal submucosa, and duodenal Brunner’s glands, the gastric mucosa, the duodenal 
epithelium, the bile ducts, and the pancreatic ductal epithelium is impaired in CF. The 
impaired bicarbonate secretion in the foregut coupled with gastric acid secretion that is 
unimpaired results in a decrease in gut pH. The more acidic intestinal milieu interferes with 
and delays the dissolution of the enteric coating of pancreatic enzymes in the duodenum, 
resulting in fat malabsorption. 
The SmartPill® is an ingestible wireless capsule that was initially designed to study gut 
motility through the measurement of intestinal transit time, however, it is also able to 
measure intraluminal pH in real-time18, 19. Gelfond et al19 have demonstrated a significant 
delay in the small intestinal transit and deficient buffering capacity required to neutralize 
gastric acid in the proximal small bowel of people with CF compared to healthy controls. 

 
  
 
 
 
3 
Gastric acid suppression with PPI have been shown in some studies to improve nutrient 
absorption in CF8. Omeprazole in combination with PERT may reduce gastric acidity and 
increase the duodenal pH, resulting in improved fat absorption in the gut. In this study, we 
will use the SmartPill® to explore the effects of acid suppression on duodenal pH and the 
association with fat absorption in people with CF. 
The MBT is a novel method that has potential to provide an accurate, specific, and 
acceptable method for patients and research subjects with pancreatic-based fat 
malabsorption diagnoses. The formulation probe of the MBT consists of simultaneous oral 
doses of two odd number carbon chain length fatty acids, pentadecanoic acid (PA), a free 
fatty acid, and triheptadecanoic acid (THA), a triglyceride composed of glycerol with three 
heptadecanoic (HA) fatty acids. PA (C15:0) and HA (C17:0) are both saturated fatty acids 
that are present in small amounts in dairy products and synthesized in only small amounts 
by humans. PA, the free fatty acid, is absorbed without hydrolysis by pancreatic lipase, 
while THA, a triglyceride, requires hydrolysis before HA is absorbed. The extent of HA 
absorption following administration of the MBT reflects the degree of fat malabsorption 
due to available pancreatic lipase activity, while PA absorption is unaffected by reduced 
lipase. Therefore, PA and HA pharmacokinetic characteristics in combination, and 
particularly the HA/PA ratio, are used in the MBT to evaluate pancreatic-based fat 
malabsorption. As proof of concept, we have demonstrated the ability of the MBT to 
detect a reduction in fat absorption in healthy subjects receiving a lipase inhibitor, in 
subjects with CF and EPI not administered their routine PERT compared to when they were 
administered PERT, and in subjects with CF and EPI compared to healthy subjects3, 4. 
Furthermore, we have recently demonstrated that the MBT detects differences in fat 
absorption depending upon the timing of administration of PERT around meals (before, 
during, after)4. In this proposed study, the MBT will be utilized to characterize the degree 
of fat absorption in people with CF using omeprazole vs. placebo in combination with PERT.  
1.5 
Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, and 312.. All episodes of 
noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent and assent, 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 
The purpose of the study is to determine if a proton-pump inhibitor will improve 
the efficacy of pancreatic enzyme replacement therapy as evidenced by changes in 

 
  
 
 
 
4 
fat absorption and to characterize the mechanism by which this improvement 
occurs.Primary Objective (or Aim) 
2.2 
The primary objective of this study is to determine if a proton-pump inhibitor 
improves fat malabsorption in subjects with CF and EPI who are on pancreatic 
enzyme replacement therapy. The primary outcome measure of fat absorption will 
be the gold standard coefficient of fat absorption (CFA). Secondary Objectives (or 
Aim) 
The secondary objectives are to: 
• Determine if changes in duodenal pH on and off acid suppression occur using the 
SmartPill®, and if such changes correlate with changes in fat absorption. 
• Characterize changes in triglyceride absorption on and off acid suppression using the 
malabsorption blood test. 
• Explore associations among changes in nutrition status (weight, height, BMI), GI 
symptoms, and quality of life in subjects treated with omeprazole vs. placebo in 
combination with PERT. 
3 
INVESTIGATIONAL PLAN 
3.1 
General Schema of Study Design 
This is a randomized placebo-controlled double-blinded trial with a crossover design to 
determine the efficacy of omeprazole as an adjunct to PERT to improve dietary fat 
absorption in 24 adolescent (12+ years) and adult subjects with CF and EPI. Refer to Table 3 
for a description of the flow of the study design. 
3.1.1 Screening Phase 
Subjects will be recruited from the CF Centers at the Children’s Hospital of Philadelphia 
(CHOP), hospitals affiliated with University of Pennsylvania, and other regional CF Centers. 
Potential subjects will be screened using the protocol inclusion and exclusion criteria. 
Twenty-four subjects with CF and EPI, 12 years of age and older, will be recruited, with a 
goal of 50% of subjects between the ages of 12 and 18. Subjects who are receiving PPI or 
H2 medication will be eligible, but must be willing to discontinue this medication use as 
needed to comply with the protocol. Subject or parent/guardian informed consent and, if 
applicable, child assent, will be obtained prior to any study-related procedures being 
performed, including discontinuation of current therapy. A stool sample will be collected to 
confirm eligibility based on exocrine pancreatic insufficiency as measured indirectly by 
fecal elastase if a fecal elastase has not already been documented in the medical record. 
Height and weight will also be obtained as a baseline. Subjects will be asked to follow a 
moderate to high fat diet and also to continue their clinically-established standard PERT 
dose for the duration of the study. 

 
  
 
 
 
5 
3.1.2 Study Treatment Phase (start of the study intervention) 
There will be a 14-day period prior to the start of the study intervention during which time 
all subjects will maintain a standard diet/PERT dose. Subjects who were taking PPIs or H2 
medication at the time of the screening/consent visit, will discontinue these medications 
for the duration of the study. This 14-day period prior to the start of the intervention will 
also serve as a washout period from these medications for these subjects. After this 14-day 
period, treatment with omeprazole or placebo will commence. After completing 28 days of 
treatment with omeprazole or placebo, subjects will have a second study visit, during 
which the first set of assessments will be completed. All study visits will occur at outpatient 
research offices of the Center for Human Phenomic Science (CHPS) at The Children’s 
Hospital of Philadelphia (CHOP), a pediatric health care center. Eligible subjects will be 
enrolled into the study and come to CHOP for the study visits. Refer to Table 1 for list of 
assessments and the study timeline for the pace of recruitment.  
3.1.3 Second Treatment Phase 
After completing the second study visit, there will be a 14-day washout period during 
which subjects will discontinue their study medication but continue their standard 
diet/PERT use. Subjects will then cross over to the other treatment arm and undergo an 
additional 28 days of treatment with omeprazole or placebo. At the end of this treatment 
period, they will have a third study visit that will include the outcome measure 
assessments. 
3.2 
Allocation to Treatment Groups and Blinding 
Subjects (n=24) will be randomized at the consent visit. Subjects will be randomized to 
receive either omeprazole (n=12) or placebo (n=12) for 28 days. The randomization scheme 
will be generated and executed by the University of Pennsylvania Investigational Drug 
Service (IDS) pharmacy. All other research personnel will be blinded to the randomization 
throughout the study. The randomization code will be maintained by the University of 
Pennsylvania IDS Pharmacy. In a medical emergency, the primary investigator Dr. 
Stallingswill be unblinded to the participant’s study medication at any time to provide the 
needed information for clinical care.  
3.3 
Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
The study duration per subject will be up to 100 days, with one day for screening and 
consent, up to 48 days each for Phases 1 and 2 for the washout and treatment periods, as 
well as the assessment visits, totaling approximately 100 days. No follow-up is required 
upon completion of the study procedures. 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at one investigative site in the United States, the Children’s 
Hospital of Philadelphia. Recruitment will occur across regional centers as described above. 

 
  
 
 
 
6 
Recruitment will stop when 24 subjects with CF and EPI have been enrolled. It is expected 
that 24 subjects will be enrolled to produce 22 evaluable subjects in each group to account 
for attrition.  
3.4 
Study Population 
3.4.1 Inclusion Criteria 
1) Males or females older than 12 years of age.  
- n=12 between 12 and 18 years of age 
- n=12 ≥18 years of age 
2) Subjects must have the diagnoses of cystic fibrosis and exocrine pancreatic insufficiency 
(receiving PERT), with a pancreatic elastase <200ug/g stool. 
3) In usual state of good health – no hospitalizations in the preceding two weeks.  
4) Family and subject commitment to the approximately four month study protocol. 
3.4.2 Parental/guardian permission (informed consent) and if appropriate, child 
assent.Exclusion Criteria 
1) FEV1 < 40% of predicted. 
2) Pregnant or lactating females. 
3) Other illness affecting growth, fat absorption, or nutritional status.  
4) Unwillingness to continue their clinically-established PERT dose for the duration of the 
study.  
5) Use of other medication that affects dietary fat absorption.  
6) Allergy to soy products 
7) Allergy to safflower products (microlipids) 
8) Parents/guardians or subjects who, in the opinion of the Investigator, may be non-
compliant with study schedules or procedures. 
In subjects ≥18 years of age, celiac disease or allergy to gluten will be an exclusion, as the 
SmartPill® study requires ingestion of a specialized meal that contains 
gluten.Subjects that do not meet all of the enrollment criteria may not be enrolled. 
Any  
violations of these criteria must be reported in accordance with IRB Policies and  
Procedures.  

 
  
 
 
 
7 
4 
STUDY PROCEDURES  
4.1 Consent Visit (Visit 1) 
• Review of health history including prior and concomitant medications 
• Review demographics 
• Informed Consent 
• Review of diet pattern 
• Subjects asked to maintain a moderate to high fat diet throughout the study 
• Subjects asked to maintain their clinically established PERT dose throughout the 
study 
• Subjects asked to wean PPI or H2-receptor antagonist medication, if taking 
• Simple anthropometrics 
• Stool collection if needed 
• Sexual maturity self-assessment (age <18y, n=12) 
• GI symptom questionnaire 
• Urine pregnancy test (female subjects) 
• Distribute arm 1 study medication 
Table 3 
Protocol 
Day 1 
Days 2-15 
Days 16-43 
Visit 1:  
Consent and 
Randomization 
- Consent 
- Clarify diet & PERT  
- Questionnaires 
- Elastase (if needed) 
- Anthros 
- Urine pregnancy test 
- 14-day washout period for PPI or 
H2RA medication, if applicable 
- Sustain on standard moderate to 
high fat diet 
- Confirm standardized PERT dose 
- Randomized treatment to either 
omeprazole (PPI) or placebo for 28 days 
 
  
Day 44 
Day 45 
Day 46 
Day 47 
Day 48 
Day 49 
Day 50 
Days 51-
64 
Visit 2: 
After 28-day 
treatment with 
PPI or placebo  
- Fast from 
8pm 
- No dairy 
- Remain 
on 
standard 
PERT 
- MBT  
- 7am–4pm 
- Serum labs 
- Anthros 
 
If ≥18 years: 
- SmartPill  
- Fast from 
12am 
- Resume 
moderate-
high fat diet 
If ≥18 years: 
- SmartPill at 
8am 
- 6hr fast  
- Diet 
record 
 (day 1)    
- Diet 
record 
(day 2) 
 
- 72-hr 
Stool 
(day 1) 
- Diet 
record 
(day 3) 
 
- 72-hr 
Stool 
(day 2) 
- 72-hr 
Stool 
(day 3) 
- 14-day 
washout 
period 
from 
treatment/ 
placebo 
 

 
  
 
 
 
8 
 
Days 65-92 – Randomized crossover treatment (PPI to placebo, or placebo to PPI) for 28 days 
 
 
Day 93 
Day 94 
Day 95 
Day 96 
Day 97 
Day 98 
Day 99 
Day 100 
Visit 3: 
After 28-day 
crossover 
treatment with 
placebo or PPI 
- Fast from 
8pm 
- No dairy 
- Remain 
on 
standard 
PEM 
- MBT  
- 7am–4pm 
- Serum labs 
- Anthros 
 
If ≥18 years: 
- SmartPill  
- Fast from 
12am 
- Resume 
moderate-
high fat diet 
If ≥18 years: 
- SmartPill at 
8am 
- 6hr fast  
- Diet 
record 
 (day 1) 
- Diet 
record 
(day 2) 
 
- 72-hr 
Stool 
(day 1) 
- Diet 
record 
(day 3) 
 
- 72-hr 
Stool 
(day 2) 
- 72-hr 
Stool 
(day 3) 
- Return to 
usual care 
and 
medication 
regimen 
- Return to 
usual diet 
 
4.2 
Study Treatment Phase 
After the screening and consent visit, subjects will have two visits in this study. Visit 2 will 
be after 28 days of either omeprazole or placebo. After a 14-day washout period from 
study intervention of either treatment or placebo, subjects will cross over to the opposite 
treatment and receive the alternate therapy for 28 days. Visit 3 will take place at the 
completion of this 28-day period of either treatment or placebo. Assessments at both Visit 
2 and 3 are identical.  
4.2.1 Visit 2 
Visit 2 takes place over seven total days, detailed below:  
Day 1 
• 
Regular lunch/dinner except for no intake of dairy products 
• 
No alcohol intake 
• 
Normal daily activity 
• 
Fast overnight starting at 8pm 
Day 2 – Visit to CHOP CHPS/NGL 
• 
Insert blood-drawing intravenous catheter 
• 
Baseline blood draw for MBT / study labs drawn (Vitamins A/E, Magnesium, 
essential fatty acids) 
• 
Administer MBT study meal (breakfast) 
• 
MBT – hourly blood sample for 9 hours 
• 
After hour 6, low-fat study lunch 
• 
Anthropometry (height, weight, skinfolds, circumferences) 
• 
Questionnaires: Health History and medications, Quality of life questionnaire 
(CF-QOL), PROMIS, GI symptom questionnaire, Adherence, Adverse Events 

 
  
 
 
 
9 
• 
Instructions will be given for collection and shipping for: stool collection (72-hour 
fecal fat analysis), 3-day weighed food records, and adverse events diary 
• 
Provide arm 2 study medication 
• 
SmartPill® cohort will fast overnight starting at 12:00am 
Day 3 – SmartPill® Cohort returns to CHOP CHPS/NGL 
• 
All subjects maintain events diary, continue moderate fat diet 
• 
SmartPill® cohort:  
- Takes SmartBar® study breakfast, followed by SmartPill® 
- Fasts for six hours during study  
Day 4 
• 
Moderate fat diet 
• 
3-day weighed food record begins  
• 
Food record – Day 1 
• 
Maintain adverse events diary 
• 
SmartPill® cohort monitors for passage of capsule and returns monitoring belt 
upon completion of the study 
Day 5 
• 
Moderate fat diet 
• 
Food record – Day 2 
• 
Stool collection begins (72-hour fecal fat), store frozen until brought to CHOP 
• 
72-hour stool – Day 1 
• 
Maintain adverse events diary 
• 
SmartPill® cohort monitors for passage of capsule and returns monitoring belt 
upon completion of the study 
Day 6 
• 
Moderate fat diet 
• 
Food record – Day 3 
• 
72-hour stool – Day 2 
• 
Maintain adverse events diary 
Day 7 
• 
Moderate fat diet 
• 
72-hour stool – Day 3 
• 
Maintain adverse events diary 
 
4.2.2 Visit 3 
Visit 3 takes place over seven total days, detailed below:  

 
  
 
 
 
10 
Day 1 
• 
Regular lunch/dinner except for no intake of dairy products 
• 
No alcohol intake 
• 
Normal daily activity 
• 
Fast overnight starting at 8pm 
Day 2 – Visit to CHOP CHPS/NGL 
• 
Insert blood-drawing intravenous catheter 
• 
Baseline blood draw for MBT / study labs drawn (Vitamins A/E, Magnesium, 
essential fatty acids) 
• 
Administer MBT study meal (breakfast) 
• 
MBT – hourly blood sample for 9 hours 
• 
After hour 6, low-fat study lunch 
• 
Anthropometry (height, weight, skinfolds, circumferences) 
• 
Questionnaires: Health History and medications, Quality of life questionnaire 
(CF-QOL), PROMIS, GI symptom questionnaire, Adherence, Adverse Events 
• 
Instructions will be given for collection and shipping for: stool collection (72-hour 
fecal fat analysis), 3-day weighed food records, and adverse events diary 
• 
Provide arm 2 study medication 
• 
SmartPill® cohort will fast overnight starting at 12:00am 
Day 3 - SmartPill® Cohort returns to CHOP CHPS/NGL 
• 
All subjects maintain events diary, continue moderate fat diet 
• 
SmartPill® cohort:  
- Takes SmartBar® study breakfast, followed by SmartPill® 
- Fasts for six hours during study 
Day 4 
• 
Moderate fat diet 
• 
3-day weighed food record begins  
• 
Food record – Day 1 
• 
Maintain adverse events diary 
• 
SmartPill® cohort monitors for passage of capsule and returns monitoring belt 
upon completion of the study 
Day 5 
• 
Moderate fat diet 
• 
Food record – Day 2 
• 
Stool collection begins (72-hour fecal fat), store frozen until brought to CHOP 
• 
72-hour stool – Day 1 
• 
Maintain adverse events diary 

 
  
 
 
 
11 
• 
SmartPill® cohort monitors for passage of capsule and returns monitoring belt 
upon completion of the study 
Day 6 
• 
Moderate fat diet 
• 
Food record – Day 3 
• 
72-hour stool – Day 2 
• 
Maintain adverse events diary 
Day 7 
• 
Moderate fat diet 
• 
72-hour stool – Day 3 
• 
Maintain adverse events diary 
 
4.3 
Unscheduled Visits 
Due to the complexity of the study, no unscheduled visits will be permitted. 
 
 
4.4 
Concomitant Medication 
All prior and concomitant medications and dietary supplements used within 14 days prior 
to the screening visit and through the end of the study will be recorded. The dates of 
administration, dosage, and reason for use will be included.  
4.5 
Subject Completion/Withdrawal 
For subjects with CF and EPI who were naïve to PPI at the start of the study, at the end of 
participation in the study (all collections are complete for Visit 3) omeprazole will be 
discontinued and they will and resume their usual care without acid suppression. For 
subjects with CF and EPI who were receiving acid suppression with PPI or H2RA prior to the 
start of the study, at the end of participation in the study (all collections are complete for 
Visit 3), omeprazole will be discontinued and they will resume their usual care, including 
their acid suppression product and dose they were receiving before the study began.  
Subjects may withdraw from the study at any time without prejudice to their care. They 
may also be discontinued from the study at the discretion of the Investigator for lack of 
adherence to study treatment or visit schedules, or adverse events. The Investigator or the 
Sponsor may also withdraw subjects who violate the study plan, or to protect the subject 
for reasons of safety or for administrative reasons. It will be documented whether or not 
each subject completes the clinical study. If the Investigator becomes aware of any serious, 
related adverse events after the subject completes or withdraws from the study, they will 
be recorded in the source documents and on the CRF.  

 
  
 
 
 
12 
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 record: 
• Date of birth 
• Sex 
• Weight 
• Cystic fibrosis and exocrine pancreatic insufficiency diagnoses 
• Cystic fibrosis genotype 
• Biochemical evidence of malabsorption including fat-soluble vitamin deficiency, 
essential fatty acid deficiency, and fecal elastase 
• Subjective evidence of malabsorption including poor weight gain, steatorrhea, or 
increased stool frequency 
• Past PERT use 
• Past PPI or H2RA use 
5.1.2 Laboratory Evaluations 
Fecal Elastase-1: Pancreatic function will be assessed by fecal elastase-1 to determine the 
level of pancreatic enzyme activity in the stool20, 21. Subjects will be provided with the stool 
collection kit and proper instructions and supplies, and samples will be collected during the 
day of the visit if possible, or at home and returned. The stool sample will be stored at -
20oC, and analyzed with a monoclonal enzyme-linked immunosorbent assay (CHOP Lab).  
Serum retinol and α-tocopherol: will be drawn at the assessment visits and assayed at Craft 
Laboratories.  
Serum magnesium: will be drawn at the assessments visits and processed at CHOP Core 
Lab. There is evidence to suggest that long-term use of a PPI (>1 year) impairs magnesium 
absorption and may result in hypomagnesemia22. This has not been noted in short-term 
use.  
Linoleic acid (essential fatty acid panel): will be drawn at the assessment visits and assessed 
at ARUP Laboratories. 
Any individuals from an institution 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 female subjects ³ 9 years of age who are physically 
capable of becoming pregnant. 

 
  
 
 
 
13 
5.1.3 Other Evaluations 
Anthropometric Assessment: Weight, height, and BMI will be assessed at all study visits. 
Measures of body composition will also be conducted for relative muscle and fat at Visits 2 
and 3. All anthropometric techniques will follow those described by Lohman et al23. Weight 
(0.1kg) will be measured on a digital electronic scale (Seca, Munich, Germany) and stature 
(0.1cm) on a stadiometer (Holtain, Crymych, UK). Skinfold thickness will be measured 
(0.1mm) at the triceps, biceps, subscapular, and supra-iliac sites with a skinfold caliper 
(Holtain, Crymych, UK) to assess subcutaneous fat stores. Mid upper arm circumference 
measured with a non-stretchable fiberglass tape (0.1cm) (McCoy, Maryland Heights, MO). 
Upper arm muscle and fat area Z-scores will be generated24, 25.  
Body Composition: Total body composition, total FFM and FM, and percent body fat 
(%FAT), will be assessed by the skinfolds using prediction equations adapted for children, 
adolescents, and adults26, 27. 
Pubertal Status: Pubertal status will be determined by Tanner Stages of sexual maturity 
using a validated self-assessment questionnaire developed by Morris and Udry28. The self-
assessment questionnaire will be completed at Visit 1 by all subjects 12 to 18 years of age 
(assisted by a family member as needed). Female subjects will asked a series of questions 
to determine their menarchal status, age at first menstruation, and regularity of 
menstruation. 
Dietary Intake: At Visit 1, a diet pattern history including the subject’s clinically established 
PERT use will be obtained and subjects will be asked to maintain a moderate to high fat 
diet for the duration of the study, as well as to maintain their usual PERT use. Three-day 
weighed food records will be obtained at Visits 2 and 3 and calories, macro- and micro-
nutrient content calculated. Subjects will be provided with scales, spoons and all supplies 
necessary for the collection of the dietary data and will be conducted with assistance from 
the CHPS staff and Bionutrition Unit. Dietary intake will be analyzed using Nutrition Data 
System for Research software version 2012 developed by the National Coordinating Center 
(NCC, University of Minnesota. Minneapolis, MN)29-31. The three-day weighed food records 
will coincide with the stool collection for determining the coefficient of fat absorption (see 
below). 
Demographics and Health Questionnaire: The questionnaire will be administered via 
interview by the research staff, and will consist of two sections. The Health History section 
has general questions about the subject’s health history including documentation of 
medical history, recent hospital admissions and illnesses, medication, history of pancreatic 
enzyme supplementation, and nutrient supplement use. The Health History section will be 
administered at all study visits. A Demographics section describes racial/ethnic status and 
insurance status of the research subject. 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. The demographic and contact information will be 
administered at Visit 1 only.  

 
  
 
 
 
14 
Quality of Life Questionnaires: In order to assess the health-related quality of life (QOL), 
validated questionnaires will be administered to all subjects at both Visits 2 and 3. The 
Cystic Fibrosis Questionnaire, Revised (CFQ-R, University of Miami) will be completed by 
the subjects. There is a questionnaire for subjects age 12-1332, as well as a separate 
questionnaire for subjects greater than 14 years of age that is also validated in adults33.  
Patient Reported Outcomes (PROMIS): We will assess patient reported outcomes at both 
Visits 2 and 3 using the NIH-developed pediatric PROMIS short forms assessing pain, 
fatigue, depressive symptoms, physical function (mobility), and peer relationships. Adult 
subjects will use the corresponding adult forms. All subjects will use specific PROMIS short 
forms for GI symptoms including belly pain, diarrhea, gas and bloating, constipation, 
gastroesophageal reflux, and nausea and vomiting. These are valid and reliable scales 
broadly applicable across populations, GI symptoms, GI diseases and demographics34. 
Adherence: Adherence to both PERT and PPI will be assessed at study Visits 2 and 3, as well 
as by phone calls. This time will also be used to trouble-shoot any barriers to adherence, 
and also to collect information on adverse events experienced during the course of the 
study.  
Adverse Events Diary: Subjects will be asked about all adverse events at both Visits 2 and 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 CHPS. 
5.2 
Efficacy Evaluations 
5.2.1 Diagnostic Tests, Scales, Measures, etc. 
Coefficient of Fat Absorption (CFA): The primary outcome, the coefficient of fat absorption 
(CFA%) will be determined by the 72-hour stool collections at Visits 2 and 3, and a 3-day 
weighed food record collection while consuming a moderate fat (about 80+ g/day) diet. 
These stool collections will be performed at home and returned to CHOP. Subjects will be 
given a home collection kit and detailed instructions. Specimens will be stored frozen until 
analysis of total fat content by a gravimetric method (Mayo Medical Laboratories, 
Rochester, MN). Total dietary intake of fat during the 3-day period will be assessed from 
the 3-day weighed food records which will coincide with the 72-hour stool collection, and 
the CFA% will be calculated35. The CFA% will be compared between subjects on PPI and 
PERT versus PERT and placebo. 
Malabsorption Blood Test (MBT): The MBT primary outcomes consist of parameters from 
pharmacokinetic analyses. The MBT consists of a simultaneous oral dose of pentadecanoic 
acid (PA), a free fatty acid, and triheptadecaenoin (THA), a triglyceride with three 
heptadecanoic (HA) saturated fatty acids requiring hydrolysis by pancreatic lipase before 
HA can be intestinally absorbed (Patent # US 7402405 B2, July 22, 2008). The MBT with the 
PA and THA is delivered in a breakfast test meal after a 12-hour fast and 24 hours without 
dairy foods. Serum concentration levels of PA and HA are assessed by gas-liquid 
chromatography (GC), from serum samples drawn prior to MBT and then hourly for eight 
hours. The MBT test meal is prepared immediately before consumption, with 5.0g of PA 

 
  
 
 
 
15 
and 5.5g of THA blended into a test meal composed of 64g vanilla Scandishake (Axcan 
Scandipharm, Birmingham, AL), 6oz Silk Light vanilla soy milk, 15mL Hershey’s chocolate 
syrup, and 10mL microlipids (www.nestle-nutrition.com). The 8oz MBT test meal contains 
~550 calories, 32 g fat, and 52% of calories from fat. The test meal was designed to be 
similar to a high fat dinner meal. Prior to administration of the MBT test meal, an 
indwelling catheter is placed for baseline (0 Hour) and subsequent blood draws at Hour 1, 
2, 3, 4, 5, 6, 7, 8, and if possible, 9 post-ingestion for quantification of serum PA and HA. 
The MBT test meal is consumed within five minutes of the baseline blood draw. After the 
Hour 5 or 6 blood draw, subjects consume a 1000 kcal, low fat (12g) lunch meal, and 
further blood samples will follow this meal. During the protocol period, subjects are 
offered non-caloric and non-caffeinated beverages ad libitum.  
Each subject will have two MBT, the first after the initial 28 day treatment course of PPI or 
placebo (Visit 2), and the second after completing the second 28 day treatment course of 
PPI or placebo (Visit 3), when subjects will be on the opposite treatment. Plasma samples 
will be analyzed by a GC method at Wake Forest University (Winston-Salem, NC). Utilizing 
the relative absorption of HA to PA, the MBT has been shown to respond to changes in fat 
absorption in healthy adult subjects using a lipase inhibitor and in subjects with CF and PI 
while on and off pancreatic enzyme therapy3, and is also sensitive to enzyme dose 
titration36.  
SmartPill® – The SmartPill® (Given Imaging) is an ingestible capsule that will measure 
pressure, pH and temperature in the 12 subjects ≥18 years of age (Visits 2 and 3) as it 
travels through the gastrointestinal (GI) tract to assess GI motility and pH19, 37-39. The 
subject will be required to fast for at least 8 hours prior to the test and 6 hours after the 
SmartPill® is taken. The subject will be provided with a SmartBar®, which is a standardized 
meal replacement (similar to a granola bar) that is eaten just prior to swallowing the 
capsule. The specific nutritional make-up and calorie content of the bar are important for a 
valid test result. The capsule will travel through the GI tract and wirelessly transmit data to 
a recorder worn on a belt clip or lanyard. The SmartPill® capsule is 26mm x 13mm and is 
slightly larger than a multi-vitamin. It is naturally passed during a bowel movement, usually 
within a few days. The SmartPill® is FDA-approved and will be used in accordance with its 
approved labeling.  
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. 

 
  
 
 
 
16 
6 
STATISTICAL CONSIDERATIONS 
6.1 
Primary Endpoint 
The primary hypotheses of this study: The use of omeprazole, a proton pump inhibitor 
medication, in combination with PERT will significantly improve dietary fat absorption 
compared to placebo in subjects with CF and EPI as indicated by CFA%. Our previous 
experience in subjects with CF and EPI receiving PERT, CFA% was 81±14% in one study40, 
83±10% in another41, and more recently, 89.5±7.4% in subjects with CF gating mutations 
and EPI42. In comparison, in healthy subjects, CFA% is typically ≥93%. We will use a 
randomized placebo-controlled double blinded crossover trial to investigate the efficacy of 
omeprazole. The crossover design allows subjects to serve as their own controls to 
evaluate outcomes with and without omeprazole treatment. 
 
6.2 
Secondary Endpoints 
The secondary objectives are exploratory, 1) to determine if changes in duodenal pH on 
and off acid suppression occur using the SmartPill®, and if such changes correlate with 
changes in fat absorption; 2) to characterize changes in triglyceride absorption on and off 
acid suppression using the MBT; 3) to explore associations among changes in nutrition 
status (weight, height, BMI), GI symptoms, and quality of life in subjects treated with 
omeprazole vs. placebo in combination with PERT. 
6.3 
Statistical Methods 
6.3.1 Baseline Data  
Descriptive statistics for CFA%, duodenal pH, MBT, and QOL outcomes (mean, standard 
deviation, median, range, 95% CI) will be calculated at baseline for the total group for 
continuous variables and c-squared or Fisher’s exact tests for categorical variables. 
Differences between randomization groups at each time point and differences in the 
change over time with treatment will be assessed with unpaired t tests or Mann Whitney U 
rank sum tests as appropriate. 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. 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 metrics3. 
Using this method, population PK modeling is conducted by simultaneously fitting 
structural PK models to both PA and HA concentrations4. 

 
  
 
 
 
17 
6.3.2 Efficacy Analysis 
Descriptive statistics for CFA%, duodenal pH, MBT and QOL outcomes (mean, standard 
deviation, median, range, 95% CI) will also be calculated for the total group comparing on 
and off omeprazole treatment using pair t-tests or Wilcoxon sign rank tests as appropriate. 
Changes within randomization groups over time will also be explored using paired t tests 
Differences between randomization groups (12 randomized initially to placebo vs. 12 to 
omeprazole treatment) on visit 1 will also be tested using unpaired t tests or Mann 
Whitney U rank sum test as appropriate. Significance of the differences on and off 
treatment assessed with paired t tests or Wilcoxon sign rank tests as appropriate. PK 
parameters can then be compared for the total group comparing on and off omeprazole 
treatment using pair t-tests or Wilcoxon sign rank tests as appropriate, and between 
randomization groups at each time point using an unpaired t-test or Mann Whitney U rank 
sum test as appropriate. 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, MD)43. HA and PA concentrations will be 
transformed to molar quantities and the ratios for HA to PA Cmax and AUC and the 
associated 95% confidence interval will be calculated. A mixed-effects modeling approach 
will be employed to examine the correlation of subject characteristics (age, BMI, sex, 
disease status, etc) to CFA%, duodenal pH, QOL parameters and to PA and HA exposure 
metrics derived from the non-compartmental analysis to assess change over time in MBT 
response to PERT administration in subjects with CP. Metrics to be tested will be CFA%, 
duodenal pH, QOL parameters, PA and HA Cmax, AUC, HA/PA Cmax and AUC ratio and the 
%HA response comparing subjects when on or off omeprazole treatment and also 
comparing randomization groups at each time point. A value of p<0.05 will be considered 
statistically significant.   
6.3.3 Safety Analysis 
All subjects entered into the study at Visit 1 will be included in the safety analysis. Safety 
will be monitored by adverse event reporting. The frequencies of AEs by type, body system, 
severity and relationship to study drug will be summarized. SAEs (if any) will be described 
in detail.  
6.4 
Sample Size and Power 
The primary hypotheses of this study: 1) The use of omeprazole, a proton pump inhibitor 
medication, in combination with PERT will significantly improve dietary fat absorption 
compared to placebo in subjects with CF and EPI as indicated by CFA%. Our previous 
experience in subjects with CF and EPI receiving PERT, CFA% was 81±14% in one study40, 
83±10% in another41, and more recently, 89.5±7.4% in subjects with CF gating mutations 
and EPI42. In comparison, in healthy subjects, CFA% is typically ≥93%. In the study of 
subjects with gating mutations in which CFA% was assessed before and after 3- months of 
ivacaftor treatment, there was a significant increase in CFA% of 3.1±3.0% (p<0.01) with 
ivacaftor treatment in the 15 subjects with EPI and were receiving PERT during the study. 

 
  
 
 
 
18 
There is limited evidence from randomized placebo-controlled trials that agents such as 
omeprazole that reduce gastric acidity, when used as adjunctive therapy with PERT are 
associated with improvement in fat absorption2. Heijerman and colleagues6, in a 
randomized controlled trial with a crossover design, found a reduction of 4.8% in fecal fat 
excretion in 11 subjects receiving 14-days of omeprazole compared to when they received 
14-days of placebo (18.1 % vs. 22.9%, respectively). In another study using a similar 
crossover design, the same authors found a reduction in fecal fat excretion of 8.9%, from 
19.6% after 14-day placebo treatment to 10.7% after 14-day omeprazole treatment in 9 
subjects on high dose pancreatic enzyme therapy7. Proesmans et al, using a randomized 
crossover design in a study of 15 children with CF and confirmed steatorrhea, found a 
reduction 7.5 g of fecal fat (from 13.0 to 5.5 g) and an increase in CFA of 7% (from 87 to 
94%) after one month of omeprazole use8. In other clinical trials of H2 acid blockers as 
adjunctive therapy to PERT, CFA% improved from 77.1 to 83.6% in a study of 10 children 
with CF receiving PERT only, compared to PERT plus cimetidine over 14-day periods9, and 
from 74.4% to 87.3% in 10 CF children receiving PERT only and PERT plus famotidine over 
6-month periods10. In our proposed randomized controlled trial with a crossover design, 22 
subjects (11 randomized to 28-day treatment and 11 to placebo at Visit 1, then crossing 
over to the alternate treatment for 28-days) will have 80% power to detect an increase of 
3% with omeprazole treatment compared to no change (0%) when on placebo with a 
common SD of 5% using a paired t-test with α =0.05.  
We have not based the samples size upon the secondary exploratory hypotheses, however, 
the effect sizes that can be detected with our sample size of 22 subjects can be estimated. 
For the MBT method, the sample size is based upon our previous experience in CF with 
detecting differences in Cmax and AUC for HA and the HA/PA ratio4, and in detecting the 
percent change in HA absorption (from pharmacokinetic modeling) compared to healthy 
subjects5. For our proposed study, with the crossover design, 22 subjects (11 in each 
randomization group) will have 80% power to detect a difference in means of 0.60 (the 
difference in Cmax (in AUC) HA/PA ratio, with a mean of 1.62 (1.30) for omeprazole 
treatment, compared to 1.02 (0.70)) for placebo: this is a 37% increase in Cmax and 46% 
increase in AUC with omeprazole treatment compared to placebo, assuming that the 
common SD is 0.68 using a paired t-test with α =0.05. For the CFQ-R domain scores, a 
sample size of 22 subjects with provide 80% to see an increase of 9 points (i.e. from 80 to 
89) with omeprazole treatment compared to placebo with a common SD of 15 points using 
a paired t-test with α=0.05. For the SmartPill®, Gelfond has demonstrated significantly 
lower duodenal pH in subjects with CF compared to healthy controls19. The outcome of 
interest is the time that it takes for the pH to reach 5.5, the minimum level required to 
dissolve the enteric coating from PERT so that they are effective for nutrient absorption. In 
a study of 10 subjects with CF compared to 10 healthy controls using the SmartPill® 
methodology, the time required to reach a pH of 5.5 in CF was 17.7±6.8 compared to 
6.3±6.4 In controls (p=0.004)19. We expect a subsample of 12 subjects to be 18+ years of 
age and use the SmartPill® for duodenal pH assessment. A sample of 10 subjects is required 
for 80% power to see a reduction in time to pH of 5.5 in the GI tract from 17 to 11 minutes 

 
  
 
 
 
19 
with omeprazole treatment compared to placebo, with a common SD of 7 minutes, using a 
paired t-test with α=0.05. 
 
Using this randomized crossover design, a total sample of 22 subjects, 11 in each 
randomization group will be needed. Therefore, enrolling 24 subjects (12 in each group) 
will result in 22 subjects completing the study if we experience 10% attrition.  
6.5 
Interim Analysis 
No interim analysis is planned. 
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) 
7.1 
Description 
Omeprazole is a proton-pump inhibitor that is available both over-the-counter and as a 
prescription for multiple indications, including treatment in adults of duodenal ulcers, 
gastric ulcers, and eradication of Helicobacter pylori infection, as well as in adults and 
children for gastroesophageal reflux disease, maintenance of healing of erosive 
esophagitis, and treatment of hypersecretory conditions. The omeprazole in this study will 
be overencapsulated so as to be identical to an inert placebo, which will not affect 
pharmacokinetics or pharmacodynamics. 
7.1.1 Packaging 
Omeprazole 20mg capsules or an identical placebo will be provided to patients in a 
medication bottle at Visit 1 and Visit 2. Subjects will be given a 33-day supply for 28 days of 
use (28 days plus 20% for extra doses). Subjects will return unused capsules to the study 
team at Visit 2 and Visit 3. All research personnel will be blinded to the randomization 
throughout the study. In a medical emergency, Dr. Stallings (or designee) will be unblinded 
to the participant’s study medication at any time, day or night to provide the needed 
information for clinical care. 
7.1.2 Labeling 
Omeprazole capsules and placebo capsules will look identical. They will be distributed in 
bottles labeled by the study team as “Study Drug.” Storage will be in a locked room 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 
The medication will be dosed per the standard over the counter dosing of 20 mg per day. 
This dose is an appropriate dose for all participants. 
7.1.4 Treatment Compliance and Adherence 
Adherence will be systematically assessed using the following methods: 

 
  
 
 
 
20 
• A 33-day supply of medication will be given to subjects at Visit 1, and again at Visit 
2. Subjects will be asked to return the unused capsules at Visits 2 and 3, and the 
number of unused capsules will be recorded. 
• The study team will maintain regular contact with participants via phone calls 
and/or text message to ensure the subject has an adequate supply and to obtain a 
cursory assessment of barriers to adherence, so that the team can develop 
individualized strategies to overcome these barriers. 
• Subjects will be provided with calendars at Visit 1 as a scheduling aid for study visits 
and a reminder to adhere to the medication. 
7.1.5 Drug Accountability 
Records of study medication 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 study medication will not be distributed to any person who is not a study 
subject under the terms and conditions set forth in this protocol. Omeprazole will be 
prescribed for all subjects in the study by Dr. Stallings, the Primary Investigator, and 
dispensed to the subjects by Dr. Brownell, the Co-Investigator. Study medication may not 
be used for any purpose other than that described in this protocol. At study completion, all 
left over study medication will be returned to the study team and this will be used as one 
estimate of adherence. Once the dataset is closed, leftover study medication will be 
destroyed by the pharmacists at the Penn Investigational Drug Service.  
8 
SAFETY MANAGEMENT 
Given the nature of this study and the patient population, we request that scheduled 
hospitalizations related to cystic fibrosis care be excluded from inclusion as an SAE. 
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) they 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 received an 
intervention (drug, biologic, or other intervention). The occurrence does not necessarily 

 
  
 
 
 
21 
have to have a causal relationship with the treatment. 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 medicinal product. 
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 drug experience occurring at any dose 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, or 
• 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 drug 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. 
A distinction should be drawn between serious and severe AEs. A severe AE is a major 
event of its type. A severe AE does not necessarily need to be considered serious. For 
example, nausea which persists for several hours may be considered severe nausea, but 
would not be an SAE. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but would be an SAE.  
8.4.1 Relationship of SAE to study drug or other intervention 
The relationship of each SAE to the study intervention 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 AEs that 
are related to the research activity. Other unanticipated problems related to the research 
involving risk to subjects or others will also be reported promptly. Written reports will be 
filed using the eIRB system and in accordance with the timeline below. External SAEs that 
are both unexpected and related to the study intervention will be reported promptly after 
the investigator receives the report.  

 
  
 
 
 
22 
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) will 
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 omeprazole will be reported to the 
sponsor, Chiesi USA, Inc., within 24 hours of learning of the event regardless of the 
relationship of the event to omeprazole. The PI shall make available to Chiesi USA, Inc., 
promptly such records as may be necessary and pertinent to investigate any such event, if 
specifically requested by Chiesi USA, Inc. For medical emergencies, we will follow the CHOP 
procedures for medical emergencies that may occur for adult visitors to CHOP. 
8.7 
Medical Emergencies 
The PI and study team will respond to any study-related medical emergencies that may 
arise during protocol visits and notify the IRB and CHPS as directed by procedures and 
policies. Subjects who are <18 years of age or are patients at CHOP (who may be ≥18 years 
of age) and experience a medical emergency will be escorted by study staff or Emergency 
Medical Services to the CHOP Emergency Department. If subjects are ≥18 years of age and 
not established patients at CHOP, they will be escorted to the Hospital of the University of 
Pennsylvania by study staff or Emergency Medical Services as appropriate in the event of a 
medical emergency. 

 
  
 
 
 
23 
9 
STUDY ADMINISTRATION 
9.1 
Treatment Assignment Methods 
9.1.1 Randomization 
A total of 24 subjects will be recruited for this study. Subjects will be stratified by age and 
gender. As this is a crossover trial, subjects will act as their own controls, and therefore 
randomization will be to receive omeprazole versus placebo for the first treatment arm of 
the study, before crossing over to the other arm after Visit 2. The randomization scheme 
will be generated by a biostatistician provided by CHPS.  
9.1.2 Blinding 
All study personnel will be blinded to the randomization throughout the study. Omeprazole 
capsules and the placebo capsules are identical in size and color. Capsule bottles will be 
labeled by the study team and labeling will be identical in appearance. 
9.1.3 Unblinding 
Two individuals at CHOP will be designated to access the randomization code in the case 
that unblinding is clinically necessary. These two individuals will be physicians trained in 
nutrition research who will not be participating in any aspect of the study. In a medical 
emergency, the PI, Dr. Stallings (or designee) will be unblinded to the participant’s study 
medication at any time to provide the needed information for clinical care.  
9.2 
Data Collection and Management 
We will establish a database to store study data using standard software, the REDCap 
database. REDCap (Research Electronic Data Capture) is a secure, web-based application 
designed to support data capture for research studies, providing an intuitive interface for 
validated data entry; audit trails for tracking data manipulation and export procedures; 
automated export procedures for seamless data downloads to common statistical 
packages; and procedures for importing data from external sources. 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 regularly by the LI. The LI, or study staff, will review all data 
collection forms on an ongoing basis for data completeness and accuracy as well as 
protocol compliance. Following data entry, all primary and secondary endpoint data will be 
verified against original source documents. Data verification will be performed by someone 
other than the individual originally collecting and entering the data.  
All subjects will be assigned a unique identification number that will be used to ensure 
strict confidentiality. The databases are secured with password protection to ensure 
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, 

 
  
 
 
 
24 
information. A master list containing PHI and subject ID number will be kept separate from 
the data forms and the database that will only have a study ID number. The master list will 
be on a separate computer (password protected). Copies of the master list with PHI will 
also be stored on the CHOP secured server. All source documents including case report 
forms, laboratory results, and subject study binders will be kept in secured locked cabinets 
on the 14th floor of the Roberts Center for Pediatric Research. The 14th floor is only 
accessible via key card by CHOP research personnel and is not open to the general public. 
9.3 
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 CHPS Informatics Core will create 
case report forms, set up the database in REDCap, and provide oversight for data 
entry and quality assurance for this study. 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. 
No identifiable data will be used for future study without first obtaining IRB approval.  
9.4 
Regulatory and Ethical Considerations 
9.4.1 Data and Safety Monitoring Plan 
The Principal Investigator (PI) (Dr. Stallings) is ultimately responsible for monitoring data 
integrity and patient safety and for overall study oversight. The study will be monitored 
regularly by the PI. The study protocol will be carried out in accordance with OHRP and NIH 
guidelines and requirements. Unexpected AEs and SAEs will be managed by the PI in 
consultation with both the cystic fibrosis physician and the primary care physician 
identified by the participant upon enrollment in the study, who both will be immediately 
notified. SAEs will also be reported to the IRB, CHPS, all members of the research team, the 

 
  
 
 
 
25 
clinical care team, and sponsor in accordance with requirements. There will be ongoing 
collection of data on adverse events and compliance to the treatment protocol throughout 
the study by research staff and which will be reviewed regularly by the PI. 
9.4.2 Risk Assessment 
Overall, this study presents minimal risk to subjects.  
Fewer than 7% of patients taking omeprazole report the following adverse events: 
• Headache, dizziness 
• Abdominal pain, diarrhea, nausea, vomiting, flatulence, acid regurgitation, 
constipation 
• Upper respiratory infection, cough 
• Rash 
As these events are rare and the medication is commonly-prescribed in this population, 
there is minimal risk involved. In subjects who take long-term acid suppression for a 
diagnosis of gastroesophageal reflux, there is a minimal risk involved in discontinuing the 
medication, which may cause a temporary exacerbation of reflux symptoms, specifically 
abdominal/chest pain and frequent eructation. These risks with omeprazole will be 
discussed with patients at Visit 1, and are included on the consent form. For subjects who 
are taking acid suppression at the beginning of the study and would like to participate, the 
LI will provide, in consultation with the subject’s prescribing physician, a taper schedule to 
further minimize this risk.  
Otherwise, 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 hep-lock catheter. 
However, this is considered a minimal risk and skilled research staff will insert the 
intravenous catheter. Each subject will have approximately 45.7 mL or 3 tablespoons of 
blood drawn (4-5 tablespoons when accounting for tubing and possible redraws).  at Visits 
2 and 3. According to the NIH “Guidelines for Limits of Blood Drawn for Research 
Purposes,” pediatric subjects may not have >5mL/kg of blood drawn in a single day for 
research purposes. 100cc would approach this limit in a subject weighing no more than 
20kg. The youngest subjects in our study will be 12 years of age. According to the CDC, the 
third percentile weight for both 12 year old females and males is 30kg. Therefore, it is 
highly unlikely that the blood draw will approach the 5mL/kg threshold given the paucity 
of subjects who are malnourished. The same NIH guidelines suggest that the daily blood 
draw limit should not exceed 550mL in adult subjects; we will not approach this threshold 
based on current tests required. 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). Containers 

 
  
 
 
 
26 
are opaque to minimize patient discomfort from visualizing the specimens. For subjects 
≥18 years of age who participate in the SmartPill® subset, risks include discomfort from 
swallowing the pill, as well as theoretical complications from capsule retention including 
partial or complete obstruction, as well as gastrointestinal tract damage if the pill is 
retained and the subject requires magnetic resonance imaging. These complications have 
not been reported. 
Private health information will be collected, accessed and stored according to HIPAA 
guidelines, including the use of multilevel password protection and enforcement of 
system user privileges on the database. To minimize the risk of disclosure, all direct 
identifiers will be removed as soon as possible and codes will be substituted for personal 
identifiers. Records of individuals are stored with ID numbers and a code with no 
discernible personal identifiers. Code lists and data files will be stored in separate, secure 
locations. Data will be accessed and stored on password-protected computers. To 
maintain confidentiality, codes will be used in the database, presentations and 
publications.  
9.4.3 Potential Benefits of Trial 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 cystic fibrosis and exocrine pancreatic 
insufficiency in the United States and around the world. This study may contribute to 
knowledge about the mechanism by which acid suppression may improve the efficacy of 
pancreatic enzyme replacement therapy.  
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 CF and EPI. The alternative to 
participating in the research study is not to participate, and thus undergo standard of 
care. The current standard of care is not to use acid suppression as an adjunct to 
pancreatic enzyme replacement therapy; however, it is common for acid suppression to 
be used clinically in cystic fibrosis. 
9.5 
Recruitment Strategy 
Subjects will be recruited from both CHOP and University of Pennsylvania (UPenn) Cystic 
Fibrosis Centers, and if necessary, from regional CF centers. The Cystic Fibrosis Foundation 
recognizes the CHOP and UPenn CF Centers as a single entity, and an HIPAA agreement is in 
place to allow seamless research between the two ‘sides’ of the joint center. Similar to the 
process at CHOP, approval is obtained by the adult CF Attendings prior to contacting any 
patient for any research studies they may be eligible for. Patients enrolled in the port CF 
database will be screened for eligibility by CF research nurses, who will provide the study 
team with eligible subjects. For any other regional centers that may become involved, the 

 
  
 
 
 
27 
care team at these locations will identify subjects with cystic fibrosis and pancreatic 
insufficiency and gauge interest during clinic visits. It is expected that these care teams will 
provide the study team with contact information for subjects who are interested in 
participating in the study, as well as potential subjects as identified in the medical record. 
Study team members will then contact potential subjects who have expressed interest or 
who meet inclusion criteria via secure e-mail or telephone interview. Flyers will be posted 
in Children's Hospital of Philadelphia facilities. 
9.6 
Informed Consent/Assent and HIPAA Authorization 
All team members are Human Subject Research certified and are aware of time and level of 
appropriate explanations that are necessary for adults to be fully informed. Only eligible 
subjects and their guardians if necessary will be approached in a private setting, either 
during their regular clinic visit in a private room or over the telephone (in this case, the 
clinic or study staff would inquire if it is a good time to discuss a matter or if it would be 
more appropriate to call back at another time). In each instance, the subject will be asked if 
they are interested in participating in a research study at CHOP. Only if the subject and 
guardian indicate that they are interested would the clinic or study staff continue to 
describe the study.  
Once a subject and guardian have expressed interest in participating, a CHOP-based 
research team member will contact the subject and guardian via telephone and continue 
the introduction of the study to subject or guardian. If necessary, an HIPAA release form 
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 and guardians will be asked to review the study consent 
form with HIPAA authorization. An investigator or other member of the clinical research 
team will meet with the subject to confirm the subject or guardian understands the study, 
and to answer any questions they may have. A physician-level study team member will be 
available in person, by phone, or by email to answer any questions that may arise as well. 
After all study-related questions are answered and subjects and guardians have had time 
to consider their decision, the investigator or member of the clinical research team will 
obtain fully informed, written consent from the subjects or their guardians as needed. The 
consent and HIPAA authorization will be signed in the presence of a team member. 
Subjects and their guardians will be given a printed copy of the signed informed consent. 
9.7 
Payment to Subjects/Families 
Families and subjects will be compensated at a standard rate to offset incurred expenses 
(travel, meals, time, etc.) associated with each study visit. All subjects and their families will 
receive a combined $50 for the Visit 1, and $150 for Visits 2 and 3 for a combined total of 
$350 to complete the study.  

 
  
 
 
 
28 
9.7.1 Reimbursement for travel, parking and meals 
Free parking passes will be provided to subjects and families for every study visit.  
9.7.2 Payments to parent for time and inconvenience (i.e. compensation) 
Parents of subjects <18 will receive $250 of the total $350: $30 at Visit 1 and $110 at each 
subsequent study visit, to compensate for time and effort. 
9.7.3 Payments to subject for time, effort and inconvenience (i.e. compensation) 
Subjects age <18 will receive $100 of the total $350: $20 at the Visit 1 and $40 at each 
subsequent study visit, to compensate for time and effort. 
Subjects ≥18 years of age or older will receive the full $350. For the additional time 
required for the SmartPill® protocol, subjects in this cohort will also receive $25 at Visits 2 
and 3 for a study total of $400.  
9.7.4 Gifts 
No tokens of appreciation will be given to subjects or families. 
10 PUBLICATION 
The research data obtained through the study outlined in this protocol will be shared with 
the research community, both through oral presentation at scientific meetings, and in 
written form, as published manuscripts. Reported factual material (primary data on which 
summary statistics and tables are based), commonly accepted in the scientific community 
as necessary to document and support research findings, will be provided in a timely 
fashion upon request by members of the scientific community to the principal investigator 
for a period of three years following acceptance for publication. The CHOP investigator will 
have access to the complete study data. 
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Stallings, V.A., et al., Diagnosing malabsorption with systemic lipid profiling: 
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Mascarenhas, M.R., et al., Malabsorption Blood Test: Assessing Fat Absorption in 
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Lightdale, J.R., et al., Gastroesophageal reflux: management guidance for the 
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Fibrosis Patients Measured by Wireless Motility Capsule. Dig.Dis.Sci., 2012. 
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Borowitz, D., R. Lin, and S.S. Baker, Comparison of monoclonal and polyclonal 
ELISAs for fecal elastase in patients with cystic fibrosis and pancreatic insufficiency. 
J Pediatr Gastroenterol Nutr, 2007. 44(2): p. 219-223. 
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Nehra, A.K., et al., Proton Pump Inhibitors: Review of Emerging Concerns. Mayo 
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Lohman, T., A. Roche, and R. Martorell, Anthropometric Standardization Reference 
Manual. 1988, Champaign, IL: Human Kinetics. 

 
  
 
 
 
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24. 
Kuczmarski, R.J., et al., CDC growth charts: United States. Adv Data, 2000(314): p. 
1-27. 
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Questionnaire in the United States: a health-related quality-of-life measure for cystic 
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34. 
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theory to improve assessment of patient-reported outcomes. Clin Exp Rheumatol, 
2005. 23(5 Suppl 39): p. S53-S57. 
35. 
Borowitz, D., et al., Coefficients of fat and nitrogen absorption in healthy subjects 
and individuals with cystic fibrosis. J Pediatr Pharmacol.Ther., 2007. 12(1): p. 47-52. 
36. 
Mascarenhas, M.R., J.I. Schall, and J.T. Mondick, Malabsorption Blood Test (MBT): 
Pilot study to detect effects of pancreatic enzyme dose titration on fat absorption. 
Pediatr Pulmonol, 2008. Suppl 31: p. 423. 
37. 
Saad, R.J. and W.L. Hasler, A technical review and clinical assessment of the 
wireless motility capsule. Gastroenterol.Hepatol.(N.Y.), 2011. 7(12): p. 795-804. 
38. 
Rao, S.S., et al., Evaluation of gastrointestinal transit in clinical practice: position 
paper of the American and European Neurogastroenterology and Motility Societies. 
Neurogastroenterol.Motil., 2011. 23(1): p. 8-23. 
39. 
Rao, S.S., et al., Investigation of colonic and whole-gut transit with wireless motility 
capsule and radiopaque markers in constipation. Clin.Gastroenterol.Hepatol., 2009. 
7(5): p. 537-544. 
40. 
Cohen, J., et al., Pancreatic status verification in children with cystic fibrosis: fecal 
elastase status predicts prospective changes in nutritional status. J Pediatr 
Gastroenterol Nutr, 2005. 40: p. 438-444. 

 
  
 
 
 
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41. 
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42. 
Sainath, N.N., et al., Improvement in weight, pulmonary function and other outcomes 
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Appendix for MBT Quality Improvement Project 
- 
The primary objective of this Quality Improvement Project is to enroll two adults, the PI and 
the lead investigator of this sub study to have an MBT. The results will be used to determine 
which laboratory the research group will use for future processing and analysis of the MBT 
samples. 
 Inclusion Criteria 

 
  
 
 
 
32 
- 
Two Healthy Adults 
Exclusion Criteria 
• Pregnant or lactating females  
• Use of other medication that affects dietary fat absorption  
• Allergy to soy products  
MBT QUALITY IMPROVEMENT PROJECT VISIT SCHEDULE 
MBT Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Endpoint 
The primary endpoint of this quality improvement project is to determine which laboratory 
will be used for future processing and analysis of MBT samples. After the MBT is 
completed on healthy volunteers, the samples will be sent to each laboratory.  
We will visually assess the measurements obtained from the 2 subjects (10 data points each) 
and 3 laboratories by generating profile plots (i.e., 3 plots for each subject from three 
laboratories) for each outcome, the PA and HA fatty acid concentrations at baseline and then 
each hour for nine hours post consumption of MBT meal. We may use the Bland-Altman 
analysis for repeated measurements to account for the correlation among the measurements 
taken from the two subjects to examine the agreement between each pair of laboratories 
(labs 1 & 2, labs 1 & 3 and labs 2 & 3 compared).  Combining the two subjects, we will 
have 20 data points (10 data points for each subject) for PA and HA concentrations 
separately.  We summarize the lack of agreement by calculating the bias (estimated by the 
mean difference between two laboratories) and standard deviation of the differences. We can 
estimate the standard deviation of the difference using the mixed-effects models accounting 
for correlations among the observations within subjects. We will report the intraclass 
Day 0 (day before MBT) (24 Hours) 
• 
Regular lunch/dinner except for no intake of dairy products 
• 
No alcohol intake 
• 
Normal daily activity 
• 
Fast overnight starting at 8pm 
Day 1 – Visit to CHOP CHPS/NGL (~9 hours)  
• 
Insert blood-drawing intravenous catheter 
• 
Baseline blood draw for MBT  
• 
Administer MBT study meal (breakfast) 
• 
MBT – hourly blood sample for 9 hours, 4-5 tablespoons of blood  
• 
After hour 6, low-fat study lunch 
• 
Anthropometry (height, weight) 

 
  
 
 
 
33 
correlation coefficient from the mixed-effects models. We will plot the difference against 
mean plot for measures obtained from each pair of two different laboratories (Bland-Altman 
plot) to examine any possible relationship between the measurement error and true value.  
The goal is to assess the agreement between laboratories. 
Recruitment Strategy 
Only the primary investigator and the lead investigator will be enrolled in this study. There 
are no formal recruitment methods.  
Risk of Coercion 
The two subjects participating will be the PI and the lead investigator. We are well aware of 
the risk for coercion, and want to acknowledge that the lead investigator as well as the PI are 
well aware of the study procedures and risks of the MBT test.