A Food Additive Removal Diet for Pediatric Eosinophilic Esophagitis
Phase: NA
Conditions: Eosinophilic Esophagitis
Sponsor: Nemours Children's Clinic

 
A Food Additive Removal Diet for Pediatric Eosinophilic Esophagitis (FREE) 
Principal Investigator: James P. Franciosi, MD  
Funded by: Anonymous Donor to the Nemours Foundation 
Version Number:  v.13 
22JUL2020 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1-9 
v.2 
Eliminated SST group.  
Eliminated previously required 8- week PPI 
trial.  
Added 4 week PPI washout period.  
Added 12 week swallowed steroid washout 
period. 
Extended duration of treatment to 12 
weeks 
 
 
ESPGHAN guidelines on EoE have 
recently changed. The diagnosis of 
PPIREE has been retracted as it is 
histologically indistinguishable from EoE. 
Therefore, PPIs are considered a 
treatment option, not a diagnostic 
prerequisite. Comparison of two diets 
and randomization to both groups 
ensures a comparison of the effects of 
eliminating additives vs traditional 
elimination diets, ensures equal 
allocation to groups, and reduces 
selection bias. A PPI and steroid 
washout period is recommended to 
determine the true severity of the 
esophagitis.  
1,2,8 
v.3 
Removed the additional biopsy 
Investigators at our satellite sites 
expressed slight concern regarding the 
need to take an additional biopsy. The  
biopsy was dropped from the protocol 
as it was intended for future research 
and was not critical to this study.  
5.1 
 
 
 
1-4, 6, 8-9 
v.4 
Limited time since diagnostic biopsy 
 
 
Changed the nature and names of the diets 
To minimize changes in the eosinophil 
count since time of biopsy. Eight weeks 
was allowed because this is a realistic 
time frame for the next expected visit 
after the biopsy is taken. 
The feasibility of the diets was of some 
concern to the team, particularly 
difficulty recruiting, high drop-out, and 

 
 
the potential for nutritional deficiencies 
given that formula would not be 
allowed. Therefore, the study will 
compare a dairy free diet to dairy free 
plus additive free diet given that dairy 
accounts for the majority of allergic 
reactions. This will make the diets much 
more acceptable/feasible to the 
patients/parents and will still answer the 
question of whether food additives play 
a role in EoE.  
 
 
5.3, 8.0 
 
 
 
 
 
 
5.1 
 
 
 
10.1.4.3 
 
 
 
1.1, 5.2 
 
 
 
v.5 
Added language to clarify the role of the 
local vs the central pathologist 
 
 
 
 
 
 
Changed the window since the diagnostic 
biopsy to 12 weeks 
 
 
Removed language regarding storage of 
samples 
 
v. 6 
Removed exclusion criteria for 
anaphylactic food allergies 
 
 
 
Local pathologists will identify patients 
with >15 eos/hpf. There will only be one 
central pathologist (review by two 
pathologists was previously planned but 
determined impractical). Samples from 
standard of care biopsies will be batch 
shipped to the central pathologist and 
shipped back to originating sites after 
analysis. 
 
An 8 week window for the diagnostic 
biopsy was considered too restrictive by 
some team members due to practical 
issues with scheduling follow up visits. 
 
Samples will not be stored for future 
research use 
 
 
This criteria was too restrictive as the 
majority of EoE patients have one or 
more food allergies 
 

 
 
1.1, 5.2 
v.7 
 
 
Allowed inhaled steroids. Specified 
washout period for prednisone, 
fluticasone and budesonide  
 
1.1, 5.2 
v.8 
Expanded the age range 
 
Allows the inclusion of patients over age 
17  
1.1, 5.1, 5.2 
v. 9 
Expanded the age range 
removed the PPI washout period 
requirement 
 
removed the exclusion regarding food 
impaction 
 
Allows the inclusion of patients 3 to 18 
Allows the inclusion of patients that 
have not responded to PPI  without the 
required 4 week washout 
 
Allows the inclusion of patients with 
food impaction 
 
 
5.2, 8 
v. 10 
Added dietician follow up calls to 
description of procedures. 
Added current PPI use to exclusion criteria 
(previous protocol identified PPIs as a 
medication that was not allowed but this 
was not in the list of exclusion criteria). 
Added previously failed or currently on 
dairy elimination therapy to the exclusion 
criteria. 
The protocol now includes previously 
omitted information 
 
1.1, 10.1 
v. 11 
Adding the option of consenting over the 
phone/remote participation 
 Allows remote recruitment 
5.1 
v. 12 
Changing the age range to > 2 years to 18 
years 
Allows the inclusion of children age 24 
months to 3 years 

 
 
1.2, 1.3, 8 
v. 13 
Removed all language pertaining to 24 
hour diet recalls (NASR) 
The 24 hr diet recalls were discontinued 

A Food Additive Removal Diet for Pediatric Eosinophilic Esophagitis (FREE) 
 
 
 
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Table of Contents 
1 
PROTOCOL SUMMARY..................................................................................................................................... 1 
1.1 
Synopsis ...................................................................................................................................................... 1 
1.2 
Schema ........................................................................................................................................................ 2 
1.3 
Schedule of Activities................................................................................................................................ 4 
2 
INTRODUCTION................................................................................................................................................... 5 
2.1 
Study Rationale .......................................................................................................................................... 5 
Eosinophilic Esophagitis (EoE) is a food antigen driven inflammatory condition that continues to increase 
in prevalence.  Commonly used food additives have been shown to promote intestinal inflammation in 
animal models2, yet research is needed to further assess the impact of food additives on inflammatory 
conditions in humans.  We hypothesize that dairy + food additive elimination (FREE) will show improved 
efficacy when compared dairy elimination alone (DED). .......................................................................................... 5 
2.2 
Background ................................................................................................................................................. 5 
2.3 
Risk/Benefit Assessment ......................................................................................................................... 7 
2.3.1 
Known Potential Risks ......................................................................................................... 7 
2.3.2 
Known Potential Benefits .................................................................................................... 7 
2.3.3 
Assessment of Potential Risks and Benefits .................................................................. 7 
3 
OBJECTIVES AND ENDPOINTS ..................................................................................................................... 8 
4 
STUDY DESIGN ................................................................................................................................................... 8 
4.1 
Overall Design ............................................................................................................................................ 8 
4.2 
Scientific Rationale for Study Design .................................................................................................... 8 
4.3 
End of Study Definition ............................................................................................................................. 9 
5 
STUDY POPULATION......................................................................................................................................... 9 
5.1 
Inclusion Criteria ........................................................................................................................................ 9 
5.2 
Exclusion Criteria ....................................................................................................................................... 9 
5.3 
Strategies for Recruitment and Retention..........................................................................................10 
6 
STUDY INTERVENTION ..................................................................................................................................11 
6.1 
Study Intervention(s) Administration ...................................................................................................11 
6.1.1 
Study Intervention Description .........................................................................................11 
6.2 
Measures to Minimize Bias: Randomization .....................................................................................11 
6.3 
Study Intervention Compliance.............................................................................................................11 
6.4 
Concomitant Therapy .............................................................................................................................11 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .........................................................................................................................11 
7.1 
Discontinuation of Study Intervention .................................................................................................11 
7.2 
Participant Discontinuation/Withdrawal from the Study ..................................................................12 
7.3 
Lost to Follow-Up .....................................................................................................................................12 
8 
STUDY ASSESSMENTS AND PROCEDURES..........................................................................................13 
8.1 
Adverse Events and Serious Adverse Events ..................................................................................15 
8.1.1 
Definition of Adverse Events (AE) ...................................................................................15 
8.1.2 
Definition of Serious Adverse Events (SAE).................................................................15 
8.1.3 
Adverse Event Reporting ..................................................................................................15 
8.1.4 
Serious Adverse Event Reporting ...................................................................................15 
8.1.5 
Definition of Unanticipated Problems (UP)....................................................................16 
8.1.6 
Unanticipated Problem Reporting ...................................................................................16 
9 
STATISTICAL CONSIDERATIONS................................................................................................................16 
9.1 
Statistical Hypotheses ............................................................................................................................16 

A Food Additive Removal Diet for Pediatric Eosinophilic Esophagitis (FREE) 
 
 
 
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9.2 
Sample Size Determination ...................................................................................................................16 
9.3 
Populations for Analyses .......................................................................................................................16 
9.4 
Statistical Analyses .................................................................................................................................17 
9.4.1 
Safety Analyses...................................................................................................................17 
9.4.2 
Baseline Descriptive Statistics .........................................................................................17 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS................................17 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .............................................................17 
10.1.1 
Informed Consent Process ...............................................................................................18 
10.1.2 
Study Discontinuation and Closure.................................................................................18 
10.1.3 
Confidentiality and Privacy................................................................................................19 
10.1.4 
Data Handling and Record Keeping ...............................................................................19 
10.1.5 
SAFETY MONITORING PLAN ........................................................................................19 
10.1.6 
QualitY Assurance and Quality Control .........................................................................20 

 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
 
Title: 
 
Food Additive Removal Diet for Pediatric Eosinophilic Esophagitis (FREE) 
 
Study Description: 
 
Prospective, pragmatic standard of care clinical trial comparing dietary 
therapies of dairy elimination diet (DED) to dairy + food additive 
elimination diet (FREE) in children with eosinophilic esophagitis.  
 
Objectives: 
 
 
Primary Objective: To compare histologic outcomes (eosinophils per high 
power field: eos/hpf) of dairy elimination diet (DED) to dairy + food 
additive elimination diet (FREE) in children with eosinophilic esophagitis. 
 
 
 
Secondary Objective: To compare endoscopic outcomes (Eosinophilic 
Esophagitis Endoscopic Reference scores: EREFs) of dairy elimination diet 
(DED) to dairy + food additive elimination diet (FREE) in children with 
eosinophilic esophagitis  
Tertiary Objectives: To compare symptomatic (Pediatric Eosinophilic 
Esophagitis Symptom Severity Module v2.0: PEESS) and quality of life 
(Peds-QL EoE Module 1) outcomes of dairy elimination diet (DED) to dairy 
+ food additive elimination diet (FREE) in children with eosinophilic 
esophagitis 
 
Endpoints: 
Primary Endpoint: (1) Histologic change differences of maximum eos/hpf 
baseline vs 12 week endoscopy 
 
Secondary Endpoint: (1) EREFs: Eosinophilic Esophagitis Endoscopic 
Reference Score baseline vs 12 weeks 
 
Tertiary Endpoints: (1) Patient Reported Outcomes (Pediatric Eosinophilic 
Esophagitis Symptom Severity Module (PEESS) baseline vs 12 weeks, (2) 
quality of life (PedsQL-EoE)1 baseline vs 12 weeks 
 
 
Study Population: 
We will plan to enroll 72 patients. Based on histologic primary outcome 
efficacy estimates of DED (50%) compared to FREE (estimated 70%) and a 
sample size of 36 enrolled patients per group (72 total) with 88% power, 
we will be able to demonstrate a detectable difference of 30% among two 

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group comparisons.  We estimate a 20% drop out rate among the diet 
elimination groups and analysis based on intention to treat. 
Patients > 2 - 18 years of age with isolated esophageal eosinophilia (>15 
eos/hpf).  Patients with peripheral eosinophilia > 1,500 µL, concomitant GI 
inflammatory conditions, history of upper GI tract surgery (e.g. 
fundoplication), acid reflux by pH probe, severe developmental delay, 
have other medical conditions likely interfere with the study, has a 
significant psychiatric condition, has taken swallowed steroids in the last 8 
weeks, or are not fluent in spoken and written English will be excluded.  
 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
Participants will be enrolled nationally. 
 
 
Description of Study 
Intervention: 
Once patients meet eligibility criteria, they will be randomized to DED or 
FREE study groups.  Participants will receive dietary education.  Lead 
dietitians from each site will be identified and the approaches to dietary 
education will be standardized.  Dietary education will be completed at 
the baseline visit and during follow up phone calls throughout the study. 
 
Study Duration: 
We anticipate this study will take 30 months to complete. 
 
[December 31, 2017-----------------------------------------------------July 31, 2020] 
 
Pre-trial                 Enrollment/Intervention               
Activities                 
[-------------------]  [------------------------------------------------------] 
      7 mos                                          16 mos                                         
                               Data Collection 
                              [---------------------------------------------------------------]                   
                                                           19 mos                                  
                                                                                                              Data Analysis 
                                                                                                                    [----------] 
                                                                                                                      4 mos 
 
 
Participant Duration: 
 
Each participant will complete all study visits in 12 weeks +/-14 days.  
 
 
1.2 
SCHEMA 

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Day 1 
Screening 
Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1 / Week 1 
Baseline 
 
 
 
 
Weeks 1-11  
(+/- 14 
Days) 
 
 
 
 
 
 
 
 
 
 
Week 12 (+/- 14 
Days) 
End of Study 
Assessment 
 
 
 
 
Total N  72 
Obtain informed consent. Screen potential participants by inclusion and exclusion 
criteria, Medical History, Peak eos/hpf, Concomitant Medication review 
 
Perform baseline assessments:  
Demographics, Height, Weight, AE reporting (Safety Q), Endoscopist 
Questionnaire (Eosinophilic Esophagitis Endoscopic Reference Score: EREFs), 
Quality of Life (PedsQL-EoE)(*Parent and Child), Pediatric Eosinophilic 
Esophagitis Symptom Severity Module (PEESS)(*Parent and Child)  
Randomization  
Dietary Counseling & Three-day Diet Diary  
 
Follow Up Endoscopy / Final Visit 
Height, Weight,  
Pathologist Questionnaire indicating maximum eos/hpf, Endoscopist 
Questionnaire (Eosinophilic Esophagitis Endoscopic Reference Score: EREFs),  
Three-day Diet Diary 
Study Surveys (REDCap) 
Pediatric Eosinophilic Esophagitis Symptom Severity Module 
(PEESS)(*Parent and Child), Quality of Life (PedsQL-EoE)(*Parent and Child), 
AE reporting (Safety Q) 
Follow Up Calls (Dietician: Weeks 1, 4, 7, and 11) Dietary Counseling/Review 
Follow Up Calls (Coordinator: Weeks 2, 3, 5, 6, 8, 9, and 11) Review adverse 
events (AEs), withdrawal criteria, concomitant meds, diet/medication adherence, 
survey reminder 
Study Surveys (REDCap: Weeks 4, 8, and 12) Pediatric Eosinophilic 
Esophagitis Symptom Severity Module (PEESS)(*Parent and Child), Quality 
of Life (PedsQL-EoE)(*Parent and Child), AE reporting (Safety Q), concomitant 
medication review 
 
Randomization 
Arm 1 
DED 
 
N = 36  
Arm 2  
FREE 
N = 36  

A Food Additive Removal Diet for Pediatric Eosinophilic Esophagitis (FREE) 
 
 
 
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1.3 
SCHEDULE OF ACTIVITIES  
 
 
Procedures 
Screening Day -7 to 1 
Enrollment/Baseline 
Visit 1, Day 1 
Study Visit 2 (FUP Call) 
Day 7 (week 1)  +/-2 days 
Study Visit 3 (FUP Call) 
Day 14 (week 2) +/- 2 days 
Study Visit 4 (FUP Call) 
Day 21 (week 3) +/-2 days 
Study Visit 5 (FUP Call) 
Day 28(week 4)  +/-2 days 
Study Visit 6(FUP Call) 
Day  35 (week 5) +/-2 days 
Study Visit 7 (FUP Call) 
Day 42 (week 6) +/-2 days 
Study Visit 8 (FUP Call) 
Day 49 (week 7) +/-2 days 
Study Visit 9 
Day 56 (week 8) +/-14 days 
Study Visit 10 
Day  63 (week 9) +/-14 
Study Visit 11 
Day  70 (week 10) +/-14 
Study Visit 12 
Day  77 (week 11) +/-14 
Study Visit 13 
Day  84 (week 12) +/-14 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pathologist 
Questionnaire / Peak 
Eosinophils per high 
power field (Eos/hpf) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Personal Information 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height and Weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Eosinophilic 
Esophagitis 
Endoscopic Reference 
Score (EREF) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Diet Education  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dietician Follow Up 
Calls 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Three-day Diet Diary  
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Quality of Life 
(PedsQL EoE)(Parent 
& Child) 
 
X 
 
 
 
X* 
 
 
 
X* 
 
 
 
X* 
Pediatric Eosinophilic 
Esophagitis Symptom 
Severity Module 
(PEESS)(Parent & 
Child) 
 
X 
 
 
 
X* 
 
 
 
X* 
 
 
 
X* 
Adverse Event 
Reporting (Safety Q) 
 
X 
 
 
 
X* 
 
 
 
X* 
 
 
 
X* 

A Food Additive Removal Diet for Pediatric Eosinophilic Esophagitis (FREE) 
 
 
 
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Procedures 
Screening Day -7 to 1 
Enrollment/Baseline 
Visit 1, Day 1 
Study Visit 2 (FUP Call) 
Day 7 (week 1)  +/-2 days 
Study Visit 3 (FUP Call) 
Day 14 (week 2) +/- 2 days 
Study Visit 4 (FUP Call) 
Day 21 (week 3) +/-2 days 
Study Visit 5 (FUP Call) 
Day 28(week 4)  +/-2 days 
Study Visit 6(FUP Call) 
Day  35 (week 5) +/-2 days 
Study Visit 7 (FUP Call) 
Day 42 (week 6) +/-2 days 
Study Visit 8 (FUP Call) 
Day 49 (week 7) +/-2 days 
Study Visit 9 
Day 56 (week 8) +/-14 days 
Study Visit 10 
Day  63 (week 9) +/-14 
Study Visit 11 
Day  70 (week 10) +/-14 
Study Visit 12 
Day  77 (week 11) +/-14 
Study Visit 13 
Day  84 (week 12) +/-14 
Concomitant 
medication review 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Coordinator Call 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
Payment to Part. for 
Completed Visit 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
* REDCap survey – completed by participant/parent 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Eosinophilic Esophagitis (EoE) is a food antigen driven inflammatory condition that 
continues to increase in prevalence.   Commonly used food additives have been 
shown to promote intestinal inflammation in animal models2, yet research is needed 
to further assess the impact of food additives on inflammatory conditions in 
humans.  We hypothesize that dairy + food additive elimination (FREE) will show 
improved efficacy when compared dairy elimination alone (DED). 
2.2 
BACKGROUND  
 
Eosinophilic esophagitis (EoE) is a chronic allergen driven inflammatory disorder histologically 
characterized by the abnormal infiltration of eosinophils in the esophagus (maximum eosinophil count 
>15 ). Primary symptoms manifest while eating and include dysphagia, chest pain, and food impaction. 
EoE was first described in the 1990s, but is increasingly recognized worldwide. It affects both adults and 
children with an estimated prevalence of 56.7/100,000.3   
The treatment of EoE aims to reduce inflammation, thereby reducing symptoms. The recommended 
clinical pathway for the initial treatment of EoE includes high-dose proton pump inhibitor (PPI) therapy 
followed by either topical steroids or elimination diet in patients unresponsive to PPIs.4  
PPIs: The relationship between acid suppression and EoE is unclear. Nevertheless, a subset of EoE 
patients are responsive to acid suppression medications such as PPIs (a condition referred to as Proton 
Pump Inhibitor Responsive Eosinophilic Esophagitis or PPIREE).5,6 PPIs may benefit patients with EoE by 

A Food Additive Removal Diet for Pediatric Eosinophilic Esophagitis (FREE) 
 
 
 
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29 JAN 2020 
  
 
reducing acid or by an unclear anti-inflammatory mechanism. Because some patients are responsive to 
PPIs, the diagnosis of eosinophilic esophagitis has included the demonstration of persistent esophageal 
eosinophilia after a two-month course of high dose PPI therapy.4 However, ESPGHAN guidelines have 
recently changed and the diagnosis of PPIREE has been retracted as it is histologically indistinguishable 
from EoE. Therefore, PPIs are considered a treatment option, not a diagnostic prerequisite.  
Steroids: Oral steroids, such as budesonide, are a preferable alternative to systemic steroids that have 
numerous and well documented adverse effects. Oral topical steroids have anti-inflammatory effects 
(i.e., fluticasone or budesonide, swallowed rather than inhaled, for an initial duration of 8 weeks) and 
are, therefore, another first-line pharmacologic therapy for the treatment of EoE.7  
With the use of budesonide, studies show significant histological and symptomatic remission in 80-90% 
of patients.8-11 Unfortunately, symptoms recur when steroids are discontinued. Although the majority of 
evidence suggests that adverse effects of short-term budesonide use are not common12, several studies 
concluded that children treated with oral budesonide for one to six months experienced adrenal 
suppression.13-15  
Dietary Treatments: Given that EoE is thought to be an antigen/immune-mediated disease, elimination 
diets are considered logical and safe first-line treatment options. Elimination diets focus on the removal 
of the allergens most likely to evoke the inflammatory response. Recent studies have demonstrated a 
response to elimination diets in 30-60% of EoE patients.16,17 The diets, however, vary regarding the 
number and types of foods eliminated. Three main strategies evolved in the last decade: (1) the 
elemental diet, which uses exclusively amino acid enteral formula, (2) the skin prick testing directed 
diet, which eliminates foods with positive allergy testing, and (3) empiric elimination in which the most 
common allergenic foods are avoided.20   The elemental diet, although highly effective in inducing 
remission, is impractical for long term use given its high cost. In addition, refraining from eating any solid 
foods for an extended period of time is extremely difficult.  Results regarding allergen directed diets 
have been mixed17 presumably because of the lack of reliability and specificity of allergy tests. 
Therefore, empirical elimination diets might be the easiest treatment option to implement and to 
maintain.  
 
Elimination Diets and EoE:  Studies have shown that a six-food elimination diet (6FED)(cow’s milk, 
wheat, peanuts and tree nuts, soy, and fish/shellfish) induces remission in most children and adults 
with EoE17 but that only one in four patients sustain remission at nine months. Patients tend to 
relapse because the diet is difficult to follow and very restrictive.  In addition, the 6FED includes a 
complex plan for the reintroduction of foods over specified time frames. A four-food elimination 
diet (4FED)(cow’s milk, wheat, egg, and soy) is far less restrictive and more likely to encourage 
adherence. In addition, these four food groups appear to be the most commonly associated with the 
inflammatory response in EoE patients.19-20 Preliminary studies report a 54% histological remission 
rate with 4FED.20-22 However, studies also show a 30-50% remission rate when eliminating dairy 
alone. More research is needed before concluding which diet is reliably effective in the majority of 
EoE patients.   
 
 
The widespread use of food additives in modern-day diets might contribute to the increased 
incidence of inflammatory diseases such as EoE.  Food additives are substances added during 

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production, processing, packaging, or storage of food products. They are intended to enhance or 
preserve flavor, appearance, and durability. Some food additives are natural (e.g. vinegar for 
pickling, salted ham), but the additives of concern here are the artificial ones more recently 
introduced into the food supply.  
 
Commonly used artificial food additives have been shown to promote intestinal inflammation in 
animal models2. In addition, food additives are excluded from some diets that induce remission in 
Crohn’s disease. In fact, the lack of food additives is likely one of the reasons enteral nutrition is so 
effective.  As inflammatory bowel disease and eosinophilic esophagitis share GI tract mucosal 
immune dysregulation, dietary intervention with anti-inflammatory properties may be of benefit for 
patients with EoE.  
There is a need to establish optimal treatment pathway(s) not only for the initial remission of EoE, but 
also for the long-term maintenance of remission. The adverse effects of long-term PPI and SST therapy 
are unknown. In addition, adherence rates to medications and to highly restrictive diets are poor. 
Elimination diets such as 4FED and FREE are less restrictive than other diets, which might improve 
outcomes. A preservative-free diet for EoE has not been evaluated. Finally, the current literature does 
not address patient reported outcomes or patient reported quality of life, which might be associated not 
only with efficacy, but also with rates of adherence, thereby impacting the sustainability of treatment.   
 
2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS 
 
Elimination diets: Elimination diets may affect nutritional status, eating pleasure, and quality of life.23  
However, again, given that the study duration is 8 weeks, significant nutritional deficiencies are unlikely.  
 
2.3.2  KNOWN POTENTIAL BENEFITS  
 
Elimination Diets: Benefits include relative safety and potential long-term maintenance. Recent studies 
have demonstrated a response to elimination diets in 30-60% of EoE patients. However the effects of 
the FREE diet have not been evaluate in patients with EoE. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND 
BENEFITS  
 
This is a pragmatic trial comparing two standard of care treatments for EoE. Therefore, the risks are no 
greater than those ordinarily encountered in daily life. Furthermore, there is the prospect of benefit to 
enrolled patients (e.g. symptom reduction and improved quality of life). The risks are considered low 
and the benefit to the overall group of patients with EoE would be considered significant. 

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3 
OBJECTIVES AND ENDPOINTS 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
Prospective, pragmatic standard of care clinical trial comparing dietary therapies of dairy elimination 
diet (DED) vs. dairy elimination and food additive elimination (FREE). After obtaining informed consent, 
participants will perform screening procedures. If all eligibility criteria are met, the patient will be 
randomized to one of the two diet regimens. Patients will receive dietary counseling at baseline. All 
participants will be followed via phone calls and REDCap surveys for the duration of the study.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Food elimination diets have resulted in remission in an estimated 30-60% of patients. Typically, a six-
food elimination diet is successful, yet it is difficult to maintain long-term adherence.  Because the 
majority of allergens are found in four of these six foods, a four-food elimination diet has been 
suggested and demonstrated 60% remission in children in one study. Furthermore, other studies shown 
up to a 50% response rate when eliminating dairy alone. The dairy free diet has not been directly 
compared to a dairy free plus additive free diet.  
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
To compare histologic outcomes of 
DED and FREE among children 
with eosinophilic esophagitis 
Maximum eos/hpf (primary) 
Eosinophils are a biomarker of 
inflammation. Current diagnostic 
criteria specify >15 eos/hpf. A 
reduction in eos/hpf should 
correlate with a reduction in 
symptoms. A successful treatment 
outcome is <15 eos/hpf. 
Secondary 
 
 
To compare endoscopic outcomes   
DED and FREE among children 
with eosinophilic esophagitis 
Eosinophilic Esophagitis 
Endoscopic Reference Score 
(EREFs)(secondary) 
 
Includes additional eosinophil 
morphology and associated 
histopathologic features (e.g. 
degranulation, microabscesses, 
superficial layering, basal zone 
hyperplasia)  
Tertiary/Exploratory  
 
 
To compare quality of life and 
patient reported outcomes of  DED 
and FREE among children with 
eosinophilic esophagitis 
PedsQL-EoE (tertiary) 
Pediatric Eosinophilic Esophagitis 
Symptom Severity Module (PEESS) 
(tertiary) 
 
Determines the impact of  DED 
and FREE  on QOL and symptom 
severity, which is not routinely 
assessed.  

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4.3 
END OF STUDY DEFINITION 
 
The end of the study will be the point at which all required data has been collected or the date of the 
last patient visit.  
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met: 
 
1. An Institutional Review Board (IRB) approved written Parental Permission form is signed and dated by 
the parent or legal representative/caregiver. 
 
2. An Institutional Review Board (IRB) approved written Assent form is signed and dated by the 
participant. 
 
3. The participant/parent(s) or legal representative(s)/caregiver(s) are considered reliable and capable 
of adhering to the protocol call schedule and dietary requirements. 
 
4. The participant is > 2 years to 18 years of age. 
 
5. The participant has isolated esophageal eosinophilia (>15 eos/hpf).  
6. The biopsy used to diagnose eosinophilic esophagitis was taken no more than 12 weeks prior to the 
date of enrollment. 
7. The family has access to the internet to complete weekly surveys and to a telephone to complete 
weekly follow up calls.  
 
5.2 
EXCLUSION CRITERIA 
 
1. The participant has peripheral eosinophilia > 1,500 µL  
2. The participant has concomitant GI inflammatory conditions (e.g. celiac disease, inflammatory bowel 
disease).  
3. The participant has a history of upper GI tract surgery (e.g. fundoplication) 

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4. Acid reflux by pH probe is suggested (*A pH probe is not required, but may be done as standard of 
care)  
5.  The participant has severe developmental delay that, in the opinion of the investigator, could 
jeopardize the participant’s ability to participate in the study.  
6. The participant has taken prednisone in the last 12 weeks, or has taken fluticasone or budesonide in 
the last 8 weeks  
7. The participant has other significant medical conditions that, in the opinion of the provider, would 
impact the participant’s ability to participate in the study. 
8. The participant has a psychiatric condition that, in the opinion of the investigator, could jeopardize 
the participant’s ability to participate in the study. 
9. The participant does not speak or read English fluently. 
10. The participant is currently taking a PPI (If discontinued, no washout is required.)  
11. The participant is currently on or has previously failed dairy elimination therapy. 
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Providers at participating sites will be educated on the study protocol. Local pathologists will notify 
study coordinators of patient eligibility. Samples from standard of care biopsies will be batch shipped to 
the lead site for analysis by the central pathologist. The samples will be identified by the study ID only. 
Only the originating site can link the codes to the patient.  
M. Collin’s recommended criteria for the diagnosis of eosinophilic esophagitis (EE) will be used to 
evaluate the esophageal biopsies.24  The central pathologist, who has extensive experience in the 
diagnosis of EE will review all biopsies, blind to patient’s dietary status. The grading and staging of EE will 
be based on Collin’s criteria, especially to be focused on eosinophilic inflammation, epithelial basal zone 
changes, eosinophilic abscess, and lamina propria fibrosis. Samples will be returned to the originating 
sites after central pathology review.   
Patients (or in the case of children, the pediatric patient and their parent/legal guardian) will be 
approached for participation after a clinical assessment has been performed by a GI provider. Study 
procedures will be performed after obtaining proper consent and/or child assent.  In addition, the clinic 
schedule will be reviewed each week for potential participants. If possible, patients or families will be 
contacted ahead of time to determine their interest in the study, should they qualify for participation. 
 
Participants will be paid the following: Baseline Visit $25.00 + 2 weeks of surveys X $25 + Final Visit 
$50.00 = $125.00 per participant. The telephone follow up and the participant questionnaires must be 
completed at each designated visit to receive payment. Gift cards will be mailed to participants upon the 
completion of each eligible visit.  

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6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Beginning from the date of enrollment/randomization, participation will last 12 weeks (+/- 14 days). 
Participants will be randomized to DED or FREE study groups. Participants will receive dietary education 
at the baseline visit.   
 
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION 
 
A randomization table will be generated for each site via randomization.com and will be used for 
assigning eligible participants to a treatment regimen.  
 
To enroll a participant (Visit 1), the investigator (or designee) will assign each participant a 5-digit 
number which serves as the participant identifier throughout the study.  
 
To randomize a participant (Visit 1), the investigator (or designee) will notify the lead site that a 
participant has been enrolled. The lead site will randomize the patient.  
 
6.3 
STUDY INTERVENTION COMPLIANCE 
 
Study Coordinators will call participants/parents at weeks 2, 3, 5, 6, 8, and 10 to assess difficulty 
adhering to dietary protocols. If a participant is found to be persistently noncompliant with the diet, the 
investigator will make a decision as to whether the participant should be withdrawn from the study. 
 
6.4 
CONCOMITANT THERAPY 
 
The following concomitant medications are prohibited during the study: 
1. Oral corticosteroids 
2. Proton Pump Inhibitors (PPIs) 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Withdrawal criteria 

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Participants must be withdrawn from the study if any of the following events occur: 
 
1. Participant experiences intolerable AEs, including clinically relevant abnormal laboratory 
findings that, in the opinion of the investigator, preclude further participation in the study. 
 
2. Participants who are unable to tolerate study diet and/or for whom the provider discontinues study 
diet will be withdrawn from the study. 
 
3. Participants unable or unwilling to adhere to dietary restrictions will be withdrawn from the study.  
 
4. Investigator's decision that withdrawal from further participation would be in the participant’s 
best interest. 
 
Participants may be withdrawn from the study if any of the following events occur: 
 
1. Participant has any clinically relevant change in medical or psychiatric condition and in the 
opinion of the investigator, the condition warrants discontinuation from the study. 
 
2. Participant requires a medication that is not permitted by the protocol. 
Investigators should attempt to obtain information for participants who withdraw or discontinue. For 
participants considered as lost to follow up, the investigator should make an effort (at least 1 phone call 
and 1 written message to the parent[s] or legal representative[s]/caregiver[s]), and document his/her 
effort (date and summary of the phone call and copy of the written message in the source documents), 
to complete the final evaluation. All results of these evaluations and observations, together with a 
narrative description of the reason(s) for removing the participant, must be recorded in the source 
documents. The Case Report form (CRF) must document the primary reason for withdrawal or 
discontinuation. 
 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
The participant and/or the parent(s)/legal representative(s) are free to withdraw the participant from 
the study at any time, without prejudice to continued care.  
 
 
7.3 
LOST TO FOLLOW-UP 
 
Participants will be withdrawn from the study / considered LTFUP if the coordinator is unable to make 
contact by telephone to complete weekly assessments for at least 3 sequential weeks.   

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8 
STUDY ASSESSMENTS AND PROCEDURES 
 
At all visits and telephone contacts, participants will be instructed to call the investigator if any 
intolerable and/or serious AEs (SAEs) occur before the next visit or contact. After participants begin 
study medication, if any AEs necessitate a participant’s withdrawal from the study, the participant 
should come in for a clinic visit as soon as possible after the occurrence of the AE. Planned clinic visits 
should be scheduled as indicated in Section 1.3  
 
Screening/Baseline: Visit 1 (Day 1) 
 
At Visit 1, participants will be evaluated for their suitability for enrollment. It is acceptable for this visit 
to be conducted on more than 1 day; however, all results of Visit 1 assessments should be available 
prior to randomization. Prior to the conduct of any study-related procedures, a complete explanation 
(both verbal and written) of the nature and purpose of the study will be given to the participant’s 
parent(s)/legal representative(s) by the investigator (or designee). The parent(s)/legal representative(s) 
of the participant is required to sign and date the IRB approved informed consent if he/she decides to 
participate in the study. 
 
The participant’s eligibility for the study will be determined on the basis of the inclusion/exclusion 
criteria, signature of an informed consent prior to any study-related procedures or evaluations, and the 
results of the following assessments.  
  
Screening Procedures 
1. Informed consent 
2. Review Inclusion/exclusion criteria 
3. Medical History 
4. Demographics  
5. Concomitant Medications 
 
Baseline Procedures 
1. Randomization 
2. EREF** score 
3. PedsQL-EoE  
4. PEESS 
5. Diet Counseling 
6. Three-day diet diary 
7. Concomitant Medications (review if baseline and screening visits do not take place on the same day)  
8. Payment to Participant for Completed Visit 
  
* Histological  outcomes (e.g. maximum eos/hpf) will be assessed by an experienced study pathologist.  
** All GI providers will be trained to assess EREFs prior to the initiation of the trial. They will complete 
the evaluation for all suspected cases of EoE.  
 
Randomization 

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Participants will be randomized to either the DED or FREE diet.  
Intervention 
Participants will receive diet education.  A trained nutritionist/dietician will provide counseling regarding 
the foods allowed and foods not allowed on each diet. Participants will be given written instructions and 
daily diet diaries for their own use.  
 
Coordinator Telephone Contacts: (Weeks 2, 3, 5, 6, 8, 9, and 11; days 7 through 77) 
Beginning with Telephone Contact at Day 7, the coordinator will assess AEs, review concomitant 
medications, review withdrawal criteria, and assess difficulty adhering to the diet. Participants will be 
sent invitations from REDCap to complete required questionnaires. The coordinator will remind 
participants to complete the questionnaires. The participant will be instructed to call the investigator if 
any intolerable and/or SAEs occur. If any change in the study medication is required, the participant 
should come in for a clinic visit as soon as possible. 
 
Coordinator Call: 
1. Diet/Medication Review & Adherence Assessment 
2. Review concomitant medications 
3. Review withdrawal criteria 
4. Review previously reported AEs 
5. Survey reminder 
 
Dietician Telephone Contacts: (Weeks 1, 4, 7 and 11; days 7 through 77) 
Beginning with Telephone Contact at Day 7, the Dietician will assess adherence to the diet, answer 
questions regarding the diet, assess changes in weight, and assess difficulty adhering to the diet.   
 
Participant Questionnaires (Baseline, Week 4, Week 8, and Week 12; days 1 through 84) 
Participant Questionnaires (via REDCAP) 
1. PEESS 
2. PedsQL-EoE 
 
Final Assessment: (Week 12; day 84 +/- 14 days) 
6. Pathologist Questionnaire (*maximum eos/hpf) 
7. EREFs: Eosinophilic Esophagitis Endoscopic Reference Score) 
8. PedsQL-EoE  
9. PEESS 
10. Three-day diet diary  
11. Review concomitant medications 
12. Diet Review & Adherence Assessment 
13. AE reporting 
 
 

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8.1 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-
existing medical condition in a patient or clinical investigation participant administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of 
investigational product, whether or not considered related to the investigational product. Adverse 
events can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. (In order to prevent reporting bias, participants should not be questioned 
regarding the specific occurrence of one or more AEs.) 
 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
 
results in death 
 
is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe) 
 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
 
results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect 
 
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.)  
 
8.1.3 ADVERSE EVENT REPORTING  
 
All adverse events will be reported to the principle investigator as soon as study staff are aware of the 
event. AEs that are not determined to be serious, will be recorded and reported to the IRB at the time of 
Continuing Review. 
 
8.1.4 SERIOUS ADVERSE EVENT REPORTING  
 
All SAEs will be reported to the lead coordinator/principle investigator within one business day of the 
first awareness of the event. The lead coordinator will complete the SAE CRF.  

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If the event meets fatal or life threatening criteria, it will be reported to the IRB within 24 hours of the 
first awareness of the event.  
 
The Investigator must complete, sign and date the SAE CRFs and verify the accuracy of the 
information recorded on the SAE CRF with the corresponding source documents. 
 
8.1.5 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
In the event of an unanticipated problem, the investigator must assess whether it is expected, whether 
it is related to the research, and whether it puts other participants at increased risk for harm.  
 
 
8.1.6  UNANTICIPATED PROBLEM REPORTING  
 
If the event is unexpected, related, and puts participants at increased risk, the lead coordinator will 
notify the IRB immediately via the submission of a Report of Unanticipated Problems. 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
 
Based on histologic primary outcome efficacy estimates DED without PPI therapy (50%) compared to 
FREE (estimated 70%) a sample size of 36 enrolled patients per group (72 total) with 88% power, we will 
be able to demonstrate a detectable difference between the three groups, we assume the standard 
deviation for both groups to be 30%. We hypothesize that changes in primary and secondary endpoints 
for FREE participants will be superior to DED.  
9.2 
SAMPLE SIZE DETERMINATION 
 
The sample size was determined by pragmatic estimation of available EoE patients at each participating 
site. Data queries of EMRs were requested from respective IT departments to determine the number of 
EoE patients diagnosed in the past 12 months.  Approximately 72 participants may be enrolled in the 
study in order to get an appropriate number of assessable participants. 
 
9.3 
POPULATIONS FOR ANALYSES 
Safety analysis will be conducted on all patients evaluable for safety, defined as those patients who 
received any amount of study drug and provide any post-treatment safety data.  
 
Efficacy analyses will be conducted on the intent-to-treat population, defined as all patients enrolled in 
the study who received patient IDs regardless of whether they received study drug or not. 
 

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9.4 
STATISTICAL ANALYSES 
 
Primary analyses will assess effectiveness endpoints, including eos/hpf and EREFs. Efficacy variables will 
be summarized descriptively and compared between treatment groups.  
Secondary analyses include descriptive statistics of the patient population (patient demographics, 
clinical characteristics, and comorbid conditions), concomitant medications used in this patient 
population and changes to these treatments.  
 
Categorical variables will be described using frequencies and percentages while continuous variables will 
be described using means, standard deviations, medians, and inter-quartile ranges. 
 
Independent sample t-tests will be conducted to compare outcomes between groups.   
 
Additional analysis plans may be developed based on clinical considerations. 
 
9.4.1 SAFETY ANALYSES 
 
Adverse events will be recorded. The number and percent of patient incidence of all AEs, AEs related to 
study drug, serious adverse events (SAEs), SAEs related to study drug, deaths during the study, and 
study drug discontinuations due to an AE or study withdrawals due to an AE will be calculated. Patient 
listings will be recorded for SAEs, deaths, and AEs leading to study drug discontinuation, or study 
withdrawals. Patients will be followed for 30 days after completion or study discontinuation for the 
occurrence of any SAE. 
 
9.4.2 BASELINE DESCRIPTIVE STATISTICS 
 
Demographic variables will include age, race, ethnicity, sex, height, and weight. Participant 
demographics will be summarized with descriptive statistics, as appropriate. Clinical characteristics will 
also be summarized. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonization (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50). 
 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent and assent forms (if applicable) will receive Institutional 

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Review Board approval prior to initiation of the study. 
 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s). 
 
10.1.1 INFORMED CONSENT PROCESS 
 
Investigators will ensure that participants, or, in those situations where consent cannot be given by 
participants, their legally acceptable representatives, are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding the study. 
 
10.1.1.1 CONSENT PROCEDURES AND DOCUMENTATION 
 
The PPF for parent(s)/legally designated representative and the Assent Form for developmentally 
capable participants will be provided in English. Distinct assent forms are provided per age categories (7-
11, 12-17). Site personnel authorized to participate in the consent/ assent process and/or to obtain 
consent/assent from the parent(s)/legally designated representative and participant will be listed on the 
Delegation of Authority form. The consent process will take place in a quiet, private exam room or over 
the phone. If over the phone, a copy of the consent and assent, if applicable, will be mailed or emailed to 
the parent or legal guardian prior to the phone consent conversation. Parent(s)/legally designated 
representatives and participants will be given ample time to review the consent forms and ask 
questions.  A study physician will be available to answer medical questions or questions regarding 
alternative therapies. 
 
The parent(s)/legally designated representative and/or participant must sign and personally date (if the 
first study-mandated procedure is to be performed on the same day informed consent is obtained) the 
PPF before any study-related procedures (i.e., any procedures required by the protocol) begin. The 
PPF/Assent must also be signed and personally dated (if the first study-mandated procedure is to be 
performed on the same day informed consent is obtained) by the authorized site 
personnel listed on the Delegation of Authority form. 
 
If consented via phone, parents and participants will mail the signed consent and assent forms to study 
staff. The individual responsible fore consenting the parent and participant will then sign the form(s) and 
mail a copy of the signed forms back to the parent. If consented in person, a copy of the signed and 
dated PPF/Assent will be given to the parent(s)/legally designated representative at the time of the visit; 
the original will be filed in the site documentation. The informed consent process as well as the assent 
process will be fully documented in the participant’s medical records. This will include the study title, 
the participant number, the date and, if applicable, time when the participant’s parent(s)/legally 
designated representative was first introduced to the study, the date of consent, who participated in the 
consent discussion, who consented the participant ’s parent(s)/legally designated representative, and 
any additional person present during the consent process (e.g., participant, any other family member), 
and a statement that a copy of the signed PPF/Assent has been given to the participant’s 
parent(s)/legally designated representative. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 

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The study starts with the first patient recruited (i.e., Informed Consent Form [ICF] signed) and ends with 
the last visit/contact of the last participant. The study is considered completed when the last participant 
completes the study (i.e. last final follow-up contact). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
All efforts will be made to protect the privacy of individuals in this study. All health information and 
study data will be entered into REDCap.  REDCap is a secure online database management tool. Only 
authorized users will have access to the study in REDCap. All authorized users will sign a REDCap user 
agreement. Data will secured with a backup client. 
 
 
 
10.1.4 DATA HANDLING AND RECORD KEEPING  
 
Medical histories and demographics will be obtained through electronic medical record review, 
pathologist questionnaire, and endoscopic questionnaire. Remote participants will be asked to sign an 
authorization for the release of medical information from their local provider and records will be 
requested by study staff. Data will be recorded by the enrolling site on a case reporting form (CRF) that 
will be filed and stored on site in the patient binder. Data will also be entered into REDCap by the site 
coordinator.  
 
10.1.4.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Coordinators will enter CRF data into REDCap. The lead coordinator will monitor data completeness and 
queries as needed. The Assistant Research Scientist will extract data from REDCap for analysis at the end 
of the study. 
 
10.1.4.2 STUDY RECORDS RETENTION  
 
The Investigator will retain copies of the approved protocol, completed CRFs, informed consent 
documents, relevant source documents and all other supporting documentation related to the project 
for 7 years. These files will be made available for inspection upon reasonable request by authorized 
representatives of Sponsor and/or the relevant regulatory agencies. 
 
 
 
10.1.5 SAFETY MONITORING PLAN 
 
 
Safety oversight will be under the direction of the PI. Adverse events will be reviewed immediately after 
they occur or are reported, with follow-up through resolution. The PI will also meet with GI providers 
and the lead coordinator once per month to review adverse events. The PI and GI providers will evaluate 

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individual and cumulative participant data when making recommendations regarding the safe 
continuation of the study. 
 
 
10.1.6 QUALITY ASSURANCE AND QUALITY CONTROL 
 
All research team members will take part in a 1-2 hour protocol training session. Documentation of 
training will be kept in the study binder. Subsequently, all research team members will take part in a bi-
weekly conference call to discuss adherence to the protocol and review of the data received by the lead 
coordinator. Missing or invalid data will be discussed and, if possible, corrected by the lead coordinator. 
The lead coordinator and the PI will also review source files (consents, CRFs, questionnaires) for 
completeness and accuracy.  
 
 
 
 
 

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