Clinical trial NCT02019758
Conditions: Eosinophilic Esophagitis
Sponsor: University of North Carolina, Chapel Hill
Start date: 2015-01-01; Completion date: 2019-04-01
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Purpose: To determine whether oral viscous budesonide (OVB) or fluticasone metered dose inhaler (MDI) most effectively treats EoE by improving histologic findings and symptoms, which medication provides a more durable treatment response, and whether biomarkers can predict treatment response.

Participants: A total of up to 200 16-80 year old patients with a new diagnosis of eosinophilic esophagitis (EoE) who are referred for upper endoscopy will be consented with a target of 122 randomized.

Procedures: This will be a prospective, randomized, double-blind, double-dummy, clinical trial comparing OVB to fluticasone MDI for treatment of EoE. This overall study design will generate data for all three Aims

Detailed description:
This will be a prospective, randomized, double-blind, double-dummy, clinical trial comparing oral viscous budesonide (OVB) to fluticasone metered dose inhaler (MDI) for treatment of EoE. A total of 122 subjects aged 16-80 years old will be randomized in a 1:1 fashion to one of two active treatment arms: OVB + placebo inhaler or fluticasone MDI + placebo slurry.

In the first arm, subjects will be treated with OVB at a dose of 1 mg twice daily, and they will also be instructed to use a placebo inhaler identical to the fluticasone MDI, with instructions to swallow 4 puffs twice daily. The OVB is a slurry equivalent to what is used clinically: 1 mg/4 mL aqueous budesonide mixed with 10 g of sucralose. Rather than asking the subjects to mix the slurry on their own and risk inconsistent formulations, the University of North Carolina (UNC) investigational drug pharmacy (IDP) will provide pre-mixed OVB to all patients. The IDP will also provide placebo inhalers to all patients. The dose for OVB has been chosen because it is the most commonly studied dose, including one prior study led by this Principal Investigator, so we can accurately estimate response rates.

In the second arm, subjects will be treated with fluticasone MDI at a dose of 880 mcg twice daily (4 puffs of a 220 mcg inhaler twice daily), and they will also be instructed to take 4 mL twice daily of a placebo slurry of sucralose identical in consistency and taste to the OVB. The UNC investigational drug pharmacy (IDP) will provide the fluticasone MDIs and pre-mixed placebo slurries to all patients. The dose for fluticasone MDI has been chosen because this is the most commonly used dose in adolescents and adults with EoE, so effect estimates are also available.

For both arms, the slurry will be administered first, the MDI will be administered 15 minutes later, and patients will take nothing by mouth for an additional 30 minutes.

Subjects will receive 8 weeks of treatment and will then be monitored for up to 52 weeks for recurrence of symptoms.

Arms: arm 1: Subjects will be treated with OVB at a dose of 1 mg twice daily, and they will also be instructed to use a placebo inhaler identical to the fluticasone MDI, with instructions to swallow 4 puffs twice daily. arm 2: Subjects will be treated with fluticasone MDI at a dose of 880 mcg twice daily (4 puffs of a 220 mcg inhaler twice daily), and they will also be instructed to take 4 mL twice daily of a placebo slurry of sucralose identical in consistency and taste to the OVB.
Interventions: intervention 1: Oral Viscous Budesonide intervention 2: Fluticasone MDI intervention 3: Placebo slurry intervention 4: Placebo inhaler
Intervention descriptions: intervention 1: Oral Viscous Budesonide - 1 mg/4 mL, 4 mL of slurry twice daily intervention 2: Fluticasone multi-dose inhaler - 4 puffs twice daily (880 mcg, twice daily) intervention 3: Slurry of sucralose - 4 mL twice daily intervention 4: Placebo inhaler - 4 puffs twice daily

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Budesonide Versus Fluticasone for Treatment of Eosinophilic Esophagitis 
 
NCT number 02019758 
Document Date 14Mar2019 
 


 
CONFIDENTIAL 
CLINICAL RESEARCH PROTOCOL 
 
 
 
BUDESONIDE VERSUS FLUTICASONE FOR TREATMENT OF 
EOSINOPHILIC ESOPHAGITIS 
 
Principal Investigator: 
Evan S Dellon, MD, MPH 
Associate Professor of Medicine 
University of North Carolina School of Medicine 
Chapel Hill, NC  
Co-Investigators: 
John A Baron, MD 
Professor of Medicine 
University of North Carolina School of Medicine 
Chapel Hill, NC 
 
Joseph A Galanko, PhD 
Research Assistant Professor of Medicine 
University of North Carolina School of Medicine 
Chapel Hill, NC 
 
Nicholas J Shaheen, MD, MPH 
Professor of Medicine and Epidemiology 
Director, Center of Esophageal Diseases and Swallowing 
University of North Carolina School of Medicine 
Chapel Hill, NC 
 
John T Woosley, MD 
Professor of Pathology and Lab Medicine 
University of North Carolina School of Medicine 
Chapel Hill, NC 
 
Study Product: 
Budesonide, Pulmicort 
Fluticasone, Flovent 
Funding Sponsor: 
National Institute of Diabetes and Digestive and Kidney 
Diseases (NIDDK – R01DK101856) 
IND Number: 
105981 
Registration: 
Clinicaltrials.gov – NCT02019758 
IRB approval: 
UNC IRB # 13-4047 
 
Initial version: June 21, 2016 
Version 2.0: 
March 16, 2017 
Version 3.0:  
March 14, 2019 
 


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Changes from Previous Version 
 
This version includes the following changes to the previous version of the protocol, 
Version 2.0 (16Mar2017). 
 
Sections 3.2, 3.3, 3.4, 7.1 
Modified study endpoints to reference 
outcomes, and clarified primary, 
secondary, and exploratory outcomes. 
Entire document 
Administrative changes to protocol 
version number and date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1   INTRODUCTION ...................................................................................................................................... 3 
1.1 
BACKGROUND ................................................................................................................................ 3 
1.2 
INVESTIGATIONAL AGENTS .............................................................................................................. 5 
1.3 
PRECLINICAL DATA ........................................................................................................................ 6 
1.4 
CLINICAL DATA TO DATE................................................................................................................. 7 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 9 
2 
STUDY OBJECTIVES ....................................................................................................................... 10 
3 
STUDY DESIGN ................................................................................................................................. 10 
3.1 
GENERAL DESIGN ........................................................................................................................ 10 
3.2 
AIM 1 STUDY OUTCOMES ............................................................................................................. 10 
3.3 
AIM 2 STUDY OUTCOMES ............................................................................................................. 11 
3.4 
AIM 3 STUDY OUTCOMES ............................................................................................................. 11 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 12 
4.1 
INCLUSION CRITERIA .................................................................................................................... 12 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 12 
4.3 
SUBJECT RECRUITMENT AND SCREENING ..................................................................................... 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS............................................................................................... 12 
4.4.1 
When and How to Withdraw Subjects ................................................................................... 12 
4.4.2 
Lost to Follow-Up................................................................................................................... 13 
4.4.3 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 13 
5 
STUDY DRUGS ................................................................................................................................. 13 
5.1 
DESCRIPTION ............................................................................................................................... 13 
5.2 
TREATMENT REGIMEN .................................................................................................................. 13 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 13 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................... 13 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 14 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 14 
5.7 
PACKAGING AND LABELING ........................................................................................................... 14 
5.8 
BLINDING OF STUDY DRUG ............................................................................................................. 1 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................ 1 
5.9.1 
Receipt of Drug Supplies ......................................................................................................... 1 
5.9.2 
Storage .................................................................................................................................... 1 
5.9.3 
Dispensing of Study Drug ........................................................................................................ 1 
5.9.4 
Return or Destruction of Study Drug ....................................................................................... 1 
6 
STUDY PROCEDURES ....................................................................................................................... 2 
6.1 
CASE IDENTIFICATION ..................................................................................................................... 2 
6.2 
BASELINE VISIT (VISIT 1) ................................................................................................................ 2 
6.2.1 
Consenting Procedure ............................................................................................................. 3 
6.2.2 
Biopsy Collection and Processing, Research Related ............................................................ 3 
6.2.3 
Blood Sample Collection and Processing ............................................................................... 4 
6.3 
TREATMENT START (VISIT 2) .......................................................................................................... 5 
6.4 
MID-TREATMENT (VISIT 3) .............................................................................................................. 5 
6.5 
END OF TREATMENT (VISIT 4) ......................................................................................................... 5 


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6.6 
FOLLOW-UP PHONE CALLS AND EMAILS ............................................................................................ 6 
6.7 
STUDY END (VISIT 5) ...................................................................................................................... 6 
7 
STATISTICAL PLAN ........................................................................................................................... 7 
7.1 
SAMPLE SIZE DETERMINATION ........................................................................................................ 7 
7.2 
STATISTICAL METHODS .................................................................................................................. 7 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ......................................................................................... 8 
8 
SAFETY AND ADVERSE EVENTS ..................................................................................................... 8 
8.1 
DEFINITIONS .................................................................................................................................. 8 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 10 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 11 
8.3.1 
Investigator reporting: notifying the study sponsor................................................................ 11 
8.3.2 
Notifying the UNC IRB ........................................................................................................... 11 
8.3.3 
Notifying the FDA .................................................................................................................. 12 
8.4 
UNBLINDING PROCEDURES ........................................................................................................... 13 
8.5 
STOPPING RULES ......................................................................................................................... 13 
8.6 
MEDICAL MONITORING ................................................................................................................. 13 
8.6.1 
Independent Data and Safety Monitoring Board ................................................................... 13 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 14 
9.1 
CONFIDENTIALITY ......................................................................................................................... 14 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 14 
9.3 
CASE REPORT FORMS.................................................................................................................. 14 
9.4 
RECORDS RETENTION .................................................................................................................. 14 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 15 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 15 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 16 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 16 
12 
STUDY FINANCES ............................................................................................................................ 16 
12.1 
FUNDING SOURCE ........................................................................................................................ 16 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 16 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 16 
13 
PUBLICATION PLAN ........................................................................................................................ 17 
14 
REFERENCES ................................................................................................................................... 18 
 
 
 




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List of Abbreviations  
 
 
 
 
Item 
Definition 
AUC 
Area Under the Curve 
CEDAS 
Center for Esophageal Diseases and Swallowing 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EGD 
Esophagogastroduodenoscopy 
EoE 
Eosinophilic Esophagitis 
EoG 
Eosinophilic Gastroenteritis 
Eos 
Eosinophils 
EREFS Score 
EoE Endoscopic Reference Score104 
FFPE 
Formalin-fixed paraffin embedded 
H&E 
Hematoxylin & Eosin 
HPF 
High Power Field 
IDS 
Investigational Drug Service (at UNC) 
IRB 
Institutional Review Board 
MDI 
Multi-dose Inhaler 
NEB 
Nebulized and then Swallowed 
OVB 
Oral Viscous Budesonide 
PPI 
Proton-Pump Inhibitor 
 
 
 
 
 


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Study Summary 
Title 
Budesonide versus Fluticasone for Treatment of Eosinophilic Esophagitis  
Short Title 
TREET trial (TReatment of EoE with Topical steroids) 
Methodology 
Prospective, randomized, double-blind, double-dummy, single center clinical trial 
comparing oral viscous budesonide (OVB) to fluticasone multi-dose inhaler (MDI) 
for treatment of eosinophilic esophagitis (EoE). 
Study Duration 
3 years 
Study Center(s) 
University of North Carolina, Chapel Hill, NC 
Objectives 
Primary objective: To determine whether viscous budesonide is more effective than 
fluticasone MDI for improving esophageal eosinophil counts and symptoms of 
dysphagia in patients with EoE after an initial treatment course. 
 
Secondary objective: To determine whether treatment with viscous budesonide 
results in less symptomatic and histologic recurrence than fluticasone MDI one year 
after the initial treatment course.  
Number of 
Subjects 
200 
Diagnosis and 
Main Inclusion 
Criteria 
Inclusion Criteria: 
1) Age 16-80 years old 
2) New diagnosis of EoE as per consensus guidelines. Cases must have 
symptoms of dysphagia, persistent esophageal eosinophilia (≥ 15 
eosinophils in at least one high-power field) after 8 weeks of treatment with 
a twice daily proton-pump inhibitor, and other competing causes of 
esophageal eosinophilia excluded  
Exclusion Criteria: 
1) Medical instability that precludes safely performing upper endoscopy 
2) Ongoing or recent symptoms of intestinal bleeding (throwing up blood, 
passing blood in the stool) 
3) Concomitant eosinophilic gastroenteritis (EoG) 
4) Esophageal narrowing or stricturing that will not allow a standard 9 mm 
upper endoscopy scope to pass 
5) Cancer in the esophagus, stomach, or intestine 
6) Prior surgery on the esophagus (e.g., removal of part of the esophagus) 
7) Esophageal varices (dilated blood vessels in the esophagus) 
8) Current use of blood thinners like Plavix or Coumadin that are not stopped 
prior to endoscopy procedures 
9) Corticosteroid exposure within the four weeks prior to the baseline 
endoscopy.  Exclusionary corticosteroid exposure is defined as any 
swallowed topical steroids for EoE or systemic steroids for any condition 
within the four weeks prior to the baseline endoscopy.  Corticosteroids 
used for asthma or intranasal corticosteroids are not an exclusion and are 
allowable. 
10) Pregnancy 
11) Inability to read or speak English 
Study Product, 
Dose, Route, 
Regimen 
Oral Viscous Budesonide (OVB), 1 mg swallowed twice daily 
Fluticasone Multi-Dose Inhaler (MDI), 4 puffs (880mcg) swallowed twice daily 
Duration of 
administration 
8 weeks 


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Reference therapy 
Reference therapies are a placebo viscous slurry and a placebo MDI.  All patients 
will receive either active OVB/placebo MDI, or placebo slurry/active MDI, in double 
blind fashion. 
Statistical 
Methodology 
To test whether OVB is more effective than fluticasone MDI for improving 
eosinophil counts, the mean post-treatment maximum eosinophil count will be 
compared between the OVB and MDI groups using a two-sample t-test. To test 
whether OVB results in less symptomatic recurrence than fluticasone MDI, 
survival analysis will be performed with the interval between treatment end (week 
8) and recurrent symptoms or study end (week 60) as the time of interest. 
Symptoms will be measured with the Dysphagia Symptom Questionnaire, a 
validated instrument in EoE. 


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1   Introduction 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference 
on Harmonization guidelines), applicable government regulations and Institutional research policies and 
procedures.  
1.1 Background 
Eosinophilic esophagitis is a previously rare condition with a rapidly increasing incidence 
Eosinophilic esophagitis (EoE) is an immune-mediated 
clinicopathologic entity whereby abnormal infiltration of 
eosinophils into the esophageal mucosa leads to 
dysphagia, progressive esophageal stenosis, and food 
impaction.1-3 First described in 19784 and initially felt to 
be rare,5 estimates in multiple populations, including 
our center, show that incidence has increased more 
than four-fold in the last five to ten years (Figure 1).6-9 
Because EoE is chronic, the prevalence is also 
increasing.6, 7, 10, 11 Overall, between 5% and 16% of 
patients undergoing endoscopy for dysphagia will have 
EoE,12-15 and more than 50% of patients presenting to 
an emergency room with food impaction are now 
diagnosed with EoE.3, 16 Because of this dramatic 
change in epidemiology and the increasing burden of 
disease attributable to EoE, the NIDDK-sponsored 
National Commission on Digestive Diseases has made 
research in EoE a priority.17  
 
 
EoE is diagnosed by clinical and pathologic criteria 
While dysphagia is the clinical hallmark and most 
common symptom of EoE in adolescents and 
adults,1, 18, 19 other symptoms can include heartburn, 
reflux, and chest pain.2, 20, 21 When suggestive 
symptoms are present, upper endoscopy with biopsy 
is required to make the diagnosis.2 Endoscopic 
signs of EoE can include esophageal rings, 
strictures, luminal narrowing, linear furrows, white 
plaques or exudates, and a loss of vascularity 
(Figure 2).1, 18, 22, 23 On esophageal biopsy, 
demonstration of epithelial eosinophilia is required 
for diagnosis, and the current accepted threshold 
level is 15 eosinophils per high-power field (eos/hpf).2 Because the symptoms and signs of EoE can be 
non-specific, diagnostic criteria have been published and recently updated (Table 1).2 The guidelines 
require the presence of esophageal eosinophilia in the correct clinical setting. They also require exclusion 
of other conditions that may cause esophageal eosinophilia before a diagnosis of EoE can be formally 
confirmed. 
 
Table 1: Consensus diagnostic criteria for EoE2 
 
Clinical symptoms of esophageal dysfunction 
 
≥ 15 eosinophils in at least one high-power field 
 
Eosinophilia limited to the esophagus with other  
causes of esophageal eosinophilia excluded 
 
Figure 1:  Rapid increase in new cases of EoE at UNC in 
both adults and children.  This increase persists when 
normalized for endoscopy and biopsy volume, and mirrors 
national and international trends 
Figure 2:  Endoscopic views of (A) the normal 
esophagus and (B) EoE with rings and narrowing. 
Figure 1:  Rapid increase in new cases of EoE at UNC in 
both adults and children.  This increase persists when 
normalized for endoscopy and biopsy volume, and mirrors 
national and international trends 
Figure 2:  Endoscopic views of (A) the normal 
esophagus and (B) EoE with rings and narrowing. 


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The treatment approach to EoE is rudimentary, but corticosteroids are the mainstay of therapy for 
EoE 
Despite the fact that EoE has become a major cause of upper gastrointestinal morbidity in both children 
and adults, the approach to treatment of EoE is rudimentary and evidence to guide practice is sorely 
needed (Table 2). Because data suggest that a Th2-mediated response to allergic pathogens governs 
esophageal eosinophil infiltration,24 corticosteroids are currently the first-line pharmaceutical treatment 
option for patients with EoE.2, 25 However, because no medications in this class have been specifically 
formulated for EoE, patients are prescribed asthma preparations such as fluticasone in a multi-dose 
inhaler (MDI) or aqueous budesonide. Patients are asked to swallow, rather than inhale, these 
medications to coat the esophagus and provide a topical anti-inflammatory effect. For fluticasone MDI, 
patients puff the medication into their mouth during a breath hold and then swallow it.26, 27 For aqueous 
budesonide, patients mix the liquid into a slurry with a sugar substitute such as sucralose and then 
swallow it; this has been termed “oral viscous budesonide,” or OVB.28, 29 Another technique is to swallow 
the aerosolized droplets of aqueous budesonide after it has been nebulized.30 These approaches were 
first described in observational studies,28, 31-37 and several small randomized clinical trials have now 
shown that these treatment strategies can be effective for decreasing levels of esophageal eosinophilia 
and improving symptoms related to EoE.26, 29, 30, 38, 39 However, the dose ranges, length of treatments, 
method of drug delivery, assessment of symptoms, and patient inclusion criteria vary widely between 
these studies,25 so studies cannot be directly compared to draw conclusions about efficacy. 
 
Table 2: Major unanswered questions regarding EoE treatment 
1) What topical corticosteroid agent is the most effective? 
Importance: Doctors do not know what medication to use first. 
2) After an initial treatment course, what is the durability of 
response? 
Importance: Patients cannot be properly informed about 
treatment outcomes and symptom recurrence. 
3) Which patients are most likely to respond to topical 
corticosteroids? 
Importance: Patients who might not respond are subjected to 
unnecessary steroid exposure and provision of non-steroid 
therapies is delayed. 
 
The most effective topical steroid to use as a first line agent in EoE is unknown 
A major gap in the current knowledge regarding EoE treatment is that it is unknown which topical steroid 
is most effective. Because of this, practitioners do not know what medication to use first and cannot 
provide accurate information to patients about treatment outcomes. In a study of patterns of practice 
related to EoE performed by our group, the vast majority of gastroenterologists who prescribed a topical 
steroid chose fluticasone MDI as their initial steroid agent.40 However, this choice is not supported by 
comparative effectiveness data, and it is unknown whether a different medication such as OVB might be 
more effective. This question has substantial practical implications. Topical steroids are not universally 
effective, with 13% to 50% of subjects failing to respond depending on the study and outcome measure.26, 
29, 30, 41 It is possible that poor treatment responses are due to difficulties administering the medication or 
to sub-optimal formulations. For example, fluticasone MDI is designed for pulmonary deposition and may 
be inefficiently delivered to the esophagus, whereas the entire dose of OVB is delivered to the 
esophagus.42 Natural history data show that prolonged symptom duration in EoE is associated with 
increased risk of esophageal strictures,43 so there is a strong rationale to treat with the most effective 
agent available at the time of diagnosis. However, providers need efficacy data to select the best 
medication to treat patients with EoE. 
 
The durability of the treatment response to topical steroid treatment for EoE is unknown 
Another major gap in knowledge is that the durability of treatment response in EoE is unknown. The few 
data available regarding durability of response are inconclusive. In a retrospective trial of adults treated 
with an initial two-week course of fluticasone MDI, 29 of 32 patients reported recurrent dysphagia at a 


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mean of 9 months.44 In a prospective trial, subjects who 
previously responded to a two-week course of nebulized then 
swallowed budesonide were randomized to low dose 
budesonide or to placebo.45 After 50 weeks of treatment, all 
14 patients in the placebo arm had recurrent esophageal 
eosinophilia, and the median time to symptom relapse was 95 
days. However, in this study the initial treatment course (2 
weeks) was shorter than the current accepted standard of 8 
weeks, so the recurrence rates might have been higher. 
Providers need high quality data from larger studies to 
accurately inform patients when recurrent symptoms and 
esophageal eosinophilia can be expected after an initial 
treatment course. A better understanding of durability of 
response will also inform decisions regarding which patients 
with EoE might need long-term therapy.46 
 
Predictors of response to steroid therapy are unknown, 
but candidate tissue biomarkers can be identified from 
the postulated pathogenesis of EoE 
A third key issue in the treatment of EoE is that predictors of 
response to topical steroid treatment have not been studied. 
Of the four published small randomized trials in EoE comparing topical steroids to placebo,26, 27, 29, 30 only 
one attempted to assess predictors.30 Of 10 clinical and histologic factors examined in that study, none 
were predictive, but there were only 36 patients in the trial so the null result could be due to type II error. 
Identification of predictors of treatment response is important not only to target therapy to those most 
likely to respond, but to minimize unnecessary steroid exposure and institute effective non-steroid 
alternatives such as dietary elimination in those least likely to respond.2 Candidate biomarkers for 
prediction of treatment response can be selected based on the pathophysiology of EoE (Figure 3). The 
presence of eosinophils in the esophageal mucosa is abnormal,47,48 and both murine and human data 
suggest a Th2-mediated response to allergen sensitization governs esophageal eosinophil infiltration and 
activation.34, 49-56 In particular, IL-13 stimulates esophageal epithelial cells to produce eotaxin-3, a potent 
chemokine which is increased 50-fold in patients with EoE compared to controls.56-60 Once activated, 
eosinophils degranulate and release factors such as major basic protein (MBP), which can disrupt 
epithelium and is increased in patients with EoE.61-63 The Th2 response also results in mast cells 
infiltrating the esophagus, likely via IL-9.64 In addition to increased numbers of mast cells in patients with 
EoE, mast cell-associated genes are upregulated in EoE, and mast cells are an important mediator of the 
esophageal remodelling and fibrosis that causes esophageal strictures in EoE.54, 56, 57, 65-69 In addition, 
patients who successfully respond to topical steroid therapy have resolution of esophageal eosinophilia 
(and therefore a decrease in MBP release), normalization of eotaxin-3 gene expression, and resolution of 
esophageal mastocytosis.26, 30, 60 While MBP, eotaxin 3, and mast cells are candidate markers of 
treatment response in EoE, they have yet to be studied for this application. 
1.2 Investigational Agents 
Oral viscous budesonide (OVB) is a swallowed, or topical, steroid slurry.  We will formulate this to be 
equivalent to what is used clinically: 1 mg/4 mL aqueous budesonide mixed with 10 g of sucralose.28, 29, 42  
Rather than asking the subjects to mix the slurry on their own and risk inconsistent formulations, a 
weakness of prior studies, the UNC investigational drug service (IDS) will provide pre-mixed OVB to all 
patients. For the purposes of compounding the medication to be dispensed as a one-month supply, the 
constituent elements of aqueous budesonide are combined in bulk with sucralose to yield the necessary 
concentration and consistency.  The dose for OVB has been chosen because it is the most commonly 
studied dose, including our prior study, so we can accurately estimate response rates.28, 29, 39, 42  Subjects 
randomized to this arm will also be instructed to use a placebo inhaler identical to the fluticasone MDI, 
with instructions to swallow 4 puffs twice daily.  
 
Figure 3:  Proposed pathogenic pathway for EoE.  
Allergens or other yet to be determined etiologic factors, in 
the proper genetic milieu, stimulate a Th2 response leading 
to IL-13 production.  IL-13 stimulates the esophageal 
epithelial cells to produce eotaxin-3, which in turn acts as a 
chemoattractant and activates eosinophils. Eosinophils 
release MBP, a cytotoxic granule that can injure the 
epithelium.  The Th2 response also produces IL-9 which 
recruits mast cells.  Mast cells are involved in promoting 
fibrosis, which leads to esophageal strictures. 
Figure 3:  Proposed pathogenic pathway for EoE.  
Allergens or other yet to be determined etiologic factors, in 
the proper genetic milieu, stimulate a Th2 response leading 
to IL-13 production.  IL-13 stimulates the esophageal 
epithelial cells to produce eotaxin-3, which in turn acts as a 
chemoattractant and activates eosinophils. Eosinophils 
release MBP, a cytotoxic granule that can injure the 
epithelium.  The Th2 response also produces IL-9 which 
recruits mast cells.  Mast cells are involved in promoting 
fibrosis, which leads to esophageal strictures. 


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Fluticasone MDI is also topical steroid.  Subjects will swallow at a dose of 880 mcg twice daily (4 puffs of 
a 220 mcg inhaler twice daily).  The dose for fluticasone MDI has been chosen because this is the most 
commonly used dose in adolescents and adults with EoE, so effect estimates are also available.2, 25, 27, 101  
Subjects randomized to this arm will also be instructed to take 4 mL twice daily of a placebo slurry of 
sucralose identical in consistency and taste to the OVB.  
1.3 Preclinical Data 
Preliminary data and study feasibility 
The number of EoE cases seen at UNC continues to increase, providing an expanding source population 
for the proposed study. Through the UNC Center for Esophageal Diseases and Swallowing (CEDAS), 
one of the largest esophageal referral centers in the country, and two UNC GI procedure units, the PI has 
a rich patient population to draw from for research. Over the past 7 years, there has been a trend towards 
an increasing number of EoE cases, including more than 65 new (incident) cases of EoE annually for the 
past 3 years (Table 3). In addition, the number of cases in patients 16 years and older, the study 
population for this trial represents the majority of these cases, and is similarly increasing. The PI tracks 
EoE cases in an EoE Patient Registry and an EoE Clinicopathologic Database. This latter resource now 
has complete clinical and histologic information on more than 400 patients with EoE. 
 
Table 3: Incident cases of EoE at UNC 
Year 
Total # of new 
EoE cases 
New EoE cases in 
ages ≥16 years 
2006 
41 
26 
2007 
60 
39 
2008 
56 
33 
2009 
54 
30 
2010 
68 
36 
2011 
70 
43 
2012 
88 
52 
 
In addition, the PI has recently completed a prospective study of the prevalence of esophageal 
eosinophilia and EoE in the UNC GI procedure units. Of 173 patients undergoing endoscopy for 
dysphagia, 65 (38%) had esophageal eosinophilia with ≥ 15 eos/hpf, and 40 (23%) were confirmed to 
have a new diagnosis of EoE after a PPI trial as per consensus diagnostic guidelines (Table 1).98 This is 
the highest prevalence of EoE yet to be reported in patients undergoing endoscopy for dysphagia.13-15 
These statistics document how commonly EoE is seen at our center, given that in 2012 more than 1000 
upper endoscopies were done for patients with dysphagia between our two procedure units. Taking these 
data together, it is clear that our unit can support a steady recruitment of newly diagnosed EoE patients 
into a clinical trial. 
 
Enrollment rates in multiple prior prospective studies of EoE at UNC have been excellent, indicating that 
EoE patients seen by the PI and his care team are highly willing to participate in clinical studies. In the 
PI’s prospective study of eosinophil inflammation and activation funded by an UNC institutional NIH KL2 
award (KL2 RR025746), a total of 276 patients were approached for screening and 223 (81%) agreed to 
participate. In the PI’s prospective study of risk factors and biomarkers for diagnosis of EoE funded by an 
NIH K23 award (K23 DK90073), a total of 183 subjects have been screened to date with only 8 (5%) 
refusals. For both of these studies, patients undergoing outpatient upper endoscopy were approached for 
the first time prior to the procedure, and were remarkably willing to participate. For patients newly 
diagnosed with EoE, rates are even better. In the randomized study of OVB vs nebulized/swallowed 
budesonide that we conducted (see below), a total of 34 incident EoE cases were screened and 9 did not 
meet eligibility requirements. Of the remaining 25 cases, none refused participation. Similarly, we are a 
lead site for an industry-sponsored randomized trial of budesonide syrup vs placebo for treatment of 
adolescents and young adults with EoE. To date we have approached 14 patients with EoE for 
participation; only one patient refused to be enrolled. These high recruitment rates demonstrate the 


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feasibility and high likelihood of enrolling EoE patients into the proposed trial at UNC. To further confirm 
this, we performed a feasibility assessment for the proposed study. A total of 20 patients who met this 
study’s inclusion criteria were approached and 19 (95%) indicated that they would be willing to be 
randomized. 
 
The PI has helped to standardize methodology for determining esophageal eosinophil counts, the primary 
histologic outcome used in clinical trials of EoE. Because esophageal eosinophilia is required for 
diagnosis of EoE and is central to the pathophysiology of the condition, the eosinophil count is the most 
commonly used outcome for EoE treatment trials. In early work, the PI identified a number of 
shortcomings in the way in which eosinophil counts had been determined, including inconsistent 
methodology to quantify cells and variable definitions of microscope high-power fields.21 To address these 
issues, in collaboration with the study pathologist (Dr. Woosley), a protocol using digitized histology slides 
to quantify eosinophil counts was developed and validated. This method has been documented to have 
excellent intra- and inter-observer reliability for determining cell counts (see appendix and Aim 1 methods, 
below),82 and will form the basis of the histologic analysis used for the proposed study.   
 
The PI has participated in a multicenter collaboration to develop and validate a dysphagia symptom score 
in adults and adolescents with EoE which will be used as a primary symptom outcome in EoE studies. 
While a number of clinical trials of topical steroids in EoE have attempted to assess symptoms as an 
outcome, none have used a validated symptom score.26, 29, 30, 38, 39, 42 Recently, the PI has participated in a 
multicenter study that developed and validated the Dysphagia Symptom Questionnaire in adolescents 
and adults with EoE, the first such measure that is available.99 This is a daily symptom diary with three 
questions that assess the frequency and severity of dysphagia. The one and two week composite scores 
strongly correlate with the frequency of dysphagia, distinguish patients on topical steroids from those not 
treated (by showing that untreated patients had more dysphagia), and strongly correlate with a dysphagia 
measure that has been responsive in a previous trial of EoE.30 This instrument will form the basis of the 
symptom analysis used for the proposed study. 
 
1.4 Clinical Data to Date 
The PI has conducted the only randomized clinical trial comparing 
two formulations of topical steroids, demonstrating that OVB is 
superior 
to 
nebulized/swallowed 
budesonide 
for 
improving 
esophageal eosinophilia. In this study, a viscous slurry of budesonide 
(OVB) was compared with budesonide that was nebulized and then 
swallowed (NEB).42 This was the first study to compare two topical 
steroid formulations, and also the first to use OVB in an adult 
population. These two formulations were chosen because OVB has 
been shown to be effective in children and NEB has been shown to 
be effective in adults.29, 30 In addition, because we were assessing 
medication deposition in the esophagus, these formulations were 
amenable to being tagged with a radiotracer.  
 
A total of 25 patients were randomized, 13 to NEB and 12 to OVB, 
and 11 were analyzed in each group. Even with this small sample 
size, the results were dramatic. First, the post-treatment esophageal 
eosinophil counts were significantly lower in the OVB group 
compared with NEB (Figure 4). Second, this response was largely 
explained by the difference in esophageal medication contact time 
(Figure 5). Specifically, the OVB group had a significantly higher 
esophageal medication contact time (as measured by the area under 
the esophageal emptying curve) compared with the NEB group. 
Responders in both groups had increased esophageal medication 
contact time compared to non-responders. 
 
Figure 4:  Histologic response in EoE 
with NEB vs OVB.  Baseline eosinophil 
counts (blue bars) are similar between 
OVB and NEB.  After treatment (green 
bars), there is near normalization of the 
eosinophil count in OVB, but no change 
in NEB. 


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These data strongly implicate the medication formulation as a key 
variable in the response of EoE to topical steroids, and provide 
support for our hypothesis that OVB will be more effective than 
fluticasone MDI, which is analogous to NEB in that it is a medication 
formulation that is optimized for pulmonary deposition. We have 
selected fluticasone MDI as a comparator for OVB rather that NEB 
because fluticasone MDI is the most commonly used topical 
corticosteroid in EoE40 and because patients in our previous trial 
study found NEB to be a cumbersome delivery method. In fact, of the 
11 patients randomized to NEB, all but one opted to switch to OVB 
when given the choice at study end. Overall, data from this study 
provide strong justification for moving forward with the proposed 
study and show that the assembled research team has already 
successfully completed a randomized trial of topical steroid use in 
EoE, and therefore will also be able to complete the proposed study.  
 
The PI has demonstrated that staining esophageal biopsies for MBP, 
eotaxin-3, and mast cell tryptase is technically feasible and has 
substantial diagnostic utility for EoE. We have conducted two case-
control studies of the utility of using immunohistochemistry (IHC) to 
stain esophageal biopsies for biomarkers to diagnose EoE. In the 
first, tryptase was used to stain mast cells, and this stain had an 
excellent utility for distinguishing EoE and GERD patients 
(area under the receiver operator characteristic curve (AUC) 
= 0.84).69 In the second, both MBP and eotaxin-3 were 
assessed, and the combination of these two stains had 
outstanding utility for diagnosing EoE (AUC = 0.96).62 These 
published data show not only that we have technical 
expertise in staining for and quantifying these biomarkers 
(Figure 6) but that these stains have clinical utility for 
diagnosis of EoE. 
 
Preliminary data suggest that increased staining of eotaxin-3 
and tryptase, but not MBP, in esophageal biopsies at 
baseline prior to treatment with topical steroids is associated 
with treatment response. While no published studies have 
examined MBP, eotaxin-3, and tryptase staining at baseline 
to predict outcomes of topical steroid therapy, we have 
generated preliminary unpublished data that suggests that 
these markers do, in fact, have promise for this. Using stored 
samples in the UNC EoE Registry and Biobank, we identified 
patients who did (n = 20) and did not (n = 20) have a 
complete histologic response (defined as < 5 eos/hpf) to 
topical steroid therapy. We stained the baseline (pre-steroid treatment) biopsies for MBP, eotaxin- 3, and 
mast cell tryptase. The results showed that EoE patients who responded to topical steroid therapy had 
Figure 5:  Representative nuclear scintigraphic 
studies showing cumulative esophageal deposition 
of OVB (A) and NEB (B) over 10 minutes after 
dosing.  OVB coats the esophagus and enters the 
stomach.  NEB has pulmonary uptake with poor 
esophageal deposition. 
Figure 6:  IHC staining for tryptase, MBP, and eotaxin-3 in 
a representative GERD and EoE patient.  In all cases, 
increased staining is seen in EoE. 
Figure 5:  Representative nuclear scintigraphic 
studies showing cumulative esophageal deposition 
of OVB (A) and NEB (B) over 10 minutes after 
dosing.  OVB coats the esophagus and enters the 
stomach.  NEB has pulmonary uptake with poor 
esophageal deposition. 
Figure 6:  IHC staining for tryptase, MBP, and eotaxin-3 in 
a representative GERD and EoE patient.  In all cases, 
increased staining is seen in EoE. 


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significantly higher levels of staining for 
eotaxin-3 and tryptase than did patients who 
did not respond (Figure 7).  This was not the 
case with MBP. While the underlying 
mechanism for this finding is not known, we 
hypothesize that patients with a more 
inflammatory milieu in the esophagus as 
evidenced by increased eotaxin-3 levels and 
the presence of mast cells, are more steroid 
responsive than those who do not have this 
milieu. Because MBP levels correlate closely 
with eosinophil levels,62 and because it is 
thought that the baseline severity of 
esophageal eosinophilia itself does not predict 
treatment response,2 it is not surprising that 
MBP was not associated with treatment 
response. However, we plan to include MBP 
in our panel of biomarkers to confirm our 
finding and to provide a negative control stain. 
These preliminary data provide justification for 
including Aim 3 in the proposed study. 
1.5 Dose Rationale and Risk/Benefits 
OVB dose of 1 mg twice daily is a slurry equivalent to what is used clinically: 1mg/4mL aqueous 
budesonide mixed with 10 g of sucralose. The dose for OVB has been chosen because it is the most 
commonly studied dose, including our prior study, so we can accurately estimate response rates. 28,29,39,42  
 
Fluticasone MDI dose of 880 mcg twice daily (4 puffs of a 220 mcg inhaler twice daily) has been chosen 
because this is the most commonly used dose in adolescents and adults with EoE, so effect estimates 
are also available.2, 25, 27, 101 
 
For both arms, the slurry will be administered first, the MDI will be administered 15 minutes later, and 
patients will take nothing by mouth for an additional 30 minutes. This schedule is based on our previously 
published esophageal emptying data for OVB demonstrating that the half-life for OVB in the esophagus is 
<2 minutes.42 Therefore, the swallowed slurry will be out of the esophagus prior to swallowing the MDI, so 
interaction between the two is not a concern. For both arms, the treatment period will be 8 weeks. There 
is no placebo arm in this trial because the goal is to compare two active agents and determine which is 
more effective. Of note, no dietary changes or changes in baseline PPI medication dose will be allowed 
during the study period. 
 
There are risks associated with the study medications. Both budesonide and fluticasone are 
corticosteroids, and while these medications have been shown to be well-tolerated in several prior studies 
of EoE when compared to placebo, 26,29,38,39 adverse effects are still possible. Local effects such as mouth 
irritation or sore throat are expected in less than 5% of subjects. Oral candidiasis is also expected in less 
than 5% of subjects. Candidal esophagitis can occur in 10-20% of subjects treated with swallowed 
corticosteroids, with most cases detected on follow-up endoscopy. This is readily treated with an 
antifungal agent such as nystatin or fluconazole.  Adrenal insufficiency is a theoretic concern with any 
corticosteroid medication. However, at the doses proposed for this study and with an 8 week treatment 
period, there have been no reports of adrenal axis suppression in EoE and we do not expect this adverse 
event during the proposed study.29,38,39,42 Other steroid-related side effects such as bone mineral loss, 
cataracts, skin fragility, and diabetes have not been reported with initial short-term topical steroid use in 
EoE.26,29,38,39,42 It is important to note that while there are some risks associated with taking these 
medications, for patients diagnosed with EoE it is likely that they would be treated with one of these 
agents even if they were not participating in this study, so the medication risks related to the study are 
may not be higher than those of routine clinical care. 
Figure 7:  EoE patients who responded to topical steroids 
(blue bars) had higher levels of staining for tryptase (A) and 
eotaxin-3 (B) then non-responders (green bars), but this 
was not the case for MBP (C) 
Figure 7:  EoE patients who responded to topical steroids 
(blue bars) had higher levels of staining for tryptase (A) and 
eotaxin-3 (B) then non-responders (green bars), but this 
was not the case for MBP (C) 


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The major direct potential benefit to the patient is that all subjects will receive active medication to treat 
EoE.  Another benefit is that they will receive structured follow-up care and active monitoring for symptom 
recurrence. There is also potential benefit to society is based on scientific knowledge to be gained. 
Eosinophilic esophagitis is a newly recognized disease entity, and data supporting the best approach to 
pharmacologic treatment are lacking in the medical literature. 
 
Given the discussion of the risks above, many of which are related to testing and treatments that could be 
ordered during the course of routine care were the patients not participating in this study, we feel the risks 
to subjects are acceptable in relation to the potential benefits. 
2 Study Objectives 
 
Specific Aim 1. To determine whether viscous budesonide is more effective than fluticasone MDI for 
improving esophageal eosinophil counts and symptoms of dysphagia in patients with EoE after an initial 
treatment course.  
  
Specific Aim 2.  To determine whether treatment with viscous budesonide results in less symptomatic and 
histologic recurrence than fluticasone MDI one year after the initial treatment course. 
 
Specific Aim 3. To determine whether increased baseline staining of esophageal biopsies for major basic 
protein, eotaxin-3, and mast cell tryptase is associated with histologic response in EoE patients treated with 
topical corticosteroid therapy.   
3 Study Design 
3.1 General Design 
This is a prospective, randomized, double-blind, double-dummy, clinical trial comparing OVB to 
fluticasone MDI for treatment of EoE.  This over study design will generate data for all three Aims, 
reporting will comply with the CONSORT statement100 and will be registered with clinicaltrials.gov.  
 
3.2 Aim 1 Study Outcomes 
The primary outcome for the study will be the post-treatment maximum eosinophil count (measured in 
eos/hpf). Eosinophil counts will be determined by the study pathologist both for the screening (baseline) 
and post-treatment exams using our previously validated protocol.82 In brief, 4 esophageal biopsies will 
be obtained from both the distal (3 cm above the gastroesophageal junction) and proximal (15 cm above 
the junction) esophagus to maximize sensitivity of detecting eosinophils.102 On each biopsy fragment, 5 
high-power fields (hpf area = 0.24mm2) will be examined and the maximum eosinophil count determined 
at each level. The overall maximum count in the esophagus will be the primary outcome measure 
because there is no consensus in the literature about what eosinophil cut-point constitutes a “histologic 
non-responder” and different studies use different definitions.25, 103  
 
The co-primary outcome for the study will be the dysphagia score, as measured by the DSQ.99 This is a 
composite score generated by a symptom diary completed daily over the two weeks immediately prior to 
randomization (weeks -2 to 0) such that baseline symptoms take into account any dilation performed at 
the screening endoscopy. The diary will be repeated over the two weeks immediately prior to the follow 
endoscopy (weeks 6-8). Subjects will be automatically emailed a daily secure link to the three question 
survey to complete each night. The DSQ score (range: 0-6; higher is more severe) is calculated by 
dividing the sum of the daily scores by the number of days in which the diary was filled out. The two-week 
observation period will minimize the effect of symptom variation. Subjects will also be given the option of 
completing the diary and questionnaires on paper; capturing the date and time of each response. 
 


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Pre-specified secondary outcomes include: 1) Endoscopic findings of EoE, including esophageal rings, 
white plaques/exudates, linear furrows, edema/decreased vascularity, and strictures, will be measured 
using the recently validated EoE Endoscopic Reference Score (EREFS);104 2) Levels of histologic 
response (ie <15 eos/hpf; 3) Medication compliance as measured by percentage of medication 
appropriately used in each arm; and 4) symptoms of dysphagia as measured by the Eosinophilic 
Esophagitis symptom Activity Index (EEsAI). 
3.3 Aim 2 Study Outcomes 
Secondary outcomes to be assessed under Aim 2 are: 
- Symptomatic recurrence will be defined as at least a 1 point increase in the DSQ score over the post-
treatment score. When the study coordinator receives a report of dysphagia, the DSQ will be re-
administered over a 2 week period to determine if the subject meets the criteria for recurrent symptoms. 
 
- Histologic recurrence will be defined as recurrent esophageal eosinophilia ≥15 eos/hpf. This will be 
detected on the follow-up endoscopy, using the identical biopsy protocol and pathology interpretation 
protocol as described in Aim 1. 
 
- Other secondary outcomes will include: 1) Endoscopic findings of EoE measured by the EREFS; and 2) 
Levels of recurrent esophageal eosinophilia as measured by the maximum eosinophil count (eos/hpf). 
 
3.4 Aim 3 Study Outcomes 
For the IHC sub-analysis to be performed after study completion, the exploratory outcome of histologic 
response will be defined as a maximum eosinophil count <15 eos/hpf on post-treatment biopsies (the 
same definition asin Aim 1).  
For the methods, quantification of IHC staining will be performed with a protocol that mirrors the one used 
for the eosinophil counts and that has been successfully used in our previous studies.62, 69, 82 The IHC 
glass slides will be scanned, converted to digital slides, and viewed with Aperio ImageScope (Aperio 
Technologies, Vista, CA).82 The maximum density of cells that stained positive for each antibody of 
interest in the esophageal epithelial layer will be quantified  (cells/mm2) in five microscopy fields using the 
Aperio Positive Pixel Count Algorithm (version 9.1, Aperio Technologies).62, 69, 76 
 
 


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4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1) Age: 16-80 years 
2) Subject is having a clinically indicated endoscopy (Baseline visit 1) for suspicious EoE and has 
been on BID PPI for at least 8 weeks. OR New diagnosis of EoE as per consensus guidelines.2 
Cases must have symptoms of dysphagia, persistent esophageal eosinophilia (≥ 15 eosinophils 
in at least one high-power field) after 8 weeks of treatment with a twice daily proton-pump 
inhibitor, and other competing causes of esophageal eosinophilia excluded.  
4.2 Exclusion Criteria 
1) Medical instability that precludes safely performing upper endoscopy 
2) Ongoing or recent symptoms of intestinal bleeding (throwing up blood, passing blood in the stool) 
3) Concomitant eosinophilic gastroenteritis (EoG) 
4) Esophageal narrowing or stricturing that will not allow a standard 9 mm upper endoscopy scope to 
pass 
5) Cancer in the esophagus, stomach, or intestine 
6) Prior surgery on the esophagus (e.g., removal of part of the esophagus) 
7) Esophageal varices (dilated blood vessels in the esophagus) 
8) Current use of blood thinners like Plavix or Coumadin that are not stopped prior to endoscopy 
procedures 
9) Corticosteroid exposure within the four weeks prior to the baseline endoscopy.  Exclusionary 
corticosteroid exposure is defined as any swallowed topical steroids for EoE or systemic steroids 
for any condition within the four weeks prior to the baseline endoscopy.  Corticosteroids used for 
asthma or intranasal corticosteroids are not an exclusion and are allowable. 
10) Pregnancy 
11) Inability to read or speak English 
4.3 Subject Recruitment and Screening 
Patients with a new diagnosis of EoE or who are undergoing routine care upper endoscopy for a clinical 
suspicion of EoE will be screened by research personnel. These patients will be identified by screening 
the endoscopy and CEDAS clinic schedules or via referrals from other physicians. Once a potential 
subject is identified, study personnel will contact the potential subject to describe the study and gauge 
interest in participating.  Initial contact may be in person or on the phone using an IRB approved phone 
script.  If the patient is interested in participating, then the study coordinator or other study staff will obtain 
written informed consent from the subject. In practice, the vast majority of patients who would qualify for 
this study are seen by the PI in clinic prior to endoscopy, and this greatly simplifies the logistics of 
identifying patients, enrolling them, and collecting baseline data. At the time of enrollment, the coordinator 
will collect information about subject demographics, symptom duration, and concomitant atopic conditions 
(asthma, atopic dermatitis, allergic rhinitis/sinusitis, and food allergies). 
 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects have the right to withdraw from the study at any time, for any reason, and without repercussion. 
The sponsor-investigator, Dr. Evan Dellon, has the right to withdraw a patient from the study in the event 
of an intercurrent illness, adverse event (AE), treatment failure, protocol violation, and for administrative or 
other reasons. An excessive rate of withdrawals would reduce the amount of data available for analysis 
and limit the ability to interpret the study results; therefore, unnecessary withdrawal of patients should be 
avoided.  
 


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If a subject withdrawals prematurely, either due to voluntary withdrawal or discontinuation by the sponsor-
investigator, Dr. Evan Dellon, then they will be asked to return for a final visit to return unused study drug 
as well as to complete safety assessments (adverse events).  
4.4.2 Lost to Follow-Up 
A subject will be considered lost to follow-up after documentation has been made of at least two 
documented attempts to contact (via phone or email).  At that point a certified letter should be mailed to the 
subject’s home address.  If there is still no response after the certified letter is delivered, then the subject 
will be withdrawn from the study as lost to follow-up. 
4.4.3 Data Collection and Follow-up for Withdrawn Subjects 
Patients who withdraw prematurely from the study may be asked to complete an end of study visit per the 
study procedures.  In addition, any ongoing adverse drug reactions or study-related adverse events will be 
followed until resolution or documentation of why there will be no resolution if the event will be ongoing. 
5 Study Drugs  
5.1 Description 
Oral viscous budesonide (OVB) topical steroid slurry 1 mg/4 mL aqueous budesonide mixed with 10g of 
sucralose.  At total of 300mL of slurry will be provided to the patient in a 16oz plastic bottle every 4 weeks 
during the 8 week treatment period.  For the purposes of compounding the medication to be dispensed as 
a one-month supply, the constituent elements of aqueous budesonide are combined in bulk with 
sucralose to yield the necessary concentration and consistency.  The placebo oral suspension will also be 
300mL of an indistinguishable solution also provided in a 16oz. plastic bottle every 4 weeks during the 8 
week treatment period.  
 
Fluticasone MDI will be provided in a 220 mcg metered dose inhaler that has 120 actuations.  Subjects 
will receive 2 MDIs every 4 weeks during the 8 week treatment period.  As similar number of placebo 
inhalers will be provided as well.  For the inhalers, the UNC IDS pharmacy will prepare and blind these.  
All inhalers will be provided in a featureless white plastic shell with no labels.  The containers with 
medication or placebo will also have no labels, and will be sealed inside the container with tamper-proof 
tape.  
5.2 Treatment Regimen 
Arm 1: OVB 1 mg swallowed at a dose of 1mg twice daily and placebo inhaler 4 puffs twice daily for 8 
weeks.    
 
Arm 2: Fluticasone 220 mcg MDI is swallowed at a dose of 880 mcg twice daily (4 puffs of a 220 mcg 
inhaler twice daily) and placebo slurry 4mL twice daily for 8 weeks.   
5.3 Method for Assigning Subjects to Treatment Groups 
Subjects will be randomized in 1:1 fashion to either OVB + placebo inhaler or fluticasone MDI + placebo 
slurry using a blocked randomization protocol with computer-generated variable block sizes. The 
randomization sequence will be provided to the UNC investigational drug service (IDS) and allocation will 
be concealed from all investigators, subjects, and data analysts. The IDS will ensure that all study 
medications are appropriately blinded.  At the time of randomization (study visit 2; Figure 8), the study 
coordinator will be provided with the appropriate study medications for the patient, but will not know the 
allocation. 
5.4 Preparation and Administration of Study Drug 
Triangle Compounding Pharmacy will provide OVB 1mg/4ml aqueous suspension and placebo 
suspension to the UNC IDS.  The OVB will be the equivalent of a slurry of 1mg/4mL aqueous budesonide 


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mixed with 10g of sucralose.  The placebo OVB slurry will be aqueous sucralose. Triangle Compounding 
Pharmacy will provide all of the necessary ingredients and devices to compound the medications, such 
that they are indistinguishable by sight, appearance, and taste.  For the purposes of compounding the 
medication to be dispensed as a one-month supply, the constituent elements of aqueous budesonide are 
combined in bulk with sucralose to yield the necessary concentration and consistency.  The medications 
will be prepared in a powder containment hood following USP 795 guidelines.  The UNC IDS will 
purchase fluticasone MDI, and the PI has purchased the equivalent placebo inhalers and has provided 
them to the IDS.  The IDS will then blind the inhalers, as noted above.  All study drug and placebos will be 
stored and dispensed from the UNC IDS.  UNC IDS will determine randomization and dispense blinded 
study drug and placebo to a study coordinator who will then dispense to the subject.   
 
There may be instances in which the participation of an eligible subject is limited only by the ability to 
come to the site for study only visits (Treatment Start Visit 2,and/or Mid-Treatment Visit 3. In these cases, 
study drug may be shipped to the subject only after Study PI approval, using the IDS approved Shipping 
Standard Operating Procedure. Visit assessments would be completed by phone, email, and on paper as 
applicable.   
 
UNC Investigational Drug Services: 919-966-8739 
5.5 Subject Compliance Monitoring 
Budesonide medication compliance will be measured by residual OVB slurry remaining in the bottle.  
Study coordinator will measure the amount and calculate volume remaining to compare to expected 
volume remaining.  The fluticasone medication compliance will be measured using an actuation counter 
as well as by weight of the inhaler before and after use. Medication compliance will be assessed at the 
mid-treatment visit, and subjects who are non-compliant will be trained on appropriate study medication 
dosage and counseled on the importance of being compliant with the study medication.  Medication 
compliance will also be assessed at the end of treatment visit.   
5.6 Prior and Concomitant Therapy 
All past and current EoE medical therapies (including medication, dilation, etc.) will be collected along 
with all current concomitant medications.  Any swallowed topical corticosteroid exposure for EoE or 
systemic steroids for any condition within the 4 weeks prior to baseline EGD and during the treatment 
phase are not permitted for the study.  No dietary changes or changes in baseline PPI medication dose 
will be allowed during the study period. 
5.7 Packaging and Labeling 
UNC IDS will dispense active study medication and placebo.  Specifically, they will provide the pre-mixed 
16oz bottles containing 300mL of OVB slurry, the identical-tasting 16oz bottles containing 300mL OVB 
placebo slurry, the 220mcg fluticasone inhaler, and the placebo inhaler.  All inhalers will be provided in a 
featureless white plastic shell with no labels.  The containers with medication or placebo will also have no 
labels, and will be sealed inside the container with tamper-proof tape.  Based on the blinded 
randomization schedule, IDS will assemble and label subject drug kits to include either:  
 
1 16oz bottle of OVB slurry with 1 measuring device (syringe) and 2 placebo MDIs or  
 
1 16oz bottle of placebo with 1 measuring device (syringe) and 2 fluticasone MDIs   
 
All investigational products dispensed for this study will be in compliance with labeling requirements per 
21CFR312 and include the following statement: “Caution: New Drug-Limited by Federal law to 
investigational use” 
 
In addition, product labeling will include: 
 
IDS contact information 
 
Study IRB number 
 
Study IDS number 
 
Subject medical record number 


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 
Subject name 
 
Dosing instructions 
 
Drug expiration date 
 
Prescription number 
 
Lot number 
 
Quantity 
 
Number of refills 
 
Pharmacist information 
 
Sample labels are provided below. 
 
IP Label: 
 
 
 
 


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Bag Label: 
 
 
5.8 Blinding of Study Drug  
UNC IDS will implement the blinding of the study drugs.  All study medication will be labelled with unique 
study identification numbers, and the only link between the study ID and the randomization sequence will 
be kept on file by the IDS.  In this manner, study subjects and all other study personnel (investigators, 
endoscopists, nurses, statisticians, and study staff) will remain masked as to allocation. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Triangle Compounding Pharmacy will deliver OVB and OVB placebo to IDS as patients are enrolled in the 
study.  Upon receipt of the of the study treatment supplies, IDS will inventory the drug and a drug receipt 
log will be filled out and signed by the person accepting the shipment.  IDS study staff will count and 
verify that the shipment contains all the items noted in the shipment inventory.  Any damaged or unusable 
study drug in a given shipment (active drug or comparator) will be documented in the study files.   
5.9.2 Storage 
All slurry and inhalers will be stored at room temperature in the IDS. 
5.9.3 Dispensing of Study Drug 
Regular study drug reconciliation will be performed to document drug assigned, drug consumed, and drug 
remaining.  This reconciliation will be logged on the drug accountability form, and signed and dated by 
IDS. UNC IDS is responsible for maintaining all drug accountability including receipt, dispensation, and 
destruction. 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and 
drug remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of 
unused study drug.  Drug destroyed on site will be documented in the study files.  UNC IDS is responsible 
for maintaining all drug accountability including receipt, dispensation, and destruction. 
 
 
 


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6 Study Procedures 
 
 
 
Figure 9. Study overview of procedures at each visit.  Baseline Visit: Clinically indicated routine care EGD 
to determine eligibility. Treatment Start Visit: If subject is eligible, subject is randomized and starts study 
medication.  End of Treatment Visit: Clinically indicated routine care EGD to determine response to 
treatment.  Follow-up Phase: No study medication taken; subject symptoms are assessed by phone calls 
or via email. Study End: Occurs 60 weeks post Treatment Start Visit or when dysphagia symptoms recur.  
Of note, all CFRs will be entered in a custom electronic data capture and management system designed 
expressly for this trial. 
 
6.1 Case Identification 
During case identification, eligibility is assessed (based on inclusion/exclusion criteria) and those eligible 
and interested in participating will be consented during the Baseline Visit.  Potential cases will be 
identified by screening the endoscopy and CEDAS clinic schedules.  This will require approval of a limited 
HIPAA waiver to access the personal health information (PHI) of potential research subjects prior to their 
formal enrollment during Baseline Visit.     
 
6.2 Baseline Visit (Visit 1)  
The baseline visit is a clinically indicated and clinically scheduled EGD appointment that is performed per 
routine care.  The subject is responsible for all associated costs of the EGD.  


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The following procedures will be completed during the baseline visit: 
 
Informed consent 
 
Inclusion/exclusion criteria review to determine eligibility  
 
EoE medical history review and demographics collection 
 
Concomitant medications collected 
 
EGD with EREF score and biopsies for pathology, per routine care 
 
Sample collection, research related 
 
Adverse events noted 
 
Daily Symptoms Questionnaire (DSQ) administration – DSQ will be explained and subject will be 
instructed to begin completing daily entries in the evening for 2 weeks after receipt of pathology 
results and confirmation of eligibility by Dr. Dellon 
 
The Baseline Visit Case Report Form (CRF) will be completed by the study coordinator. This form 
captures demographics including race, ethnicity, gender, and date of birth, adverse events, EoE medical 
history including documentation of endoscopic procedures to date as well as pathology findings and 
concomitant medications related to EoE and current concomitant medications. CRF will also include EGD 
data with EREFS score.    The Pathology CRF will be completed by the study pathologist.  This form 
captures eosinophil counts and associated histologic findings. 
 
Patients may also be identified after routine care EGD by the study physician or a UNC GI colleague. 
Patients that are referred will be contacted by Dr. Dellon to discuss the option to participate in EoE 
research studies. If subjects have already had a confirmatory EGD for EoE, subjects may be consented 
into the study by phone and email; sending a signed consent form to study personnel before beginning 
DSQ. See section 6.2.1 for details. Pathology review will occur using previous clinical or research 
samples.  
6.2.1 Consenting Procedure 
If a subject is screened eligible and interested in the study, the subject will be consented on the study 
prior to any study procedure. Written informed consent will be obtained by qualified study personnel.  
Documentation of the consent process will be maintained in the subject’s research record. 
 
Subjects will be given ample time to review the consent document and ask any questions they may have.  
A copy of the written consent form will be provided to the subject and the original maintained in the 
subject’s research record.   
 
If subjects meet all inclusion and none of the exclusion criteria and consent to the study, they will be 
enrolled in the study. Subjects will be assigned a unique subject code.   
 
If a previous EGD result is being used for eligibility purposes, consent will be obtained before all other 
Baseline study procedures. Subjects will be provided the consent form by mail or email and the consent 
interview will be conducted by telephone while the subject can read the consent form during discussion. 
The subject will then sign and date consent forms and email, mail, or return signed copy at next visit. The 
subject will be provided with a staff signed copy of the consent form.  
 
6.2.2 Biopsy Collection and Processing, Research Related 
Biobanking will be performed during this study to archive specimens for future research purposes.  During 
the clinically indicated EGD, clinical biopsies will be obtained for pathology assessment. In addition, 4 
research-specific biopsies will be obtained from each of the following locations:  Distal esophagus (3cm 
from TGF), middle esophagus (8cm from TGF), and proximal esophagus (13cm from TGF). Additionally, 
2 research-specific biopsies will be obtained from the duodenum, and 2 research-specific biopsies will be 
obtained from the stomach (1 from antrum, 1 from body).  The 4 distal biopsies will be separated into 4 


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cryovials: 2 filled with formalin for histology, 1 filled with RNALater, and 1 empty to be frozen immediately 
in liquid nitrogen.        
 
 
Cryovial depiction: 
 
 
 
Research Related Biopsy Collection Protocol: 
 
Biopsy Location 
Description 
Processing/Labeling Instructions 
4 distal esophageal 
4 single biopsies 
3cm from GEJ 
 
 2 formalin: Label: PID1_eh2,3_d4_date5 and 
PID_eh_d2_date 
 1 RNALater: Refrigerate, store long term in -
80deg.F  Label: PID_er_d_date 
 1 frozen: Label: PID_ef_d_date 
4 mid esophageal 
4 single biopsies 
8cm from GEJ 
 1 formalin: Label: PID_ eh_m_date 
 1 RNALater: Label: PID_er_m_date 
 2 frozen: Label: PID_ef_m_date and 
PID_ef_m2_date 
4 proximal 
esophageal 
4 single biopsies 
13cm from GEJ 
 2 formalin: Label: PID_eh_p_date and 
PID_eh_p2_date 
 1 RNALater: Label: PID_er_p_date 
 1 frozen: Label: PID_ef_p_date  
Figure 10. Research related biopsy tissue collection outline.  Specimen labels include: participant 
identifier1_tissue type2_ fixitive/sample processing3_ esophageal location4_date collected5   
 
1participant identifier (PID) 
2tissue type: “e” is esophageal 
3fixitive/sample processing: r, h, or f where “r” is RNALater, “h” is histology/formalin, and “f” is frozen/empty 
cryovial 
4esophageal location: d, m, or p where “d” is distal, “m” is middle, and “p” is proximal 
5date collected: MMDDYYYY 
 
A reduced number of biopsies may be collected at the discretion of the endoscopist performing the 
procedure.  Biopsy samples missed will not be considered protocol deviations or violations.  
6.2.3 Blood Sample Collection and Processing  
Blood tube 
Processing/Labeling Instructions 
2 
red 
top 
serum 
separators 
Centrifuge, aliquot serum into 9 cryovials, store in refrigerator and transfer 
to -80 
Label: PID_s1, PID_s2, PID_s3, etc. 
1 yellow top plasma 
buffy separator 
Centrifuge, aliquot plasma into 9 cryovials  
Label: PID_p1, PID_p2, PID_p3, etc. 


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buffy into 1 cryovial 
Label: PID_b 
1 purple top whole blood 
Aliquot whole blood into 5 cryovials 
Label: PID_w 
1 PAXgene blood RNA 
Store PAXgene tube upright at room temperature for a minimum of 2hrs and 
maximum of 72hrs before transferring to refrigerator then  freezer 
Label: PID 
 
Missed blood samples are allowable, and will not be considered protocol deviations or violations. 
 
Urine or saliva samples may be collected for future testing at Enrollment, End of Treatment, and Study 
End Visits. 
6.3 Treatment Start (Visit 2) 
At treatment start, the subject will come for a study visit, and the following procedures will be performed: 
 
Inclusion/exclusion criteria will be reviewed 
 
TREET Trial Questionnaire, completed by subject by email (or provided on paper) 
 
EEsAI Questionnaire, complete by subject on paper 
 
Study Medications dispensed to subject- the subject will be provided with specific 
instructions about how to use the medications and the timing of administration.  
Additionally, an information sheet will be provided with this information.   
 
Prior to this visit, the coordinator will receive the set of study medications from the 
IDS that are labelled and coded for that patient, according to the randomization 
scheme.  The coordinator, subject, and all study personnel remain blinded to 
treatment allocation. If determined applicable by the Study PI, the medication can 
be mailed to the subject with confirmation of receipt provided to the study staff. 
 
Mid treatment (visit 3) and end of treatment (visit 4) appointments will be scheduled. The Treatment Start 
CRF will be completed by the Study Coordinator. 
6.4 Mid-treatment (Visit 3) 
At the mid treatment visit, the subject will come for a study visit, and the following procedures will be 
performed: 
 
Adverse Events noted 
 
Subject will return used medications  
 
The coordinator will assess compliance based on subject report, and identify any barriers to 
compliance with the subject, including retraining on medication administration if necessary 
 
Coordinator will measure the remaining medications returned for compliance assessment, as 
noted above.  
 
Study medications dispensed to subject. Prior to this visit, the coordinator will receive the set of 
study medications from the IDS.  If determined applicable by the Study PI, the medication can be 
mailed to the subject with confirmation of receipt provided to the study staff. 
 
The mid-treatment CRF will be completed by the Study Coordinator. 
6.5 End of treatment (Visit 4) 
This visit is similar to the treatment start visit.  It is a clinically indicated and clinically scheduled EGD 
appointment that is performed per routine care for follow-up of treatment response.  The subject is 
responsible for all associated costs of the EGD.  
 
 
The following procedures will be completed during the baseline visit: 


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 
EGD with EREF score and biopsies for pathology, per routine care 
 
Sample collection, research related 
 
Adverse events noted 
 
Daily Symptoms Questionnaire (DSQ) administration confirmation – DSQ will have been sent 2 
weeks prior to the endoscopy. 
 
TREET Trial follow-up questionnaire and the EEsAI, will be completed by subject 
 
Subject will return used medications  
 
The coordinator will assess compliance based on subject report 
 
Coordinator will measure the remaining medications returned for compliance assessment, as 
noted above.  
 
The Follow-up Visit Case Report Form (CRF) will be completed by the study coordinator. This form 
captures adverse events, and EGD data with EREFS score.    The Pathology CRF will be completed by 
the study pathologist.  This form captures eosinophil counts and associated histologic findings. 
 
After this visit, the PI will review biopsy results.  Subjects who do not have a histologic response (defined 
by <15 eos/hpf) will be exited from the study and can resume routine clinical care.  Subjects with a 
histologic response will continue on in the follow-up phase of the study, and will be observed without any 
study medication. 
6.6 Follow-up phone calls and emails 
During the follow-up phase, subjects will receive automated email follow-up questions from the electronic 
data management system at weeks 12, 20, 30, 40, and 50.  They will also be instructed to contact study 
staff with any recurrent symptoms or issues.  Participation in this phase will last up to one year (study 
week 60) or until symptoms recur, whichever is first.  During the follow-up phase, the patients will be 
contacted by email and/or phone five times by the study staff to screen for adverse events and symptom 
recurrence.  If there is symptom recurrence, the patients will fill out a repeat DSQ, and then will proceed 
to endoscopy.  If there is no symptom recurrence, the patients will proceed to surveillance endoscopy in 1 
year (see section 6.7).   
6.7 Study end (Visit 5) 
This visit occurs if symptoms have recurred during the 1 year follow-up phase, or at study week 60, 
whichever comes first.  This visit is similar to the treatment start visit.  It is a clinically indicated and 
clinically scheduled EGD appointment that is performed per routine care for follow-up of treatment 
response.  The subject is responsible for all associated costs of the EGD.  
 
The following procedures will be completed during the baseline visit: 
 
Concomitant medications collected 
 
EGD with EREFS score and biopsies for pathology, per routine care 
 
Sample collection, research related 
 
Adverse events noted 
 
Daily Symptoms Questionnaire (DSQ) administration confirmation – DSQ will have been sent 2 
weeks prior to the endoscopy. 
 
TREET Trial follow-up questionnaire 
 
EEsAI questionnaire 
 
Symptom assessment 
 
The End-of study Case Report Form (CRF) will be completed by the study coordinator. This form 
captures adverse events, and EGD data with EREFS score.    The Pathology CRF will be completed by 
the study pathologist.  This form captures eosinophil counts and associated histologic findings. 
 
After this procedure, the subject has completed the study and will return to routine care with their referring 
provider. 


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7 Statistical Plan 
7.1 Sample Size Determination 
The overall study is powered for the co-primary histologic and symptom outcomes.  Based on estimates 
of histologic improvements from our study of topical budesonide formulations as well as the other 
published studies of topical steroids in adults and children (Table 4),26, 27, 29, 39, 41, 42, 101, 105 we estimate that 
average baseline maximum eosinophil counts will be 80 eos/hpf and that average post-treatment 
maximum eosinophil counts will be 10 ± 10 eos/hpf in the OVB arm and 20 ± 20 eos/hpf in the fluticasone 
MDI arm.  To detect this different with a power of 0.9, 53 subjects per arm are needed (Table 5).  
Assuming a drop-out rate of 15%, which is what we observed in our budesonide trial,42 we will randomize 
to treatment 61 subjects in each arm, for a total of 122.  This sample size will also allow us to detect with 
a power of 0.9 a DSQ difference of as little as 1 point, which was the average difference between those 
patients on topical steroids and those not on topical steroids in the validation study of the DSQ.99  This is 
a clinically significant difference equivalent to having one day less of dysphagia per week.  We are 
planning a 36 month enrollment phase, which averages to 40 subjects per year.  This is substantially less 
than the number of incident cases in the study age range diagnosed at UNC in the last two years (Table 
3) and is a realistic goal.  
 
For Aim 2, based on estimates in the literature, we would expect at least 80% of subjects in the OVB 
arm,29, 30, 39, 42 and at least 50% of subjects in the fluticasone MDI arm,26, 27, 41, 101, 105 to have a 
symptomatic and histologic response (<15 eos/hpf) after the initial treatment period.  Therefore, 
approximately 42 subjects in the OVB arm and 27 subjects in the MDI arm will enter the follow-up period.  
There are no prospective comparative data on symptomatic or histologic recurrence rates for these two 
medications.  However, based on these sample sizes and estimating a recurrence rate of 80% in the MDI 
group, we would be able to detect a hazard ratio for symptomatic recurrence of 0.43 or lower with a 
power of 0.8 for OVB compared with MDI.  Similarly, for histologic recurrence, we would be able to detect 
a difference as low as 36% with a power of 0.8 for OVB compared with MDI. 
 
For Aim 3, based on estimates in the literature and our own preliminary data, we expect 60% of subjects 
in the OVB arm,29, 39, 42 and 40% of subjects in the MDI arm,26, 27, 41, 101, 105 to have a complete histologic 
response of <5 eos/hpf.  Therefore, we expect a total of 53 histologic responders and 53 non-responders.  
With this sample size, we will be able to detect a difference between the responders and non-responders 
as low as 100 cells/mm2 for tryptase staining and 1250 cells/mm2 for eotaxin-3 staining with a power of 
0.9.  Both of these values are less than or equivalent to the differences we observed in our preliminary 
data.  While we do not expect to see a difference in MBP staining, with this sample size we would be 
powered to find a difference of 750 cells/mm2 or greater if such a difference exists 
7.2 Statistical Methods 
For Aim 1, to test whether OVB is more effective than fluticasone MDI for improving eosinophil counts, the 
mean post-treatment maximum eosinophil count will be compared between the OVB and MDI groups 
using a two-sample t-test.  The pre- and post-treatment counts will also be compared within study groups 
using a paired t-test.  To test whether OVB 
is more effective than MDI for improving 
symptoms of dysphagia, the mean DSQ 
scores will be compared between the OVB 
and MDI groups using a two-sample t-test, 
and within groups using a paired t-test.  For 
the secondary outcomes, means will be 
compared for the post-treatment endoscopy 
score with t-tests, and proportions will be 
compared with chi-square for the levels of 
histologic response.  For all analyses, if data 
distributions are not normal, non-parametric 
testing will be used. All analyses will be by intention-to-treat and performed using SAS (version 9.2).  All 
Table 5:  Sample size calculations for primary histologic outcome 
Post-treatment 
eosinophil counts (mean 
eos/hpf)* 
 
 
 
OVB 
MDI 
α 
Power 
N per group 
15 
20 
0.05 
0.8 
157 
10 
20 
0.05 
0.8 
40 
5 
20 
0.05 
0.8 
18 
15 
20 
0.05 
0.9 
211 
10 
20 
0.05 
0.9 
53 
5 
20 
0.05 
0.9 
24 


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tests will be two-sided with a significance level set at p < 0.05.  To account for the possibility that baseline 
subject characteristics are unevenly distributed between study groups, we will perform an additional 
analysis with multiple linear regression to control for possible confounders including co-existing atopic 
disease (asthma, atopic dermatitis, allergic rhinitis/sinusitis, food allergies), symptom duration prior to 
diagnosis, esophageal stricture on baseline endoscopy, and esophageal dilation on baseline endoscopy. 
 
For Aim 2, to test whether OVB results in less symptomatic recurrence than fluticasone MDI, survival 
analysis will be performed with the interval between treatment end (week 8) and recurrent symptoms or 
study end (week 60) as the time of interest.  A Kaplan-Meier curve will be constructed comparing the time 
until symptom recurrence in both study groups using the log-rank test.  Hazard ratios will be calculated 
using Cox proportional hazards models, and we will adjust for potential confounders including age, 
gender, atopic status, symptom duration prior to EoE diagnosis, and presence of esophageal strictures on 
endoscopy.  To test whether OVB results in less histologic recurrence than fluticasone MDI, the 
proportion of subjects with ≥15 eos/hpf at follow-up endoscopy in each group will be compared using chi-
square.  This analysis cannot be time-dependent because the eosinophil count is not known for all 
subjects until the follow-up exam is complete. 
 
For Aim 3, to test the hypothesis that elevated levels of eotaxin-3 and tryptase, but not MBP, will predict 
histologic response after treatment with topical steroids, we will perform three identical analyses.  In the 
first, the mean baseline cellular staining for eotaxin-3 will be compared between the responder and non-
responder groups using a two-sample t-test.  This same analysis will be repeated for tryptase and MBP.  
We also plan a multivariable analysis to determine if these biomarkers independently predict response.  
For this, logistic regression modeling will be performed controlling for factors such as age, gender, atopic 
status, symptom duration prior to EoE diagnosis, and presence of esophageal strictures on endoscopy.  
For the secondary analyses, we will assess staining using other levels of histologic response (partial 
response with 5-14 eos/hpf and non-response with ≥15 eos/hpf) and by formulation of topical steroid 
(OVB vs fluticasone MDI).  We will also determine if baseline staining was associated with decreased 
post-treatment symptoms of dysphagia measured by the DSQ, and whether the biomarkers correlate with 
each other.  For all analyses, if data distributions are not normal, non-parametric testing will be used. All 
tests will be two-sided with a significance level set at p < 0.05. 
7.3 Subject Population(s) for Analysis 
The subject population for analysis will be by intention-to-treat, and will include all patients who are 
randomized and who complete the protocol to have follow-up data available.  
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRSOs) 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research, 
 Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
Adverse Event 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human subject, including 
any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, experience, or 
disease, temporally associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research. Adverse events encompass both physical and 


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psychological harms. Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal 
results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
Serious vs. Severe 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, moderate, 
or severe); the event itself, however, may be of relatively minor medical significance (such as severe 
headache).  This is not the same as “serious,” which is based on patient/event outcome or action criteria 
usually associated with events that pose a threat to a patient’s life or functioning.  Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
 
Adverse Drug Reaction (ADR) 
Any adverse event caused by a drug.  An ADR can be considered a “suspected” adverse drug reaction if 
there is a reasonable possibility that the drug caused the adverse event.  “Reasonable possibility” means 
there is evidence to suggest a causal relationship between the drug and the adverse event. 
 
Unexpected Adverse Drug Reaction 
An adverse drug reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. package insert or investigator’s brochure). 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from the 
initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
 
 


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General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an adverse 
event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.  The investigator 
should notify the study sponsor of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this study.  The sponsor 
should also be notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that has participated in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the criteria for 
and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation should be 
recorded and reported immediately. 


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8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible, but at a minimum those events that must 
be reported are those that are: 
 related to study participation, 
 unexpected, and  
 serious or involve risks to subjects or others  
(see definitions, section 8.1).   
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the 
initial report includes: 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study treatment was discontinued 
 
The reason why the event is classified as serious 
 
Investigator assessment of the association 
between the event and study treatment 
 
8.3.1 Investigator reporting: notifying the study sponsor 
Any study-related unanticipated problem posing risk of harm to subjects or others, and any type of study-
related serious adverse event, must be reported to the study sponsor by telephone within 24 hours of the 
event.  To report such events, a Serious Adverse Event (SAE) form must be completed by the investigator 
and faxed to the study sponsor within 24 hours.  The investigator will keep a copy of this SAE form on file 
at the study site.  Report serious adverse events by phone and facsimile to the PI, and the study coordinator, 
who in turn will communicate to the UNC IRB, and if necessary, NIH. 
 
Within the following 48 hours, the investigator must provide further information on the serious adverse event 
or the unanticipated problem in the form of a written narrative.  This should include a copy of the completed 
Serious Adverse Event form, and any other diagnostic information that will assist the understanding of the 
event.  Significant new information on ongoing serious adverse events should be provided promptly to the 
study sponsor 
8.3.2 Notifying the UNC IRB 
Dr. Evan Dellon is responsible for reporting adverse events to the UNC IRB per the UNC IRB SOPs for 
reporting adverse events. Federal regulations require investigators to report unanticipated problems 
involving risks to subjects or others to the IRB. Historically, there has been confusion about what needs to 
be reported. OHRP and FDA have issued guidance that clarifies that investigators need only report 
“unanticipated problems involving risks to subjects or others” (or UPIRSOs). The UNC-Chapel Hill policy is 
based on this guidance. “Adverse events” that are not UPIRSOs are not required to be reported to the IRB. 
8.3.2.1 
Differentiating between an UPIRSO and an Adverse Event 
By definition, an UPIRSO is unexpected, whereas an “adverse event” may be anticipated or unanticipated. 
Additionally, an UPIRSO may involve the increased risk of harm—whether or not any actual harm occurred. 
In order to decide which events or circumstances constitute an UPIRSO, it is important to bear in mind the 
following: 
• 
Not all Adverse Events are UPIRSOs. Only a small subset of “adverse events” occurring in FDA-
regulated clinical trials and other types of studies constitute UPIRSOs. Many events that are 
required to be reported to the sponsor or federal agency are not UPIRSOs. 
• 
An UPIRSO may not be an adverse event. It is possible for an event that does not involve actual 
physical, psychological, social, or economic harm to a research subject or another person 
nevertheless to constitute an UPIRSO that must be reported to the IRB. This is the case if the event 
places subjects or others at increased or different risk of harm, regardless of whether actual harm 
has occurred. 
 


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There are other types of incidents, experiences and outcomes that occur during the conduct of human 
subjects research that represent UPIRSOs but are not considered adverse events. Some UPIRSOs involve 
social or economic harm instead of the physical or psychological harm associated with adverse events. In 
other cases, UPIRSOs place subjects or others at risk of harm, but no harm occurs. For example, an 
investigator conducting behavioral research collects individually identifiable sensitive information about illicit 
drug use and other illegal behaviors by surveying college students. The data are stored on a laptop 
computer without encryption, and the laptop computer is stolen from the investigator’s car. This is an 
UPIRSO and must be reported because the incident was (a) unexpected (i.e., the investigators did not 
anticipate the theft); (b) related to participation in the research; and (c) placed the subjects at a greater risk 
of psychological and social harm from the breach in confidentiality of the study data than was previously 
known or recognized. 
Other examples of UPIRSOs that should be reported to the IRB, even though they are not adverse events, 
include: 
• 
Publication in the literature, safety monitoring report (e.g., DSMB report), interim result, or other 
finding that indicates an unexpected change to the risk/benefit ratio of the research; 
• 
Breach in confidentiality resulting from a disclosure of confidential information or from lost or stolen 
confidential information; 
• 
Unresolved complaint of a participant, family member or other individual; 
• 
Laboratory or medication errors that may involve potential risk to that individual or others; 
• 
Change in FDA labeling because of adverse consequences or withdrawal from marketing of a drug, 
device, or biologic used in a research protocol; 
• 
Disqualification or suspension of investigators; 
• 
Accidental or unintentional change to the IRB-approved protocol that involves risks or has the 
potential to recur; 
• 
Deviation from the protocol taken without prior IRB review to eliminate apparent immediate hazard 
to a research participant 
• 
Any deviation from the IRB-approved protocol that increases the risk or affects the participant’s 
rights, safety, or welfare. 
8.3.2.2 
UNC IRB Reporting Timelines 
Reporting is required of all UPIRSOs, including those which may occur after the participant has completed 
or is withdrawn from the study, or following study closure. Reporting is completed via IRBIS, UNC’s online 
IRB information system. 
 
Events that meet the criteria for an UPIRSO and are also serious adverse events should be reported to the 
IRB within one (1) week of the investigator becoming aware of the event. 
 
Any other events that meet the criteria for a UPIRSO should be reported to the IRB within two (2) weeks 
of the investigator becoming aware of the problem. 
 
If the report cannot be completed in its entirety within the required time period, a preliminary report should 
be submitted. The report should be amended once the event is resolved and/or more information becomes 
available. 
8.3.3 Notifying the FDA 
As the sponsor, Dr. Evan Dellon is required to report certain study events in an expedited fashion to the 
FDA.  These written notifications of adverse events are referred to as IND safety reports. The following 
describes the safety reporting requirements by timeline for reporting and associated type of event per 
21CFR312.32: 
 
 Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug 


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– unexpected,  
– fatal or life-threatening, and  
 
 Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, teratogenicity, 
or carcinogenicity. 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning similar adverse 
events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse events requiring reporting to FDA per the above may be submitted on FDA Form 3500A or in a 
narrative format. If supplied as a narrative format, the minimum information to be supplied is noted above 
at the beginning of section 8.3. 
8.4 Unblinding Procedures 
If an AE or other clinical event necessitates unblinding the patient, this decision will be made by the PI in 
consultation with the DSMB.  Actions will be reported to the UNC IRB and the DSMB. 
8.5 Stopping Rules  
This study does not have stopping rules, and there are no plans for an interim analysis. 
8.6 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan (see section 
10).  Medical monitoring will include a regular assessment of the number and type of adverse events. 
8.6.1 Independent Data and Safety Monitoring Board 
The DSMB will regularly review interim data to assess compliance, monitor toxicity, and recommend 
whether the trial should continue.  Members will be independent experts not otherwise affiliated with the 
trial or UNC as an institution, and will be chosen on the basis of their expertise and scientific rigor.  The 
areas of expertise for the DSMB members span the disciplines relevant to the conduct of GI clinical trials, 
including epidemiology, trial design and conduct, and clinical care of EoE patients. The members will be: 
 
Ikuo Hirano (Chair) 
Professor of Medicine 
Northwestern University 
Chicago, IL 
David A. Katzka 
Professor of Medicine 
Mayo Clinic 
Rochester, MN 
Gary W. Falk 
Professor of Medicine 
University of Pennsylvania 
Philadelphia, PA 
 
The DSMB will meet via conference call at the beginning of the study, and then at 6-month intervals until 
the study is complete.  The PI (Dr. Dellon) as well as the study biostatistician (Dr. Galanko) will participate 
in the open portion of the meetings.  If needed, the DSMB’s voting members may then choose to discuss 


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issues in a closed session kept confidential from the investigators.  The DSMB has the responsibility to 
review the research protocol and to evaluate the progress of the trial overall.  It will also evaluate participant 
risk and benefit as the trial progresses, considering evolving scientific discoveries or treatment options that 
may affect the desirability of continued treatment. At the conclusion of each meeting, the DSMB will 
recommend whether the trial be continued.  The specific information it will review include: current status of 
study enrollment; level of medication compliance; medication-related adverse events; endoscopy-related 
adverse event; and subject-reported events.  Unexpected serious adverse events will be reported to the 
DSMB between meetings as needed, as well as to the UNC IRB as noted above. 
 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect 
at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical trial. 
9.3 Case Report Forms 
The study will utilize electronic case report forms (eCRFs). All data requested on the CRF must be recorded.  
All missing data must be explained in the comments section of the eCRF.  The electronic data capture 
system (EDC) will maintain an audit trail. 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents should be retained for a longer period 
if required by an agreement with the sponsor.  In such an instance, it is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained.  
 


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10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored regularly by the coordinator and investigator to ensure accurate data entry and 
reporting.   If other agencies choose to monitor the site such as the sponsor (NIH), FDA, or institution (UNC),  
then the Investigator will ensure the monitor or other compliance or quality assurance reviewer is given 
access to all the above noted study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
The monitor is responsible for ensuring:  
(a) the rights and well-being of trial participants are protected, 
(b) reported trial data are accurate, complete, and verifiable from source documents,  
(c) the conduct of the trial is in compliance with the currently approved 
protocol/amendments, with GCP, and with the applicable regulatory requirements, and 
(d) data reported are verifiable to support meeting the study objectives.  
Procedures and sources of information:  
Protection of the rights and well-being of study subjects by verifying: 
1. Investigator(s) have adequate qualifications, education and training, and resources 
necessary to conduct the study. 
2. Verify the investigator and his staff follow the approved protocol and all approved 
amendments, if any 
3. The investigator personally conducts or adequately supervises his study staff  
4. Study staff are adequately trained and study functions are delegated to authorized individuals 
5. Written informed consent was obtained before each subject’s participation in the study 
6. Enrollment of only eligible subjects 
7. Subjects are instructed in the proper use, storage and return of the investigational product 
8. Adequate and accurate case histories that record all observations are maintained 
9. Unanticipated adverse events are reported in accordance with the protocol 
 
Trial data are accurate, complete and verifiable from source documents as verified from review of subject 
file, case report forms, and medical procedures reports 
1. Verify that the investigative staff are performing the specific trial functions in accordance 
with the protocol  
2. Checking the accuracy and completeness of case report form entries, source documents 
and other trial related records against each other 
3. Adequate and accurate case histories that record all observations are maintained 
4. All withdrawals and dropouts are properly reported and explained 
5. Investigator is informed of protocol deviations, data entry errors and omissions and 
illegibility  
Study is conducted in compliance with the currently approved protocol/amendments, with GCP, and 
applicable regulatory requirements 
1. Verify the investigator follows the approved protocol and all approved amendments, if any 
2. Ensuring that an IRB approval is obtained prior to study initiation and that the IRB is kept 
informed of changes in research activity and unanticipated problems involving risk to 
subjects 
3. Determine if investigator is maintaining essential documents in a regulatory binder 
4. Investigational product is properly procured, stored and destroyed accordingly 
5. Documenting deviations from the protocol, SOPs, GCP and applicable requirements to 
the investigator and taking appropriate action designed to prevent recurrence of the 
detected deviations. 
6. Monitor will provide a written report after each study visit or study visit communication 
 


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10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This trial will be conducted in compliance with institutional review board (IRB) and ICH GCP Guidelines 
including Title 21 Part 56 of the United States of America (USA) Code of Federal Regulations (CFR) relating 
to IRBs and GCP as described in the United States Food and Drug Administration (FDA) CFR (21 CFR § 
50, 56, 312) in accordance with applicable ICH regulations regarding clinical safety data management (E2A, 
E2B(R3)), with ICH regulations regarding scientific integrity (E4, E8, E9 and E10) and with FDA regulations 
regarding financial disclosure (21 CFR § 54). In addition this trial will adhere to all local regulatory 
requirements, and requirements for data protection. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of EC/IRB members and their affiliate 
to the sponsor. 
 
All subjects for this study will be provided an IRB-approved consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this study.  The 
formal consent of a subject, using the EC/IRB-approved consent form, must be obtained before that subject 
undergoes any study procedure.  The consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent.  
12 Study Finances 
12.1 Funding Source 
This study is funded by a grant from NIH (R01 DK101856). 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that has 
been reviewed and approved by the study sponsor prior to participation in this study.  All University of North 
Carolina investigators will follow the University conflict of interest policy. 
12.3 Subject Stipends or Payments 
Subject incentives are graded, with increasing payments for each phase of the study to maximize subject 
retention in the trial ($25 at the baseline visit, $25 at randomization, $50 at the mid-treatment visit, $50 at 
treatment end, and $50 at the study end/recurrent symptoms visit).  Subjects are paid only for visits 
completed. This total of $200 per subject for 122 subjects randomized to treatment will be distributed over 
the 36 month enrollment period.  


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13 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the study sponsor.  Any investigator involved with this study is 
obligated to provide the sponsor with complete test results and all data derived from the study. 
 
 


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