A Phase II, Randomized, Placebo-controlled Study Evaluating the Efficacy of Antihistamines in the Treatment of Eosinophilic Esophagitis (the ATEE Study)
Phase: PHASE2
Conditions: Eosinophilic Esophagitis
Sponsor: Mayo Clinic

A PHASE II, RANDOMIZED, PLACEBO-
CONTROLLED STUDY EVALUATING THE 
EFFICACY OF ANTIHISTAMINES IN THE 
TREATENT OF EOSINOPHILIC 
ESOPHAGITIS (THE ATEE STUDY) 
NCT04248712 
11/22/2019 

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A PHASE II, RANDOMIZED, PLACEBO-CONTROLLED STUDY 
EVALUATING THE EFFICACY OF ANTIHISTAMINES IN THE 
TREATENT OF EOSINOPHILIC ESOPHAGITIS (THE ATEE 
STUDY) 
 
 
 
 
Study Product: 
Famotidine and loratidine 
Protocol Number: (IRBe) 
19-005510 
 
 
 
 
 
 
Initial version: [11/22/19] Version (1.2)  
 
 

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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 5 
1 
INTRODUCTION ................................................................................................................................. 6 
1.1 
BACKGROUND .................................................................................................................................... 6 
1.2 
INVESTIGATIONAL AGENT .................................................................................................................... 7 
1.3 
CLINICAL DATA TO DATE..................................................................................................................... 8 
1.4 
DOSE RATIONALE................................................................................................................................ 8 
1.5 
RISKS AND BENEFITS ........................................................................................................................... 8 
2 
STUDY OBJECTIVES .......................................................................................................................... 8 
3 
STUDY DESIGN ................................................................................................................................... 9 
3.1 
GENERAL DESCRIPTION ....................................................................................................................... 9 
3.2 
NUMBER OF SUBJECTS ......................................................................................................................... 9 
3.3 
DURATION OF PARTICIPATION .............................................................................................................. 9 
3.4 
PRIMARY STUDY ENDPOINTS .............................................................................................................. 10 
3.5 
SECONDARY STUDY ENDPOINTS ......................................................................................................... 10 
3.6 
PRIMARY SAFETY ENDPOINTS ............................................................................................................ 11 
3.7 
IDENTIFICATION OF SOURCE DATA ...................................................................................................... 11 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ...................................................... 11 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 12 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ....................................................................... 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .................................................................................................... 13 
4.4.1 
When and How to Withdraw Subjects ........................................................................................ 13 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 13 
5 
STUDY DRUG .................................................................................................................................... 14 
5.1 
DESCRIPTION .................................................................................................................................... 14 
5.2 
TREATMENT REGIMEN ....................................................................................................................... 14 
5.3 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................................... 14 
5.4 
SUBJECT COMPLIANCE MONITORING ................................................................................................... 14 
5.5 
PRIOR AND CONCOMITANT THERAPY .................................................................................................. 15 
5.6 
PACKAGING ...................................................................................................................................... 15 
5.7 
MASKING/BLINDING OF STUDY........................................................................................................... 15 
5.8 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................. 15 
5.8.1 
Receipt of Drug Supplies .......................................................................................................... 15 
5.8.2 
Storage ................................................................................................................................... 15 
5.8.3 
Dispensing of Study Drug ......................................................................................................... 16 
5.8.4 
Return or Destruction of Study Drug ......................................................................................... 16 
6 
STUDY PROCEDURES ...................................................................................................................... 16 
6.1 
VISIT 1 (ENROLLMENT) ...................................................................................................................... 16 
6.2 
VISIT 2 (4 WEEK FOLLOW-UP) ............................................................................................................. 16 
6.3 
VISIT 3 (8 WEEK FOLLOW-UP) ............................................................................................................. 16 
6.4 
VISIT 4 (12 WEEK FOLLOW-UP) ........................................................................................................... 16 
7 
STATISTICAL PLAN ......................................................................................................................... 18 
7.1 
SAMPLE SIZE DETERMINATION ........................................................................................................... 18 
7.2 
STATISTICAL METHODS ..................................................................................................................... 18 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ............................................................................................. 19 

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8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 20 
8.1 
DEFINITIONS ..................................................................................................................................... 20 
8.2 
RECORDING OF ADVERSE EVENTS ....................................................................................................... 22 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .......................................... 22 
8.4 
UNMASKING/UNBLINDING PROCEDURES ............................................................................................. 22 
8.5 
STOPPING RULES ............................................................................................................................... 22 
8.6 
MEDICAL MONITORING ..................................................................................................................... 23 
9 
DATA HANDLING AND RECORD KEEPING .................................................................................. 23 
9.1 
CONFIDENTIALITY ............................................................................................................................. 23 
9.2 
SOURCE DOCUMENTS ........................................................................................................................ 23 
9.3 
RECORDS RETENTION ........................................................................................................................ 24 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 24 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 24 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 25 
11 
ETHICAL CONSIDERATIONS ......................................................................................................... 25 
12 
STUDY FINANCES ............................................................................................................................ 25 
12.1 
FUNDING SOURCE ......................................................................................................................... 25 
12.2 
CONFLICT OF INTEREST ................................................................................................................. 25 
13 
PUBLICATION PLAN ....................................................................................................................... 26 
14 
REFERENCES ................................................................................................................................... 26 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
 
 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
EoE 
Eosinophilic esophagitis 
EGD  
 
 
  Esophagogastroduodenoscopy 
DSQ  
 
 
  Dysphagia Symptom Questionnaire 
EREFS 
 
 
  EoE endoscopic Reference Score 
 
 
 

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Study Summary 
Title 
A phase II, randomized, placebo-controlled study evaluating the 
efficacy of antihistamines in the treatment of eosinophilic esophagitis 
(the ATEE study). 
 
Running Title 
Antihistamines in eosinophilic esophagitis 
Protocol Number 
19-005510 
Phase 
phase II 
Methodology 
Prospective, randomized, placebo-controlled trial 
Overall Study 
Duration 
Two years 
Subject Participation 
Duration 
14 weeks 
Single or Multi-Site  
Single 
Objectives 
To assess the efficacy of antihistamines in the treatment of eosinophilic 
esophagitis. Primary outcomes are the number of eosinophils on 
histology and safety.  Secondary outcomes are changes in dysphagia 
symptom questionnaire score, EoE endoscopic reference score, and the 
percentage of patients with histologic response of ≤15 eos/hpf on 
biopsy. 
Number of Subjects 
The planned sample size is 20 patients in each arm, for a total of 40 
study patients.  Assuming a dropout rate of 20%, the goal is to enroll 
50 patients. 
Diagnosis and Main 
Inclusion Criteria 
Consentable, nonpregnant adults with a diagnosis of eosinophilic 
esophagitis 
Study Product, Dose, 
Route, Regimen 
Famotidine 40 mg tab twice daily by mouth and loratadine 10 mg tab 
once daily by mouth for 12 week duration. 
Duration of 
Administration 
12 weeks 
Reference therapy 
Placebo 
Statistical 
Methodology 
Patients will be randomized in a 1:1 fashion by a computer generated 
program. The changes in peak counts and questionnaire scores in the 
treatment arm from baseline to 12 weeks will be compared using a 
paired t-test or signed rank test.  Categorical demographic variables 
and percentage of patients with histologic response of ≤15 eos/hpf at 
12 weeks will be compared between the two arms using Chi-squared 
test or Fisher’s exact test.  
 

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1 Introduction 
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
1.1 
Background 
 
Eosinophilic esophagitis (EoE) is a clinicopathologic condition generally occurring in children 
and young adults characterized by symptoms of esophageal dysfunction and histologically by ≥ 
15 eosinophils per high power field. It is hypothesized to be an immune and antigen-driven 
effect, which is limited to the esophagus. [1] First characterized less than 30 years ago, it is the 
most prevalent cause of esophageal symptoms among children and young adults. [2] The most 
prominent symptom in adults is the feeling of food sticking in the chest after swallowing, and 
EoE is the most common cause of food bolus obstruction.[1] Prominent symptoms of dysphagia 
are secondary to inflammation leading to progressive esophageal fibrosis, strictures, and 
narrowing.[3] 
 
Guidelines on the diagnosis and management of EoE were first published in 2007, and updated 
in 2011. [4] These guidelines required clinical and/or histologic unresponsiveness to a PPI trial 
for the diagnosis of EoE, with the elimination of other causes of esophageal eosinophilia.[2] EoE 
and GERD were felt to be mutually exclusive. [4] A new condition was defined in guidelines 
published in 2011, 2013, and 2014 describing PPI-responsive esophageal eosinophilia (PPI-
REE). [4]  These patients had evidence of esophageal dysfunction and lacked the typical features 
of GERD, however responded to treatment with a high dose PPI trial. More recently, consensus 
guidelines have advocated for the removal of a PPI trial in the diagnosis of EoE. [5]  Recent 
studies have shown that the clinical, histologic, and endoscopic features of EoE and PPI-REE are 
indistinguishable, and that GERD and EoE may share a complex relationship and can occur 
together.[4] 
 
To date, the optimal therapy for EoE is undetermined, and limited by a lack of approved 
medications. [4] Treatment options include PPIs, corticosteroids, and diet modifications.   
Currently, PPIs are the first line treatment option. In a systematic review and meta-analysis, PPI 
therapy was found to have a clinical response in 60.8% of patients and histologic remission in 
50.5%. [2] Proton pump inhibitors have two hypothesized mechanisms of action.  First, they 
reduce the acidity of stomach fluids, and may reduce symptoms when reflux occurs.  However, 
the role of reflux in the pathogenesis of EoE is unclear.  Secondly, PPIs may also reduce 
inflammation in the esophageal epithelium by direct effects on the eotaxin-3-eosinophil pathway, 
reducing the eosinophil response. [6] The response to PPI therapy is higher in patients with 
documented GERD (70%) versus those with negative esophageal pH monitoring (29%).[2] 
 
In patients who do not respond to a PPI, corticosteroids are the next preferred treatment.  Topical 
corticosteroids have established efficacy in EoE, however their use remains off-label which 
limits insurance coverage. [7, 8] Additionally, there are no formulations specifically for 
esophageal delivery, and asthma preparations such as fluticasone inhalers or aqueous budesonide 
are used.  For inhalers, the medication is swallowed rather than inhaled to coat the esophagus and 

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provide an anti-inflammatory effect. [9]  The dosing and delivery method may be confusing for 
patients when compared to the instructions on the package insert. [5] Side effects of 
corticosteroids include oral and esophageal candidiasis. [5]  Other long-term side effects include 
bone thinning, weight gain, and diabetes.  Although studies have evaluated the ability of 
corticosteroids to induce remission, EoE is a chronic disease and further studies are needed to 
assess long term management.  Symptoms of EoE generally relapse within several weeks of 
discontinuation of topic corticosteroid treatment. [10]  Other medications under evaluation 
include prostaglandin receptor antagonists, immunomodulators such as azathioprine and 6-
mercaptopurine, and biologic agents. [10] 
 
Treatment also includes diet modification. The “six food elimination diet” is the most common 
dietary approach, with elimination of dairy, wheat, eggs, soy, nuts, seafood, and shellfish. [1] If 
symptoms improve, repeat endoscopy is performed after 12 weeks to document resolution of 
inflammation.  This strategy is resource and cost intensive.[1] With the use of the six food 
elimination diet, triggers are identified, however long-term adherence to a specific diet is 
difficult. [5] 
 
Allergists are well-established in the understanding and pathogenesis of EoE. They play a role in 
the management of atopic comorbidities, including asthma, allergic rhinitis, atopic dermatitis, 
and food allergies.  Although the pathophysiology of EoE suggests an immune, antigen-mediated 
reaction, no study has evaluated the efficacy of antihistamines for treatment.  Histamine is well 
characterized in the acute inflammatory and allergic response, and histamine receptors are 
present on eosinophils, T cells, monocytes, and dendritic cells. All are capable of producing and 
secreting histamine.[11]  The histamine 1 and 2 receptors (H1R and H2R) are expressed not only 
on these immune cells, but ubiquitously throughout the gut wall. [12] In the gastrointestinal tract, 
histamine has three major functions; the enhancement of gastric acid production, modulation of 
gastrointestinal motility, and alteration of mucosal ion secretion. [12] There is a strong hereditary 
pattern of EoE with multiple implicated genes, which are more closely related to those involved 
in allergen sensitization and squamous epithelial cell dysfunction.[13]  Based on the evidence 
that the allergic response plays an important role in the pathogenesis of EoE, anti-histamines 
may provide treatment benefit. 
 
The purpose of this study is to evaluate the efficacy of anti-histamines in the treatment of EoE. 
 
1.2 
Investigational Agent 
 
The investigational agents are famotidine 40 mg tablet twice daily by mouth and loratadine 10 
mg tablet once daily by mouth for 12 week duration.  Famotidine is an H2-receptor antagonist 
that inhibits the action of histamine at the histamine H2-receptors.  Famotidine is FDA approved 
for the treatment of duodenal ulcer disease, erosive esophagitis, gastric hypersecretion, gastric 
ulcer, gastroesophageal reflux disease, and indigestion.  Loratadine is a long-acting tricyclic 
antihistamine, which selectively blocks histamine H1 receptor activity.  FDA approved uses 
include idiopathic urticaria and seasonal allergic rhinitis. 
 

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1.3 
Clinical Data to Date 
 
Although there is published data supporting the use of famotidine in peptic ulcer disease and 
gastroesophageal reflux disease, there currently is not study data for its use in EoE.  Loratadine 
has published data for the treatment of urticaria and seasonal allergies, however has not been 
used in the treatment of EoE. 
1.4 
Dose Rationale  
 
Loratadine 10 mg tablet daily is the standard dosage for the treatment of seasonal allergic rhinitis 
and idiopathic urticara. As EoE is an immune and allergen-mediated disease, we hypothesize the 
standard dosage will be effective in EoE.  Similarly, famotidine 40 mg tablet twice daily is the 
standard dose for the treatment of peptic ulcers and gastroesophageal reflux disease. As stated in 
the background, gastroesophageal reflux may play a role in the pathogenesis of EoE.  We 
hypothesize the standard dose of famotidine will be effective in EoE. 
 
1.5 
Risks and Benefits 
 
Both famotidine and loratadine are over-the-counter medications, which are available to the 
general population without a prescription. Risks associated with these medications include their 
known common side effects, such as headache, dizziness, constipation, diarrhea, dry mouth, 
fatigue, somnolence, esophagitis, abdominal pain, constipation, and diarrhea. Other rare but 
serious side effects include rash (including but not limited to Stevens-Johnson syndrome and 
toxic epidermal necrolysis), arrhythmia, pancreatitis, bone marrow suppression (including but 
not limited to agranulocytosis, aplastic anemia, pancytopenia, thrombocytopenia), liver 
injury/failure, rhabdomyolysis, seizure, anaphylaxis, angioedema, and pneumonia.  The risks are 
reasonable in relation to the anticipated benefits of a therapeutic response as these medications 
are generally well tolerated, over-the-counter, and used at the same dosing in other allergic and 
gastrointestinal disorders. The risks will be stated in the consent form. 
 
2 Study Objectives 
Primary Objective 
 
To assess the efficacy of H1 and H2 antihistamines in the treatment of EoE through a decrease in 
the esophageal eosinophil count on biopsy. To assess the safety and tolerability of H1 and H2 
antihistamines in subjects with EoE. 
 
 
Secondary Objective 
 
To determine whether loratadine and famotidine are effective for improving symptoms of EoE as 
measured by the Dysphagia Symptom Questionnaire (DSQ).   To assess the percentage of 
patients with histologic response of ≤15 eos/hpf on biopsy.  To assess the percentage of patients 
with endoscopic response as measured by the EoE Endoscopic Reference Score (EREFS). 

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3 Study Design 
3.1 
General Description 
 
This is a randomized, placebo-controlled phase II trial of the safety and efficacy of loratadine 
and famotidine in the treatment of EoE.  Response to treatment will be assessed by 
questionnaires and endoscopy with histopathology.  The expected duration of subject 
participation is 14 weeks. Subjects will be screened at outpatient clinic visit appointments and 
interested qualified subjects will be consented and offered participation in this trial.  Once 
consent has been obtained, subjects complete the Dysphagia Symptom Questionnaire daily for 
two weeks. At week two, subjects will begin treatment and follow-up for the next 12 weeks.  The 
study will be preceded by a washout period of at least 6 weeks followed by daily completion of 
DSQ for two weeks and active or placebo administration for 12 weeks.  Participants will have 
monthly phone visits to monitor for adverse events and monitor compliance while on treatment.  
A final office visit for evaluation and repeat endoscopy will be conducted at the end of the study.  
During the final two weeks of treatment, subjects will again complete the DSQ daily.  All data 
will be entered in a prospective automated institutional database (Redcap). 
 
 
3.2 
Number of Subjects 
 
The planned sample size is 20 patients in each arm, for a total of 40 study patients.  Assuming a 
dropout rate of 20%, the goal is to enroll 50 patients.  The estimated baseline mean eosinophil 
count is expected to be between 80-110 eos/hpf, with an estimated standard deviation of change 
from baseline in eosinophil counts of 30-50 eos/hpf.  Using a conservative standard deviation 
assumption of 50 eos/hpf, a sample size of 25 patients in each arm provides 80% power to detect 
a significant between group difference of 40%.  Using a conservative standard deviation 
assumption of 50 eos/hpf, a sample size of 16 patients in each arm provides 80% power to detect 
a significant between group difference of 50%. 
 
3.3 
Duration of Participation 
 
Each subject will participate for 12 weeks randomized to the study drugs or placebo.  
 
 
 

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3.4 
Primary Study Endpoints 
 
To determine whether loratadine and famotidine are effective for improving maximum 
eosinophil counts (eos/hpf) after 12 weeks of therapy with antihistamines in patients with EoE. 
To assess the safety and tolerability of H1 and H2 antihistamines in subjects with EoE. 
 
3.5 
Secondary Study Endpoints 
 

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To determine whether loratadine and famotidine are effective for improving symptoms of EoE as 
measured by the validated Dysphagia Symptom Questionnaire after 12 weeks of therapy with 
antihistamines. 
 
 
To determine whether loratadine and famotidine are effective for improving the percentage of 
patients with histologic response of ≤15 eos/hpf after 12 weeks of therapy with antihistamines. 
 
To determine whether loratadine and famotidine are effective for improving the endoscopic 
manifestations of EoE as measured by the validated EoE Endoscopic Reference Score. 
 
3.6 
Primary Safety Endpoints 
 
All adverse events will be reported.  A safety assessment will be performed monthly via phone 
visits after initiation of treatment, and at the 12-week follow-up visit with vital signs and a 
physical examination.   
 
The EGD with biopsies to be performed at 12 week follow-up carries the standard risks 
associated with this procedure: complications from conscious sedation, performing endoscopy 
and biopsies.  These risks include cardiac or respiratory compromise, allergic reactions to the 
medications used for sedation, perforation, bleeding and aspiration.   The most significant risk is 
that of cardiovascular events estimated at .003%.[14]   Though these risks are present, they are 
very low. 
 
3.7 
Identification of Source Data 
 
The DSQ and EREFS scores will be entered into a computer database along with the patients’ 
age, gender, and endoscopy and pathology reports from the electronic medical record.  The data 
will be stored on the Mayo network hard-drive through the principal investigator’s account. 
 
 
4 Subject Selection Enrollment and Withdrawal 
 
4.1 
Inclusion Criteria 
 
 
1. Patients over the age of 18, male and female. 
2. Patients who carry the diagnosis of EoE based on esophageal biopsies obtained within 6 
months prior to enrollment (>15 eosinophils per hpf on at least 2 esophageal levels)  
3. Subjects must be able to give appropriate informed consent 
 
 

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4.2 
Exclusion Criteria 
1. Not willing or able to sign consent. 
2. Patients who have used topical or systemic corticosteroid therapy for any reason in the 
previous 6 weeks. 
3. Patients who have been treated with acid-suppressing medications (PPI or H2 receptor 
antagonists) in the previous 6 weeks. 
4. Patients on immunosuppressive or immunomodulating medications in the previous 6 
weeks. 
5. Patients with known allergies or hypersensitivity to anti-histamines. 
6. Patients who have contraindications to the procurement of biopsies including patients 
who have known bleeding disorders, a history of bleeding diathesis, or who are currently 
using warfarin or clopidogrel. 
7. Patients who have a contraindication to the performance of an 
esophagogastroduodenoscopy (EGD) including previous cardiopulmonary arrest during 
an endoscopic procedure. 
8. Patients who are pregnant. 
 
4.3 
Subject Recruitment, Enrollment and Screening 
 
After institutional review board approval, all patients who present to the Mayo Clinic Florida 
Esophageal Diseases Clinic or General Gastroenterology Clinic with the diagnosis of EoE who 
meet enrollment criteria will be offered enrollment into the study.  All enrolled patients will be 
entered by the physician through written informed consent.  
 
The appointment schedule for the Esophageal Diseases clinic and the General Gastroenterology 
clinic at the Mayo Clinic Florida will be reviewed 1-5 days in advance by the study coordinator 
to determine which patients are coming for dysphagia or EoE.  If the indication for the 
appointment is dysphagia, the study coordinator will review the patient’s chart or outside records 
to determine if there is evidence of EoE.  The physician that is scheduled to see any patient that 
is identified as having EoE will be contacted prior to the patients’ appointment and asked if he or 
she agrees to have the patient approached for study enrollment.   
 
We will also make general announcements to our Gastroenterology Division about the study in 
an attempt to recruit patients with EoE at our center. 
 
Once patients are identified, they will be approached by our study coordinator and informed of 
the study.  They will be provided with a consent form.  The consent form will be documented by 
their signature on the consent form and this will be entered into the patient’s permanent medical 
record. 
 
Consent will either be performed in person face-to-face on the Mayo Clinic Florida Campus in a 
private meeting room, or via Zoom meeting, in the setting of the coronavirus pandemic.  This 
will be per the patient preference. If consent is performed via Zoom meeting, the study 
coordinator or investigator will teleconference from a private exam or conference room  on the 
Mayo Clinic Florida campus, and the study participant will teleconference from a private 

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location of their choosing. To confirm the study participant’s identity by Zoom, the coordinator 
or investigator will ask them to confirm their name and date of birth. All included study 
participants must be willing and able to sign consent and be age 18 or older. The study will not 
include adults lacking capacity. The link for the Zoom meeting and consent will be emailed to 
the patient at an email of their choice, in the week prior to the Zoom meeting. If study 
participants request a hard copy of the consent, this will be mailed at the request of the study 
participant.  
 
Women of child-bearing age (18-50) and potential will be given a urine pregnancy test prior to 
enrollment in the trial. 
 
In the Mayo Clinic Florida Esophageal Diseases Clinic, we see approximately 3-5 patients with 
EoE per week.  This amounts to an estimated 150 patients per year.  Assuming we can enroll at 
least half of these patients in our study, the study will take approximately 12 to months complete. 
 
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
 
Subjects may be withdrawn from the study for safety issues, failure of subject to adhere to 
protocol requirements, and subject decision to withdraw from the study.  Safety issues include 
adverse effects from the study drugs, or inability to tolerate the study drugs.  Failure of subjects 
to adhere to protocol requirements includes adherence to the medication regimen, absence of 
follow-up visits, or not completing study questionnaires.  As there is a 6 week wash out period 
prior to study inclusion, patients may have worsening of symptoms of EoE while off prior 
medications.  Patients who have worsening or relapse of symptoms of EoE while enrolled in the 
trial will be removed from the study. 
 
For patients who do not tolerate the study drug, other treatment alternatives will be offered, 
including PPIs, corticosteroids, and/or diet modification. 
 
Data will be collected on withdrawn subjects up until the point of study withdrawal.  A 
scheduled follow-up appointment will be ordered in clinic following study withdrawal. 
 
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
A follow-up appointment will be ordered at the 12 week period after initiation of the study drug 
or placebo. 
 

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5 Study Drug  
5.1 
Description 
 
Loratadine is an oral non-sedating anti-histamine which is highly selective for H1-receptors.  H1-
antagonists such as loratidine compete with free histamine for binding at H1-receptor sites, 
which blocks the effects of histamine on H1-receptors in the GI tract through competitive 
antagonism. Compared to traditional sedating anti-histamines, loratadine is not associated with 
QT prolongation and has less central nervous system effects. Compared to first generation anti-
histamines, loratadine has reduced penetration of the blood brain barrier and greater specificity 
for the H1 receptor with fewer anti-cholinergic effects.  Loratadine is used in the pediatric and 
adult population for allergic rhinitis and chronic idiopathic urticaria. The standard dose is 10 mg 
PO once daily. After oral administration, the onset of action occurs within 1-3 hours with peak 
effects in 8-12 hours and duration of action greater than 24 hours.  
 
Famotidine is an oral histamine type 2 receptor antagonist that inhibits the action of histamine at 
the histamine H2-receptors, including gastric cells, used for gastrointestinal disorders including 
gastroesophageal reflux disease and peptic ulcer disease. Oral absorption is approximately 40-
45%, and the elimination half-life is 2.5-3.5 hours.  
5.2 
Treatment Regimen 
 
Famotidine will be taken 40 mg twice daily by mouth for 12 weeks.  Loratadine will be taken 10 
mg daily by mouth for 12 weeks. 
 
 
Patients will be randomly assigned to either the treatment or placebo group by a blocked 
randomization protocol from a computer generated program via the Mayo Clinic statistical team. 
 
5.3 
Preparation and Administration of Study Drug 
 
Preparation of the study drug will be performed in the pharmacy for both famotidine and 
loratadine, and 12 week supplies given to the patient.  Famotidine should be taken by mouth 30-
60 minutes before the morning and evening meals, and Loratadine should be taken 30-60 
minutes before the morning meal. 
 
Similarly, the placebo drugs will be prepared by the pharmacist, with identical instructions for 
administration as the treatment drugs. 
 
5.4 
Subject Compliance Monitoring 
 
In a diary, patients will record time of medication administration before breakfast and evening 
meal.  At the follow-up visit following the 12 week intervention period, a pill count will be 
performed.  Patients who are not more than 70% compliant will be withdrawn from the study. 

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5.5 
Prior and Concomitant Therapy 
 
During the study, participants may not take proton pump inhibitors, local or systemic 
corticosteroids, or other immunomodulatory or immunosuppressive medications (anti-TNF for 
example).  Patients may not take other anti-histamines.  For symptoms of dyspepsia or 
abdominal discomfort, patients may take over-the-counter medications including bismuth 
subsalicylate, sucralfate, and calcium carbonate.  
 
No major dietary changes will be allowed during the study period. 
 
5.6 
Packaging 
 
Patients will pick up the study drugs at the Mayo Clinic pharmacy. Loratadine will be dispensed 
as 10 mg tablets, count of 84.  Famotidine will be dispensed as 40 mg tablets, count of 168.  This 
is a 12 week supply of both study medications. 
 
Patients randomized to the placebo arm will receive placebo pills dispensed in similar shape, 
size, and color.   
 
5.7 
Masking/Blinding of Study  
 
Subjects will be masked as to the treatment allocation. The study PI and co-investigator AK will 
be unblinded to monitor for adverse events.  The study pharmacy will be unblended for the 
allocation of the study medications. Patients will be randomized in a 1:1 fashion to the two study 
arms using a blocked randomization protocol with a computer generate program. 
 
5.8 
Receiving, Storage, Dispensing and Return 
5.8.1 Receipt of Drug Supplies 
 
 
Study participants will pick up the study medications, either treatment or placebo arm, at the 
Mayo Clinic pharmacy. 
 
 
5.8.2 Storage 
 
Medications (loratadine, famotidine, and/or placebo) should be stored at room temperature in a 
dry location and protected from light. 
  

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5.8.3 Dispensing of Study Drug 
 
On the 12 week follow-up appointment, the treating physician will perform a pill count to 
document the amount of drug remaining.  The pill count will be entered into the study database. 
 
5.8.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug remaining at the 12 
week follow-up visit.  This reconciliation will be logged into the study database.  Any 
discrepancies noted will be documented and investigated, prior to return or destruction of unused 
study drug.  Drug destroyed on site will be documented in the study files. 
 
6 Study Procedures 
 
6.1 
Visit 1 (Enrollment) 
 
Once patients have met enrollment criteria and consented to enrollment in the study, they will be 
given the Dysphagia Symptom Questionnaire to complete daily for two weeks. All study subjects 
will be given famotidine 40 mg oral twice daily and loratadine 10 mg once daily for 12 weeks or 
placebo pills for 12 weeks duration dispensed from the Mayo Clinic pharmacy which will be 
started after completing the DSQ for two weeks. Subjects will receive a diary to track medication 
administration and symptoms. The patient consent can performed via Zoom per patient preference. 
 
6.2 
Visit 2 (4 week follow-up after starting study drugs) 
 
This visit will occur per participant preference, either via phone call or in person by appointment, 
with the study coordinator and will occur at 4 weeks plus or minus a one week period after 
initiation of the study drugs.  Study participants will review medication compliance and adverse 
effects. 
6.3 
Visit 3 (8 week follow-up after starting study drugs) 
This visit will occur per participant preference, either via phone call or in person by appointment, 
with the study coordinator and will occur at 8 weeks plus or minus a one week period after 
initiation of the study drugs.  Study participants will review medication compliance and adverse 
effects. 
6.4 
Visit 4 (12 week follow-up) 
 
At the 12 week follow-up visit with a physician, we will review the results of the DSQ to be 
completed for weeks 10-12 of the study drugs.  The 12 week follow-up appointment will occur no 
earlier than 12 weeks after initiation of the study drug and no later than 14 weeks after initiation.  
The patient will meet with one of the study investigators, and be consented for an EGD.  An EGD 
with esophageal biopsies will be performed.  Prior to EGD, a complete blood count and basic 

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metabolic panel will be ordered as routine per institutional policy.  Either KD or DF will perform 
the EGD in the endoscopy suite, per our institution’s standard protocol. Any macroscopic 
abnormalities seen in the esophagus will be documented and photographed. Any lesions in the 
upper digestive tract seen on EGD will be biopsied and treated as deemed appropriate by the 
performing endoscopist. Biopsy specimens will be labeled and placed in a container and labeled 
with the patient’s ID number.   
 
The eosinophil count will be determined by the study pathologist for the post-treatment exam using 
a previously validated protocol. [2, 3]  Four esophageal biopsies will be sampled from both the 
distal esophagus (3cm above the GE junction) and proximal esophagus (at least 10 cm above the 
GE junction) to maximize sensitivity of detecting eosinophils.[1]  On each biopsy fragment, 5 
high-power fields will be examined and the overall peak eosinophil count determined from the 
field deemed to be most inflamed from all esophageal levels and all high power fields. [4] 
 
Symptomatic improvement will be defined as at least 2 levels on the dysphagia questionnaire.   
 
 
 
 
 
Study Activity 
Week 0 (initial 
enrollment 
appointment) 
Week 6 
Week 10 
Weeks 14-16 
(follow-up 
appointment) 
Study Agent(s) (weeks 2-14) 
 
X 
X 
 
Informed consent 
X 
 
 
 
Physician office visit with 
medication review and 
physical exam
X 
 
 
X 
Phone or office visit with study 
coordinator 
 
X 
X 
 
Pill count 
 
X 
X 
X 
Drug diary 
 
X 
X 
 
Adverse event evaluation 
 
X 
X 
X 

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B-HCG (non-menopausal 
females) 
X 
 
 
 
Dysphagia Symptom 
Questionnaire (complete 
weeks 0-2 and 12-14) 
X 
 
 
X 
CBC and BMP 
 
 
 
X 
EGD w/ biopsy 
 
 
 
X 
 
 
 
 
 
 
7 Statistical Plan 
7.1 
Sample Size Determination 
 
The planned sample size is 20 patients in each arm, for a total of 40 study patients.  Assuming a 
dropout rate of 20%, the goal is to enroll 50 patients.  The estimated baseline mean eosinophil 
count is expected to be between 80-110 eos/hpf, with an estimated standard deviation of change 
from baseline in eosinophil counts of 30-50 eos/hpf.  Using a conservative standard deviation 
assumption of 50 eos/hpf, a sample size of 25 patients in each arm provides 80% power to detect 
a significant between group difference of 40%.  Using a conservative standard deviation 
assumption of 50 eos/hpf, a sample size of 16 patients in each arm provides 80% power to detect 
a significant between group difference of 50%. 
 
Pilot studies evaluating other medications in EoE have used similar sample sizes. [15, 16] 
 
7.2 
Statistical Methods 
 
Descriptive Statistics 
 
Means and standard deviations will be used to summarize quantitative and continuous variables.  
These will include age, dysphagia questionnaire scores, and eosinophils per hpf on histology.  
Frequencies and percentages will be used to summarize categorical variables including gender; 
the proportion of patients that have symptomatic and histologic improvement in symptoms on 
placebo; and the proportion of patients that have symptomatic and histologic improvement in 
symptoms on anti-histamines. 
 

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Handling of Missing Data 
 
We will perform data queries for missing dysphagia questionnaires and pathology reports. 
 
 
Primary Hypothesis: Antihistamines are effective for the treatment of EoE and will result in 
symptomatic improvement as assessed by patient questionnaires and endoscopic and histologic 
improvement as assessed by endoscopic score and by eosinophil counts on biopsy. 
 
Continuous demographic variables,  peak eosinophil counts and dysphagia and GERD 
questionnaire scores at baseline and 12 weeks will be compared between the treatment and 
placebo arms using a two-sample t test or Wilcoxon rank sum test where appropriate. Categorical 
demographic variable and percentage of patients with histologic response of ≤15 eos/hpf  at 12 
weeks will be compared between the two arms using Chi-squared test or Fisher’s exact test. The 
changes in peak counts and questionnaire scores in the treatment arm from baseline to 12 weeks 
will be compared suing a paired t-test or signed rank test 
 
All tests will be two-sided with alpha level set at 0.05 for statistical significance. 
 
 
 
 
Interim Analysis 
 
7.3 
Subject Population(s) for Analysis 
 
• 
All-randomized population:  Any subject randomized into the study, regardless of 
whether they received study drug 
• 
All-treated population:  Any subject randomized into the study that received at least one 
dose of study drug 
• 
Protocol-compliant population:  Any subject who was randomized and received the 
protocol required study drug exposure and required protocol processing 
• 
All-completed population:  Only subjects who completed ALL study related procedures 
and follow-up will be included 
 
 
 
 
 
 

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8 Safety and Adverse Events 
 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, DSMB reports, interim findings, product labeling change) that in the opinion 
of the local investigator may adversely affect the rights, safety, or welfare of the subjects 
or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
 
Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include; 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant disability or incapacity 
• birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. 
 
 

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All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period 
 
For this study, the study treatment follow-up period is defined as from the initiation of the study 
drugs or placebo until the 12 week follow-up appointment. 
 
 
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. 
 
 
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 sponsor-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 sponsor-investigator should instruct each subject to report, to the sponsor-
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if they are 
considered clinically significant or require therapy.  
 
 
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 an 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. 

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• 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 study team 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 section of the event tracking log (see attached form).  All clearly related signs, symptoms, 
and abnormal diagnostic, laboratory or procedure results should recorded in the source 
document. 
 
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 ultimately 
determined that the study treatment or participation is not the probable 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 during the Adverse Event Reporting 
Period and is considered to be at least possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event Worksheet 
and log.  The sponsor-investigator will evaluate the event and determine the necessary follow-up 
and reporting required. 
 
8.4 
Unmasking/Unblinding Procedures 
 
The PI and co-investigator AK will be unblinded to monitor for adverse events.  In the 
circumstance that an event occurs which may require unbinding of a study participant, the study 
team including the PI will meet and discuss the event.  Unblinding will be reported in a timely 
manner using the same requirements for the reporting of serious adverse events. 
 
 
8.5 
Stopping Rules  
 
Adverse events will be continuously monitored by the study team for patient safety.   It is 
unknown how many adverse events will occur during this study.   If an adverse event occurs, it 

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will be evaluated by the study team and PI with creation of a management plan, including 
stopping the study as applicable. 
 
If a death is observed at any point in the trial, the study will stop.  We will evaluate the study 
after the first 25 patients.  If no more than 2 adverse events have occurred, the study will 
continue to its full enrollment of 50 patients. 
 
 
8.6 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  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  “Study Monitoring, Auditing, and Inspecting”).  Medical monitoring will include 
a regular assessment of the number and type of serious adverse events. 
 
 
 
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 (long term survival status 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. 
 

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Data Management 
 
Data will be captured in an electronic fashion via institutional database (RedCap). 
 
 
Data Security and Confidentiality 
 
Access to the data will be provided to only necessary persons, those that collect the data, or need 
to analyze the data. Data will be stored in a password-protected folder behind the Mayo firewall 
(Redcap database). All data collection and analysis will be done behind the firewall. 
 
 
Data Quality Assurance 
 
All data will be entered by appropriately trained personnel.  Questionnaires will be collected by 
the physicians.  
 
Data Clarification Process 
 
Incomplete or erroneous data will be corrected by analyzing the original patient electronic record 
and case report forms. 
 
9.3 
Records Retention 
 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study.  These will include subject case histories and regulatory documents. 
 
The sponsor-investigator will retain the specified records and reports for; 
1. Up to 2 years after the marketing application is approved for the drug; or, if a marketing 
application is not submitted or approved for the drug, until 2 years after shipment and 
delivery of the drug for investigational use is discontinued and the FDA has been so 
notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” 
   
Whichever is longer 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to 

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all the study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
 
 
Please see the attached data safety and monitoring plan. 
 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, and government regulatory agencies, 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 compliance offices. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the Approved IRB consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent. 
 
12 Study Finances 
12.1 Funding Source 
 
Financing for this study will occur through Mayo Internal Funding and/or from grants from the 
National Institute of Health.  Applications for grants will be submitted the 2019 application year. 
 
12.2 Conflict of Interest 
 

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None. 
 
Any study team member 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-investigator prior to participation in this study. 
 
13 Publication Plan 
 
Subsequent to trial closure, data will be analyzed, and a manuscript will be submitted to the 
appropriate journal, after consensus among all the investigators.  Dr. Dawn Francis holds the 
primary responsibility for publication of the results of the study.  The study will be registered to 
clinicaltrials.gov prior to subject recruitment and enrollment, and the results posted to 
clinicaltrials.gov within 12 months of final data collection for the primary outcomes. 
 
 
 
14 References 
 
1. 
Attwood, S.E., Overview of eosinophilic oesophagitis. Br J Hosp Med (Lond), 2019. 80(3): p. 132-
138. 
2. 
Lucendo, A.J., A. Arias, and J. Molina-Infante, Efficacy of Proton Pump Inhibitor Drugs for 
Inducing Clinical and Histologic Remission in Patients With Symptomatic Esophageal 
Eosinophilia: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol, 2016. 14(1): 
p. 13-22.e1. 
3. 
Dellon, E.S. and I. Hirano, Epidemiology and Natural History of Eosinophilic Esophagitis. 
Gastroenterology, 2018. 154(2): p. 319-332.e3. 
4. 
Dellon, E.S., et al., Updated International Consensus Diagnostic Criteria for Eosinophilic 
Esophagitis: Proceedings of the AGREE Conference. Gastroenterology, 2018. 155(4): p. 1022-
1033 e10. 
5. 
Hirano, I., How to Approach a Patient With Eosinophilic Esophagitis. Gastroenterology, 2018. 
155(3): p. 601-606. 
6. 
Cheng, E., et al., Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from 
patients with eosinophilic oesophagitis and GORD. Gut, 2013. 62(6): p. 824-32. 
7. 
!!! INVALID CITATION !!! [7]. 
8. 
Hirano, I., et al., White Paper AGA: Drug Development for Eosinophilic Esophagitis. Clin 
Gastroenterol Hepatol, 2017. 15(8): p. 1173-1183. 
9. 
Dellon, E.S., et al., Efficacy of Budesonide vs Fluticasone for Initial Treatment of Eosinophilic 
Esophagitis in a Randomized Controlled Trial. Gastroenterology, 2019. 
10. 
Straumann, A. and D.A. Katzka, Diagnosis and Treatment of Eosinophilic Esophagitis. 
Gastroenterology, 2018. 154(2): p. 346-359. 
11. 
Jutel, M., et al., Immune regulation by histamine. Curr Opin Immunol, 2002. 14(6): p. 735-40. 
12. 
Sander, L.E., et al., Selective expression of histamine receptors H1R, H2R, and H4R, but not 
H3R, in the human intestinal tract. Gut, 2006. 55(4): p. 498-504. 
13. 
O'Shea, K.M., et al., Pathophysiology of Eosinophilic Esophagitis. Gastroenterology, 2018. 
154(2): p. 333-345. 
14. 
Gangi, S., et al., Cardiovascular complications after GI endoscopy: occurrence and risks in a 
large hospital system. Gastrointest Endosc, 2004. 60(5): p. 679-85. 

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15. 
Miehlke, S., et al., A randomised, double-blind trial comparing budesonide formulations and 
dosages for short-term treatment of eosinophilic oesophagitis. Gut, 2016. 65(3): p. 390-9. 
16. 
Lieberman, J.A., et al., A randomized, double-blinded, placebo-controlled study of the use of 
viscous oral cromolyn sodium for the treatment of eosinophilic esophagitis. Ann Allergy Asthma 
Immunol, 2018. 120(5): p. 527-531.