Clinical trial NCT02371941
Conditions: Eosinophilic Esophagitis
Sponsor: University of Tennessee
Start date: 2014-12-01; Completion date: 2017-12-01
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled study of oral cromolyn sodium when made into a viscous preparation for the treatment of eosinophilic esophagitis.

Detailed description:
Eosinophilic esophagitis is an antigen-mediated allergic disease of the esophagus characterized by symptoms of gastrointestinal complaints and eosinophilic inflammation limited to the esophagus. Currently, first line therapeutic recommendations include swallowed, topical steroids or dietary therapy. While both work for the majority of patients, they both have limitations.

The investigators are examining the use of oral cromolyn sodium as a treatment for this condition. This medication is a non-steroid that is already approved for other conditions. When taken orally, it is essentially not absorbed systemically, so side effects are minimal. There is only 1 brief, retrospective report of its use in this condition suggesting it does not work. However, from studying swallowed, topical steroids, it may require formulating the medication into a viscous preparation for it to work.

Arms: arm 1: Subjects randomized to the experimental arm will receive oral cromolyn sodium. The dose will be per current package insert for oral cromolyn:

Subjects 2-12 years of age - 100 mg (1 ampule) 4 times daily Subjects 13-18 years of age - 200 mg (2 ampules) 4 times daily arm 2: Subjects randomized to placebo will receive normal saline ampules Subjects 2-12 years of age - 1 ampule 4 times daily Subjects 13-18 years of age - 2 ampules 4 times daily
Interventions: intervention 1: oral cromolyn sodium intervention 2: Placebo
Intervention descriptions: intervention 1: Oral cromolyn sodium intervention 2: Saline

Protocol documents:
Prot_SAP_000.pdf: 
 
A Randomized, Double-blind, Placebo-controlled Study of the Use of Oral Cromolyn 
Sodium for the Treatment of Eosinophilic Esophagitis 
 
Unique Protocol ID:  13-02521-FB 
 
NCT02371941 
 
Document Date: Created 3/21/2014 
 
Document IRB approval 3/10/2015 
 
 
 
 
 
 


 
 
Abstract 
 
 
Eosinophilic esophagitis (EoE) is an increasingly prevalent disease that affects both 
children and adults.  The disease is defined by both its clinical presentation and pathologic 
findings on biopsy.  Pediatric patients typically present with abdominal pain, regurgitation, 
nausea, and trouble swallowing; with possible ultimate consequences of failure to thrive, food 
impaction, or esophageal wall rupture.  The diagnosis must be confirmed with esophageal biopsy 
that shows eosinophilic infiltrates specific to the esophagus, after ruling out gastroesophageal 
reflux disease.   
 
The goal of current therapies for EoE include resolving both tissue eosinophilia and 
symptoms and to prevent long-term consequences of the disease.  The current therapies for EoE 
are limited to specialized diets and/or pharmacotherapy with swallowed, topical corticosteroids.  
Unfortunately, while both can be effective, each has its own limitations and risks.  Specialized 
diets can be very difficult to adhere to, can potentially lead to malnutrition, and there is currently 
no perfect test to identify specific foods that should be removed from the diet.  Topical 
corticosteroids, as an alternative to dietary therapy, can lead to systemic side effects, such as 
reduction in bone mineral density, poor growth, candidiasis, adrenal suppression, glaucoma, and 
cataracts.  In addition, there is currently no data to suggest if, and when, patients can stop the 
specialized diets or the swallowed corticosteroids. 
 
There is currently a great need for alternative therapies, especially for children with EoE.  
The ideal therapy would be effective, safe in children (preferably already studied in children for 
other conditions), cost-effective, and immune-modulatory.  Cromolyn sodium, a medication 
approved for asthma and systemic mastocytosis, may be an ideal candidate therapy. 
 
Hypothesis: 
 
 
 
Oral cromolyn sodium, when made into a viscous preparation, will lead to a decrease in 
esophageal eosinophilia and in symptoms related to esophageal dysmotility in patients with 
eosinophilic esophagitis. 
 
Specific Aims: 
 
1. Specific Aim 1:  To assess the efficacy of orally ingested viscous cromolyn sodium in 
reducing the esophageal eosinophilic infiltrate in children with eosinophilic esophagitis. 
 
2. Specific Aim 2:  To assess the efficacy of orally ingested viscous cromolyn sodium in 
reducing the symptoms associated with eosinophilic esophagitis in children. 
 
Background and Significance: 
 
 
Eosinophilic esophagitis (EoE) is a clinicopathologic disease that is increasing in 
prevalence in the United States.1  The disease is defined by the presence of symptoms of 
esophageal dysmotility with concomitant findings of eosinophlic infiltrates (>15 eosinophils per 
high powered field on light microscopy) localized to the esophagus, in the absence of other 


causes of esophageal eosinophilia (namely gastroesophageal reflux disease).2  In the pediatric 
population, the disease typically manifests as abdominal pain, dysphagia, reflux, nausea, and 
vomiting; a symptom pattern that can lead to failure to thrive.3  While few natural history studies 
exist, available data suggest that if left untreated, EoE may lead to food impactions requiring 
emergent removal food boluses and possible esophageal wall rupture.4-5 
The exact etiology of EoE has not yet been elucidated, however most data suggest that 
the disease is immune-mediated and antigen-driven.  This has been proven clinically by 
demonstrating that the majority of patients will have resolution of both symptoms and histologic 
findings after treatment with an amino-acid based formula that is devoid of protein antigens.6-7  
In addition, most patients with EoE show an immune deviation that differs from healthy 
controls.8  A genome wide association study has shown common variants at chromosome 5q22, 
the location of the thymic stromal lymphopoeitin gene, a gene associated with immune skewing 
toward a T-helper (Th) type 2 response.9  In addition, expression of eotaxin-3, interleukin(IL)-4, 
and IL-5 (Th2 cytokines) have all been shown to be increased in patients with active EoE.10  
These findings suggest that patients with EoE have a genetic predisposition that leads them to an 
aberrant Th2 type response to non-pathogenic antigens.  As would be expected from this 
hypothesis, the majority of patients with EoE, have some form of atopic/allergic disease.11  
Currently, Treatment options for patients with EoE include dietary therapy and/or 
pharmacotherapy.2  Dietary therapy consists of avoiding antigenic triggers of the disease, and 
can be in the form of an elemental diet or an elimination diet.  An elemental diet can be very 
difficult to adhere to, even for infants and toddlers, as it allows the patient to only ingest an 
amino acid-based formula and one other food as their source of nutrition.  The elimination diet is 
more flexible, and can be based on testing or can be done empirically by removing common food 
triggers (namely milk, egg, soy, wheat, nuts, fish, and shellfish).  Unfortunately, there are 
currently no reliable tests to predict which foods will be the trigger in any given patient, and 
therefore trial and error of food elimination and re-introduction must constantly be undertaken. 
Pharmacotherapy for EoE entails swallowing topical corticosteroids, with the goal of 
prolonged exposure of the corticosteroid to the esophagus, thus limiting systemic absorption.  In 
fact, double-blind, randomized, placebo-controlled trials have shown efficacy of both swallowed 
fluticasone and swallowed budesonide.12-13  Unfortunately, there is no consensus on the duration 
of therapy, and studies to date have shown recurrence of eosinophilia and symptoms within 
months of stopping therapy, even with addition of steroid-sparing agents, such as montelukast.14-
15 
Given that none of the current treatment options are ideal, there is clearly a need for 
novel and effective therapies for EoE.  One candidate therapy that is yet to be studied is oral 
cromolyn sodium.  Oral cromolyn is an attractive alternative to swallowed steroids for EoE for a 
number of reasons.   
First, oral cromolyn has minimal to any systemic absorption. In fact, in studies of adults 
and children, less than 1% of orally administered cromolyn gets absorbed.16  Due to this, 
cromolyn is a first line agent in the treatment of the gastrointestinal manifestation of systemic 
mastocytosis, but not for the systemic manifestations of the disease. Second, due to its poor 
absorption, the side effect profile of cromolyn sodium is almost non-existent, and it is FDA-
approved for use down 2 years of age.17  Third, data exist to show increased numbers of mast 
cells in the esophageal tissue of patients with EoE, and that these mast cells are associated with 
smooth muscle contraction, and thus are perhaps the cause of the symptomatology of EoE.18  
Therefore, by targeting and stabilizing mast cells (the major action of cromolyn), in addition to 


eosinophils, one may be able to effectively treat EoE with non-steroid medications.  Finally, 
cromolyn, when inhaled and used in asthmatics, causes a reduction in sputum eosinophils; and 
the clinical benefit in asthma has been directly linked to a reduction in eosinophils in bronchial 
alveolar lavage specimens.19  This suggests that in addition to its known mast cell stabilizing 
properties, cromolyn exerts some effect on eosinophils as well.  In fact, after 16 weeks of 
treatment with inhaled cromolyn, researchers have shown a significant decrease in activated 
eosniophils in bronchial submucosa; an effect that was similar to treatment with fluticasone 
propionate, but not seen with placebo or salmeterol (a long acting β2-agonist).20 
 
Given these properties of cromolyn sodium, we propose that it would be an ideal 
candidate to investigate as a treatment option for patients with EoE.  
 
Protocol Design and Experimental Methods: 
 
The proposed research protocol design is a randomized, double blind, placebo-controlled trial to 
determine if oral administration of viscous cromolyn sodium will be effective in the treatment of 
eosinophilic esophagitis. 
 
Primary Outcome Measure: 
The primary outcome measure will be the change in esophageal eosinophilia after 8 weeks of 
treatment with cromolyn as compared to placebo.  
 
Secondary Outcome Measures: 
1. The change in symptoms scores from baseline and at weeks 0, 4, and 8. 
2. The incidence of adverse events throughout the study 
 
Inclusion Criteria: 
- 
Established diagnosis eosinophilic esophagitis. 
- 
>2 years of age, < 18 years of age 
 
Exclusion Criteria: 
- 
Concomitant treatment with swallowed corticosteroids.  Any prior use of swallowed 
corticosteroids will require a 4 week washout period. 
- 
Pregnancy 
- 
Evidence of pathologic eosinophilia in other locations in the GI tract. 
- 
Participation in another research protocol 
- 
Renal or Hepatic Insufficiency 
 
Study Medication 
The study medication is oral cromolyn sodium, made into a viscous preparation by the addition 
of powdered sugar. 
The medication is supplied as a 100 mg/5 mL suspension and should be made into a thickened 
slurry prior to ingestion with 1 tablespoon of powdered sugar.  This should also make the 
medication more palatable for children. 
Dosing will be 100 mg 4 times daily for children ages 2 – 12 years of age and 200 mg 4 times 
daily for children ages 12 – 18 years of age.  The medication should be taken 30 minutes before 
meals and before bedtime. 


This dosing regimen is based on current dosing strategies for systemic mastocytosis. 
 
Randomization /Placebo Administration 
Cromolyn/Placebo will be administered in a blinded fashion. The pharmacist will perform the 
randomization and will allocate 8 weeks of cromolyn/placebo to the patient. The patient and 
physicians caring for the patient will be blinded as to which medication the patient is receiving.  
 
Symptom Scores 
Symptoms will be assessed at baseline, week 4, and week 8 by the patients and caregiver.  This 
will done using an established symptom scoring diary known as the Pediatric Eosinophilic 
Esophagitis Symptom Score (PEESS).21  Figure 2. 
 
FIGURE 2. The Pediatric Eosinophilic Esophagitis Symptom Score 
 
 
 
In past studies using this diary, parents/caregivers helped with the survey for younger children 
<10 years of age, and children older than 10 years of age were typically able to complete it on 
their own. 
 
Monitoring During Study 


Patients will have a baseline physical exam performed at the initial study visit by the prinicipal 
investigator.  They will be supplied with 8 weeks of study medication to be administered at 
home.  They will have a study visit (Visit 2) done at week 4 for recording of vital signs, review 
of adverse events, and symptom assessment.  Finally they will have a physician visit at the 8 
weeks for physical exam and endoscopy with biopsies. 
 
Adverse events will be recorded on a blank calendar for each month that the patient is enrolled in 
the study. 
 
Endoscopy with biopsy: 
All qualifying subjects will have had an upper gastrointestinal endoscopy with biopsies 
performed prior to the baseline visit to establish a diagnosis of EoE. 
As part of routine clinical care, all subjects will again have post-therapy endoscopy with biopsies 
performed at week 8.  
 
Allergy Skin Prick Testing: 
As part of routing clinical care, all patients will have allergy skin prick testing performed to 
evaluate for environmental and food allergies.  The allergens tested will be tree pollens, grass 
pollens, weed pollens, molds, dust mite, cockroach, cat, dog, milk, egg white, soy, wheat, peanut, 
walnut, shrimp, and catfish. 
 
Study Protocol and Timeline: 
The proposed study timeline is shown in Figure 3. 
 
Figure 3. Study Timeline 
 
 
 
 
 
 
 
 
 
 
 
The a priori power of the primary end-point analysis was estimated using Fisher's exact test 
with .05, two-tailed significance level. Assuming a histologic response rate of 80% in the oral 
viscous cromolyn group and 10% in the placebo group, there was 85% power to detect a 
significant between-group difference with sample sizes of 10 subjects in each group. 
 
 
REFERENCES: 
 
1. Prasad GA, Alexander JA, Schleck CD, et al. Epidemiology of eosinophilic esophagitis over 
three decades in Olmsted County, Minnesota. Clin Gastroenterol Hepatol. 2009 Oct;7(10):1055-
61. 
Week 8 - 
Visit 3 
Exam, 
PEESS, 
Endoscopy 
Oral Viscous Cromolyn Sodium, n=10  
Placebo, n=10  
Day 0 - 
Visit 1 
Randomization 
Week 4 -  
Visit 2 
Vital signs, 
Review of 
adverse events, 
PEESS 


 
2. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus 
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