Evaluating Adrenal Insufficiency in Adults With Eosinophilic Esophagitis on Chronic Swallowed Topical Steroids
Conditions: Eosinophilic Esophagitis
Sponsor: University of Colorado, Denver

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COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW 
BOARD 
CAMPUS BOX F-490     
TELEPHONE:  303-724-1055  Fax:  303-724 0990 
 
 
 
Protocol #: 21-4826 
 
Project Title: Evaluating Adrenal Insufficiency in Adults with Eosinophilic Esophagitis on 
Chronic Swallowed Topical Steroids  
 
Version Date: 12/10/2021 
 
 
 
 
  
 
I. Hypotheses and Specific Aims:  Eosinophilic esophagitis (EoE), a chronic inflammatory 
disease of the esophagus, is a clinical and financial burden to patients if left untreated. Often the 
natural history of the disease includes development of fibrosis and stricturing of the esophagus, 
acute food impactions, unplanned emergency room visits, and invasive procedures such as 
endoscopy. Currently there are no Food and Drug Administration (FDA) approved medications 
for the treatment of EoE. As such, pharmacologic options approved for use in asthma are used 
for treatment of EoE and include proton pump inhibitors and swallowed topical steroids. These 
medications are prescribed chronically as EoE is considered a lifelong disease. Chronic 
administration of exogenous steroids, when given in inhaled or systemic preparations, can lead 
to adrenal insufficiency (AI). AI is seen in 7.8% of patients receiving chronic inhaled steroids 
and 48.7% of patients receiving chronic systemic steroids (10). The administration of steroids in 
EoE is unique, as patients typically swallow topical preparations of the drug. The risk of 
secondary AI from taking swallowed topical steroids is currently unknown, as there has been no 
study in an adult population assessing this risk as a primary endpoint. Pediatric studies of 
patients with EoE have shown the risk of AI from swallowed topical steroids to be 5-10% (1, 4, 
5). Based on the risk of AI with inhaled steroids (7.8% prevalence) and the prevalence of AI 
from swallowed topical steroids in pediatric populations (5-10%), we hypothesize that the risk 
with swallowed topical steroids is >5%. This could warrant consideration of screening given the 
potentially serious consequences of undiagnosed AI. To address this hypothesis, this project 
aims to define the prevalence of developing AI in adults with EoE taking swallowed topical 
steroids and compare that prevalence to a similar control population of adults with EoE who are 
taking proton pump inhibitors.  
 
Aim 1: To measure the prevalence of adrenal insufficiency in adult patients with eosinophilic 
esophagitis taking chronic swallowed topical steroids. 
 
Approach in Aim 1: We will collect questionnaire data and perform diagnostic testing in 
patients followed in the University of Colorado - Anschutz Digestive Diseases clinic for the 
diagnosis of eosinophilic esophagitis.  
 
Aim 2: Determine if any clinical parameters are associated with an increased risk of developing 
AI.  
 

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Approach in Aim 2: We will collect clinical and lab data, then analyze any relationships to 
development of AI using multivariate statistics. 
 
II. Background and Significance: Adrenal insufficiency (AI) occurs when the exogenous 
administration of corticosteroids causes the human body to stop producing steroids on its own, 
manifesting as vital sign abnormalities, electrolyte changes, and severe symptoms such as 
vomiting, fatigue, and light-headedness. If left untreated or undiagnosed adrenal crisis can 
occur, often necessitating the need for hospitalization. Exogenous steroids have been 
extensively shown to cause AI in systemic and inhaled delivery preparations, however the risk 
with swallowed topical steroids is less certain. Swallowed topical steroids have high “first-pass 
metabolism” with less systemic absorption, thus they are given chronically with little care or 
monitoring for the development of AI. There is a paucity of literature investigating the risk of 
AI with swallowed topical steroids in adult patients, leaving many prescribers without objective 
data in which to counsel patients.   
 
Current literature surrounding this topic exists primarily in pediatric populations, where three 
large studies showed the incidence of AI from swallowed topical steroids for EoE to be 5-10% 
(1, 4, 5). Hsu et al (5) additionally identified that patients concurrently taking inhaled or 
systemic preparations of steroids for asthma, which is commonly encountered as patients with 
EoE often suffer from other atopic conditions, is a risk factor for the development of AI.  
 
In adults with EoE, two randomized controlled trials indirectly tried to measure the effect of 
swallowed topical steroids and development of AI (3, 6). Both studies found no statistically 
significant increased risk for development of AI from swallowed topical steroids, though there 
were limitations to these studies that may question wide applicability. Both studies excluded 
patients on concurrent steroid formulations and the length of treatment was only 12 weeks or 
less. Dellon et al (3) revealed that AI occurred in 5.9% of patients receiving swallowed topical 
steroids compared to 4.8% in the placebo arm. Similarly, Miehlke et al (6) demonstrated AI in 
1.8% of patients on swallowed topical steroids, compared to 0% receiving placebo. While the 
randomized controlled trials failed to detect statistically significant changes in the incidence of 
adrenal function, they were likely underpowered for these secondary outcomes. 
 
Given the ongoing need for chronic steroid administration in EoE, the morbidity associated with 
adrenal crisis should AI occur, and the lack of dedicated research in this area, we feel there 
exists a need to define the prevalence of AI in adults taking long term swallowed topical 
steroids.  
 
III. Preliminary Studies/Progress Report:  No preliminary studies have been 
performed as of yet, however an analysis using Epic’s SlicerDicer found that there 
were a total of 497 patients with a diagnosis of eosinophilic esophagitis who were 
seen in the University of Colorado - Anschutz Digestive Disease clinic over the last 
12 months. 
 
IV. Research Methods 
 

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Aim 1: To measure the prevalence of adrenal insufficiency in patients with eosinophilic 
esophagitis taking chronic swallowed topical steroids.  
 
Study design: This will be a prospective observational study. A cohort of patients with 
eosinophilic esophagitis will be enrolled and placed into two groups, those taking swallowed 
topical steroids (budesonide, fluticasone) and those taking proton pump inhibitors. The 
patients will be recruited during visits in the University of Colorado - Anschutz Digestive 
Diseases clinic, where they will already be following up for treatment of their eosinophilic 
esophagitis. All study participants will participate in a written questionnaire as well as 
undergo one diagnostic test (morning serum cortisol level), with remaining diagnostic testing 
performed depending on the findings of the initial test. A power analysis to determine sample 
size estimated 304 patients were needed for our primary endpoint (prevalence of adrenal 
insufficiency) to be adequately powered. The power analysis was performed with Stata using 
a two-sample proportion Pearson’s chi-squared test with variable as follows: power 0.8, 
significance level 0.05, risk of AI in budesonide group of 5%, and risk of AI in PPI group (1 
in 1 million). If the prevalence of AI is closer to 10%, which was seen in pediatric 
populations, then even less patients would be needed for the primary endpoint to be 
sufficiently powered.  
 
Description of Population to be Enrolled:   
a) Inclusion Criteria: 300 adult male or female patients between 18 and 85 years of age 
with a diagnosis of EoE who have been on swallowed topical steroids or proton pump 
inhibitor therapy (any dosing) for at least 3 months. 
b) Exclusion criteria: We will exclude control patients on proton pump inhibitor therapy if 
they have used any form of exogenous steroids within the past one year.  
 
Protocol: All subjects will be enrolled during clinic visits, where they will complete a written 
questionnaire about any baseline symptoms they may be experiencing. From there they will 
present to the outpatient laboratory for collection of a fasting morning serum cortisol level. 
The labs will be drawn between 7-9am with the patient holding their morning steroidal dose. 
If the level is normal, defined as greater than 5µg/dL, they are done with the study protocol. If 
the level is abnormal, defined as less than 5µg/dL, another blood specimen will be collected at 
a follow up visit to confirm the abnormal result. If the 2nd sample is again abnormal the 
subject will undergo an adrenocorticotrophic stimulation test, which is a 3rd blood collection. 
This testing is performed by administering cosyntropin, a synthetic version of 
adrenocorticotrophic hormone, then collecting serum cortisol levels prior to injection, 30 
minutes after injection, and 60 minutes after the injection. If that result is abnormal, defined as 
failure to achieve a cortisol level above 20µg/dL, they will be diagnosed with adrenal 
insufficiency and referred to our collaborating endocrinologist for further management. 
Additionally, for all subjects enrolled in the study we will perform a chart review and 
document clinical parameters as follows: basic demographic information (age, sex, BMI, 
ethnicity), medical history, medication history (dose of steroid, duration of use, any additional 
steroids they are taking for unrelated condition), basic labs (complete blood count, metabolic 
panel, liver function tests), and recent endoscopic findings (endoscopic reference score, 
presence of esophageal strictures).  
 

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Data analysis plan: First we will generate descriptive data of cohort demographics, medical 
history, steroid dose/duration, basic labs, symptoms, and diagnostic testing results. Patient 
information will be collected using REDCap, where it will stored securely in a HIPAA-
compliant manner. The only people with access to the database will be study collaborators 
with individual, password-protected access logins. We will then perform descriptive statistics, 
including chi square, Fisher’s exact test, t-tests, and Mann-Whitney U testing when 
appropriate comparing attributes in subjects taking chronic swallowed topical steroids with 
those taking chronic proton pump inhibitors. Specifically, we will use a paired t-test to 
compare the mean prevalence of AI between the two groups. We will also use Mann-Whitney 
U testing to compare differences between cortisol levels in both groups. We will then use 
multivariable logistic regression in order to identify factors associated with AI from the 
gathered clinical parameter data. Using forward selection, we will then conduct exploratory 
multivariable analyses between significant univariable predictors and AI.  
 
Risks to subjects: For the blood collection patients will be at risk for typical venipuncture 
risks including a small chance of extravasation, bruising, and infection. Administration of 
cosyntropin can cause transient flushing, anxiety, nausea, and sweating (9). Because 
cosyntropin is administered as an intravenous “push,” patients are additionally at risk for 
phlebitis, extravasation, venous spasm, and medication error. Lastly, patients will be at risk of 
loss of confidentiality during the protocol process. 
 
 
Aim 2: Determine if any clinical parameters are associated with an increased risk of 
developing AI. 
 
Protocol: As outlined in Aim 1, for all subjects enrolled in the study we will perform a chart 
review and document clinical parameters as follows: basic demographic information (age, sex, 
BMI, ethnicity), medical history, medication history (dose of steroid, duration of use, any 
additional steroids they are taking for unrelated condition), basic labs (complete blood count, 
metabolic panel, liver function tests), and recent endoscopic findings (endoscopic reference 
score, presence of esophageal strictures). Additionally, symptoms will be noted and organized 
using a symptom questionnaire recorded during their clinic visit. 
 
Data analysis plan: Descriptive data of cohort demographics, medical history, steroid 
dose/duration, basic labs, symptoms, and diagnostic testing results will be generated. Patient 
information will be collected using REDCap, where it will stored securely in a HIPAA-
compliant manner. The only people with access to the database will be study collaborators 
with individual, password-protected access logins. We will then perform descriptive statistics, 
including chi square, Fisher’s exact test, t-tests, and Mann-Whitney U testing when 
appropriate comparing attributes in subjects taking chronic swallowed topical steroids with 
those taking chronic proton pump inhibitors. Specifically, we will use a paired t-test to 
compare the mean prevalence of AI between the two groups. We will also use Mann-Whitney 
U testing to compare differences between cortisol levels in both groups. We will then use 
multivariable logistic regression in order to identify factors associated with AI from the 
gathered clinical parameter data. Using forward selection, we will then conduct exploratory 

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multivariable analyses between significant univariable predictors and AI. then conduct 
exploratory multivariable analyses between significant univariable predictors and AI.  
 
Risks to subjects: For the blood collection patients will be at risk for typical venipuncture 
risks including a small chance of extravasation, bruising, and infection. Administration of 
cosyntropin can cause transient flushing, anxiety, nausea, and sweating (9). Because 
cosyntropin is administered as an intravenous “push”, patients are additionally at risk for 
phlebitis, extravasation, venous spasm, and medication error. Lastly, patients will be at risk of 
loss of confidentiality during the protocol process. 
 
V.  Summarize Knowledge to be Gained:  Upon completion of this study we will be able to 
define the prevalence of adrenal insufficiency from taking chronic swallowed topical steroids 
for eosinophilic esophagitis in an adult population. We hope information from this study will 
help inform providers in the future regarding monitoring for adrenal insufficiency and be used 
to create guidelines surrounding prescribing practices. 
 
 
VI. References: 
 
1) Bose, Paroma, et al. "Adrenal insufficiency in children with eosinophilic esophagitis 
treated with topical corticosteroids." Journal of pediatric gastroenterology and 
nutrition 70.3 (2020): 324-329. 
 
2) Choi, Inseon S., et al. "Adrenal insufficiency associated with long-term use of inhaled 
steroid in asthma." Annals of Allergy, Asthma & Immunology 118.1 (2017): 66-72. 
 
3) Dellon, Evan S., et al. "Budesonide oral suspension improves symptomatic, endoscopic, 
and histologic parameters compared with placebo in patients with eosinophilic 
esophagitis." Gastroenterology 152.4 (2017): 776-786. 
 
4) Golekoh, Marjorie C., et al. "Adrenal insufficiency after chronic swallowed glucocorticoid 
therapy for eosinophilic esophagitis." The Journal of pediatrics 170 (2016): 240-245. 
 
5) Hsu, Stephanie, et al. "Adrenal insufficiency in pediatric eosinophilic esophagitis patients 
treated with swallowed topical steroids." Pediatric allergy, immunology, and 
pulmonology 30.3 (2017): 135-140. 
 
6) Miehlke, Stephan, et al. "A randomised, double-blind trial comparing budesonide 
formulations and dosages for short-term treatment of eosinophilic oesophagitis." Gut 65.3 
(2016): 390-399. 
 
7) Philpott, Hamish, and Evan S. Dellon. "The role of maintenance therapy in eosinophilic 
esophagitis: who, why, and how?." Journal of gastroenterology 53.2 (2018): 165-171. 
 

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8) Philpott, Hamish, et al. "Systematic review: adrenal insufficiency secondary to swallowed 
topical corticosteroids in eosinophilic oesophagitis." Alimentary pharmacology & 
therapeutics 47.8 (2018): 1071-1078 
 
9) Hamilton, David D., and Bryan A. Cotton. "Cosyntropin as a diagnostic agent in the 
screening of patients for adrenocortical insufficiency." Clinical pharmacology: advances 
and applications 2 (2010): 77. 
 
10) Broersen, Leonie HA, et al. "Adrenal insufficiency in corticosteroids use: systematic 
review and meta-analysis." The Journal of Clinical Endocrinology & Metabolism 100.6 
(2015): 2171-2180.