A Pilot Trial of Baked Milk Introduction in Patients With Milk-triggered Eosinophilic Esophagitis
Phase: NA
Conditions: Eosinophilic Esophagitis
Sponsor: Mayo Clinic

Version #4 10/26/2023 
A Pilot Trial of Baked Milk Introduction in Patients with 
Milk-triggered Eosinophilic Esophagitis 
 
 
Principal Investigators: Karthik Ravi, M.D., Anupama Ravi, M.D. 
 
Coinvestigators: Alyssa Kerber, M.D., Jeffrey Alexander, M.D., Roger Moreira, 
M.D., Diana Snyder, M.D., Phillip Link, M.D. 
 
Study Coordinators: Mariah Robran, CRC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Background 
 
Dietary Therapy has been shown to be successful [1] in the treatment of adult and pediatric 
patients with eosinophilic esophagitis (EoE) [2-5]. Dietary studies were initially reported in 
children, but the results appear to be similar in adult patients. Elemental diets are successful in 
70-95% of patients but are poorly tolerated [1, 2]. A six-food-group elimination diet (SFGED) 
has been effective in about 70% of adult patients with EoE [3, 4]. In these adults, skin prick 
testing was not helpful in predicting which foods would lead to flare of disease when 
reintroduced into the diet.  
Both empiric and directed methods for antigen elimination show that milk is the most common 
food trigger for EoE in children, and it is also a common trigger in adults [4, 6]. Among adult 
patients, 43% respond to milk and wheat elimination diets and of these, 52% had only milk as a 
trigger [7]. Strict milk elimination may have negative effects on patient quality of life. Prior 
evidence has shown that some patients with milk-triggered EoE are able to tolerate milk in a 
baked form [8]. In patients with IgE-mediated cow’s milk immediate hypersensitivity, the 
denaturing of the conformational epitopes of cow’s milk due to extensive heating is suggested as 
the underlying mechanism of baked milk tolerance of a majority of these patients [9]. In 
addition, evidence shows that inclusion of extensively heated cow’s milk regularly in the diet 
may accelerate the development of tolerance to unheated forms of cow’s milk in patients with 
IgE-mediated hypersensitivity [10].  
 
 
 
 
 
 
 

We will perform a pilot study to assess tolerance of baked milk introduction in patients with milk 
triggered EoE, followed by re-introduction of varying amounts of straight milk to see if there is a 
threshold amount of milk that is tolerable.  
Hypothesis: Most patients with milk triggered EoE will be able to tolerate baked milk. In patients 
tolerate baked milk, there is a threshold amount of straight milk that is tolerated. 
Aims: 
1. Assess how many patients with milk triggered EoE can tolerate re-introduction of baked milk 
2. Determine if there is a threshold amount of straight milk that is tolerated  
 
 
Methods 
Design: Prospective trial  
Patients previously referred to the Mayo Clinic Rochester with an establish diagnosis of EoE 
who were responsive to elimination diet with milk and up to one additional food trigger will be 
identified (as defined below).   
 
Inclusion Criteria: 
 18 to 90 years of age 
 Diagnosed with Eosinophilic esophagitis ≥ 15 eosinophils per HPF 
 Going through or completed the six-food elimination diet, with milk only or milk 
plus one additional food identified as a trigger 
Exclusion Criteria: 
 Patients with conditions known to be associated with esophageal eosinophilia, 
including Crohn’s disease, Churg-Strauss, achalasia, and hypereosinophilic 
syndrome 
 Topical swallowed steroids within 8 weeks of study enrollment 
 Inability to read due to: Blindness, cognitive dysfunction, or English language 
illiteracy 
 

Timeline:  
Entry 
• Patients will be recruited from the Esophageal Clinic. 
• Meet with study investigator (AAK, KR, DLS, JAA). Patients will complete the EEsAI 
(Appendix #1), EHAS-7 (Appendix #2) and EoE QOL A (Appendix #3).  
• Patients will meet with a study team member for an educational session to review a 
standardized recipe for a muffin containing baked milk (Appendix #4).  
• Patients will undergo baseline cytosponge to ensure they are in remission  
 
Study Period 
Baked Milk 
• Patients will eat one baked milk muffin at least 5 days a week for a period of 6 weeks. 
• Patients will log their baked milk intake in a diary. 
• Patients will be contacted via phone call every 2 weeks for EEsAI questionnaire 
completion and to inquire about any issues with the baked milk diet 
• At the end of the 6-week period, the following will be assessed: 
o Repeat cytosponge 
o EEsAI questionnaire 
o EHAS-7 questionnaire 
o EoE-QOL A questionnaire 
o Review of the patient’s food diary to ensure compliance   
 If significant noncompliance is observed, the patient will be offered repeat 
consultation with dietitian and extension of baked milk for 6 weeks 
• If a patient has clinical recurrence with baked milk, they will undergo an elimination 
period of 6 weeks, followed by cytosponge to confirm resolution. If symptoms have 
resolved and they have confirmed histologic resolution, they will proceed to straight milk 
intervention. 

• If a patient has evidence of subclinical histologic recurrence, defined as ≥15 eos per HPF, 
a washout period of 6weeks will be pursued, followed by repeat sponge to ensure 
histologic remission. They will be deemed a failure and not proceed with intervention of 
straight milk. 
• If a patient has histologic recurrence after baked milk, they will have elimination of 
baked milk for 6 weeks followed by cytosponge to confirm resolution. They will be 
deemed a failure and not proceed with straight milk. 
Straight Milk  
Patients with confirmation of histologic remission (<15 eos per HPF) after the baked milk trial 
will move onto introduction of straight cow’s milk. 
• Patients will drink one glass (8 oz) of cow’s milk a week for 4 weeks 
• Patients will log a food diary for compliance  
• Following the 4-week period, patients will complete the EEsAI and EoE-QOL A 
questionnaires and be evaluated with sponge. If still in histologic remission, then the 
amount of milk will be sequentially increased to 3 glasses, 5 glasses, 7 glasses and 10 
glasses a week every 4 weeks (8 oz per serving) until patient develops symptoms or ≥15 
eos per HPF when assessed with sponge. During this time period, we will have patients 
come into the office every 4 weeks for repeat sponge and questionnaire completion prior 
to proceeding to the higher amounts of milk. 
• If patients have histologic recurrence at any point during the straight milk intervention, 
they will eliminate straight milk for 6 weeks, followed by cytosponge to confirm 
resolution. 
• If patients have subclinical histologic recurrence at any point during the straight milk 
intervention, they will eliminate straight milk for 6 weeks, followed by cytosponge to 
confirm resolution.  
• If a patient has clinical recurrence without histologic recurrence, they will not proceed 
further with straight milk. 
 
Analysis  

Sample Size 
20 patients. 
 
 
Definitions of histologic remission: 
• <15 eos per HPF on cytosponge 
Definitions of symptomatic remission: 
• Symptoms: A complete response will be defined by 
o EEsAI PRO score of <20 
 
Primary Endpoint: 
1) The proportion of patients in histologic remission at the end of a 6 week trial of baked 
milk 
 
Secondary Endpoints: 
1) The proportion of patients in symptomatic remission after a 6 week trial of baked milk 
2) The proportion of patients who remain in histologic remission after 1, 3 5, 7 and 10 
glasses of milk a week 
3) The proportion of patients who remain in symptomatic remission after 1, 3 5, 7 and 10 
glasses of milk a week 
4) The numerical improvement of quality of life after baked milk and sequential addition of 
straight milk 
5) Correlation of symptomatic and histologic disease activity 
 
Analysis of Safety 

The sponge has been found to be very well tolerated [11]. Any symptoms post sponge study will 
be evaluated by the MD investigator as clinically indicated. All sponge studies will be performed 
by the MD investigator. 
We do not feel a safety board is needed for this study.  
 
Remuneration 
Participants will be provided with remuneration of up to $200 for their time and travel to and 
from the clinic.  Participants will be eligible to receive $100 for completing the baked milk 
portion of the study (must complete the 6-week visit).  Participants will then be eligible to 
receive an additional $20 per visit during the straight milk portion of the study, for up to 5 
visits.  Participants will be paid at the completion of the study in a manner compliant with Mayo 
Clinic’s research participant remuneration policy. 
 
Feasibility/ Time frame 
A total of 26 EoE patients meeting inclusion criteria (responsive to dietary therapy with milk and 
up to one additional trigger) have been identified from a prospectively maintained clinical 
database.  In addition, each year approximately 150 new EoE patients are seen in the Esophageal 
Clinic at Mayo Clinic Rochester.  We therefore anticipate a time frame of 6 to 12 months for 
study completion. 
Strengths/ Limitations 
The strength of this study is its simplicity and very high probability of being completed within a 
40 week (10 month)  time frame.  It is limited by its small sample size and lack of control group, 
however this is acceptable given its novel design as a pilot study. 
Human Issues: 
Treatment office visits and sponge costs will be covered by research funds. Upon publication, we 
will mail all participants a thank you note, with a copy of the manuscript, explaining the results 
in layman terminology, as a way of providing feedback for their participation.  

Gender/ Minority Mix 
All patients meeting criteria will be offered enrollment in this study. We expect the 
gender/minority mix of the subjects to reflect that of the Rochester community adjusted for the 
increased prevalence of eosinophilic esophagitis in males. We therefore anticipate approximately 
70% male and 30% female with 85% Caucasian and 15% minority origin (Black, Hispanic, and 
Asian). 
Budget 
Funding will be provided by the Mayo Clinic benefactor funds and CCaTS Small Grant 
Program. 
 
Bibliography 
1. 
Liacouras, C.A., et al., Eosinophilic esophagitis: a 10-year experience in 381 children. Clin 
Gastroenterol Hepatol, 2005. 3(12): p. 1198-206. 
2. 
Peterson, K.A., et al., Elemental diet induces histologic response in adult eosinophilic esophagitis. 
Am J Gastroenterol, 2013. 108(5): p. 759-66. 
3. 
Gonsalves, N., et al., Elimination diet effectively treats eosinophilic esophagitis in adults; food 
reintroduction identifies causative factors. Gastroenterology, 2012. 142(7): p. 1451-9 e1; quiz 
e14-5. 
4. 
Lucendo, A.J., et al., Empiric 6-food elimination diet induced and maintained prolonged remission 
in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the 
disease. J Allergy Clin Immunol, 2013. 131(3): p. 797-804. 
5. 
Kagalwalla, A.F., et al., Effect of six-food elimination diet on clinical and histologic outcomes in 
eosinophilic esophagitis. Clin Gastroenterol Hepatol, 2006. 4(9): p. 1097-102. 
6. 
Spergel, J.M., et al., Identification of causative foods in children with eosinophilic esophagitis 
treated with an elimination diet. J Allergy Clin Immunol, 2012. 130(2): p. 461-7 e5. 
7. 
Molina-Infante, J., et al., Step-up empiric elimination diet for pediatric and adult eosinophilic 
esophagitis: The 2-4-6 study. J Allergy Clin Immunol, 2018. 141(4): p. 1365-1372. 
8. 
Leung, J., et al., Tolerance of baked milk in patients with cow's milk-mediated eosinophilic 
esophagitis. J Allergy Clin Immunol, 2013. 132(5): p. 1215-1216 e1. 
9. 
Nowak-Wegrzyn, A., et al., Tolerance to extensively heated milk in children with cow's milk 
allergy. J Allergy Clin Immunol, 2008. 122(2): p. 342-7, 347 e1-2. 
10. 
Kim, J.S., et al., Dietary baked milk accelerates the resolution of cow's milk allergy in children. J 
Allergy Clin Immunol, 2011. 128(1): p. 125-131 e2. 
11. 
Katzka, D.A., et al., Accuracy, safety, and tolerability of tissue collection by Cytosponge vs 
endoscopy for evaluation of eosinophilic esophagitis. Clin Gastroenterol Hepatol, 2015. 13(1): p. 
77-83 e2.