Conditions: Cow's Milk Allergy
Keywords: food allergy oral immunotherapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether baked milk oral immunotherapy is safe in the treatment of cow's milk allergy.

Detailed description:
This study is designed to assess the safety of baked milk oral immunotherapy among patients who are milk allergic and who do not pass a baked milk challenge.

Arms:
arm 1: Subjects will receive baked milk oral immunotherapy with baked non-fat cow's milk powder as the intervention. Subjects will undergo an initial dose escalation, build-up, and then a maintenance period. arm 2: Subjects will receive oral immunotherapy with the placebo control (tapioca powder). Subjects will undergo an initial dose escalation, build-up, and then a maintenance period.

Interventions: intervention 1: Baked non-fat cow's milk powder intervention 2: Placebo: Tapioca Powder
Intervention descriptions: intervention 1: Oral immunotherapy with increasing quantities of baked milk. intervention 2: Placebo control.

Protocol document:
Prot_SAP_000.pdf: 
 
  
 
 
 
 
 
 
 
BAKED MILK ORAL IMMUNOTHERAPY 
FOR THE TREATMENT OF COW’S 
MILK ALLERGY 
 
 
 
 
 
 
NCT03462030 
 
 
 
 
 
 
July 9, 2020 
 
 
 
 
 


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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Version 14 Dated:   2/2020  
  
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JHM IRB - eForm A – Protocol  
  
  
  
  
1.  
Abstract  
  
Food allergies affect approximately 2-3% of adults and 6-8% of children in the US population.1-4  
Cow’s milk allergy (CMA) is the most common food allergy in young children, affecting 2-3% of 
preschool age children.5   This allergy is often outgrown, but approximately 20% persists into 
adolescence and adulthood.   A study of our clinic population showed that 19% of CMA resolves by 4 
years, 42% by 8 years, 64% by 12 years, and 79% by 16 years.5 An observational cohort study showed 
a 50% resolution rate through age 5 years.6   
  
Current treatment options for CMA include avoidance and emergency medications for treatment 
of reactions.  Due to the ubiquitous nature of milk, avoidance is particularly difficult leading to frequent 
and often severe reactions.   Furthermore, children with milk allergy have been shown to have lower 
intake of calcium, zinc, and vitamin B27 and lower weight and BMI.8  Further, food restrictions have a 
major impact on quality of life.9-11 For all of these reasons, effective treatment of food allergy would be 
highly desirable.  
  
Over the past decade, studies have demonstrated promising results for food oral immunotherapy 
(OIT), which is a process of providing gradually increasing doses of allergenic proteins with the goal of 
inducing desensitization.  However, OIT studies to date have shown high rates of adverse reactions.12  In 
addition, 10-20% of subjects have dropped out of OIT trials due to adverse reactions, most commonly 
chronic abdominal pain.12  Treatment approaches that could reduce adverse reactions while maintaining 
or even improving the development of tolerance are therefore of interest.  In that regard, recent studies 
have shown that extensive heating of milk proteins makes them less allergenic, while still maintaining 
the antigenic properties needed to induce tolerance.  It has been shown that 50-75% of children with 
CMA tolerate baked milk at full servings, such as a cupcake or muffin, 13 and that children with regular 
exposure to baked milk will progress to tolerance of unheated milk at a significantly accelerated rate.14   
  
While the introduction of baked milk to children with CMA has now become a clinical practice, 
this is not an option for those patients with more severe milk allergy.  These patients can react to even 
trace amounts of milk in any form and are far less likely to naturally outgrow their CMA.  We therefore 
propose to approach this group of patients in this study by combining our experience with milk OIT with 
the advantages of utilizing extensively heated milk to make OIT safer. Our hypothesis is that children 
with severe CMA who are reactive to baked milk can be desensitized to cow’s milk protein via baked 
milk OIT.  We propose to explore the safety and efficacy of baked milk OIT in a double-blind, 
placebocontrolled study in children with persistent CMA, focusing on the more allergic children who are 
1) unable to tolerate baked milk at even small servings; 2) very unlikely to naturally outgrow their milk 
allergy; and 3) more likely to have difficulty tolerating OIT with uncooked milk.  If successful, this 
study could provide a much needed alternative to traditional CMA OIT, providing a safer and more 
tolerable approach to treatment due to heat-modification of the allergen.   


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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2.  
Objectives  
  
  
Primary Objective:  The primary endpoint of this study is the safety of baked milk OIT, defined 
as the incidence of adverse events on baked milk OIT compared to adverse events on placebo.  
  
Secondary Objectives include:  
• 
Exploration of the clinical effects of baked milk OIT, defined as tolerating 4 grams of 
baked milk protein without adverse reactions after 12 and 24 months of treatment  
• 
Exploration of the clinical effects of baked milk OIT, defined as tolerating 2 grams of  
unheated milk protein without adverse reactions at the end of study year 2   
 The change in maximum tolerated dose of baked milk from baseline to end of year 1 and  
end of year 2  
 The exploration of biomarkers and mechanistic correlates of desensitization including 
milk-specific IgE and IgG4, milk skin prick test responses, T cell responses.  
 The exploration of the impact of milk allergy and its treatment on quality of life.  
 Differences in clinical response rates based on duration of treatment (1 year versus 2  
years)  
 The proportion of subjects that achieve desensitization in the placebo crossover group after 
1 year of dosing at the year 2 study time point.  
 The proportion of subjects who tolerate 8030 mg of unheated milk protein at the end of 
study year 2  
 The incidence of adverse events in the unblinded year of treatment 
 Incidence of adverse events after stopping OIT (year 3 and 4)  
Impact of cow’s milk OIT on goat and sheep milk-specific IgE  
 Comparison of maximum tolerated dose of baked milk compared to maximum tolerated 
dose of unheated milk at the end of year 2  
  
3.  
Background   
  
Food allergy is a common disease for which there is currently no effective treatment.  Food 
allergies affect 2-3% of adults and up to 8% of children in the US population.1-4 Cow’s milk allergy 
(CMA) is the most common food allergy in young children, affecting 2-3% of preschool age children.5  
This allergy is often outgrown, but approximately 20% persists into adolescence and adulthood.  A study 
of our clinic population showed that 19% resolve by 4 years, 42% by 8 years, 64% by 12 years, and 79% 
by 16 years.5    
  
Current treatment options for CMA include avoidance and emergency medications for treatment 
of reactions.  Due to the ubiquitous nature of milk, avoidance is particularly difficult and reactions are 
common and often severe.   Gupta et al conducted an electronic survey of US households and found that 


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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among children with CMA, 31% had a history of severe reactions (low blood pressure, anaphylaxis, 
trouble breathing, or wheezing) and 69% had a history of mild-to-moderate reactions.2  Furthermore, 
strict avoidance can have nutritional consequences.  Children with CMA have been shown to have lower 
intake of calcium, zinc, and vitamin B27 and lower weight and BMI.8  Food restrictions and the fear of 
accidental food exposures also have a significant impact on quality of life.9-11   
  
Allergen immunotherapy is a process of providing gradually increasing doses of allergenic 
proteins over a period of time with the goal of developing desensitization.  For the past century, 
subcutaneous specific immunotherapy (SCIT) has been effectively used to treat various IgE-mediated 
hypersensitivity reactions, including allergic rhinitis, asthma, and venom hypersensitivity.  The first trial 
of food immunotherapy conducted in the 1990s with subcutaneous administration of peanut extract had 
an unacceptably high rate of systemic reactions.15,16    
  
  
Subsequent approaches have therefore focused on different routes of delivery or modification of 
the allergens to reduce risk but still achieve desensitization.   One such approach is referred to as oral 
immunotherapy (OIT), which involves consuming gradually increasing doses of an allergenic food in 
some vehicle.  Protocols vary widely with regard to type of food and vehicle used.12  Most current OIT 
protocols begin with an initial oral food challenge (OFC), followed by an initial dose escalation day.  
Then there is build-up dosing with dose increases provided under observation weekly or biweekly, with 
daily home dosing in between until maintenance dosing is achieved.  Doses and the duration of 
maintenance vary greatly between studies.  Maintenance dosing is then typically followed by an OFC to 
assess clinical desensitization.17    
  
Several studies have shown effectiveness in desensitization for milk, egg, and peanut.12,17-24   In  
2012, a systematic review and meta-analysis of milk OIT found that 62% of individuals who underwent  
OIT were able to consume at least 200 mL of cow’s milk, compared to 8% of controls.25  More recently, 
Wood and Vickery completed a review of OIT for food allergy, which summarized clinical trials for 
peanut, egg, and milk.12  Their table summarizing milk OIT studies is listed below.  These have all been 
small studies which have varied in study design, maintenance dose, and duration.  All used unheated 
milk as the OIT allergen.  Overall, these studies have shown promising results for achieving 
desensitization and increasing milk challenge thresholds.  
  
Table 1.  Milk OIT Studies12,26  
  
Reference  
  
Year  
  
Design  
  
Sample 
Size  
  
Subject 
Age  
  
Maintenance 
dose  
  
Duration  
  
Conclusions  
Meglio20  
2004  
Open label  
n=21  
6-10  
200 mL  
6 months  
72% achieved  
desensitization to 200 mL 
of cow’s milk daily  
Longo21  
2008  
Randomized 
open label  
n=30  
5-17  
150 mL  
10-day rush 
escalation,   
1 year 
maintenance  
36% completely tolerant 
(150 mL or more) and 54%  
partially tolerant (5-150 
mL)  


Date: _7/9/2020   
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Application Number: _ IRB00099590__________  
  
  
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Skripak22   
2008  
Randomized,  
placebocontrolled 
n=13  
6-17  
500 mg milk 
protein  
23 weeks  
Median milk challenge 
threshold rose from 40 mg 
at baseline to 5140 mg 
after OIT   
Nariesty23   
2009  
Open label 
(Follow up)  
n=13  
6-16  
500 to 4,000 
mg milk 
protein  
3-17 months  
Ongoing milk intake 
demonstrated tolerance 
from 1000 to 16,000 mg 
(median  
7000) with 33% tolerating  
16,000 mg on OFC  
Pajno24  
2010  
Randomized,  
placebocontrolled 
n=15  
4-10  
200 mL  
18 weeks  
67% tolerant to 200 mL 
cow’s milk  
Martorell19  
2011  
Randomized,  
placebocontrolled 
n=30  
2-3  
200 mL  
1 year  
90% showing complete 
desensitization  
Keet18  
2012  Randomized,  
OIT vs SLIT  
n=20 for 
OIT  
6-17  
1000-2000 mg  
60 weeks  
70% of patients receiving 
OIT passed an 8g OFC. 
Only 40% passed OFC 
when treatment was 
discontinued for 6 weeks.    
Wood27  
2015  
Omalizumab 
DBPC, openlabel 
OIT  
n= 57  
7-32  
3300 mg  
24 months  
80% desensitized to 10 g 
OFC, Sustained 
unresponsiveness in 42% 
after 8 week  
  
  
However, OIT studies to date have shown high rates of adverse reactions, ranging from mild, 
local symptoms, such as oral itching, to severe systemic symptoms, such as anaphylaxis.12,26   In 2011, 
Martorell et al conducted a 1 year milk OIT study in 2-3 year old children.  While 90% were 
desensitized, 47% developed moderate reactions (rhinoconjunctivitis, wheezing, vomiting, urticaria) 
over the course of treatment.19  In 2012, we examined the safety and efficacy of OIT and SLIT  
(sublingual immunotherapy) for cow’s milk allergy.  The study reported reactions in 30% of doses with 
most confined to oral pruritus, but with more significant reactions with OIT compared to SLIT.18  In 
addition, 10-20% of subjects have dropped out of OIT trials due to adverse reactions, most commonly 
chronic abdominal pain.12,26   
  
To mitigate the risks of OIT, there is great interest in developing safer approaches that will still 
induce desensitization.  One approach is to use “modified allergens.”  The idea behind modified 
allergens is that it may be possible to alter food proteins in a way that reduces the risk of allergic 
reactions, while still maintaining the ability to induce desensitization.  Extensive heating of milk is 
attracting increasing interest for the treatment of CMA because it appears to offer the clinical advantages 
of unheated milk with fewer adverse reactions.  In addition, this modified allergen can be created using 
the simple process of baking in a typical household oven.  The current theory is that extensive heating of 
milk protein induces conformational changes to epitopes responsible for IgE binding.  These changes 
decrease the risk of allergic reactions; however, the T cell epitopes that induce the development of 
tolerance are largely unchanged.  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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There are several phenotypes of milk allergy, ranging from patients with persistent disease with a 
high risk of anaphylaxis to those with more short-lived disease who typically tolerate extensively heated 
milk.  It has been shown that 50% - 75% of children with CMA tolerate baked milk at full servings, such 
as a cupcake or muffin,13 and most importantly, that children who have regular exposure to baked milk 
will develop tolerance to unheated milk at a significantly accelerated rate.14  Phenotypic characterization 
is extremely important in the management of milk allergic patients, and usually relies on oral food 
challenges to different forms of milk, which require significant resources and highly trained staff. To 
improve diagnostics of milk and other food allergies, the underlying disease mechanisms need to be better 
understood.  
  
Many of the 25-50% of cow’s milk allergic patients who do not tolerate heated milk have a very 
severe, persistent phenotype.  These children have a high risk of reactions due to accidental exposures 
and a low likelihood of naturally outgrowing their allergy and therefore, would benefit greatly from a 
safe and effective form of treatment.  Our hypothesis is that children with IgE mediated CMA who are 
reactive to baked milk can be desensitized to cow’s milk protein via baked milk OIT, and that this 
approach will prove far safer than OIT using unheated milk.  We propose to explore the efficacy and 
safety of baked milk OIT in a double-blind, placebo-controlled study in children with persistent CMA, 
focusing on the more allergic children who are 1) unable to tolerate baked milk even at small servings; 
2) unlikely to naturally outgrow their milk allergy; and 3) more likely to have difficulty tolerating OIT 
with uncooked milk.    
  
This approach has this far been attempted in one small study in Israel with 15 baked milk 
reactive patients.28  The primary outcome was defined as attaining a maintenance baked milk dose of 1.3 
grams per day without adverse reactions at 1 year of treatment.  This study started with a baked milk 
dose of 25-120 mg. Only 3/14 (21%) patients tolerated the 1.3g goal dose.  Eight did not complete the 
program because of IgE-mediated reactions and 3 did not complete it for other reasons.   
  
While this study had discouraging results, we feel that we have a high chance of success with a 
substantially revised protocol, most importantly beginning with a far lower starting dose and using a 
more gradual dose escalation, similar to the protocols we have used with unheated milk.  If successful, 
this study will provide a much needed alternative to traditional milk OIT.  We are hopeful that this next 
generation of OIT will be safer and more tolerable due to modification of the allergen.  After becoming 
desensitized, the need for strict milk avoidance should be eliminated, which would decrease the risk of 
accidental ingestions and potentially life-threatening reactions and improve overall nutrition and quality 
of life.  We have established a collaboration with the La Jolla Institute for Allergy & Immunology with 
whom we will seek to define T cell targets from milk allergens, determine the phenotype of antigen 
specific T cells from donors with persistent cow’s milk allergy, and track the longitudinal development 
of antigen specific T cells during oral immunotherapy.  In addition, the immunoglobulin and skin prick 
studies will help characterize the biomarkers behind desensitization and tolerance.  
  
4.  
Study Procedures  
  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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To effectively address the primary objective of this study, subjects age 3-18 years of age with: 1) 
a history of cow’s milk allergy, 2) a serum cow’s milk specific IgE of > 5kU/L and a milk skin prick test 
with a wheal diameter of wheal 3 mm ≥ negative control and 3) reactivity to baked cow’s milk at ≤444 
mg of milk protein, will be enrolled, given that all other inclusion and exclusion criteria are satisfied.  
Subjects will be recruited from the Johns Hopkins Pediatric Allergy Clinic.  After obtaining informed 
consent and assent, participants will undergo an initial screening visit that will include a medical exam 
and history, quality of life questionnaire, baseline gastrointestinal assessment, blood tests, skin prick 
testing, and spirometry and/or peak flow meter.  During the baseline visit or at the next visit, participants 
will begin a double-blind placebo-controlled food challenge (DBPCFC) to baked milk /placebo with a 
maximum cumulative dose of 444 mg milk protein.  They will return for the second half of the food 
challenge within 21 days.  Eligible participants will then be randomized to active OIT or placebo and 
will return for a dose escalation day. Their starting dose for daily home dosing will be determined by the 
highest tolerated dose on the dose escalation day, with a minimum of 3 mg and a maximum of 25 
mg/day.  Participants will then return to the Pediatric Clinical Research Unit (PCRU) approximately 
every 2 weeks for observed dose escalations with a final goal of 2000 mg/day of baked milk protein or 
placebo.  After 1 year, the study will be unblinded and the placebo group will be offered active 
treatment.  The initial active treatment group will continue maintenance therapy for an additional year 
or, if they did not reach 2000 mg in the first year, they will re-start dose escalation with the goal of 
reaching 2000 mg, while the placebo group will begin dose escalation from the beginning.  Details of 
the study procedures and visits follow.  
  
  
Many of the procedures in this study are usual and customary in the care of food allergic 
children.  These include skin prick testing, blood testing for IgE levels, and oral food challenges (OFC).  
The timing of these procedures is driven by the research protocol.  Urine pregnancy testing, blood 
testing for biomarker and mechanistic studies, and oral immunotherapy are exclusively research related 
procedures.  
  
1. OFC:  The initial and year 1 and 2 food challenges will be double-blind placebo-controlled food 
challenges (DBPCFC) in which both the patient and clinician will be blinded.  The DBPCFC 
will be done in accordance with standard procedures.   All oral food challenges will be 
performed in the PCRU with direct physician supervision, emergency medications immediately 
available, and in accordance with standard procedures.  We will prepare challenge materials 
using our standard operating procedures (SOP).  The initial DBPCFC will be a challenge to 
baked milk or placebo.  Milk will be administered in the form of non-fat milk powder (provided 
by the University of North Carolina (UNC), manufactured by The Milky Whey, Inc & TMW 
International), added to a cake and baked at 350°F/180°C (at least) for at least 30 minutes.  The 
first DBPCFC will consist of a maximum cumulative dose of 444 mg of baked milk powder in 
gradually increasing doses at 15 minute intervals.  The doses will be prepared by the research 
nutrition staff and distributed as listed in table 2 below.  Frequent assessments are made for 
symptoms affecting the skin, gastrointestinal tract, cardiovascular system, and/or respiratory 
tract.  Objective symptoms indicate a positive reaction at which time dosing is terminated and 
appropriate treatment is administered.  
  
Table 2.  Baseline Food Challenge (Baked Milk) DBPCFC #1:  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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Dose #  
Dose (mg) of milk protein  
Cumulative Dose (mg)(mg)  
1  
1 mg  
1 mg  
2  
3 mg  
4 mg  
3  
10 mg  
14 mg  
4  
30 mg  
44mg  
5  
100 mg  
144 mg  
6  
300 mg  
444 mg  
  
At the end of year 1, participants will undergo DBPCFC#2 to up to maximum cumulative dose of 
4044 mg of baked milk.  The doses will be prepared by the research nutrition staff and 
distributed as listed in table 3.  The subject will return within 21 days for the second half of the 
challenge.  
  
  
  
  
  
  
Table 3.  End of Year 1 Food Challenge (Baked Milk) DBPCFC #2:  
  
Dose #  
Dose (mg) of milk protein  
Cumulative Dose (mg)  
1  
1 mg  
1 mg  
2  
3 mg  
4 mg  
3  
10 mg  
14 mg  
4  
30 mg  
44mg  
5  
100 mg  
144 mg  
6  
300 mg  
444 mg  
7  
600 mg  
1044 mg  
8  
1000 mg  
2044 mg  
9  
2000 mg  
4044 mg  
  
  
  
At the end of year 2, participants will undergo DBPCFC #3 to up to maximum 
cumulative dose of 4044 mg of baked milk.  During year 2, all participants will be on active OIT 
and are required to reach at least 750 mg of baked milk protein at least 8 weeks prior to the end 
of year 3.  Therefore, DBPCFC#3 will start at 444 mg.  The doses will be prepared by the 
research nutrition staff and distributed as listed in table 4.   
  
  
Table 4.  End of Year 2 Food Challenge (Baked Milk) DBPCFC #3:  
  


Date: _7/9/2020   
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Application Number: _ IRB00099590__________  
  
  
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Dose #  
Dose (mg) of milk protein  
Cumulative Dose (mg)  
1  
444 mg  
444 mg  
2  
600 mg  
1044 mg  
3  
1000 mg  
2044 mg  
4  
2000 mg   
4044 mg  
  
  
  
Subjects who tolerate at least 2000 mg of baked milk the DBPCFC#3 will return within 2 
weeks to undergo DBPCFC#4 to up to 8030 mg of unheated milk  in the form of non-fat milk 
powder or placebo in a blinded vehicle.  The study nutritionist will create these doses based on 
the schedule in Table 5.  
  
Table 5.  Year  2 Food Challenge (Unheated Milk) DBPCFC #4:  
Dose #  
Dose (mg) of milk protein  
Cumulative Dose (mg)  
1  
30  
30  
2  
100  
130  
3  
300  
430  
4  
600  
1030  
5  
1000  
2030  
6  
1500  
3530  
7  
2000  
5530  
8  
2500  
8030  
  
  
These challenges will be very helpful to determine the dose of milk that should be safe to 
incorporate into the diet.  All participants will be provided specific guidelines as to the amount of 
heated and unheated milk that can be introduced into their diets at study completion.  
  
  
2. Skin prick tests:  A skin prick test using cow’s milk extract will be performed using standard 
procedures.  The patient must be off antihistamines for 5 days for long acting and 3 days for 
short acting prior to skin testing.  A skin test probe (Greer Pick) is pressed through a commercial 
milk extract (Greer Laboratories) into the epidermis.  Histamine (positive) and saline-glycerin 
(negative) controls are placed to establish that the response is not blocked and to determine if 
there is dermatographism, respectively.  A study physician will be available to monitor for any 
adverse events.  
  
3. Blood draws: Standard procedures will be followed with a maximum of 3 cc/kg in any 8 week 
period.  Laboratory tests will examine milk-specific IgE and IgG4.  Laboratory studies will be 
performed at DACI Laboratory or by La Jolla Institute (LJI) for Allergy & Immunology.  LJI 
will seek to define T cell targets from milk allergens, determine the phenotype of antigen specific 
T cells from donors with persistent cow’s milk allergy, and track the longitudinal development of 
antigen specific T cells during oral immunotherapy.  Cells from the blood will be used for HLA 


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typing, to allow for the use of HLA-specific experimental assays (e.g., autoantigen-specific cells 
can be isolated by tetramer reagents) as well as analysis correlation between HLA type and 
disease or phenotype. Transcriptional profiling will also be done on these samples (e.g. RNA-seq 
and TCR sequencing).   
    
  
4. Spirometry and Peak Flow Rate (PFR):  Standard procedures will be followed.  At the 
screening visit, spirometry will be attempted in all subjects ≥6 years old.  Children < 6 years old 
will have peak flow rate (PFR) done.  If children 6-18 years of age are unable to produce valid 
spirometry results, the attempt will be documented and PFR will be performed.  If children 3-5 
years of age are unable to produce valid PFR results, the attempt will be documented.  At all 
subsequent visits, PFR will be performed in all subjects.  If children 3-5 years of age are unable 
to produce valid PFR results, the attempt will be documented.  
  
5. Urine pregnancy tests:  Urine human chorionic gonadotropin (HCG) testing for pregnancy in 
females of child bearing age will be conducted prior to administration of the study product at the 
study visits indicated.  
  
6. Quality of life questionnaire: At the baseline visit, completion of study year 1 and 2, and 
follow-up visits, the subject and/or their parent /guardian will complete a quality of life 
questionnaire.  
  
7. Gastrointestinal assessment:  At the baseline visit, all subjects and/or their parent/guardian will 
complete a baseline gastrointestinal assessment.  Follow-up assessments will be completed at 
least monthly during the build-up period, during each maintenance visit, and at the completion of 
study year 1 and 2 and during follow-up.    
Schedule of visits   
All potential participants who express interest on initial contact will receive a copy of the 
informed consent and be invited for a screening visit.  Visits will be as follows:  
  
 
A.  
Baseline Visit   
  
  
This research study will be explained in lay terms to each potential research participant.  The 
potential participant will sign an informed consent before undergoing any screening study 
procedures.  Written informed consent and HIPAA authorization will be obtained from all 
participants at the beginning of this visit.  Study procedures will be stopped and the participant will 
be deemed ineligible for the study if the participant 1) is unable to complete the procedure being 
done at any point for any reason or 2) has a result from a study procedure or question that would 
exclude them from the study.    
  
  
Historical data will be collected to include demographics (age, race, sex), medical history, 
dietary history, medications (current and in the past 12 months), and other allergies.  A quality of life 
questionnaire and baseline gastrointestinal assessment will be administered.  A physical exam will 
be conducted along with spirometry or peak flow rate.  Spirometry will be attempted in all subjects 


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≥6 years old.  Children < 6 years old will have peak flow rate (PFR) done.  If children 6-18 years of 
age are unable to produce valid spirometry results, the attempt will be documented and PFR will be 
accepted for the entry criteria if results are ≥ 80% of predicted.  Urine pregnancy testing will be 
conducted where appropriate.  Skin prick testing to milk protein extract will be performed and 
phlebotomy will be conducted.  The caregiver will be given a Food Allergy Action Plan.  
Epinephrine auto-injector teaching will be performed at the screening visit.  
  
  
In certain participants (e.g. the milk IgE result is known), the baseline visit and first half of the 
baseline food challenge will be combined.  
  
B. Initial Double Blind Placebo Controlled Oral Food Challenge (OFC):  
  
Within 21 days of the baseline visit, eligible subjects will return for DBPCFC #1 (table 2) to 
baked milk or placebo.  A limited physical exam and peak flow rate will be done.  If the exam is 
normal and PFR ≥80% of predicted, the study participant will undergo an oral food challenge with a 
cumulative dose of 444 mg of either baked milk powder or Tapioca flour (provided by the 
University of North Carolina (UNC), manufactured by Ener-G Foods, Inc.) in a blinded manner.  
The Pediatric nutrition staff will prepare doses by adding milk or Tapioca flour to a cake, which will 
be baked at 350°F/180°C (at least) for at least 30 minutes.  Participants will receive gradually 
increasing doses at 15 minute intervals as in Table 2 above.  Frequent assessments are made for 
symptoms affecting the skin, gastrointestinal tract, cardiovascular system, and/or respiratory tract.  
Dosing will be terminated with the onset of symptoms indicating a positive reaction after which 
appropriate treatment will be administered.    
  
Upon completion of the food challenge, all participants will be observed for at least 2 hours, 
unless the OFC is unblinded and the participant had a negative challenge to placebo..  For any severe 
systemic reaction, all subjects will be observed for at least 4 hours or until signs of clinical reactivity 
subside.  
  
      The second half of the DBPCFC will occur within 21 days of the initial food challenge.  If 
the participant does not react with the cumulative dose of 444 mg of baked milk or if they react to 
placebo, they will not be eligible to enter the treatment phase of the protocol.  
  
At the completion of the DBPCFC, eligible participants will be randomized to active treatment 
or placebo.  
  
C. 
Dose Escalation:  
  
  
Within 4 weeks of the DBPCFC, participants will return for the initial OIT dose 
escalation.  Again, a limited physical exam, peak flow, and urine pregnancy testing (when indicated) 
will be conducted.  If the exam is normal, urine pregnancy test is negative and the PFR is ≥80% of 
normal, escalation with OIT dosing will be performed.  Participants will begin at a dose of 0.1 mg of 
OIT with dose increases every 15 minutes to a maximum final dose of 25 mg of OIT in one day as 
listed in table 5.   


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Application Number: _ IRB00099590__________  
  
  
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Table 6: Initial Dose Escalation  
Dose #  
Milk dose (mg) of milk protein  
Interval  
1  
0.1  
Day 1  
2  
0.2  
Day 1  
3  
0.4   
Day 1  
4  
0.8   
Day 1  
5  
1.5  
Day 1  
6  
3   
Day 1  
7  
6   
Day 1  
8  
12   
Day 1  
9  
25   
Day 1  
  
  
If symptoms, including intolerable localized itching or any systemic reaction, occur, the 
dose escalation will be stopped and the participant will be sent home on daily doses of the highest 
dose tolerated (must be at least 3 mg with a maximum of 25 mg).  Mild symptoms during escalation 
can be treated with a single dose of antihistamine with continued milk dosing.    
  
D. 
Dose Build-Up:  
  
  
Further dose increases at approximately 50% increments will occur under observation 
approximately every 2 weeks as listed below in Table 7, with daily home dosing between each 
observed dose increase.  The interval history and dosing log will be reviewed. A gastrointestinal 
assessment will be done at least once a month. At each visit, alimited physical exam and peak flow 
testing will be conducted.    Urine pregnancy testing will be done every month if indicated.  If the 
participant did not reach 25 mg on the initial dose escalation, they will follow the dose escalation 
day schedule approximately every 2 weeks until they reach 25mg.  At these visits, subjects will 
demonstrate understanding of preparation and administration of the OIT doses and be observed for 
reactions for a minimum of 60 minutes.  The final dose tolerated will be taken at home for the next 2 
weeks (range of 10-21 days).   The tolerated protein dose will be dispensed in portion cups.  The 
powder will be packaged into cups by Dr. Wesley Burks’ manufacturing facility at the University of 
North Carolina and shipped to Johns Hopkins Research Pharmacy.  Drug dispensing will be 
performed by Johns Hopkins research pharmacy.  The subject’s guardian will be given detailed 
instructions on how to add the powder to a muffin or cupcake for their daily dosing, and bake at 
350°F/180°C (at least) for at least 30 minutes.    
  
  
If the dose is not tolerated, the subject will resume the highest previously tolerated dose until 
their next visit.  The minimum accepted dose for maintenance daily OIT dosing is 750 mg.  If the 
patient does not tolerate three consecutive escalation attempts, but has attained a dose of 750 mg, 
this dose will become the maintenance daily home dose until the year 1 OFC (DBPCFC #2).  If the 
patient does not tolerate three consecutive escalation attempts and 750 mg has not been obtained, 
then the study treatment will be discontinued.  In addition, OIT will be discontinued for subjects 


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Application Number: _ IRB00099590__________  
  
  
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who do not reach at least 750 mg by study week 44.  The dose achieved at study week 44 (which 
must be ≥750 mg) will be the maintenance dose used in the subsequent 8 weeks.  
  
  
 If build-up was delayed due to the stop in-person visits due to COVID-19, then the patient will 
be allowed up to an additional 8 weeks in build-up. They would then remain on the maintenance 
dose for 8 weeks and then complete the end of year OFCs   
   
Between visits, subjects will take the given dose at home daily.  It is recommended that the 
dose be taken at a consistent time (within a 4-hour time period each day) and it is critical to take the 
dose every day.  Doses should be separated by at least 12 hours. They will also be given a daily diary 
to record the time of administration, adverse events, medications given, and any other symptoms or 
exposures that may arise.  
  
Subjects may be brought back to the PCRU at any time to observe dosing at the 
investigator’s discretion.  If more than 3 consecutive home doses are missed, subjects must return to 
the PCRU to take their next dose under observation.  Subjects should withhold their daily home dose 
on the build-up day, but should take all other prescribed medications.  Blood will be collected at the 
initial visit, start of maintenance in year 1, at the year 1 and 2 OFCs (DBPCFC #2 and #3), and 
during study year 3 and 4 follow-up visits.  Skin prick testing will occur on the same schedule.      
  
  
Table 7. Dose Build-up Schedule:  
Dose #:  
Dose (mg) of milk protein  
Interval  
Comments:  
10  
37.5  
2 weeks  
  
11  
50  
2 weeks  
  
12  
75  
2 weeks  
  
13  
125  
2 weeks  
  
14  
200  
2 weeks  
  
15  
300  
2 weeks  
  
16  
500  
2 weeks  
  
17  
750  
2 weeks  
Minimum maintenance dose  
18  
1000  
2 weeks  
  
19  
1500  
2 weeks  
  
20  
2000  
2 weeks  
Goal Maintenance Dose  
  
  
E. 
OIT Maintenance:  
  
  
  
During the maintenance phase, the subject will continue daily home doses of OIT 
of 2000 mg (or the minimum tolerated dose ≥750 mg) daily for at least 8 weeks prior to 
DBPCFC #2.  Follow up visits will occur every two months to review the daily diaries and other 
interval history and to complete the gastrointestinal assessment.   A limited physical exam, peak 
flow, gastrointestinal assessment and urine pregnancy testing (if indicated) will be conducted at 


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each visit as well. Maintenance visits may occur via phone, video visit, or in-person at the 
discretion of the PI.  
  
F. 
Double Blind Placebo Control Food Challenge #2:  
  
  
At week 52, after at least 8 weeks of OIT maintenance therapy, study participants will 
undergo DBPCFC #2.  Participants will be asked to fill out a gastrointestinal assessment and quality 
of life questionnaire prior to DBPCFC #2. A limited physical exam, urine pregnancy (if indicated), 
and peak flow rate will be conducted.  Blood will be collected and skin testing will be repeated.    If 
the exam is normal, urine pregnancy test is negative, and PFR ≥80% predicted, the study participants 
will undergo an oral food challenge with a cumulative dose of 4044 mg of baked milk or placebo as 
shown above in Table 3.  Participants will receive doses every 15 minutes and will be monitored for 
symptoms of allergic reaction.  The second half of the DBPCFC will occur within 21 days.   
  
  
G. 
Unblinded Phase:  
  
  
Unblinding will occur after DBPCFC #2.   
  
1. Build-up Phase Post 1 Year OFC for Placebo-Treated Subjects:  
  
  
  
The placebo group will be offered the option of crossing over into active therapy with 
dose escalation to a maximum of 2000 mg maintenance.  They will follow the same protocol as 
the initial active treatment group.  Blood will be collected at the start of maintenance.       
  
2.  Build-up Phase Post 1 Year OFC for those in Initial Active Treatment Group  
  
  
  
Those in the initial active treatment group who were unable to reach the goal 
maintenance dose of 2000 mg by study week 44, will resume dose build-up until they reach a 
maximum of 2000 mg/day if tolerated.  They will resume the same initial protocol.  If the patient 
does not tolerate three consecutive escalation attempts, then they will remain at their current dose 
for the remainder of the study period.     
  
  
3.  Maintenance Phase Post 1 Year OFC:  
    
  
  
Those in the active treatment group that tolerated 2000 mg baked milk 
maintenance will continue maintenance for an additional 52 weeks.  Follow up visits will occur 
every three months to review the daily diaries,other interval history, and the gastrointestinal 
assessment.  A limited physical exam, peak flow, gastrointestinal assessment, and urine 
pregnancy testing (if indicated) will be conducted at each visit as well.  Maintenance visits may 
occur via phone, video visit, or in-person at the discretion of the PI.  
  


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Those who were in the initial placebo group or those in the initial active treatment 
group who were unable to reach 2000 mg by study week 44 will follow the same initial build-up 
protocol and requirements mentioned above  Their goal maintenance dose for maintenance 
period #2 will be 2000 mg.  If they are unable to reach 2000 mg by week 98, then their 
maintenance dose will be the achieved dose ≥ 750 mg at week 98. This will allow for at least 8 
weeks of maintenance prior to DBPCFC #3.  If subjects do not reach at least 750 mg by study 
week 98, OIT will be discontinued. If build-up was delayed due to the stop in-person visits due 
to COVID-19, then the patient will be allowed up to an additional 8 weeks in build-up. They 
would then remain on the maintenance dose for 8 weeks and then complete the end of year 
OFCs. Follow up visits will occur every two months to review daily diaries and interval history.  
A limited physical exam, peak flow, gastrointestinal assessment, and urine pregnancy testing (as 
indicated) will be conducted at each visit as well. Maintenance visits may occur via phone, video 
visit, or in-person at the discretion of the PI.  
  
  
4.     Study Year 2 OFC to Baked Milk (DBPCFC #3)  
  
  
At the end of study year 2 (week 106) , study participants will undergo DBPCFC #3 to 
baked milk with dosing as listed above in Table 4.  Participants will be asked to fill out a 
gastrointestinal assessment and quality of life questionnaire prior to DBPCFC #3.  A limited 
physical exam, urine pregnancy test (if indicated) and peak flow rate will be conducted.  Blood will 
be collected and skin testing will be repeated.  If the exam is normal, urine pregnancy test is 
negative, and PFR ≥80% of normal, the study participants will undergo an oral food challenge with a 
cumulative dose of 4044 mg of either baked milk or placebo in a blinded manner.  Participants will 
receive doses every 15 minutes and will be monitored for symptoms of allergic reaction.   The 
second half of the DBPCFC will occur within 21 days.  If no symptoms occur during the first half of 
DBPCFC#3, then the second half of the challenge could occur on the same day at the discretion of 
the principal investigator.   
  
  
 
  
5.    Study Year 2 OFC to Unheated Milk (DBPCFC #4)  
  
Within two weeks of the completion of DBPCFC #3, study participants who tolerated at least 
2000 mg of baked milk during DBPCFC #3 will undergo DBPCFC#4 with a cumulative of 8030 mg 
of unheated milk powder or placebo in a blinded manner with dosing as listed in table 5.  A limited 
physical exam, urine pregnancy and peak flow rate will be conducted.  If the exam is normal, urine 
pregnancy test is negative, and PFR ≥80% of normal, the study participants will undergo an oral 
food challenge to unheated milk powder or placebo.  The second half of the DBPCFC will occur 
within 21 days.  If no symptoms occur during the first half of DBPCFC#4, then the second half of 
the challenge could occur on the same day at the discretion of the principal investigator.   
  
  
H. Follow-up Period:  
  


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1. Subjects who discontinue study treatment before the end of the study will complete an 
Early Discontinuation Visit 1-2 weeks after their last dose of study treatment.  During 
that visit, they will have a physical exam and urine pregnancy test (if applicable).  Daily 
diaries and interval history will be reviewed. Subjects who complete DBPCFC#2 and 
then leave the study early will be asked to sign a consent to participate in follow-up (as 
detailed below in #4) if they have been given instructions to introduce milk at home.  
    
  
2. For those who had symptoms at <2000 mg of baked milk during DBPCFC#3, they will 
be considered to have completed the intervention period of the trial.  OIT will be stopped.  
They will be given detailed instructions for the diet to resume at home.  
  
3. For those who tolerated ≥2000 mg of baked milk during DBPCFC#3, they will then 
complete DBPCFC #4.  After the completion of DBPCFC #4, OIT will be stopped and 
they will be considered to have completed the intervention period of the trial.  They will 
be given detailed instructions for the diet to resume at home.  
  
4. All participants will then have phone follow-up quarterly for 1 year.  They will return to 
clinic after 6, 12, and 24 months.  An updated history will be obtained.  A limited 
physical exam will be performed.  Milk specific skin prick testing will be performed and 
blood for laboratory studies will be obtained.  Participants will be asked to complete a 
gastrointestinal symptom and quality of life questionnaire at the follow-up visits.    
a. Study duration and number of study visits required of research participants.  
  
The total length of time and number of study visits will vary depending on the subject’s 
response to the immunotherapy and the group to which they are randomized.  All eligible 
subjects will complete a baseline visit, initial DBPCFC (2 visits), and dose escalation day.  For 
those who remain eligible and are enrolled in the study, we anticipate variation in the amount of 
time required to complete dose escalation.  The time in dose escalation will impact the time in 
maintenance.  A subject randomized to the active treatment group who reached a 25 mg starting 
dose and completed dose escalation visits without any delays would have a minimum of 54 
weeks and 20 visits in Study Year 1 and an additional 7 visits and 54 weeks in Study Year 2.  For 
the entire study (including follow-up), a subject would have a minimum of 30 visits over 212 
weeks.    
  
During study year 1, a subject who had a lower starting dose would require additional 
biweekly visits until reaching 25 mg.  Furthermore, one who is unable to tolerate a dose 
escalation would require additional dosing build-up visits.  Study Year 1 will last 54 weeks and 
based on the above factors could require 20-25 visits.  
  
For those in the initial baked milk OIT group, the number of study visits during year 2 
will vary based on if a subject is able to achieve the goal maintenance dose of 2000 mg during 
study year 1.  In study year 2, those who started in the active treatment group, but did not reach 
2000 mg will have additional biweekly visits in build-up phase #2.  They could have a maximum 


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Application Number: _ IRB00099590__________  
  
  
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of 18 weeks (9 visits) in build-up phase #2.  Those who did achieve 2000 mg during study year 1 
will continue in the maintenance phase with visits every 12 weeks.  They will have a minimum 
of 7 visits during study year 2.  All subjects will complete study year 2 at week 108.  Those who 
tolerated ≥2000 mg of baked milk during the DBPCFC #3 will also undergo  DBPCFC #4 to 
unheated milk or placebo, which will occur as a separate visit.  
  
The placebo group should have 20 visits over 54 weeks in study year 1.  After crossover 
to active treatment, their study duration and number of visits required would be the same as 
described for the initial active treatment group.  For the initial placebo group, the total duration 
of the study (including follow-up) will be 212 weeks and will include a minimum of 40 study 
visits.  
  
b. Blinding, including justification for blinding or not blinding the trial, if applicable.  
  
The intent of blinding is to maintain maximum objectivity in confirming the diagnosis of 
food allergy, evaluating any clinical effects of OIT, monitoring adverse reactions and in 
interpreting results.  All 4 sets of food challenges will be double-blind for the same reasons. In 
addition, there is the possibility of naturally outgrowing a food allergy.  Therefore, it is crucial to 
have a blinded treatment and placebo group in order to evaluate the impact of the baked milk 
OIT compared to natural history/natural disease progression.    
  
c. Justification of why participants will not receive routine care or will have current therapy 
stopped.  
  
Standard of care for baked milk allergic individuals in this age group is total avoidance.  
There is no alternative therapy to treat milk allergy in baked milk allergic children.  This 
treatment offers a potential new therapy for baked milk allergic individuals.  Routine care for 
other allergy concerns will continue in the pediatric allergy clinic.  
  
  
Participants will be asked to stop antihistamines prior to the screening visit and prior to 
food challenges.  This is necessary to allow for accurate SPT and to avoid masking symptoms 
during food challenges.  
  
d. Justification for inclusion of a placebo or non-treatment group.  
  
The study will be double-blind, placebo-controlled for the first year.  At one year, 
unblinding will occur and participants in the placebo group will be offered crossover to active 
therapy.  This study design will maximize objectivity when evaluating the clinical effects of OIT, 
reporting of adverse reactions, and in interpreting study outcomes.  In addition, there is the 
possibility of naturally outgrowing an allergy.  Therefore, it is crucial to have a placebo group in 
order to evaluate the impact of the baked milk OIT compared to natural progression of the 
disease.     
  
e. Definition of treatment failure or participant removal criteria.  


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• 
Severe anaphylaxis secondary to OIT dosing or milk food challenge.    
• 
If the subject is deemed to have severe symptoms and requires aggressive therapy at any time 
during dose escalation or build up.  
• 
Inability to tolerate at least 3 mg by OIT on the first day of dose escalation.  
• 
Inability to tolerate a dose increase on 3 consecutive attempts during dose build up if one has 
not reached 750 mg.  
• 
Inability to tolerate 750 mg milk protein 8 weeks prior to DBPCFC #2 or DBPCFC #3 (week  
44 and week 98, respectively) (COVID-19 related exceptions deleted above)  
• 
Poor control or persistent activation of asthma or atopic dermatitis  
• 
Severe gastrointestinal symptoms related to treatment which are ongoing and persist for 
hours beyond dosing.   
• 
For subjects who gastrointestinal symptoms persist for more than 2-3 weeks beyond 
discontinuation of dosing, a referral to a gastroenterologist will be initiated.  
• 
Circumstances (e.g. concurrent illnesses) requiring missed dosing of > 4 days and 
inability/lack of desire to repeat desensitization.  
• 
Excessive missed days of home dosing protocol (i.e. >3 consecutive days missed on 3 
occasions).  
• 
The principal investigator determined that ongoing treatment is not in the subject’s best 
interest.  
• 
The participant elects to withdraw consent from all future study activities, including 
followup.  
• 
Pregnancy in study participant.  
  
f. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely.  
  
  
Those completing the treatment course will be followed as described above; those that withdraw 
or do not complete the course of treatment will have a follow-up visit within 1-2 weeks after stopping 
the study.  The study termination visit will include: 1) A final physical exam, 2) a pregnancy test for 
female participants of child bearing age, and 3) a review of the interval history and daily diary.  
  
 If subjects complete DBPCFC#2 and then leave the study early, we will ask them to sign a separate 
consent to participate study in study follow-up if they have been given instructions to introduce milk at 
home.  
  
  
All participants who complete treatment will have telephone follow-up quarterly for 1 year and 
then a clinic visit 6, 12, and 24 months post-study completion.  This follow-up visit will include a 
limited physical exam, dietary history, food reaction history, skin prick tests, blood collection, 
gastrointestinal symptom questionnaire, and a quality of life questionnaire.   
  
5. 
Inclusion/Exclusion Criteria  


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Patients who meet all of the following criteria are eligible for enrollment as study 
participants, including participants who:  
  
• 
Are age 3-18 years, either sex, any ethnicity or race  
• 
Provide signed informed consent by parent or legal guardian and informed assent if 
applicable  
• 
Have a history of symptomatic reactivity to cow’s milk (i.e. eczema, urticarial, upper or 
lower respiratory symptoms, GI disturbances, rash, oral symptoms)  
• 
Have a skin prick test positive to milk (diameter of wheal 3 mm ≥ negative control) and 
serum milk-specific IgE level >5 kU/L within the past 6-12 months  
• 
Have a positive reaction to a cumulative dose of ≤444 mg of baked milk protein in the 
initial qualifying DBPCFC.  
• 
Use an effective method of contraception by females of childbearing potential to prevent 
pregnancy and agree to continue to practice an acceptable method of contraception for 
the duration of their participation in the study.  
• 
Have self-injectable epinephrine available at all times  
  
Patients who meet any of these criteria are not eligible for enrollment as study participants, 
including participants who:  
• 
Have a history of severe anaphylaxis resulting in hypotension, neurological compromise, 
or mechanical ventilation  
• 
Have a history of intubation related to asthma   
• 
Tolerate more than 444 mg of baked milk protein at the initial qualifying DBPCFC.  
• 
Allergy to placebo ingredients OR reacts to any dose of placebo during the qualifying 
OFC.   
• 
Poor control of atopic dermatitis  
• 
Are unable to tolerate at least 3 mg of baked milk protein on dose escalation day  
• 
Are pregnant or lactating  
• 
Have severe asthma defined by 2007 NHLBI Criteria Steps 5 or 6  
• 
Have severe or poorly controlled asthma defined by with any of the following criteria:  
1. FEV1<80% of predicted   
2. ICS dosing of >500 mcg daily of fluticasone (or equivalent inhaled 
corticosteroids based on NHLBI dosing chart) or  
3. ≥ 1 hospitalization in the past year for asthma or  
4. > 1 ER visit in the past 6 months for asthma   
• 
Use of steroid medications (oral steroids, such as prednisone or Medrol, steroid 
injections, such as Kenalog, or IV or oral corticosteroid burst) in the following manners: 
History of daily oral steroid dosing within 4 weeks prior to baseline visit or for > 1 month 
during the past year or >2 burst oral steroid courses in the past 6 months.  
• 
Are unable to discontinue antihistamines for 5 days for long acting and 3 days for short 
acting prior to skin testing or food challenges  


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Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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• 
Are receiving omalizumab, mepolizumab, beta- blocker, ACE inhibitor, 
angiotensinreceptor blockers, calcium channel blockers, or tricyclic antidepressant 
therapy  
• 
Have used immunomodulatory therapy (not including corticosteroids) or biologic therapy 
within the past year  
• 
Have participated in any interventional study for treatment of a food allergy in the past 6 
months  
• 
Are on ‘build up phase’ of environmental allergen immunotherapy.  Subjects tolerating 
maintenance allergen immunotherapy can be enrolled.  
• 
Have a history of eosinophilic esophagitis in the past 3 years  
• 
Have a chronic disease (other than asthma, atopic dermatitis, rhinitis) requiring therapy 
(e.g., heart disease, diabetes)  
• 
Have used an investigational drug within 90 days or plan to use an investigational drug 
during the study period  
• 
Severe reaction at initial DBPCFC, defined as:  
o Life-threatening anaphylaxis o 
Requiring overnight hospitalization  
6. 
Drugs/ Substances/ Devices  
  
a. The rationale for choosing the drug and dose or for choosing the device to be used.  
  
The study treatment is non-fat cow’s milk powder or placebo ingested in a baked form.  The 
non-fat cow’s milk powder will be provided by the University of North Carolina (UNC).  It is 
manufactured by The Milky Whey, Inc & TMW International.  It will be refrigerated at the site 
at 2 through 8°C until provided to the participants.  Detailed instructions will be provided 
regarding how the baking should be performed.   
  
The doses chosen are based on prior milk OIT studies, which have all used unheated milk.  
We anticipate similar efficacy with greater safety using this approach.   
  
b. Justification and safety information if FDA approved drugs will be administered for 
nonFDA approved indications or if doses or routes of administration or participant 
populations are changed.  
  
Aside from the skin testing extracts, this study will not use any drugs, but rather foods 
commonly available in households, prepared using a standard oven.  Most milk OIT studies to 
date have used unheated milk at maintenance doses ranging from 500- 4000 mg.  As described in 
the background section, these have shown high rates of adverse reactions, ranging from mild, 
local symptoms, such as oral itching, to systemic allergic reactions.     
  
Baking milk has been shown to modify the allergen and make it less allergenic and 
therefore less likely to induce adverse reactions.  It has been shown that 50-75% of children with 


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CMA tolerate baked milk at full servings, such as a cupcake or muffin, and many are already 
incorporating these foods into their diet at home.13  However, the remaining 25-50% of children 
with CMA are not able to tolerate baked milk at standard doses.  Our dosing regimen will start 
with extremely small doses of baked milk protein and gradual escalation.    
  
  
  
We believe that the chemistry and manufacturing of the non-fat milk powder and Tapioca  
 
Flour does not present signals of potential human risk, beyond the inherent risk associated with  
 
the investigational treatment protocol.  This milk powder has been approved by the Food & Drug  
 
administration for use in other clinical trials (IND: 77,468) and in our study (IND: 17114).  
  
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.   
  
N/A  
  
7. 
Study Statistics  
  
a. Primary outcome variable.  
The primary objective of this trial is to study the safety of baked milk OIT, defined as the 
incidence of adverse events on baked milk OIT compared to adverse events on placebo.  
  
b. Secondary outcome variables.  
  
The secondary outcome measures are as follows:  
• 
Exploration of the clinical effects of baked milk OIT, defined as tolerating 4 grams of 
baked milk protein without adverse reactions after 12 and 24 months of treatment  
• 
Exploration of the clinical effects of baked milk OIT, defined as tolerating 2 grams of  
unheated milk protein without adverse reactions at the end of study year 
3 
end of year 
3 
 The exploration of biomarkers and mechanistic correlates of desensitization including 
milk-specific IgE and IgG4, milk skin prick test responses, T cell responses.  The 
exploration of the impact of milk allergy and its treatment on quality of life.  
Differences in clinical response rates based on duration of treatment (1 year versus 
3 
years)  
3 
 The proportion of subjects that achieve desensitization in the placebo crossover group 
after 1 year of dosing at the year 2 study time point.  The proportion of subjects who 
tolerate 8030 mg of unheated milk protein at the end of study year 
3 
 The incidence of adverse events in the unblinded year of treatment  Incidence of adverse 
events after stopping OIT (year 3 and 4)  Impact of cow’s milk OIT on goat and sheep 
milk-specific IgE  Comparison of maximum tolerated dose of baked milk compared to 
maximum tolerated dose of unheated milk at the end of year 
3 
 


Date: _7/9/2020   
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Application Number: _ IRB00099590__________  
  
  
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• 
The change in maximum tolerated dose of baked milk from baseline to end of year 1 and  
  
  
c. Statistical plan including sample size justification and interim data analysis.  
  
The primary outcome is safety, defined as the incidence of adverse events on baked milk 
OIT compared to adverse events on placebo.   
  
The main secondary outcome is a clinical response, defined as 1) the proportion tolerating 
4 grams of baked milk protein without adverse reactions after 12 and 24 months of treatment and 
2) the proportion tolerating 2 grams of unheated milk in the oral food challenge at the end of 
study year 2.  We have proposed a sample size based on 1) data from previous studies and 2) 
hypothesis testing for test of difference in proportions.  
  
Data from randomized, placebo-controlled unheated milk oral immunotherapy have 
shown various results.  Pajno et al had a maintenance dose of 200 mL and 67% were tolerant to 
200 mL of cow’s milk after 18 weeks.24  Martorell et al showed 90% desensitization after 1 year 
with a maintenance dose of 200 mL.19  We showed that 70% of patients receiving OIT with a 
maintenance dose of 1000-2000 mg for 60 weeks passed an 8g OFC.18  
  
As mentioned previously, there has only been 1 prior study using baked milk OIT.   
Goldberg et al had a different primary outcome which was the goal of attaining a maintenance 
BM dose of 1.3g/day.28  Only 21% reached that goal but as mentioned above, the study protocol 
was different than our study protocol.  
  
Based on these prior studies, we would expect that at most 10% of subjects in the placebo 
arm and at least 60% of subjects in the treatment arm would tolerate 2 grams of unheated milk at 
the 1 year OFC.  To achieve an alpha of 0.05 and a power of 0.8, 14 subjects are needed in each 
group.  15 participants per group would allow for a 7% drop out rate.  
  
  
Statistical plan:  
We will display summary statistics for each variable to keep track of missing data, and to 
be alerted to suspicious patterns in the data and outliers.  We will initially focus on the primary 
aim of the study.  We will examine adverse event endpoints to estimate 1) the risk associated 
with OIT and 2) compare the risks of OIT between the risks of adverse reactions in the placebo 
group.  We will tabulate the total number of serious adverse events (SAE) for the active 
treatment study population and construct a 95% confidence interval for this total number of 
adverse events.  We will also calculate the proportion of subjects who experienced an SAE along 
with the 95% CI.  We will calculate the proportion of doses that was associated with an SAE and 
construct the 95% CI.  We will compare the proportion of subjects who experienced an SAE 
between treatment and placebo groups and the proportion of doses resulting in an SAE between 
groups using Fisher’s exact test.  We will compare the number of adverse events between groups 
using the Kruskall-Wallis test if the variances between the groups are similar.  
  


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Application Number: _ IRB00099590__________  
  
  
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In addition to efficacy endpoints, we will tabulate data and calculate the proportion of 
subjects who achieved a clinical response and construct 95% confidence intervals.  We will do 
this for each time point being evaluated so that we have estimates of clinical response rates after 
completion of 1 year of OIT, after 2 years of OIT, and after 1 year of placebo.  
  
  
We will also compare clinical response rates between the active treatment and placebo 
groups at the year 1 and year 2 OFCs.  We will tabulate the clinical response rates by group for 
each time point and use a t-test for difference in proportions to test for statistical significances in 
response rates between groups.  
  
We will also compare change in maximum tolerated dose of baked milk from baseline to 
end of year 1 and end of year 2.  We will compare each subject’s maximum tolerated dose of 
baked milk compared to maximum tolerated dose of unheated milk at the end of year 2.  We will 
use a t-test for to test for statistical significances in change in amount tolerated between groups.  
  
Summary descriptive statistics for baseline and demographic characteristics and biomarker 
and mechanistic studies will be provided for all enrolled participants.  Demographic data will 
include age, race, sex, body weight, and height.  Biomarker and mechanistic data will include 
cow’s milk IgE and IgG4, goat and sheep milk IgE, and lymphocyte analysis.  These data will 
be presented in the following manner:  
• 
Continuous data (i.e., age, body weight, and height) will be summarized 
descriptively by mean, standard deviation, median, and range.  
• 
Categorical data will be presented as enumerations and percentages.  
Statistical presentation for baseline and demographic characteristics may be further 
summarized as appropriate.  
  
d. Early stopping rules.  
  
Study enrollment and treatment will be suspended pending expedited review of all 
pertinent data by the IRB and the DSMB if the following occur:   
• 
Any death.  
• 
More than one severe anaphylactic reaction related to baked milk immunotherapy dosing 
at any stage of the protocol.  
• 
More than three subjects require more than one injection of epinephrine during dosing of 
the baked milk immunotherapy.  
• 
The first 5 subjects cannot reach 3 mg of OIT.  
  
Additionally, the study will be stopped upon enrollment and completion of the defined 
number of participants that meet the selection criteria.  
  
  
8.  
Risks  
  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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a. Medical risks, listing all procedures, their major and minor risks and expected frequency.  
i. Baked Milk Powder administered via the oral route   
  
The escalation day followed by the build-up phase of immunotherapy is based on 
previous experience with peanut, egg, wheat, and unheated milk OIT.  In the Principal  
Investigator’s experience, the initial doses have been well tolerated.  Therefore, the initial dose 
escalation day was included to shorten the prolonged build-up phase.  The likelihood of 
participants experiencing allergic symptoms will be decreased by the OIT protocol, starting at 
extremely small amounts with gradual escalation.    
  
Unheated oral immunotherapy has shown a high rate of adverse reactions.  In 2011, 
Martorell et al conducted a 1 year milk OIT study in 2-3 year old children.  While 90% were 
desensitized, 47% developed moderate reactions (rhinoconjunctivitis, wheezing, vomiting, 
urticaria) over the course of treatment.19  In 2012, we examined the safety and efficacy of OIT 
and SLIT (sublingual immunotherapy) for cow’s milk allergy.  The study reported the reaction 
rate during the initial OIT escalation (36%), 1000 mg OIT escalation and maintenance (30%), 
and 2000 mg OIT escalation and maintenance (27%).18  The majority of symptoms were mild 
and localized to oral pruritus.18  During this study, antihistamines were used in 11% of doses 
during initial OIT escalation, 3.5% of doses in the 1000 mg escalation and maintenance, and 11% 
of doses in the 2000 mg OIT escalation and maintenance.  A β-agonist was required in  
1.5%, 2%, and 1.5% of doses in each respective group.  Epinephrine was used for 4 OIT doses.18 
In addition, 10-20% of subjects have dropped out of OIT trials due to adverse reactions, most 
commonly chronic abdominal pain.12,26     
  
We would view these risks as worst case scenario, since we expect far fewer adverse 
reaction with the heat modified milk proteins.  
  
ii. Allergy Skin Testing  
  
There is a risk of minor discomfort and itching and a transient hive.  A localized wheal 
and flare will occur at the site of the histamine control.  A similar reaction may occur at the site 
of milk extract.  Fewer than 5 in 10,000 tests results in a systemic reaction (e.g. sneezing, runny 
nose, itchy eyes, or hives), and, even more rarely, systemic reactions that can be life- 
threatening.29-32  There have been no systemic reactions in the principal investigator’s experience 
with over 75,000 skin tests.    
iii. Blood Collection   
  
There is a risk of minor discomfort or bruising at the site of the blood draw.  Some people 
may experience lightheadedness. Very rarely, an infection can develop at the site of the 
venipuncture.  
  


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Application Number: _ IRB00099590__________  
  
  
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iv. Spirometry and Peak Flow  
  
The minor risk is of slight discomfort associated with forceful expiration and, 
occasionally, lightheadedness.   
v. Oral food challenge  
  
In this study, children will undergo oral food challenges to determine baseline level of 
reactivity and response to therapy.  The risk attendant to an oral food challenge is the same as 
those that may occur from a food-allergy reaction and are typically short-lived (less than 2 
hours).  Common symptoms may include urticaria, angioedema, nausea, abdominal discomfort, 
vomiting and/or diarrhea, rhinorrhea, sneezing and/or mild wheezing.  The major risks involved 
include severe breathing difficulties, and rarely, a drop in blood pressure.  A severe outcome is 
theoretically possible and one death has occurred in a medically supervised oral food challenge.  
However, to date the primary investigators have performed more than 5000 oral food challenges 
without a serious life-threatening anaphylactic reaction or need for hospitalization.    
  
We have chosen to only challenge to baked milk at screening and at the end of year 1 in an 
effort to reduce risk, recognizing that all subjects who react to heated milk would react to 
unheated milk at the same or lower dose.   
  
vi. Medical Exams: There are no known risks for the physical exam.   
vii. Pregnancy Tests: There is a risk of loss of confidentiality of results as positive tests would 
be provided to the parents in all participants <18 years old.  
  
b. Steps taken to minimize the risks.  
  
 
i.  
Baked Milk Powder administered via the oral route   
  
The use of heated milk in this study is specifically designed to minimize the risk of 
treatment.  In addition, as with our studies using unheated milk, the initial doses are extremely 
small and subsequent dose increases will be gradual.  Dose escalation will be done under direct 
supervision of a physician.  Appropriate medications, equipment, and personnel will be available 
in case of a severe reaction, especially given that the study will be conducted in the PCRU on 
Bloomberg 9.  Upon completion of a food challenge or IDE, all participants will be observed for 
at least 2 hours, unless the OFC is unblinded and the participant had a negative challenge to 
placebo.  For any severe systemic reaction, all subjects will be observed for at least 4 hours or 
until signs of clinical reactivity subside.  Any subject with ongoing severe systemic symptoms 
(i.e. persistent vomiting, wheeze, cough, FEV1<80% baseline level, hypotension, or laryngeal 
edema manifested by difficulty breathing or speaking) will be observed in clinic until symptoms 
resolve.  If they do not resolve, the subject will be hospitalized.    In the event of a negative 
challenge to placebo, participants can be sent home after unblinding.  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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For the build-up visits, subjects will be observed for at least 1 hour after dosing.  For any 
moderate symptoms, all participants will be observed for at least 2 hours.  For any severe 
systemic reaction, all subjects will be observed for at least 4 hours or until signs of clinical 
reactivity subside.    
  
All subjects will have injectable epinephrine (available at all times, and clear instructions 
about its use.  The subject will be contacted on the day after dose escalation to monitor for 
adverse events.  A 24-hour physician emergency number will be given to the subject.    
  
  
ii. Allergy Skin Testing  
  
SPT will be performed by a trained physician or nurse.  Appropriate medications will be 
available at the time of testing (antihistamine, steroids, short-acting beta agonist, and 
epinephrine).  A designated physician will be immediately available to provide medical 
assistance if necessary.  Any participant with an asthma exacerbation at the time of the visit will 
not undergo skin testing.  He/she may return at a later date when his/her asthma is under control.  
An asthma exacerbation will be defined as wheezing on chest auscultation, currently taking oral 
corticosteroids, or having FEV1 or PEFR <70% predicted.  
iii. Blood Collection   
  
A staff member who is trained to draw blood from children will collect the samples.  We 
will not draw more than 3 cc/kg/month/subject of blood.  
  
iv. Spirometry and Peak Flow  
  
Spirometry and peak flow readings will be performed by trained personnel. v. 
Oral food challenge  
  
Trained staff will be present to administer study food challenges and a physician will be 
at the bedside to provide oversight, evaluation, and treatment as needed.  The risks of oral food 
challenges are minimized by the following procedures:  
• 
Children must have a stable baseline examination prior to undergoing the 
challenge without significant symptoms of flaring atopic dermatitis, exacerbations 
of rhinorrhea, current urticarial, or other symptoms evaluated during food 
challenges  
• 
Children must have no wheezing or repetitive cough prior to challenge  
• 
Children must have no current illnesses (e.g. fever) at time of oral challenge  
• 
Medications (epinephrine, intravenous fluids, antihistamines, ranitidine, 
vasopressors, beta-agonists, and steroids), personnel and equipment (oxygen, 


Date: _7/9/2020   
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Application Number: _ IRB00099590__________  
  
  
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resuscitation equipment) will be immediately available to treat allergic reactions 
should they occur.  
• 
Children will have discontinued antihistamines and bronchodilators for 
appropriate periods prior to challenge, thereby allowing investigators to perform 
challenges only when participants are stable without influence of medications.  
• 
The food will be provided gradually, at 15 minute intervals, beginning with a dose 
unlikely to trigger a reaction and progress stepwise with escalating doses.  
• 
Vital signs (heart rate, blood pressure, respiratory rate) and physical examination 
will be undertaken at baseline and at the end of the OFC with a focused 
examination undertaken prior to each dose  
• 
Challenges will be stopped, and medications administered, in the event of any 
objective symptoms.  
All participants will be observed for at least 2 hours, unless the OFC is unblinded 
and the participant had a negative challenge to placebo.  For any severe systemic 
reaction, all subjects will be observed for at least 4 hours or until signs of clinical 
reactivity subside.    
vi. Pregnancy Tests:   
  
Personal identifiers will not be placed on collected data.  
  
  
c. Plan for reporting unanticipated problems or study deviations.  
  
Reporting will occur as follows:   
  
i. 
Toxicity will be graded according to the NCI-CTC for application in adverse event 
reporting. The NCI-CTC has been reviewed specifically for this protocol and is 
appropriate for this study population. The purpose of using the NCI-CTC system is to 
provide standard language to describe toxicities, and to facilitate tabulation and analysis 
of the data and assessment of the clinical significance of treatment-related toxicities. The 
investigator will try to determine the relationship of toxicity to baked milk 
immunotherapy as not related, possibly related, or definitely related using standard 
criteria for clinical trials. All grades of toxicity will be noted. Toxicity grades are 
assigned by the study site to indicate the severity of adverse experiences and toxicities.   
  
ii. 
Adverse events, not included in the NCI-CTC listing, should be recorded and graded 0-4 
according to the General Grade Definition provided below:  
  
Table 7: General Grade Definitions  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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Grade 0  
Mild  
Transient or mild discomforts (< 48 hours), no or 
minimal medical intervention/therapy required, 
hospitalization not necessary (non-prescription or single-
use prescription therapy may be employed to relieve 
symptoms, e.g., aspirin for simple headache, 
acetaminophen for postsurgical pain)  
Grade 1  
Moderate  
Mild to moderate limitation in activity, some assistance 
may be needed; no or minimal intervention/therapy 
required, hospitalization possible.  
Grade 2  
Severe  
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required 
hospitalization possible.   
Grade 3  
Lifethreatening Extreme limitation in activity, significant assistance 
required; significant medical/therapy intervention 
required hospitalization or hospice care probable.  
Grade 4  
Death  
Death  
  
iii. 
Adverse Event Reporting:   
  
Within the context of this study, blood draws, allergy skin prick tests, dose increases 
and oral food allergy challenge tests will be observed and recorded. Adverse events (AEs) 
that are temporally related to these procedures or to home dosing with the study medications 
(during 3 days following the procedure) will be reportable adverse events.  Anticipated local 
reactions to prick skin tests and oral food challenges reactions occurring during the challenge 
procedure will not be additionally reported on an adverse event form unless the reaction 
results in a serious adverse event.  In that case it will be reported both on the reaction form 
and on a serious adverse event form.   
  
The following events would be considered expected events for the procedures being 
performed:   
• 
Blood draw: nausea and vomiting, local infection, and fainting  
• 
Prick skin test: Pruritus, transient hive, systemic allergic reaction  
• 
Oral food challenges and dosing with study medications: allergic reactions related to 
the skin (hives, pruritus, eczema flare), the respiratory tract (nasal congestion, 
rhinorrhea, fits of sneezing, difficulty breathing, asthma), and the GI tract 
(oropharyngeal pruritus and edema, nausea, vomiting and diarrhea).   
  
All “unanticipated” adverse events related to the experimental procedures will be 
reported to the DSMB in an expedited manner if they are Grade 2 and above in severity.  All 
“anticipated” adverse events related to the experimental procedures will also be reported in 
an expedited manner if they are Grade 2 and above in severity.  Subject deaths are reportable 
within 24 hours.  The investigator will continue to follow or obtain documentation of the 


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Application Number: _ IRB00099590__________  
  
  
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resolution course of such an event.  A copy of the annual report of adverse events will be 
reported to the IRB.   
  
iv. 
Data and Safety Monitoring:   
  
A Data Safety Monitoring Board will be convened for overview of this study.  The 
Principal Investigator and Co-Investigators are responsible for collecting and recoding all 
clinical data.  As these results are collected, all toxicities and adverse events will be 
identified and reported to the PI.  Adverse events will be reported as described above.  The 
Principal Investigator will determine the relationship of the event to the study intervention 
and decide the course of action for the study participant.   
  
Yearly reports will be made to the DSMB and proper Institutional Committees, as 
required.  All adverse events will be kept in a computerized file by numerical identifier.   
  
In the event that the study is stopped because of adverse event(s), it will not be 
resumed until information regarding the adverse event(s) has been discussed with the DSMB 
and the DSMB concurs with resumption of the studies.   
  
  
d. Legal risks such as the risks that would be associated with breach of 
confidentiality.  
  
The risk of breach of confidentiality will be minimized by using unique identifiers for 
participants and keeping the record that links the identifier to the participant in a locked file 
cabinet accessible only to the investigators.  
  
Genomic research and broad sharing of genomic data will have an “opt-in” and “opt-out” 
area on the consent and will not affect the participants’ eligibility to take part in the study.  In 
addition, personal identifying information about the subject (such as name, phone number, 
address) will NOT be included in these genomic databases or shared with others, including 
our collaborator, La Jolla Institute.  
  
e. Financial risks to the participants.  
  
The study does not provide routine care or any medications or treatments for general 
health or allergic problems (although we will be available for phone consultation regarding 
possible reactions).  All costs associated with study visits, skin testing, spirometry, blood 
drawing, food challenges, and OIT protein are covered by the investigators.  All participants 
will be required to provide a muffin/cupcake mix in which they can bake the weekly doses of 
OIT.  This will be provided by the family so that flavor/variety can be altered for each child’s 
preference.  All participants will be required to have an epinephrine auto-injector available at 


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Application Number: _ IRB00099590__________  
  
  
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home during immunotherapy treatment.  If they do not already have one, they will be 
responsible for the cost of this medication.  
  
9. 
Benefits  
  
a. 
Description of the probable benefits for the participant and for society.  
  
The benefits for the participant include the possibility of a change in sensitivity to milk 
and decreased allergic reactions following an accidental ingestion of milk.  Another possible 
benefit is the possibility of altering the natural course of the milk allergy.   
  
The potential benefit to the subject and family is that this active protocol may induce 
tolerance to milk protein in someone that is unlikely to naturally “outgrown” his/her allergy.  If 
tolerance is achieved, this then make impact quality of life.  
  
The results of this study will have important implications for the treatment of cow’s milk 
allergy and food allergy in general.  The results would add evidence regarding safety and 
efficacy of OIT in treating food allergy.  By using the baked allergen, we hope to decrease the 
adverse effects of OIT.  The laboratory studies will help us understand the underlying biomarkers 
surrounding immunotherapy and clinical desensitization.  These markers have the potential to 
serve as diagnostics to indicate progression to tolerance over time and/or to prospectively predict 
early versus late resolution of milk allergy.    
  
10. 
Payment and Remuneration  
  
a. 
Detail compensation for participants including possible total compensation, proposed 
bonus, and any proposed reductions or penalties for not completing the protocol.  
  
Subjects will receive $25 per visit and a parking coupon to cover the cost of travel and 
parking.  
  
11.  
Costs  
  
a.  
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and 
identify who will pay for them.  
  
The study does not provide routine care or any medications or treatments for general 
health or allergic problems (although we will be available for phone consultation regarding 
possible reactions).  All participants will be required to have an epinephrine auto-injector 
available at home during immunotherapy treatment.  If they do not already have one, they will be 
responsible for the cost of this medication  
  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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All costs associated with study visits, skin testing, spirometry, blood drawing, food 
challenges, and OIT are covered by the investigator.  All participants will be required to provide 
a muffin/cupcake mix in which they can baked the weekly doses of OIT.  This will be provided 
by the family so that flavor/variety can be altered for each child’s preference.  The study milk 
protein or placebo will be provided by the investigator.  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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Table 8:  Study Year 1   
  
Baseline  
DBPCFC  
#1  
Dose 
Escalation  
 
 
 
 
Build-Up Phase #1  
 
 
 
Maintenance 
Phase #1  
DBPCFC  
#2  
Week  
-3  
-2  
-1*  
0  
2  
4  
6  
8  
10  
12  
14  
16  
18  
20  
22  
30  
38  
46  
52  
54*  
Visit Number  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
14  
15  
16  
17  
18  
19  
20  
Informed Consent  
X  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
History  
X  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
Limited physical 
exam  
X  
x  
x  
x  
X  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Vital Signs  
X  
x  
x  
x  
X  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Symptom/diet 
information  
X  
 
 
x  
X  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
U HCG  
X  
x  
 
x  
X   
x  
 
x  
 
x  
 
x  
  
x  
x  
x  
x  
x  
  
Spirometry+  
x  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Peak Flow Rate+  
X  
x  
x  
x  
X  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
SPT  
X  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
x  
  
  
x  
  
Blood draw  
X  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
x  
  
  
x  
  
QOL Questionnaire  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x  
  
GI assessment  
X  
  
  
x  
  
x  
  
x  
  
x  
  
x  
  
x  
x  
x  
x  
x  
x  
  
DBPCFC #1  
 
x  
x  
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
DBPCFC #2  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
x  
x  
Randomization  
 
 
x  
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
OIT dose increase   
 
 
x  
X  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
  
  
  
  
  
*Second half of food challenge must occur within 21 days of the first half of the challenge + Spirometry will be 
attempted in all subjects ≥6 years old.  Peak Flow rate will be attempted for children < 6 years old.  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
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Table 9: Study Year 2 -4 schedule: Initial Treatment Group who Achieved 2 grams during Year 
1  
  
Maintenance Phase #2  
DBPCFC  
#3  
DBPCFC#4+  
Week  
56  
68  
80  
92  
104  
106  
108*  110  
112*  
Visit Number  
21  
22  
23  
24  
25  
26  
27  
28  
29  
Informed Consent  
  
  
  
  
  
  
  
  
  
History  
  
  
  
  
  
  
  
  
  
Limited physical exam  
x  
x  
x  
x  
X  
x  
x  
x  
X  
Vital Signs  
x  
x  
x  
x  
X  
x  
x  
x  
X  
Symptom/diet 
information  
x  
x  
x  
x  
X  
x  
x  
x  
X  
U HCG  
x  
x  
x  
x  
X  
x  
 
x  
X  
Peak Flow Rate  
x  
x  
x  
x  
X  
x  
x  
x  
X  
SPT  
 
 
 
 
 
x  
 
  
  
Blood draw  
 
 
 
 
 
x  
 
  
  
QOL Questionnaire  
  
  
  
  
  
x  
  
  
  
GI assessment  
x  
x  
x  
x  
x  
x  
  
x  
  
DBPCFC #3  
 
 
 
 
 
x  
x  
  
  
DBPCFC #4  
  
  
  
  
  
  
  
x  
x  
Randomization  
 
 
 
 
 
 
 
  
  
OIT dose increase  
 
 
 
  
  
  
  
  
  
  
*Second half of food challenge must occur within 21 days of the first half of the challenge + 
DBPCFC#4 will only be performed if subject tolerates ≥2000 mg of baked milk during DBPCFC#3  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
JHMIRB eFormA  01  
Version 14 Dated:   2/2020  
  
Page 34 of 40  
  
  
  
  
  
  
  
  
  
  
  
  
Table 10: Study Year 2 -4: Initial Treatment Group who did NOT reach 2000 mg during year 1  
  
Build-up Phase #2  
Maintenance Phase 
#2  
DBPCFC  
#3  
DBPCFC #4+  
Week  
56  
58  
60  
62  
64  
66  
68  
70  
72  
80  88  96  104  106  108*  
110  
112*  
Visit Number  
21  
22  
23  
24  
25  
26  
27  
28  
29  
30  31  32  
33  
34  
35  
36  
37  
Informed 
Consent  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Limited 
physical exam  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Vital Signs  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Symptom/diet 
information  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
U HCG  
x  
 
x  
 
x  
  
x  
  
X  
x  
x  
x  
x  
x  
x  
x  
x  
Peak Flow Rate  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
SPT  
 
 
 
 
 
  
  
  
  
  
  
  
  
x  
 
  
  
Blood draw  
 
 
 
 
 
  
  
  
  
  
  
  
  
x  
 
  
  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
JHMIRB eFormA  01  
Version 14 Dated:   2/2020  
  
Page 35 of 40  
  
QOL 
Questionnaire  
  
  
  
  
  
  
  
  
  
  
  
  
  
x  
  
  
  
GI assessment  
X  
  
x  
  
x  
  
x  
  
x  
x  
x  
x  
x  
x  
  
x  
  
DBPCFC #3  
 
 
 
 
 
  
  
  
  
  
  
  
  
x  
x  
  
  
DBPCFC #4  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x  
x  
Randomization   
 
 
 
 
  
  
  
  
  
  
  
  
 
 
  
  
OIT dose 
increase  
X  
x  
x  
x  
x  
x  
x  
x  
x  
  
  
  
  
  
  
  
  
  
*Second half of food challenge must occur within 21 days of the first half of the challenge + 
DBPCFC#4 will only be performed if subject tolerates ≥2000 mg of baked milk during DBPCFC#3  
  
  
  
  
  
  
Table 11:  Study Year 2-4: Initial Placebo Group who Crosses Over  
  
DE 
day  
Build-up Phase #2  
 
 
Maintenance Phase 
#2  
DBPCFC #3  DBPCFC #4+  
Week  
56  
58  
60  
62  
64  
66  
68  
70  
72  
74  
76  
78  
86  
94  
102  
106  
108*  
110  
112  
Visit Number  
21  
22  
23  
24  
25  
26  
27  
28  
29  
30  
31  
32  
33  
34  
35  
36  
37  
38  
39  
Informed 
Consent  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History  
x  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Limited physical 
exam  
x  
X  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Vital Signs  
x  
X  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
  
  
x  
x  
x  
x  
Symptom/diet 
information  
x  
X  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
JHMIRB eFormA  01  
Version 14 Dated:   2/2020  
  
Page 36 of 40  
  
U HCG  
x  
 
x   
x  
  
x  
  
x  
  
x  
  
x  
x  
x  
x  
x  
x  
x  
Peak Flow Rate  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
  
  
x  
x  
x  
x  
SPT  
 
 
 
 
 
  
  
  
  
  
  
  
x  
  
  
x  
 
  
  
Blood draw  
 
 
 
 
 
  
  
  
  
  
  
  
x  
  
  
x  
 
  
  
QOL 
Questionnaire  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x  
  
  
  
GI assessment  
x  
  
x  
  
x  
  
x  
  
x  
  
x  
x  
x  
x  
x  
x  
  
x  
  
DBPCFC #3  
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
x  
x  
  
  
DBPCFC #4  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x  
x  
Randomization   
 
 
 
 
  
  
  
  
  
  
  
  
  
  
 
 
  
  
OIT dose 
increase  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
  
  
  
  
  
  
  
DE: Dose Escalation  
*Second half of food challenge must occur within 21 days of the first half of the challenge  
+ DBPCFC#4 will only be performed if subject tolerates ≥2000 mg of baked milk during DBPCFC#3  
  
  
  
  


Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
JHMIRB eFormA  01  
Version 14 Dated:   2/2020  
  
Page 37 of 40  
  
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Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
JHMIRB eFormA  01  
Version 14 Dated:   2/2020  
  
Page 38 of 40  
  
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Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
JHMIRB eFormA  01  
Version 14 Dated:   2/2020  
  
Page 39 of 40  
  
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Date: _7/9/2020   
Principal Investigator: ___Robert Wood______________  
Application Number: _ IRB00099590__________  
  
  
JHMIRB eFormA  01  
Version 14 Dated:   2/2020  
  
Page 40 of 40  
  
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