Clinical trial NCT02579876
Conditions: Eosinophilic Esophagitis Milk Allergy
Keywords: Milk Allergy Viaskin Milk Epicutaneous ImmunoTherapy (EPIT) Eosinophilic Esophagitis Milk-Induced Eosinophilic Esophagitis
Sponsor: Children's Hospital of Philadelphia
Start date: 2015-10-01; Completion date: 2018-11-20
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a single-site, double-blind, placebo-controlled, randomized trial to study efficacy and safety of the Viaskin® Milk Patch for children with milk induced Eosinophilic Esophagitis (EoE). 20 subjects will be randomized 3:1 to Viaskin® Milk or placebo patch.

Detailed description:
This is a double-blind, placebo-controlled, randomized trial to study the efficacy and safety of Viaskin® Milk, an allergen extract of milk administered epicutaneously using the Viaskin® epicutaneous delivery system (EPIT) in subjects from 4 to 17 years old with a milk induced Eosinophilic Esophagitis. Subjects will be randomized in a 3:1 ratio into two different treatment groups, to receive EPIT with Viaskin® Milk (500 µg of milk proteins) or placebo.

Subjects who complete the double-blind treatment period (approximately 11 months), will automatically rollover into an open label treatment period (additional 11 months). All subjects will receive the 500 µg (micrograms) Viaskin Milk patch.

Arms: arm 1: Viaskin patch containing milk protein. The patch is applied to the skin arm 2: Viaksin patch without any milk protein.
Interventions: intervention 1: Viaskin Milk 500 mcg intervention 2: Viaskin Placebo
Intervention descriptions: intervention 1: Biological: Viaskin Milk 500 mcg Subjects epicutaneously administered daily (up to 24 hours application per day) with a patch containing 500 mcg cow's milk proteins. intervention 2: Biological: Viaskin Placebo Subjects epicutaneously administered daily (up to 24 hours application per day) with a patch containing a matching placebo formulation.

Protocol documents:
Prot_001.pdf: 
Sponsor Name: Jonathan Spergel 
 
Protocol No. SMILEE 
    
 
 
Version 8.0 (Amendment 7), 21 August 21, 2017 
 
 
 
A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED TRIAL TO STUDY 
EFFICACY AND SAFETY OF THE VIASKIN® MILK FOR TREATING MILK 
INDUCED EOSINOPHILIC ESOPHAGITIS IN CHILDREN  
(SMILEE STUDY) 
 
 
Test Drug: 
Viaskin® Milk: Allergen extract of Milk in Viaskin® epicutaneous delivery 
system 
 
 
Protocol Number: SMILEE  
 
IND number:  
16518 
Study Phase:  
IIA 
 
 
Version and Date: 
8.0, 21 August 21, 2017 
 
 
Sponsor:   
Jonathan M. Spergel, MD, PhD 
Division of Allergy and Immunology 
The Children’s Hospital of Philadelphia 
3401 Civic Center Blvd 
Philadelphia, PA 19104 
 
 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) as 
set forth in the International Conference on Harmonization (ICH) guidelines on GCP (ICH E6), 
and applicable local regulatory requirements. 
 
CONFIDENTIAL 
 
 
This document is a confidential communication. Acceptance of this document constitutes agreement by the recipient that 
no unpublished information contained herein shall be published or disclosed without prior written approval, except that this 
document may be disclosed to the appropriate Institutional Review Board(s)/Independent Ethics Committee(s) under the 
condition that they keep it confidential. 


Sponsor Name: Jonathan Spergel 
 
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1. 
SIGNATURES 
 
Representatives of Sponsor 
I have read and agree to the SMILEE protocol, entitled ‘A double-blind, placebo-controlled, 
randomized trial to Study efficacy and safety of the Viaskin® Milk for Treating milk induced 
Eosinophilic Esophagitis in children  (SMILEE study). I am aware of my responsibilities under 
the guidelines of GCP, local regulations (as applicable) and the study protocol. I agree to conduct 
the study according to these responsibilities. 
 
Jonathan Spergel, MD, PhD 
 
___________________________________              _________________ 
Signature                                                                    Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sponsor Name: Jonathan Spergel 
 
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Investigator 
 
I have read and agree to the protocol SMILEE protocol, entitled ‘A double-blind, placebo-
controlled, randomized trial to Study efficacy and safety of the Viaskin® Milk’s for Treating milk 
induced Eosinophilic Esophagitis in children (SMILEE study). I am aware of my responsibilities 
as an Investigator under the guidelines of GCP, local regulations (as applicable) and the study 
protocol. I agree to conduct the study according to these responsibilities and to appropriately 
direct and assist the staff under my control, who will be involved in the study. 
 
Clinical Site:  
The Children’s Hospital of Philadelphia 
 
 
 
Perelman School of Medicine 
 
 
Site Principal Investigator: 
 
 
Antonella Cianferoni, MD, PhD 
 
 
Assistant Professor of Pediatrics 
Print Name 
 
Title 
 
 
 
 
Signature 
 
Date 


Sponsor Name: Jonathan Spergel 
 
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2. 
SYNOPSIS 
 
NAME OF SPONSOR: Jonathan Spergel 
 
PROTOCOL No.: SMILEE 
 
NAME OF STUDY TREATMENT: Viaskin® Milk (DBV: Allergen extract of milk in 
Viaskin® epicutaneous delivery system) 
TITLE OF STUDY: A double-blind, placebo-controlled, randomized trial to Study 
efficacy and safety of the Viaskin® Milk for Treating milk induced Eosinophilic 
Esophagitis in children  
STUDY CENTERS: This is a single site study conducted in United States.  The only site 
will be The Children’s Hospital of Philadelphia.  
STUDY PERIOD: Recruitment will stop when approximately 22 
subjects have been randomized in the study. 
Subject’s participation in the study will last approximately 2 years 
PHASE OF 
DEVELOPMENT:  
Phase IIA 
PLANNED STUDY DURATION: approximately  3 years. 
OBJECTIVES: The objectives of this study are: 
• 
To assess the efficacy of Viaskin® Milk epicutaneous immunotherapy (EPIT) in 
subjects with milk-induced eosinophilic esophagitis. 
• 
To evaluate the safety of Viaskin® Milk EPIT in subjects with milk-induced 
eosinophilic esophagitis. 
 
STUDY DESIGN AND METHODOLOGY: This is a double-blind, placebo-controlled, 
randomized trial to study the efficacy and safety of Viaskin® Milk, an allergen extract of 
milk administered epicutaneously using the Viaskin® epicutaneous delivery system in 
subjects from 4 to 17 years old with a milk induced Eosinophilic Esophagitis. The trial will 
be conducted at The Children’s Hospital of Philadelphia (CHOP).  
 
The first four patients will be 8-17 years old and after these patients are randomized, we 
will open the study to all ages 4-17 years old.  
 
Subjects with a documented medical history of Eosinophilic Esophagitis after ingestion of 
milk and currently following a strict milk-free diet will be considered for participation in 
the SMILEE study. A screening/standard of care upper endoscopy and biopsy will be 
performed after introduction of milk (minimum of 30 ml/day for 1 week to 2 months). If 
the endoscopy shows greater than or equal to 15 eosinophils per high power field (HPF), it 
will confirm the diagnosis of Eosinophilic Esophagitis. In addition, milk will be removed 
from the diet and a standard of care-upper endoscopy and biopsy will be performed after a 
minimum of 6 weeks under milk-free diet to confirm the diagnosis of milk-induced 
Eosinophilic Esophagitis. If the biopsy after milk elimination shows 0 to 10 eosinophils 
per HPF, the subjects will be eligible for participation in the study, and will be randomized 
in a 3:1 ratio into two different treatment groups, to receive EPIT with Viaskin® Milk (500 
µg of milk proteins) or placebo. If a subject has SOC endoscopy in 12 months prior to 
study, they will not need repeat endoscopies to be eligible for the study and will be 
randomized as above.  A minimum of two standard of care endoscopy procedures will be 
performed to obtain milk EoE diagnostic results needed for study qualification, and the 
results of additional SOC endoscopies will be allowed to assess eligibility, if the 


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endoscopies are required for clinical care purposes.  Milk will be reintroduced into the diet 
of the subject after 9 months of treatment at equivalent amounts and duration as performed 
during the screening period.  A third research upper endoscopy and biopsy will be 
performed at the end of the milk-reintroduction period. After the 3rd upper endoscopy, all 
subjects will continue treatment with open-label Viaskin® Milk (500 µg of milk proteins).  
Subjects with ≥15 eosinophils/hpf on the 3rd upper endoscopy will restart milk-free diet for 
9 additional months while on treatment with active therapy.  Then, they will reintroduce 
milk into their diet at equivalent amounts and duration as performed during the screening 
period, at which time a 4th upper endoscopy will be done. For subject with < 15 
eosinophils/hpf on the 3rd upper endoscopy, they will continue on milk for up to 11 
additional months (if symptoms re-appear, milk-free diet should restart) while on treatment 
with active therapy, at which time a 4th upper endoscopy will be done.   A final follow-up 
visit will be done 2 weeks after completion of treatment and after the last endoscopy. 
 
In total, during this study, eligible subjects will be required to attend 17 study visits.  
 
In addition to endoscopy and biopsy, subjects will undergo other efficacy parameter 
assessments at months 1, 3, 6, 9, 11, 14, 17, 20 and 22. Key assessments of safety will be 
performed at each study visit including vital signs, physical examinations and laboratory 
assessments. In between visits, subjects will report safety data on the diary cards 
 
STUDY POPULATION AND MAIN CRITERIA FOR INCLUSION/EXCLUSION:  
Pediatric subjects, aged 4 to 17 years, with milk induced Eosinophilic Esophagitis will 
be enrolled and randomized following confirmation of all eligibility criteria.  
 
Inclusion Criteria:  
1. Subjects between 4 and 17 years of age at the time of signing the informed consent 
2. Well-documented symptoms suggestive of EoE after ingestion of milk and currently 
following a strict milk-free diet. 
3. Upper endoscopy and biopsy at clinical evaluation during screening showing greater 
than or equal to15 eosinophils per high power field (HPF) isolated to the esophagus 
meeting the consensus diagnosis of Eosinophilic Esophagitis, after milk was re-
introduced into the subject’s diet (30 ml/day for 1 week to 2 months), while the subject 
was on proton pump inhibitor. A clinical decision has been made to perform a 
minimum of two standard of care endoscopy procedures to obtain milk EoE diagnostic 
results. 
4. Upper endoscopy and biopsy at clinical evaluation during screening showing 0 to 10 
eosinophils per HPF isolated to the esophagus after a minimum of 6 weeks under milk-
free diet, and while the subject is on proton pump inhibitor.  A clinical decision has 
been made to perform a minimum of two standard of care endoscopy procedures to 
obtain milk EoE diagnostic results. 
5. Negative pregnancy test for female subjects of childbearing potential. Females of 
childbearing potential must use effective methods of contraception to prevent 
pregnancy and agree to continue to practice an acceptable method of contraception for 
the duration of participation in the study. Sexual abstinence will be accepted as an 
effective method of contraception for girls below 18 years of age. 


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6. Subjects and/or parents/guardians willing to comply with all study requirements during 
their participation in the study. 
7. Signed informed consent from parent(s)/guardian(s) of children < 18 years + children’s 
assent (for children > 7 years). 
8. Subjects agree to maintain a constant diet during the trial, with the exception of milk 
as per protocol requirement. 
9. Subjects will maintain constant medications for asthma and allergic rhinitis during the 
trial. 
 
Exclusion Criteria:  
1. Subjects with a history of severe anaphylaxis to milk with the following symptoms: 
hypotension, hypoxia, neurological compromise (collapse, loss of consciousness or 
incontinence), Quincke Edema or requiring intubation. 
2. Active IgE- mediated Milk allergy based on skin test or history.  
3. Pregnancy or lactation.  
4. Subjects with other eosinophilic gastrointestinal disorders. 
5. Subjects on swallowed corticosteroids or anti-leukotrienes for Eosinophilic 
Esophagitis. 
6. Subjects with symptomatic allergy to pollens whose symptoms during the 
corresponding pollen season might interfere with the recording of symptoms during the 
upper endoscopy/biopsy if the upper endoscopy/biopsy is conducted during the pollen 
season. The Investigator will have to ensure that the period for conducting the upper 
endoscopy for such a subject will be outside of the pollen season.  
7. Subjects treated with systemic long-acting corticosteroids (depot corticosteroids) 
within 12 weeks prior to Visit 1 and/or systemic short-acting corticosteroid within 4 
weeks prior to Visit 1 or any systemic corticosteroid at screening. 
8. Subjects with asthma conditions defined as follows: 
a. uncontrolled persistent asthma by National Asthma Education and Prevention 
Program Asthma guidelines (2007); 
b. at least two systemic corticosteroid courses for asthma in the past year or one oral 
corticosteroid course for asthma in the past three months; 
c. prior intubation for asthma in the past two years. 
9. Subjects on β-blocking agents, angiotensin-converting enzyme inhibitors, angiotensin-
receptor blockers, calcium channel blockers or tricyclic antidepressant therapy.  
10. Subjects undergoing any type of immunotherapy to any food (oral immunotherapy, 
sublingual immunotherapy, specific oral tolerance induction) within one year prior to 
Visit 1. 
11. Subjects presently on aeroallergen immunotherapy and unwilling or unable to 
discontinue. 
12. Subjects currently treated with anti-tumor necrosis factor drugs (anti-TNF) or anti-IgE 
drugs (such as omalizumab) or any biologic immunomodulatory therapy within one 
year prior to Visit 1. 
13. Allergy or known hypersensitivity to the Viaskin® patch material or excipients.  
14. Allergy or known history of reaction to Tegaderm® with no possibility to use an 
alternative adhesive dressing allowed by the Principal Investigator. 
15. Subjects suffering from generalized dermatologic diseases (e.g. severe atopic 
dermatitis, uncontrolled generalized eczema, ichthyosis vulgaris) with no intact skin 


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zones to apply the Viaskins® or urticarial and mast cell disorders such as chronic 
idiopathic urticaria.  
16. Subjects (or parents of subjects) with obvious excessive anxiety and unlikely to cope 
with the conditions of an upper Endoscopy and biopsy. 
17. Past or current disease(s), which in the opinion of the Principal Investigator, may affect 
the subject’s participation in this study, including but not limited to active autoimmune 
disorders, immunodeficiency, malignancy, uncontrolled diseases (hypertension, 
psychiatric (especially anxiety), cardiac), or other disorders (e.g., liver, gastrointestinal, 
kidney, cardiovascular, pulmonary disease, or blood disorders). 
18. Any history of drug or alcohol abuse in the past five years. 
19. Subjects unable to follow the protocol and the protocol requirements. 
20. Participation in another clinical intervention study in the three months prior to Visit 1. 
21. Subjects on any experimental drugs or treatments. 
NUMBER OF SUBJECTS: Approximately 22 subjects (16 subjects in the active 
Viaskin® Milk group and 6 subjects in the placebo group) will be randomized to obtain 18 
completed subjects. This sample size will have 90% power to detect a difference of 40 in 
mean maximum eosinophil counts between the subjects receiving Viaskin® Milk (mean 
maximum eosinophil count of 10) and the subjects on placebo (mean maximum eosinophil 
count of 50) assuming a common standard deviation of 20 using a two group t-test with a 
two-sided significance level of 0.05. 
STUDY TREATMENT(S): Viaskin Milk will be administered using the Viaskin® 
epicutaneous delivery system. Viaskin® Milk contains a dry deposit of natural milk protein 
formulated without adjuvant. The inner part of the Viaskin® Milk has a diameter of 24 mm 
(4.5 cm2 surface area). In this inner part, the milk allergen extract is deposited by 
electrospraying the liquid milk protein formulation, which dries instantly. The outer 
adhesive part of the Viaskin® is composed of a 3 mm wide band of adhesive foam to stick 
to the skin. The outer part of the Viaskin® Milk has a diameter of 30 mm. 
 
Subjects will be randomized to receive Viaskin® with milk protein (500 µg of milk 
proteins) or placebo during the first year in the study. The placebo treatment will consist 
of a similar formulation, but will be devoid of milk proteins. During the second year in the 
study (after third upper endoscopy), all subjects will receive open-label Viaskin Milk 500 
µg. Once applied to the skin, the hypoallergenic adhesive film TegaDerm® must be used 
to cover the Viaskin® to prevent it from coming off.  Other dressings could also be used as 
an alternative to TegaDerm® as allowed by the Principal Investigator.  
 
In case the Viaskin® comes off, or after removing a Viaskin®, it is recommended that the 
subjects or subject’s parent(s) wipe off the zone with a disposable napkin or a disposable 
tissue and wash their hands to prevent accidental transmission of allergenic protein. If 
possible, the subject could take advantage of their shower time to change the Viaskin®; the 
previous Viaskin® is removed just before the shower, and the new one will be applied a 
few minutes after the shower. 
 
Repeated daily applications of the Viaskin® patch will be made with progressive increase 
duration of application at the start of treatment: 6 hours per day during the first week, 12 
hours per day during the second week, and for an entire 24 hours daily from the third 


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week (Day 15) onwards. Progressive increase duration of patch application will be done 
again when starting the open-label treatment period. 
 
For all subjects (4-17 years), the patch will be applied on each side of the spine in the 
inter-scapular area. The specific place where one Viaskin® is administered will represent 
a “Zone”. In total, six zones will be used in each subject to apply the Viaskin®. The first 
Viaskin®  will be applied on zone 1, the second Viaskin®  on zone 2 (after removal of 
Viaskin®  1), etc. until all six zones have been used, and the dosing will continue with 
zone 1, zone 2 etc. 
O1 O 4 
O 2 O 5 
O 3 O 6 
 
 
DURATION OF TREATMENT:  
Repeated daily application of Viaskin® will be made from Day 1 up to Month 9 at which 
time milk will be re-introduced into the diet of the subjects. The treatment will then 
continue during the milk reintroduction period (for 1 week to 2 months) up to the last upper 
endoscopy and biopsy. The treatment with open-label Viaskin Milk could also continue for 
up to 11 additional months during the open-label period. In total, the subjects can therefore 
receive the study treatment for up to 22 months. 
 
STUDY EVALUATIONS:  
 
Primary Efficacy Endpoint:  
The primary efficacy endpoint will be each patient’s maximum esophageal eosinophil 
count on all specimens obtained on the biopsy at the end of double-blind treatment period 
(Visit 10), after milk reintroduction at Visit 9.  
 
Secondary Efficacy Endpoints: 
The following secondary efficacy endpoints will be assessed: 
• The symptom score at the end of each treatment periods at 11 months and 22 
months. 
• The change in symptom score at the end of each treatment period at 11 and 22 
months compared to baseline. 
• Mean Esophageal Eosinophil Count which is the average of all of the samples taken 
at the end of each treatment period at 11 and 22 months 
• Percentage of subjects with ≤1 eosinophils/HPF (excellent response) at the end of 
each treatment period at 11 and 22 months. 
• Percentage of subjects with 2-14 eosinophils/HPF (good response) at the end of 
each treatment period at 11 and 22 months. 
• Percentage of subjects with ≥15 eosinophils/HPF (poor response) at the end of each 
treatment period at 11 and 22 months. 
• Change in mean and maximum esophageal eosinophil count from baseline to the 
end of each treatment period at 11 and 22 months. 


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• Esophageal Endoscopy Score at the end of each treatment period at 11 and 22 
months. 
• Change in Esophageal Endoscopy Score from baseline to the end of each 
treatment period at 11 and 22 months. 
• Change in the Eosinophilic Esophagitis Quality of Life Score from baseline to the 
end of each treatment period at 11 and 22 months. 
• Combination Score of four measures (Eosinophils/HPF, EREFS, investigator 
assessment and parental assessment of symptoms) 
• Time to development symptoms after milk reintroduction at month 9 and 20. 
• Changes in exploratory biologic markers, including T-regulatory cells, thymic 
stromal lymphopoietin (TSLP), CBC with differential and milk-specific 
Immunoglobulin level, as well as epigenetic changes. 
 
Safety Measurements 
The following safety criteria will be determined: 
§ Adverse events (AEs) and Serious Adverse Events (SAEs) by 
system organ class, preferred term, severity and relatedness to 
Viaskin® Milk. 
§ Duration of local Viaskin® Milk-induced AEs as assessed by the 
subjects. 
§ Use of medication to control local AEs 
§ Systemic allergic symptoms and relatedness to Viaskin® Milk 
§ Laboratory data, physical examinations and vital signs. 
STATISTICAL METHODS:  
Demographic, baseline, disposition and enrollment data will be summarized. 
 
Primary Efficacy Analysis 
The primary efficacy endpoint will be each patient’s maximum esophageal eosinophil 
count on all specimens obtained on the biopsy at the end of treatment (Visit 10), after milk 
reintroduction at Visit 9. 
 
The null hypothesis is that the mean maximum eosinophils count in the active treatment 
group is the same as that in the placebo treatment group. This hypothesis will be evaluated 
using an analysis of covariance (ANCOVA) model with treatment group, baseline patient’s 
maximum esophageal eosinophil count, and age group (4-11 years old versus 12-17 years 
old) as covariates. The primary comparison will be tested at the 5% significance level. The 
least square means for the treatment groups, difference in least square means between the 
treatment groups, effect size calculated as the absolute difference in least square means 
between active group and placebo divided by the root mean square, and p-value for 
difference between treatment groups will be presented.  
 
Secondary Efficacy Analyses 
The mean Esophageal Eosinophil Count of the all specimens obtained at the end of 
treatment and end of the open label extension and percentage of subjects with less than 15 
eosinophils/HPF at the end of treatment will be summarized descriptively by treatment 
group. Changes in individual and total symptoms scores will be summarized descriptively 


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by treatment group. For the upper endoscopies, visual score at baseline and at the end of 
treatment at double blind and open label extension will be summarized. Comparisons 
between groups using a Student’s t-test or a Mann-Whitney test for continuous variables 
and a chi-square tests for categorical variables will be presented. 
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3. 
TABLE OF CONTENTS 
 
1. 
SIGNATURES ........................................................................................................... 2 
2. 
SYNOPSIS .................................................................................................................. 4 
3. 
TABLE OF CONTENTS ........................................................................................ 11 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................ 15 
5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........... 16 
6. 
INTRODUCTION ................................................................................................... 17 
6.1 Disease Review, an unmet medical need ................................................................................. 17 
6.2 Treatment options for Eosinophilic Esophagitis ...................................................................... 17 
6.2.1 Monitoring of EoE ................................................................................................................. 18 
6.2.2 Natural History of EoE .......................................................................................................... 18 
6.3 The New Strategy for EoE ....................................................................................................... 19 
6.4 Compound Review ................................................................................................................... 19 
6.4.1 Non-Clinical Studies ............................................................................................................. 19 
6.4.2 Clinical Studies ...................................................................................................................... 20 
6.4.3 Clinical Study Rationale ........................................................................................................ 22 
7. 
STUDY OBJECTIVES ........................................................................................... 22 
7.1 Efficacy Objectives .................................................................................................................. 22 
7.2 Safety Objectives ...................................................................................................................... 23 
8. 
INVESTIGATIONAL PLAN ................................................................................. 23 
8.1 Overall Study Design and Plan ................................................................................................. 23 
Table 3B: Study Flow Chart ........................................................................................................... 28 
8.2 Discussion of Study Design ...................................................................................................... 31 
8.3 Study Duration .......................................................................................................................... 31 
8.4 Study Population ...................................................................................................................... 31 
8.4.1 Inclusion Criteria ................................................................................................................... 31 
8.4.2 Exclusion Criteria .................................................................................................................. 32 
8.4.3 Withdrawal and Replacement of Subjects ............................................................................. 33 
8.4.3.1 Criteria for Subject Withdrawal ......................................................................................... 33 
8.4.3.2 Study Stopping Rules ......................................................................................................... 34 
8.4.3.3 Evaluations at Withdrawal ................................................................................................. 34 
8.4.3.4 Replacement of Subjects .................................................................................................... 35 
8.5 Treatment .................................................................................................................................. 35 
8.5.1 Treatments Administered ...................................................................................................... 35 
8.5.2 Study Treatment Formulation ................................................................................................ 36 
8.5.3 Study Treatment Labelling and Packaging ............................................................................ 36 
8.5.4 Blinding of Study Medication ............................................................................................... 37 
8.5.5 Study Treatment Storage and Accountability ........................................................................ 37 
8.5.5.1 Study Treatment Storage .................................................................................................... 37 
8.5.5.2 Study Treatment Accountability ......................................................................................... 37 
8.5.6 Dose Adjustments and Dose Escalation ................................................................................ 38 
8.5.7 Prior and Concomitant Therapy ............................................................................................ 38 
Prohibited Treatments during participation in the study include: .................................................. 39 


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8.5.8 Treatment Compliance .......................................................................................................... 39 
8.5.9 Assignment to Treatment ...................................................................................................... 39 
8.5.10 Unblinding Procedures ........................................................................................................ 39 
8.6 Efficacy and Safety Variables .................................................................................................. 40 
8.6.1. Efficacy Measurements ........................................................................................................ 40 
8.6.1.1 Primary Efficacy Endpoint: ................................................................................................ 40 
8.6.1.2 Secondary Efficacy Endpoints: .......................................................................................... 40 
8.6.2 Safety Measurements ............................................................................................................. 41 
9. 
STUDY EVALUATIONS BY VISIT ..................................................................... 41 
9.1 Visit 1: Screening ..................................................................................................................... 41 
9.2 Visit 2: Screening; 1 week to 2 months after Milk Re-Introduction ........................................ 42 
9.3 Visit 3: Screening; Minimum 6 weeks after Removing Milk .................................................. 42 
9.4 Visit 4: Eligibility/Randomization Treatment Period; Day 1 ................................................... 43 
9.5 Visits 5, 6 and 7: Treatment Period; Day 8 (± 3 days), Month 1 (± 7 days), Month 3 (±14 days)
 ................................................................................................................................... 43 
9.6 Visit 8: Treatment Period; Month 6 (± 14 days) ...................................................................... 44 
9.7 Visit 9: Treatment Period; Month 9 (±14 days) ....................................................................... 44 
9.8 Visit 10: Treatment period; (1 week to 2 months after Visit 9) ............................................... 44 
9.8.1 Telephone Calls: .................................................................... Error! Bookmark not defined. 
9.9 Visit 11: Treatment period; 8 days after visit 10 (3rd endoscopy) ............................................ 45 
9.10 Visits 12, 13, and 14: Treatment Period; Month 1 (± 7 days), Month 3 (±14 days), Month 6 (±14 
days), ......................................................................................................................... 46 
9.11 Visit 15: Treatment Period; Month 9 (±14 days) ................................................................... 46 
9.12 Visit 16: Treatment period; (1 week to 2 months after Visit 15) ........................................... 47 
9.13 Visit 17: End of Study; Visit 10 plus 2 weeks or Early Termination (± 7 days) .................... 48 
10. 
RISK AND RISK-BENEFIT RATIO .................................................................... 48 
10.1 Risks from epicutaneous immunotherapy (EPIT). ................................................................. 48 
10.2 Risks from Upper Endoscopy and Biopsy. ............................................................................. 48 
10.3 Risk-Benefit Ratio .................................................................................................................. 49 
11. 
METHODS OF ASSESSMENT ............................................................................. 50 
11.1 Medical History ...................................................................................................................... 50 
11.2 Pregnancy Test ....................................................................................................................... 50 
11.3 Physical Examination ............................................................................................................. 50 
11.4 Vital Signs and Weight ........................................................................................................... 51 
11.5 Eosinophilic Esophagitis Quality of Life ............................................................................... 51 
11.6 Clinical Laboratory Testing .................................................................................................... 51 
11.8 Upper Endoscopy with Biopsy ............................................................................................... 51 
11.9 Histological Evaluation .......................................................................................................... 52 
11.10 Diet Diary ............................................................................................................................. 53 
11.11 Subject Diary ........................................................................................................................ 53 
11.12 Eosinophilic Esophagitis Symptom Score ............................................................................ 53 
11.13 Skin Reaction and Photography ........................................................................................... 54 
12. 
SAFETY MEASUREMENTS AND VARIABLES .............................................. 54 
12.1 Adverse Events Definition ..................................................................................................... 54 


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12.2 Serious Adverse Events .......................................................................................................... 56 
12.3 Reporting of Serious Adverse Events, Unanticipated Problems, and Serious Unexpected Suspected 
adverse reactions ....................................................................................................... 57 
12.4 Monitoring of Subjects with Adverse Events ......................................................................... 57 
12.5 Procedures to be Followed in the Event of Abnormal Laboratory Test Values ..................... 57 
12.6 Clinical Laboratory Parameters and Abnormal Laboratory Test Results .............................. 58 
12.7 Abnormal Physical Examination Findings ............................................................................. 58 
12.8 Additional Safety Assessments .............................................................................................. 58 
12.9 Treatment of Overdose of Study Medication ......................................................................... 58 
12.10 Procedures in Case of Pregnancy ......................................................................................... 58 
12.11 Adverse Events of Special Interest ....................................................................................... 58 
13. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS .............................. 59 
13.1 Data Management ................................................................................................................... 59 
13.2 Sample Size Estimation .......................................................................................................... 59 
13.3 Statistical Analysis Plan ......................................................................................................... 59 
13.4 Randomization ........................................................................................................................ 60 
13.5 Analysis Populations .............................................................................................................. 60 
13.5.1 Safety Population ................................................................................................................. 60 
13.5.2 Intent-to-treat Population ..................................................................................................... 60 
13.5.3 Per Protocol Population ....................................................................................................... 60 
13.6 Statistical Methods ................................................................................................................. 60 
13.6.1 Missing Data ........................................................................................................................ 61 
13.6.2 Demographic and Baseline Data ......................................................................................... 61 
13.6.3 Subject Disposition .............................................................................................................. 61 
13.6.4 Efficacy ................................................................................................................................ 61 
13.6.4.1 Primary Efficacy Variable ................................................................................................ 61 
13.6.4.2 Secondary Efficacy Variables .......................................................................................... 62 
13.6.5 Pharmacokinetics ................................................................................................................. 63 
13.6.6 Safety ................................................................................................................................... 63 
13.6.6.1 Adverse Events ................................................................................................................. 63 
13.6.6.2 Laboratory Assessments ................................................................................................... 64 
13.6.6.3 Vital Signs ........................................................................................................................ 64 
13.6.6.4 Concomitant Medications ................................................................................................. 65 
13.6.7 Additional Data ................................................................................................................... 65 
13.6.8 Data and Safety Monitoring Board ...................................................................................... 65 
14. 
MONITORING PROCEDURES (QUALITY ASSURANCE) ........................... 66 
14.1 Routine Monitoring ................................................................................................................ 66 
14.2 Inspections and Auditing Procedures ..................................................................................... 66 
15. 
STUDY MANAGEMENT AND MATERIALS ................................................... 66 
15.1 Electronic Case Report Forms ................................................................................................ 66 
15.2 Data Collection ....................................................................................................................... 67 
15.3 Source Documents Maintenance ............................................................................................ 67 
15.4 Record Maintenance ............................................................................................................... 68 
15.5 Confidentiality ........................................................................................................................ 68 


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16. 
ETHICS .................................................................................................................... 69 
16.1 Ethics Committee ................................................................................................................... 69 
16.2 Ethical Conduct of the Study .................................................................................................. 69 
16.3 Subject Information and Consent ........................................................................................... 69 
17. 
ADMINISTRATION PROCEDURES .................................................................. 70 
17.1 Regulatory Approval .............................................................................................................. 70 
17.2 Protocol Amendments ............................................................................................................ 70 
17.3 Protocol Adherence and Deviations ....................................................................................... 70 
17.4 Clinical Study Report ............................................................................................................. 71 
17.5 Discontinuation of the Study .................................................................................................. 71 
17.6 Study Center File Management .............................................................................................. 71 
18. 
APPENDICE ............................................................................................................ 73 
APPENDIX 1: ENDOSCOPY SCORING SYSTEM57 ................................................................. 73 
Appendix 2: Eosinophilic Esophagitis Quality of Life Score ........................................................ 74 
Appendix 3:  CHOP Monitoring Policy ......................................................................................... 75 
Appendix 4:  Safety of 500 mcg of milk Viaskin Patch ................................................................. 77 
19. 
REFERENCE: ......................................................................................................... 78 
 
 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Term 
Definition 
AE 
Adverse event  
ANCOVA 
Analysis of covariance 
ATS 
American Thoracic Society 
CFR 
Code of Federal Regulations 
CMA 
Cow’s Milk Allergy 
CRO 
Clinical research organization 
DBPCFC 
Double Blind Placebo Control Food Challenge 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic case report form 
EoE 
Eosinophilic Esophagitis 
EPIT 
Epicutaneous immunotherapy 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GERD 
Gastro-Esophageal Reflux Disease 
GMP 
Good Manufacturing Practice 
HPF 
High Power Field 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Independent Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
OFC 
Oral Food Challenge 
PP 
Per protocol 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
TEAE 
Treatment-emergent adverse event 
TSLP 
Thymic stromal lymphopoietin 
US/USA 
United States/United States of America 
WHO 
World Health Organization 
WMA 
World Medical Association 
 
 


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5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
 
Principal Investigator: 
Antonella Cianferoni, MD, PhD 
Assistant Professor of Pediatrics 
Division of Allergy and Immunology  
The Children’s Hospital of Philadelphia 
Perelman School of Medicine at Univ. of Pennsylvania 
3401 Civic Center Blvd 
Philadelphia, PA 19104 – United States of America (USA) 
Tel: 215 590 2549 
Fax: 212 590 4529 
E-mail: CIANFERONIA@email.chop.edu  
 
Co-Investigators: 
Chris A. Liacouras, MD 
Professor of Pediatrics 
Division of Gastroenterology and Nutrition 
The Children’s Hospital of Philadelphia 
Perelman School of Medicine at Univ. of Pennsylvania 
3401 Civic Center Blvd 
Philadelphia, PA 19104 – United States of America (USA) 
 
Megan T. Ott, MSN, CRNP 
Pediatric Nurse Practitioner 
Food Allergy Research Program Manager 
Division of Allergy and Immunology 
The Children’s Hospital of Philadelphia 
3401 Civic Center Blvd 
Philadelphia, PA, 19104 (United States of America) 
 
Monitoring: 
The Office of Regulatory Compliance  
34th Street and Civic Center Blvd 
Philadelphia, PA 19104 
 
Study Coordinators 
Deirdre Burke, BS 
Courtney Rooney, BSN, RN 
Jessica Wiedmann, BSN, RN  
 


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6. 
INTRODUCTION 
 
6.1 Disease Review, an unmet medical need 
 
Eosinophilic Esophagitis (EoE) is a recently described disease with rapid rise in the last 20 years 
with a prevalence of 1/20001-7. Currently, there are no FDA approved therapies for this orphan 
disease and no cures.  EoE is characterized by eosinophilia of the esophagus, an organ typically 
devoid of eosinophils without infiltration in other parts of the gastrointestinal tract8,9.  
 
EoE is suspected in patients that have symptoms similar to those caused by gastro-esophageal 
reflux (GERD) but do not respond to medications for GERD. More specifically typical symptoms 
are vomiting, abdominal pain, regurgitation, and dysphagia and in young children and infants 
feeding difficulties and failure to thrive. Dysphagia appears to be more common in older children 
and adults7,8,10,11. Because of these diverse and non-specific symptoms, EoE can be diagnosed 
only by esophageal biopsy with the finding of 15 eos/hpf (peak value)12.   Peak value is used 
instead of mean value in the current definition due to patchy nature of the disease. 7,8,10,11  
 
EoE is a chronic disease with almost no resolution without treatment7,13. When the diagnosis is 
established, it is important to treat the disease not only to control the presenting symptoms, but 
also to prevent acute and chronic complications such as, food impaction, esophageal stricture, 
narrow-caliber esophagus, and esophageal perforation 7,9.   
 
Unlike other food allergies, EoE is probably not IgE mediated.  The evidence is based on murine 
and clinical evidence.   In murine models of EoE, IgE knockout mice still develop esophageal 
eosinophilia. Knockout of T cells eliminates T cells in esophagus. In clinical studies, food 
elimination diets based on IgE testing (skin testing or in vitro specific IgE) have not been 
successful with response rates of 16%.14 EoE is clearly an allergic disease as the patients have 
higher incidence of atopy, which has been reported with prevalence between 70% and 93% 7,15,16.  
 
EoE appears to be T cell mediated disease as Th2-cytokines, especially IL-13, are associated with 
esophageal eosinophilia17-27.  In EoE, Th2 inflammation appears to be driven by TSLP secreted 
by esophageal epithelial cells 28,29 and TSLP has been identified as a genetic risk factor18,28,29.  
 
Foods have been shown to be the cause of EoE through the use of elimination diets or elemental 
formulas in nearly all children and adults 7,30-32. The mechanism underlying the immunologic 
reaction to foods in EoE is probably NOT IgE mediated, but cell mediated.  Removal of all foods 
can induce remission in greater than 95% of children indicating that food can cause disease. Kelly 
and colleagues demonstrated that the introduction of skin test–negative foods into the diet could 
induce clinical disease meeting Koch’s postulate that food reintroduction reintroduces disease30.  
However, removal of skin test positive foods have low rate of success (13% in adults and less 
than 30% in pediatrics)10,33 further supporting that this not an IgE mediated disease.   In addition, 
the use of anti-IgE has no effect on disease state34-36. 
 
 
6.2 Treatment options for Eosinophilic Esophagitis 
 


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There are two current treatment options for EoE and neither is a cure.  One option is treating 
symptomatically with off label use of topical steroids.  Topical corticosteroids are effective in 
inducing EoE remission in 50-90% of patients depending on the dose and topical steroid used. 
The two most common topical steroids used are swallowed fluticasone or budesonide37-43.  
However, when steroids are stopped, inflammation and symptoms reoccur.  In addition, long-
term data on safety and efficacy is not available. As the concern, from experience for topical 
steroid use in asthma, we know that moderate or high dose of topical steroids like the one used 
to treat EoE, are associated with significant reduction in growth in children 44,45.  
 
The second option is through diet.  Foods have been shown to be the cause of EoE through the 
use of elimination diets or elemental formulas 7,30. The two basic approaches for elimination diets 
are removal of foods based on testing46,47 or removal of the most common food allergens31,33.  
Both methods have similar rates of improvement, about 70% of cases48. Based on reintroduction 
studies from both allergy directed diets or empiric diets, milk is the most common allergy seen 
in 50-70% of the adults and children14,49,50.  In fact, 30% of the children are just allergic to 
milk49,51.  
 
Oral desensitization to foods is a very effective treatment for several IgE-mediated food allergies 
but not for EoE. In fact, there is an increasing number of patients that resolve their IgE-mediated 
food allergy using oral desensitization but develop EoE once the food is reintroduced in the diet, 
confirming that IgE mediated food allergy and EoE have a different mechanism52,53.  Overall, the 
current oral immunotherapy induces EoE in 10 to 20% of the studies depending on the criteria. 
 
 
6.2.1 Monitoring of EoE 
 
There are no markers for the diagnosis and management of EoE.  Symptom scores do not always 
correlate with esophageal biopsies.  As patients can have esophageal inflammation with no 
symptoms or the reverse-abdominal pain with normal esophageal biopsies.54,55 Therefore, the 
current guidelines recommend an upper endoscopy with biopsy 2-3 months after any therapeutic 
measure.8,12 The current guidelines and gold standard for diagnosis recommends using maximum 
eosinophil counts due to the patchy nature of the disease. Recent work has suggested potential 
other ways of measuring EoE disease activity including patient reported symptom score54.  Thus, 
as a secondary endpoints to the study, a patient-reported symptom score, Eosinophilic 
Esophagitis Quality of Life Scale56 , and visual endoscopy scale57 will be used. 
 
 
6.2.2 Natural History of EoE 
 
Unlike most IgE-mediated food allergies, patients with food induced EoE do not outgrow it. Less 
than 5% of our patients have outgrown their food allergy based on biopsy and symptom changes.7  
Similar results have been seen in adult populations with no patients having outgrown EoE in 20 
years of follow-up.58  It is also known that a delay in diagnosis increases the risk of fibrosis and 
strictures.58,59 Therefore, a therapy that changes the natural history of EoE is needed.   
As typical standard of care, an endoscopy is performed to confirm the diagnosis. Prior to the 
endoscopy, a patient is treated with a proton pump inhibitor to treat possible reflux, which can 
mimic symptoms of EoE.  The first endoscopy includes biopsy of esophagus, stomach and 
duodenum to ensure that eosinophilic inflammation is isolated to the esophagus.  A repeat 


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endoscopy is performed 2 months after any therapeutic measure (diet or medication changes).7,9 
When a food is identified, the food is generally reintroduced about 2 years later followed by an 
upper endoscopy with biopsy as part of standard of care treatment at CHOP.   However, at other 
institutions, foods are introduced as soon as 2 months after endoscopy.  
 
 
6.3 The New Strategy for EoE 
 
Therefore, we propose to use epicutaneous (EPIT) desensitization to cure milk-induced 
Eosinophilic Esophagitis.  This technology has been successfully used to desensitize children 
with cow’s milk induced IgE mediated reactions.  Dupont and colleagues were able to 
successfully increase the cow’s milk mean cumulative tolerated dose by 12-fold in the active 
group compared to no increase in the placebo group60.   For Eosinophilic Esophagitis, Mondoulet 
and colleagues have developed a murine model based on repeat exposure to peanut.  The mice 
developed profound eosinophilic inflammation in the gastrointestinal tract (predominantly in the 
esophagus).  They have also found similar results in pig model of eosinophilic gastrointestinal 
disease.  They found that use of peanut EPIT can block this inflammation.61,62 In preliminary 
results, EPIT appears to induce both natural and induced T-regulatory cells leading to tolerance.  
 
We will measure two key endpoints for this disease 
• Maximal number of eosinophils per high power field isolated to the esophagus 
• Quality of life measures using a validated EoE module56,63 
 
6.4 Compound Review 
 
The Investigational New Drug, Viaskin® Milk is a milk immunotherapy comprised of an 
epicutaneous delivery system (Viaskin® or Viaskin® patch) containing a dry deposit of a formulation 
of cow’s milk protein extract. The milk protein allergens are deposited on the backing of an 
occlusive chamber by electrospraying a liquid formulation of the milk protein extract. The 
epicutaneous delivery system (Viaskin® or Viaskin® patch) is made of a titanium-unit comprising a 
protective liner and functional layers. 
 
The drug substance is an unmodified lyophilized milk extract produced from the extraction of 
skimmed milk powder as source material (Refer to the Viaskin® Milk Investigator Brochure for full 
details). 
 
6.4.1 Non-Clinical Studies 
Nonclinical studies have been conducted to support the safety of Viaskin® Milk for clinical 
development. These include toxicology studies performed with the combined product (Viaskin 
with milk extract deposit), i.e. repeat-dose, genotoxicity and tolerance studies, as well as ISO 
10993-compliant biocompatibility studies performed with the device component alone. 
Details regarding the nonclinical studies conducted with Viaskin® Milk are presented in the 
Investigator Brochure. 
 
Moreover, efficacy studies using EPIT were conducted in peanut-sensitized mice with 
esophago-gastro-enteropathy61 and in peanut-sensitized pigs with allergic eosinophilic gastritis. 


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6.4.2 Clinical Studies 
 
The Investigational New Drug, Viaskin® Milk is a dry deposit of a formulation of milk protein 
extract intended for EPIT. EPIT is an emerging allergen-Specific ImmunoTherapy (known as 
SIT) approach for the treatment of atopic diseases.  The Investigational New Drug called 
Viaskin® Milk is a ready-to-use and easy-to-administer form of allergen immunotherapy, 
particularly adapted to the pediatric population. Viaskin® Milk is intended to induce clinical 
desensitization/tolerization to milk in subjects with moderate to severe IgE-mediated allergy to 
milk.  Viaskin® Milk includes the natural and complete set of milk proteins that can interact with 
the local antigen presenting cells such as the epidermic Langerhans and dendritic cells and can 
initiate the process of clinical desensitization/tolerization. Moreover, by utilizing the 
epicutaneous route of administration, Viaskin® Milk is able to initiate these immunomodulatory 
processes while minimizing the potential safety concerns associated with systemic exposure to 
food allergens.  Recently, EPIT was successfully used for the treatment of IgE-mediated grass 
pollen allergy64 and peanut allergy. 
 
Milk EPIT in Food Allergy 
 
An earlier study of milk EPIT was completed by Dupont and colleagues, and involved 18 subjects 
(intent-to-treat population) 60.  This double-blind, placebo-controlled, randomized pilot study 
evaluated the safety and efficacy of EPIT for the treatment of cow’s milk allergy (CMA) in highly 
sensitive IgE-mediated CMA children. This study was performed utilizing an atopy patch test 
based on the same technology as the commercially available diallertestÒ diagnostic product. 
Diallertest is a ready-to-use cow’s milk allergen atopy patch test that has been made available by 
DBV Technologies on the French market since June 2004 for the diagnosis of CMA. The eligible 
children were randomized (1:1) to receive active treatment patch (containing cow’s milk powder) 
or placebo for 3 months of blinded therapy, followed by an open-label dosing with the active 
patch up to an additional 6 months The active treatment tended to increase the milk cumulative 
tolerated dose from a mean ± SD of 1.77 ± 2.98 mL at day 0 to 23.61 ± 28.61 mL at day 90 (p-
value of 0.18), while it did not vary in the placebo group (4.36 ± 5.87 mL at day 0 vs. 5.44 ± 5.88 
mL at day 90). The mean cumulative tolerated dose increase was 12-fold in the active group 
versus 8% in placebo group (P = .13).  Thus, milk tolerance was increased, although this 
preliminary study failed to demonstrate a statistically significant improvement of the cumulative 
tolerated dose.  
 
With regards to safety, localized eczema was more frequently observed in the active group than 
in the placebo group; topical corticosteroids were used in 1 patient from each group. There was 
no specific difference in the nature of the AEs reported between the two groups, except for the 
gastrointestinal symptoms (2 diarrheas and 1 vomiting) that were reported only in the active 
group. Treatment was well tolerated by all patients. No child interrupted treatment because of an 
AE, and none received epinephrine or was seen at the emergency department or hospital60. 
 
A Double-Blind, Placebo-Controlled, Randomized Trial to Study the Viaskin® MILk Efficacy 
and Safety for Treating IgE-Mediated Cow’s Milk Allergy in Children, (MILES study, NCT 
02223182) using Viaskin Milk as Investigational Product is ongoing. This study is divided into 
2 consecutive parts (Part A and Part B). Part A initially evaluated the safety of 3 escalating doses 


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of Viaskin Milk (150 µg, 300 µg and 500 µg) over 3 weeks of treatment. Part B will evaluate the 
efficacy and safety of the 3 doses of Viaskin Milk versus Placebo.  
 
Peanut EPIT in Peanut Allergy 
 
Several clinical studies have also been conducted with another product called Viaskin® Peanut, 
in peanut-allergic subjects. These studies include a completed Phase 1b safety study (100 
subjects, NCT 01170286), a pilot Phase 2 study called Arachild (54 pediatric subjects, NCT 
01197053) and a recently successfully completed Phase 2b study called VIPES (221 subjects, 
NCT 01675882), and its follow-up study OLFUS-VIPES (NCT 01955109) currently ongoing. 
 
Results of the VIPES study have been released by DBV Technologies. The trial was prospectively 
organized across three dose levels (50, 100, 250 µg peanut proteins) with two patient 
strata composed of three different patient age groups; children (113 subjects, ages 6-11) for the first 
stratum and adolescents (73 subjects, ages 12-17) plus adults (35 subjects, ages 18-55) for the other 
stratum. All patients received a daily application of the Viaskin
® Peanut patch over a 12-month 
treatment period. Trial responders were defined as patients who, after 12 months of treatment 
with Viaskin
® Peanut and using a double-blind, placebo controlled food challenge, started to react 
at a dose of peanut protein equal to or greater than 1,000 mg, or at least a 10-fold increase in the 
eliciting dose of peanut protein compared to baseline. As a secondary efficacy endpoint, Cumulative 
Reactive Dose, or CRD, was also used to establish the total quantity of peanut protein that begun 
triggering patient reactions at month 12 versus placebo. Serological markers were also measured as 
additional secondary endpoints at baseline, 3, 6, and 12 months in order to characterize the 
immunological changes in subjects. Overall, the 250 μg dose showed the highest efficacy with 
statistical significance for these endpoints. In terms of peanut consumption and immunological 
changes, a consistent dose effect was observed. A total of 56 patients were randomized to 
the Viaskin
® Peanut 250 μg dose. In this arm, 50% of patients responded, compared to 25% in the 
placebo group, showing statistical significance (p=0.0108). 
 
Specifically, 53.6% of children responded to treatment compared to a 19.4% response in 
placebo (p=0.008). Children treated with Viaskin
® showed a strong increase in peanut 
consumption, with an increase in LS mean (Least Squares Mean is a statistical model adjusted 
for multiple factors including both categorical, such as treatment, country and continuous 
covariates, such as baseline peanut dose measures allowing to better isolate solely the effect of 
treatment) change of CRD from baseline of 390.4 mg (p<0.001). Serological responses also 
showed treatment effect. In treated children, peanut-specific immunoglobulin E (IgE) increased 
over the first 3 months before decreasing toward initial levels at 12 months, while peanut-specific 
immunoglobulin G4 (IgG4) increased by more than 19 times over 12 months of treatment with 
the highest dose of Viaskin
® Peanut. Both biomarkers suggest a powerful desensitization effect. 
 
Animal Studies of EPIT in EoE 
 
In animal models of Eosinophilic Gastrointestinal disease, treatment with peanut EPIT lead to 
resolution of esophageal eosinophilia.  Mice were sensitized with peanut allergen via oral route 
and sustained oral exposure to peanuts with cholera toxin in sensitized mice led to severe 
esophageal eosinophilia and intestinal villus sub-atrophia, i.e. significantly increased influx of 


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eosinophils into the esophageal mucosa (136 eosinophils/mm2) and reduced villus/crypt ratios 
(p<0.001 compared to naïve mice). In the sera, specific IgE levels significantly increased as did 
secretion of Th2 cytokines by peanut-reactivated splenocytes. 
 
For mice treated 8 weeks with peanut EPIT, there was significantly reduced Th2 immunological 
response (IgE response and splenocyte secretion of Th2 cytokines) as well as esophageal 
eosinophilia (49.6 compared to Sham 136.2 eosinophils/mm2, p < 0.05), mRNA expression of 
Th2 cytokines in tissue (eotaxin (p<0.05), IL-5 (p<0.05), and IL-13 (p<0.05), GATA-3 (p<0.05)) 
and intestinal villus sub-atrophia (2.3 +/- 0.18 vs Sham, p < 0.01)61. EPIT also increased specific 
IgG2a (p<0.05) and mRNA expression of Foxp3 (p<0.05) in the esophageal mucosa.61   
 
In an additional experiment aiming at evaluating the crucial role of intact skin for epicutaneous 
treatment, it was confirmed that EPIT on intact skin significantly reduced Th2 immunological 
response as well as esophageal eosinophilia (p<0.01 compared to Sham), mRNA expression of 
Th2 cytokines in tissue and intestinal sub-atrophia (p<0.05 compared to Sham).62 By contrast, 
EPIT on stripped skin reinforced Th2 systemic immunological responses as well as eosinophil 
infiltration, mRNA expression of Th2 cytokines and duodenal villus/crypt-ratio. 
 
In another pre-clinical study, the efficacy of EPIT was evaluated in piglets sensitized to peanuts, 
followed by the induction of eosinophilic gastritis. The analysis of histological samples showed 
a high level of eosinophils in stomach mucosa. In that model, EPIT was efficient to decrease 
eosinophils infiltration in stomach to the levels observed in control animals.  
 
Based on immunological changes seen in murine and pig models as well as changes seen in EPIT 
therapy in human, we will examine T regulatory cell expression and cytokine expression in the 
peripheral blood.  Epigenetics changes have been seen in animal model using EPIT65 and milk 
oral immunotherapy.66  Therefore, epigenetic changes in T cells with changes in GATA-3 will 
be explored.  As we found a strong molecular and genetic link for TSLP in EoE28, we will also 
assess expression of TSLP as an exploratory endpoint.  
 
6.4.3 Clinical Study Rationale 
 
The SMILEE study is the first pilot study to assess the efficacy and safety of Milk-EPIT using 
Viaskin® Milk in Eosinophilic Esophagitis subjects. It is acting as a proof of concept study. 
 
7. 
STUDY OBJECTIVES 
 
• To assess the efficacy of Viaskin® Milk EPIT in subjects with milk-induced 
eosinophilic esophagitis 
• To evaluate the safety of Viaskin® Milk EPIT in subjects with milk-induced 
eosinophilic esophagitis. 
 
7.1 Efficacy Objectives 
 
The main efficacy objective is to determine the efficacy of Viaskin® Milk to significantly 
desensitize milk-induced Eosinophilic Esophagitis subjects at the end of treatment period.  


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The study will analyze the maximum eosinophil count on all specimens obtained at the end of 
treatment period in esophageal biopsy after milk reintroduction in subjects with Eosinophilic 
Esophagitis. This is the gold-standard for the diagnosis of EoE. 7,8,10,11 
 
7.2 Safety Objectives 
 
The study will evaluate the safety of Viaskin® Milk EPIT treatment in children and adolescents 
with milk-induced Eosinophilic Esophagitis.  
 
Adverse events (AEs) and Serious Adverse Events (SAEs) by system organ class, severity and 
relatedness to Viaskin® Milk, duration of local skin reactions induced by Viaskin® Milk, use of 
medications to treat AEs, systemic allergic symptoms and relatedness to Viaskin® Milk, changes 
in laboratory results, physical exams and vital signs will be assessed. 
 
8. 
INVESTIGATIONAL PLAN 
 
8.1 Overall Study Design and Plan 
 
This is a double-blind, placebo-controlled, randomized trial to study the efficacy and safety of 
Viaskin® Milk, an allergen extract of milk administered epicutaneously using the Viaskin® 
epicutaneous delivery system in children (4 to 17 years old) with milk-induced Eosinophilic 
Esophagitis (EoE). The trial will be conducted at The Children’s Hospital of Philadelphia, who 
has Investigators and staff trained and experienced in the diagnosis and the management of 
Eosinophilic Esophagitis and who are experienced in performing an upper endoscopy with 
biopsies. Viaskin® Milk will be evaluated in this study versus placebo.  
 
Patients suspected of having milk-induced Eosinophilic Esophagitis will be eligible to participate 
in the study and will perform screening visits (Visits 1-3) to confirm their diagnosis and eligibility 
in the study. After confirmation of the diagnosis of milk-induced Eosinophilic Esophagitis by a 
minimum of two clinical care endoscopies, eligible subjects will be enrolled and randomized in 
a 3:1 ratio into two different treatment groups, to receive EPIT with Viaskin® Milk (500 µg of 
milk proteins) or placebo. Double-blind treatment will last up to 11 months (from visits V4 to 
V10). Each eligible subject will undergo a minimum of two clinical care upper endoscopies and 
biopsies, and one research procedure during their participation in the study: a clinical care 
endoscopy with biopsies during screening after milk-introduction, a clinical care endoscopy with 
biopsies during screening while on milk-free diet, and a third endoscopy with biopsies for 
research at the end of the double-blind treatment period after milk-reintroduction (Visit 10). If 
additional SOC endoscopies are required for clinical purposes, the results of these SOC 
endoscopies can be used to help establish eligibility for this study.  For example, if a patient is 
discovered to not be following a clinically prescribed diet or taking recommended medications, 
the gastroenterologists may place the patient on the more restrictive diet (which the patient was 
supposed to be on) and then follow-up with SOC endoscopy to confirm diagnosis. Milk will be 
reintroduced at 9 months after the second endoscopy.  Results of the clinical care procedures, 
and study-mandated endpoints (Table 3) during the screening period will be available to confirm 
eligibility for enrollment and randomization to the two study arms (at Visit 4).   


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The rationale for up to 11 months of therapy (9 months off milk and up to 2 months after milk 
reintroduction) is based on preliminary data for IgE-mediated food allergy with efficacy being 
generally evaluated after 12 months of epicutaneous therapy (EPIT).  In addition, the pre-clinical 
data in the pig model of eosinophilic gastritis was seen after around 3 months of therapy.  It was 
extrapolated that between 9 to 11 months of EPIT in this pilot study, would be adequate. After 
the third endoscopy at the end of the double-blind treatment period (Visit 10), the study will be 
extended by one additional year and all subjects will receive open-label Viaskin® Milk (500 µg 
of milk proteins) for up to 11 months. A fourth endoscopy with biopsies for research will be done 
at the end of the open-label treatment period (Visit 16). The extension of the study will permit to 
assess the long-term safety and efficacy of Viaskin® Milk for up to 22 months of treatment in 
subjects with milk-induced Eosinophilic Esophagitis. 
 
For EoE, there is no definitive treatment to mitigate disease progression of disease except for 
avoidance.  In the standard of care, it is considered normal to periodically reintroduce foods to 
see if the subject has outgrown it. The first two endoscopies will be standard of care. The first 
endoscopy will permit to confirm the diagnosis of EoE and the second endoscopy will be used 
to confirm the diagnosis of milk-induced EoE.  In our typical standard of care, the endoscopy 
will be performed, after treatment with proton pump inhibitor.   The first endoscopy (standard of 
care) includes biopsy of esophagus, stomach and duodenum to ensure that eosinophilic 
inflammation is isolated to the esophagus. The second (standard of care), third (research) and 
fourth (research) endoscopies will include biopsies of esophagus only. 
 
For safety purposes and to minimize risk, the first four patients will be 8-17 years old and after 
these patients are randomized, we will open the study to all ages 4-17 years old.  
 
 
Table 2: Upper Endoscopies with Biopsies 
1 Initial Endoscopy 
Standard of 
Care 
Biopsies of esophagus, stomach and 
duodenum 
2 Second Endoscopy 
Standard of 
Care 
Biopsies of esophagus 
3 Third Endoscopy (post 
double-blind 
treatment) 
Research  
Biopsies of esophagus 
4 Fourth Endoscopy 
(post open-label 
treatment) 
Research  
Biopsies of esophagus 
 
Study Visits: 
There are at least three visits during the screening period that will occur before enrollment and 
randomization to the active treatment phase of the SMILEE study. The timing of Visits 2 and 3 
are not mandated as part of this study protocol, since these two visits are standard of care 
(during which study endpoint information is collected, Table 3). After confirmation of 
eligibility, subjects will be enrolled to the active phase of the study, randomized to study arms, 


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and treated with either Viaskin Milk EPIT or Viaskin placebo patch. Fully eligible subjects will 
be required to attend 17 study visits in total as follows: 
 
• 
Screening Period: 
- 
The GI collaborative team will help identify potentially eligible SMILEE study 
participants. Potentially eligible subjects will be enrolled to the study (Visit 1), to 
confirm Treatment Period study eligibility and obtain a number of study endpoints (see 
Table 3). The GI group will follow standard of care procedures, but the dates of the first 
(Visit 2) and second (Visit 3) endoscopies with biopsies will not be mandated by the 
investigative team, but by the GI group for clinical care. The second upper 
endoscopy/biopsy will be done at a minimum of 6 weeks after milk-removal, per clinical 
care. If a patient meets eligibility criteria for the Treatment Period of SMILEE, s/he will 
be referred to the Allergy / Immunology division for continuation in the study. If the 
results of the first or second endoscopy with biopsies confirm ineligibility, the subject 
may be considered as screen failed and may not continue in the study. However, if the 
GI group decides to obtain additional clinical care endoscopies with biopsies for 
confirmation or clarification of clinical diagnosis, results from these additional biopsies 
are allowed in the screening period (see Table 3, Study Flow Chart, below).   
- 
Visit 1: Informed Consent obtained. Milk introduction. 
- 
Visit 2: 1 week to 2 Months after milk-introduction. Standard of Care Upper 
endoscopy/Biopsy. Milk removed from the diet. 
- 
Visit 3: 6 weeks minimum after Milk-free diet. Standard of Care upper 
endoscopy/biopsy. 
 
• If a patient has endoscopies that confirm milk responsive EoE in the preceding 12 
months, they will not need a repeat endoscopy to be eligible for the study. 
• A minimum of two standard of care endoscopy procedures will be performed to 
obtain milk EoE diagnostic results needed for study qualification. Results from 
additional endoscopy procedures are allowed, if required for clinical purposes    
• Subjects’ clinical care GI and Allergy physicians will determine the order of 
screening standard of care endoscopies.   
 
• 
Treatment Period: 
- 
Visit 4 (Day 1): Chart review, confirmation of eligibility. Randomization. Treatment 
start. 
- 
Visit 5 (Day 8) 
- 
Visit 6 (Month 1) 
- 
Visit 7 (Month 3) 
- 
Visit 8 (Month 6) 
- 
Visit 9 (Month 9): Milk reintroduction. 
- 
Visit 10: 1 week to 2 Months after milk reintroduction. (During this time, subjects will 
have weekly calls to monitor symptoms) End of double-blind treatment. 
- 
Upper endoscopy/biopsy (research). 
In addition, the patients could be contacted via telephone calls or email between visits to 
monitor symptoms, when symptoms reoccur-research endoscopy will be scheduled.  The 
open-label treatment period will start on that day. 


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Open label Extension 
- 
Visit 11: Day 8 after the Visit 10 research biopsy  
- 
Visit 12: Month 1 after the Visit 10 research biopsy 
-     Visit 13: Month 3 after the Visit 10 research biopsy 
- 
Visit 14: Month 6 after the Visit 10 research biopsy 
- 
Visit 15: Month 9: 1 week to 2 months for milk reintroduction 
- 
Visit 16: Upper endoscopy/biopsy (research) 
 
• Last Assessment and End of Study Period/ Early Withdrawals: 
- 
Visit 17: 2 weeks after Visit 16. 
 
It is planned to randomize approximately 22 subjects in the study (16 Viaskin® Milk subjects 
and 6 Placebo subjects).  A flowchart outlining study assessments and time of assessments is 
shown in Table 3. A schematic diagram of the study design is shown in Figure 1. 


Sponsor Name: Jonathan Spergel 
 
 
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Page 27 of 82 
Table 3A: Study Flow Chart (Visits 1 to 10) 
Study Assessments 
Screening Period# 
 
 
 
 
Double-blind Treatment Period 
V1 
V2* 
V3 
V4*
* 
V5 
V6 
V7 
V8 
V9 
 
V10* 
 
1 week to 
2 months 
after 
Milk Re-
Intod. 
Minimu
m 
6 weeks 
after 
Removin
g Milk 
D1 
D8 ±
 
	 
M1 ±
	 
M3 ±

	 
M6 ±

	 
M9 ±

	 
Telephon
e 
calls**** 
1 
week 
to 2 
month
s after 
V9 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History1 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 2 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Quality of Life 
 
X 
X 
 
 
 
 
 
 
 
X 
Symptom Score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Laboratory Tests6 
X 
 
 
 
 
 
 
X 
 
 
X 
Urine Pregnancy Test7  
X 
 
 
X 
 
 
 
 
 
 
X 
Milk Introduction 
X 
 
 
 
 
 
 
 
X 
 
X10 
Milk-free Diet 
 
X# 
X 
X 
X 
X 
X 
X 
 
 
 
Diet History/Diary 
X 
X 
X 
 
 
 
 
 
X 
 
X 
Standard of Care Upper Endoscopy and Biopsy 
 
X 
X 
 
 
 
 
 
 
 
 
Research Upper Endoscopy and Biopsy 
 
 
 
 
 
 
 
 
 
 
X 
Research Bloods 
 
X 
X 
 
 
 
 
 
 
 
X 
Endoscopy Score 
 
X 
X 
 
 
 
 
 
 
 
X 
Check Eligibility/Randomization 
 
 
 
X 
 
 
 
 
 
 
 
Adverse Events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/ Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Diary Cards (dispense/check) 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Dispense the investigational product to the subject8 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Apply Viaskin® patch(es) on site 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Check the used/unused investigational product dispensed to the 
subject 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
Check skin reaction under the Viaskin® patch and grade it9 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Photography of the site(s) of application of the Viaskin® patch 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Footnotes are 2 pages forward 
 


Sponsor Name: Jonathan Spergel 
 
 
 
 
Protocol No. SMILEE 
    
 
 
 
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Table 3B: Study Flow Chart (Visits 11 to 17) 
Study Assessments 
 
Open-Label Treatment Period 
Last Assessment and End 
of Study/Termination 
V11 
 
V12 
V13 
V14 
V15 
 
V16* 
V17*** 
Post V10- 
D8 ± 	 
 
Post V10 
M1 ±	 
Post V10 
M3 ±	 
Post V10 
M6 ±	 
Post V10 
M9 ±	 
Telephone 
calls**** 
1 week to 2 
months after V15 
2 weeks after V16 or ET 
± 	 
Informed Consent 
 
 
 
 
 
 
 
 
Medical History1 
 
 
 
 
 
 
 
 
Demographics 2 
 
 
 
 
 
 
 
 
Physical Examination3 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs4 
X 
X 
X 
X 
X 
 
X 
X 
Quality of Life 
 
 
 
 
 
 
X 
 
Symptom Score 
X 
X 
X 
X 
X 
 
X 
X 
Laboratory Tests6 
 
 
 
 
 
 
X 
 
Urine Pregnancy Test7  
 
 
 
 
 
 
X 
 
Milk Introduction 
X% 
X% 
X% 
X% 
X% 
 
X10 
X10 
Milk-free Diet 
X% 
X% 
X% 
X% 
X% 
 
 
 
Diet History/Diary 
X 
 
 
 
X 
 
X 
 
Standard of Care Upper Endoscopy and Biopsy 
 
 
 
 
 
 
 
 
Research Upper Endoscopy and Biopsy 
 
 
 
 
 
 
X 
 
Research Bloods 
 
 
 
 
 
 
X 
 
Endoscopy Score 
 
 
 
 
 
 
X 
 
Check Eligibility/Randomization 
 
 
 
 
 
 
 
 
Adverse Events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/ Concomitant Medications 
X 
X 
X 
X 
X 
 
X 
X 
Diary Cards (dispense/check) 
X 
X 
X 
X 
X 
 
X 
X 
Dispense the investigational product to the 
subject8 
X 
X 
X 
X 
X 
 
 
 
Apply Viaskin® patch(es) on site 
X 
X 
X 
X 
X 
 
 
 
Check the used/unused investigational product 
dispensed to the subject 
X 
X 
X 
X 
X 
 
X 
 
Check skin reaction under the Viaskin® patch 
and grade it9 
X 
X 
X 
X 
X 
 
X 
X 
Photography of the site(s) of application of the 
Viaskin® patch 
X 
 
 
 
X 
 
X 
X 
Footnotes are on the next page 


Sponsor Name: Jonathan Spergel 
 
 
 
 
Protocol No. SMILEE 
    
 
 
 
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#- If a patient has a endoscopies that confirm milk responsive EoE in the preceding 12 months, they will not need a repeat endoscopy to be eligible 
for the study. 
*: Visit 2 (screening period) Visit 10, and Visit 16 have to be performed after 1 week to 2 months of milk introduction. The milk introduction period 
should be the same, as much as possible, as compared to that which occurred during the screening period for an individual subject.  
 
*During screening, a minimum of two standard of care endoscopy procedures will be performed to obtain milk EoE diagnostic results needed 
for study qualification.  Scopes may be repeated if clinically necessary and may affect screening visit timelines and total time on study. The results 
of additional SOC endoscopies will be allowed to assess eligibility, if the endoscopies are required for clinical care purposes.  The order of the 
endoscopies will be determined by clinical care. 
**: Visit 4 can be performed as soon as the results of the upper endoscopy and biopsy at Visit 3 are available and confirmed eligibility into the study. 
***: Procedures at Visit 17 have to be performed 2 weeks after Visit 16 for completers. These procedures have also to be performed for subjects 
prematurely withdrawing. This will also be their End of Study Visit. 
****: Patients may be contacted via telephone calls or email between visits to monitor symptoms, when symptoms reoccur-research endoscopy will 
be scheduled.  Telephone calls will be made monthly between visit 5 and 16 
#:  Milk free diet starts after the visit 
 
*Milk free diet may be extended if additional SOC scopes are needed.  As mentioned above, the order of the endoscopies will be determined 
by clinical care. 
%  Milk free if upper endoscopy ≥15 eosinophils/hpf isolated in the esophagus; may continue milk if upper endoscopy is <15 eosinophils/HPF in 
the esophagus 
 
1. Including history of milk allergy and other allergies. 
2. Including weight (kg) and height (cm). 
3. Including a complete skin examination. 
4. Heart rate, blood pressure, respiratory rate, temperature. 
6. Laboratory tests. Hematology: hemoglobin, hematocrit, platelets, red blood cells, white blood cells. Biochemistry: aspartate aminotransferase, 
alanine aminotransferase, total bilirubin, total protein, blood urea nitrogen, creatinine. 
7. Urine pregnancy test for female of childbearing potential only. 
8.    One Viaskin® patch will be applied each day: 6 h/day during the first week, 12 h/day during the second week and for an entire 24h daily from 
the third week (Day 15) onwards during the Double-Blind Treatment period. The first application of Viaskin® patch during the Open-Label 
Treatment period will occur at V10 with again progressive increase duration of patch application: 6h/day during the first week, 12h/day during 
the second week and for an entire 24h daily from the third week onward. 
9.   Check the reaction of the skin during the recommended period of observation of the subject on site at the following time points: 1 hour, 2 
hours and 3 hours after the Viaskin® is applied depending on the required duration of observation at each visit;. Grading to be done per Section 
11.13 Table5.  
10.  Patient may continue with milk introduction if improved on Viaskin® patch 
11.  Research bloods-TSLP, Epigenetics, T cell studies 
V = visit, D = day, M = month, ET = Early Termination 
 
Figure 1: Diagram of Study Design 


Sponsor Name: Jonathan Spergel 
 
 
 
 
Protocol No. SMILEE 
    
 
 
 
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Page 30 of 82 
 
 
 
* ≥15 eosinophils/hpf on upper endoscopy and biopsy is diagnostic of Eosinophilic Esophagitis; 0-10 eosinophils/HPF is considered normal 


Sponsor Name: Jonathan Spergel 
 
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Page 31 of 82 
8.2 Discussion of Study Design 
 
The current study is a pilot study powered to show statistical significance versus placebo. The design 
of this study is based on standard procedures used in clinic practice.  
 
This study is also randomized and double-blinded with regard to treatment with Viaskin® Milk and 
matching placebo in order to prevent bias in treatment allocation and in the assessment of both safety 
and efficacy. The use of a placebo group in this trial is justified to obtain reliable scientific evidence 
for the evaluation of new medicinal products. The overall benefit to risk ratio for this trial is 
favorable. Subjects eligible to participate in this study must have a positive upper endoscopy with 
biopsy showing greater than or equal to 15 eosinophils/hpf when on milk containing diet, and that 
normalized (0-10 eosinophils/hpf) when milk was removed from the diet.  The prospect of direct 
benefit is resolution of food allergy in EoE, which will be the first cure in the disease.  The risk of 
the trial is due to the Viaskin® Milk EPIT patch, which resulted in non-serious adverse events in the 
phase 1 trial.  The other risks are one research upper endoscopy with biopsies under sedation or 
general anesthesia, which the investigative team believes is a minor increase above minimal risk 
procedure when done by board certified gastroenterologist. The second risk is reoccurrence of EoE 
symptoms in placebo group or non-responders.  Therefore, we have incorporated a period of 1 week 
to 2 month to milk re-exposure to minimize symptoms of EoE. The primary endpoint in this study 
will be assessed at the end of the treatment period, after up to 11 months of EPIT treatment.  After 
the initial double-blind phase, all subjects will receive open-label active treatment for up to 
additional 11 months for collection of safety and efficacy data.  
 
8.3 Study Duration 
 
The planned duration of the clinical study is approximately 3 years (Start-up + Screening period + 
Treatment period + Closeout). Subject participation will be approximately 2 years (including up to 
3 months and 2 weeks screening period, 11 months treatment period, 11 month open label extension 
and 2-week follow-up). Recruitment into the study will stop when approximately 22 subjects have 
been randomized to treatment. The study will be stopped when the last subject receiving the double-
blind treatment completes the study or when the last ongoing subject has discontinued treatment, 
whichever occurs first. 
 
8.4 Study Population 
 
Pediatric subjects (4 to 17 years old) with milk-induced Eosinophilic Esophagitis will be randomized 
in this study. 
 
8.4.1 Inclusion Criteria 
 
Subjects MUST satisfy all of the following entry criteria: 
 


Sponsor Name: Jonathan Spergel 
 
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1. Subjects between 4 and 17 years of age at the time of signing the informed consent. 
2. Well-documented symptoms suggestive of EoE after ingestion of milk and currently 
following a strict milk-free diet. 
3. Upper endoscopy and biopsy at clinical evaluation during screening showing greater than 
or equal to 15 eosinophils/HPF isolated to the esophagus meeting the consensus diagnosis 
of Eosinophilic Esophagitis, after milk was re-introduced into the subject’s diet (30 
ml/day for 1 week to 2 months), while the subject was on proton pump inhibitor (PPI).  
Patients will be on PPI for the length of the study as that is standard of care for the 
treatment of EoE.  A clinical decision has been made to perform a minimum of two 
standard of care endoscopy procedures to obtain milk EoE diagnostic results. 
4. Upper endoscopy and biopsy at clinical evaluation during screening showing 0 to 10 
eosinophils per HPF isolated to the esophagus after a minimum of 6 weeks under milk-
free diet, and while the subject is on proton pump inhibitor.  (Standard of care for EoE is 
an upper endoscopy with biopsies to evaluate for disease activity).  A clinical decision 
has been made to perform a minimum of two standard of care endoscopy procedures to 
obtain milk EoE diagnostic results. 
5. Negative pregnancy test for female subjects of childbearing potential. Females of 
childbearing potential must use effective method of contraception to prevent pregnancy 
and agree to continue to practice an acceptable method of contraception for the duration 
of participation in the study. Sexual abstinence will be accepted as an effective method 
of contraception for girls below 18 years of age. 
6. Subjects and/or parents/guardians willing to comply with all study requirements during 
their participation in the study. 
7. Signed informed consent from parent(s)/guardian(s) of children < 18 years + children’s 
assent.  
8. Subjects agree to maintain a constant diet during the trial, with the exception of milk. 
9. Subjects will maintain constant medications for asthma and allergic rhinitis during the 
trial. 
 
8.4.2 Exclusion Criteria 
 
If any of the following apply, the subject MUST NOT enter the study: 
1. 
Subjects with a history of severe anaphylaxis to milk with the following symptoms: 
hypotension, hypoxia, neurological compromise (collapse, loss of consciousness or 
incontinence), Quincke Edema or requiring intubation. 
2. 
Active IgE- mediated milk allergy based on skin test or history. 
3. Pregnancy or lactation. 
4. Subjects with other eosinophilic gastrointestinal disorders. 
5. Subjects on swallowed corticosteroids or anti-leukotrienes for Eosinophilic Esophagitis. 
6. Subjects with symptomatic allergy to pollens whose symptoms during the corresponding 
pollen season might interfere with the recording of symptoms during the upper 
endoscopy/biopsy, if the upper endoscopy/biopsy is conducted during the pollen season. The 
Investigator will have to ensure that the period for conducting the upper endoscopy for such 
a subject will be outside of the pollen season. 
7. Subjects treated with systemic long-acting corticosteroids (depot corticosteroids) within 12 
weeks prior to Visit 1 and/or systemic short-acting corticosteroid within 4 weeks prior to 
Visit 1 or any systemic corticosteroid at screening.  
8. Subjects with asthma conditions defined as follows: 


Sponsor Name: Jonathan Spergel 
 
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a. Uncontrolled persistent asthma by National Asthma Education and Prevention Program 
Asthma guidelines (2007). 
b. At least two systemic corticosteroid courses for asthma in the past year or one oral 
corticosteroid course for asthma in the past three months; 
c. Prior intubation for asthma in the past two years. 
9. Subjects 
on 
β-blocking 
agents, 
angiotensin-converting 
enzyme 
inhibitors, 
angiotensin-receptor blockers, calcium channel blockers or tricyclic antidepressant therapy.  
10. Subjects undergoing any type of immunotherapy to any food (oral immunotherapy, 
sublingual immunotherapy, specific oral tolerance induction) within one year prior to Visit 
1. 
11. Subjects presently on aeroallergen immunotherapy and unwilling or unable to discontinue. 
12. Subjects currently treated with anti-tumor necrosis factor drugs or anti-IgE drugs (such as 
omalizumab) or any biologic immunomodulatory therapy within one year prior to Visit 1. 
13. Allergy or known hypersensitivity to the Viaskin® patch material or excipients. 
14. Allergy or known history of reaction to Tegaderm® with no possibility to use an alternative 
adhesive dressing allowed by the Principal Investigator. 
15. Subjects suffering from generalized dermatologic diseases (e.g. severe atopic dermatitis, 
uncontrolled generalized eczema, ichthyosis vulgaris) with no intact skin zones to apply the 
Viaskin®, or urticarial and mast cell disorders such as chronic idiopathic urticaria.  
16. Subjects (or parents of subjects) with obvious excessive anxiety and unlikely to cope with 
the conditions of an upper endoscopy and biopsy. 
17. Past or current disease(s), which in the opinion the Principal Investigator, may affect the 
subject’s participation in this study including but not limited to active autoimmune disorders, 
immunodeficiency, malignancy, uncontrolled diseases (hypertension, psychiatric (especially 
anxiety), cardiac), or other disorders (e.g., liver, gastrointestinal, kidney, cardiovascular, 
pulmonary disease, or blood disorders). 
18. Any history of drug or alcohol abuse in the past five years. 
19. Subjects unable to follow the protocol and the protocol requirements. 
20. Participation in another clinical intervention study in the three months prior to Visit 1. 
21. Subjects on any experimental drugs or treatments. 
 
8.4.3 Withdrawal and Replacement of Subjects 
 
8.4.3.1 Criteria for Subject Withdrawal 
 
In accordance with the Declaration of Helsinki (Appendix 1) and other applicable regulations, a 
subject has the right to withdraw from the study at any time for any reason without prejudice to his 
or her future medical care by the physician or at the institution. 
 
Subjects may withdraw from the study/schedule of assessments for any of the following reasons: 
• Adverse Event. The patch treatment will be temporary discontinued for 
any subject with Grade 4 local skin reactions possibly, probably, or 
definitely related to the investigational product. 
• A subject will be discontinued from further participation in the study for 
>2 grade 4 local skin reaction possibly, probably or definitely related to 
investigational product 


Sponsor Name: Jonathan Spergel 
 
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Page 34 of 82 
• The Investigator decides that it is the subject’s best interest to be 
withdrawn from the study.  
• The subject is unwilling to continue in the study (consent withdrawal). 
• Lack of compliance with protocol requirements and procedures. 
• The Sponsor- Investigator or Regulatory Authorities, for any reason, stops 
the study. 
• The subject fails to return to the clinic for scheduled visits and does not 
respond to telephone or written attempts at contact (lost to follow-up).  
• Subject’s death 
 
The reason for withdrawal will be recorded in the clinical records and the electronic Case Report 
Form (eCRF) and reported annually in the IND Annual Report (21 CFR 312.33). All subjects who 
are withdrawn or discontinue should be provided with alternative medical care, if applicable. 
 
8.4.3.2 Study Stopping Rules 
 
Study enrollment will be suspended pending an expedited safety review by an independent DSMB 
if any of the following occur: 
1. Any death related to Viaskin® dosing.  
2. Any Stage 3 anaphylaxis related to Viaskin® application. 
3. Marked increase in EoE symptoms with daily vomiting or severe abdominal pain in more 
than one patient 
4. ≥ 1 SAE related to the investigational product or a study intervention 
5. ≥ 2 Grade 3 AEs related to the investigational product 
 
Upon safety review, one of the following outcomes will be determined: 
• Accrual to the study may continue without modification. 
• Accrual to the study may continue with modifications as prescribed by the DSMB. 
• Accrual to the study should be discontinued. 
 
All actions will be reported in compliance with local and federal regulations. 
 
8.4.3.3 Evaluations at Withdrawal 
 
For any subject who is withdrawn before completing all study visits, the Investigator should: 
• Perform an end of study visit: all subjects who are withdrawn early from the trial 
will undergo the procedures planned for Visit 17 (see Section 9). End of study visits 
will be performed no later than 2 weeks after withdrawal/discontinuation. 
• Complete all appropriate subject Diary and eCRF pages, providing the date and 
explanation for the subject’s withdrawal/discontinuation. 
• When indicated, arrange for appropriate follow-up and/or alternative medical care of 
the discontinued subject. 


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Protocol No. SMILEE 
    
 
 
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Page 35 of 82 
 
If the subject fails to attend for a scheduled end of study visit, there will be at least two attempts to 
contact the subject via telephone and written communication. If these receive no reply, the subject 
will be considered lost to follow-up. 
 
8.4.3.4 Replacement of Subjects 
 
Subjects who are withdrawn after beginning the treatment phase of the study will not be replaced. 
However, sufficient subjects will be included to ensure the minimum sample size (see Section 
12.2). 
 
8.5 Treatment 
 
8.5.1 Treatments Administered 
 
The Investigator must ensure that the investigational product will be used only in accordance with 
the protocol. 
 
Following the confirmation of milk-induced Eosinophilic Esophagitis at screening, subjects will 
be randomized in a 3:1 ratio at Visit 4 (Day 1) into two different double-blind treatment groups 
to receive EPIT with Viaskin® Milk (500 µg of milk proteins) or placebo.  
 
Repeated daily application will be made from Day 1 up to Month 9 at which time milk will be re-
introduced into the diet of the subjects. The treatment will then continue during the milk re-
introduction period (for 1 week to 2 months) up to the last endoscopy and biopsy. In total, the 
subjects can therefore receive the study treatment for up to 11 months. 
 
Application of the Viaskin® patch will be made with progressive increase duration of application at 
the start of treatment: 6 hours/day during the first week, 12 hours/day during the second week, and 
for an entire 24 hours daily from the third week (Day 15) onwards. During the period of 24 hours of 
daily application, flexibility of 24 hours ± 4 hours of daily application is permitted. 
 
For all subjects (4-17 years), the patch will be applied on each side of the spine in the inter-scapular 
area. The specific place where one Viaskin® is administered will represent a “Zone”. In total, six 
zones will be used in each subject to apply the Viaskin® : the first Viaskin® will be applied on zone 
1, the second Viaskin® on zone 2 (after removal of Viaskin® 1), etc. until all six zones have been 
used, and the dosing will continue with zone 1, zone 2 etc. 
 
 
O 1 
O 4 
 
O 2 
O 5 
 
O 3 
O 6 
 
Once applied to the skin, Tegaderm® must be used to cover the Viaskin® to prevent it from coming 
off. Other dressings could also be used as an alternative to Tegaderm® as allowed by the Principal 
Investigator. 
 


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In case the Viaskin® comes off, or after removing a Viaskin®, it is recommended that the subjects 
or subject’s parent(s) thoroughly wipe off the zone with a moist disposable napkin or a disposable 
tissue and wash their hands to prevent accidental transmission of allergenic protein. If possible, 
the subject could take advantage of their shower time to change the Viaskin®. The previous 
Viaskin® is removed before the shower (or bath) and discarded, and the new one applied a few 
minutes after the shower (or bath) and after careful drying the skin. 
 
The time of application and removal of each Viaskin® will be noted on the subject diary cards 
(see Section 10.10), along with any observed AE(s) (local and/or distant). Application of the 
Viaskin® at a similar time for each application (am or pm) is recommended. 
 
After Visit 10, all subjects will continue treatment with open-label Viaskin® Milk 500 µg for up 
to 11 additional months. It is permitted at the discretion of the Investigator, to postpone the 
application of the first patch up to a maximum of 7 days after V10.  
 
To increase the safety of subjects at the beginning of the open-label treatment period, in particular 
for subjects crossing over from placebo to the active Viaskin Milk treatment, the daily duration 
of application will again be adapted from Visit 10 for the first weeks of treatment: 6 hours/day 
during the first week, 12 hours/day during the second week, and for an entire 24 hours daily from 
the third week onwards. During the period of 24 hours of daily application, flexibility of 24 hours 
± 4 hours of daily application is permitted. 
 
8.5.2 Study Treatment Formulation 
 
Viaskin® Milk will be administered using the Viaskin® epicutaneous delivery system. 
Viaskin® Milk contains a dry deposit of milk protein formulated without adjuvant. The 
Viaskin® is round-shaped. The inner part of the Viaskin® Milk has a diameter of 24 mm 
(4.5 cm2 surface area). In this inner part, the milk allergen extract is deposited by 
electrospraying the liquid milk protein formulation, which dries instantly. The outer 
adhesive part of the Viaskin® is composed of a 3 mm wide band of adhesive foam to stick 
to the skin. The outer part of the Viaskin® Milk has a diameter of 30 mm. 
 
The placebo treatment will consist of a similar formulation, but will be devoid of milk proteins. 
Once applied to the skin, the hypoallergenic adhesive film TegaDerm® must be used to cover the 
Viaskin® to prevent it from coming off. Other dressings could also be used as an alternative to 
Tegaderm® as allowed by the Principal Investigator.  
 
AMATSI, Saint Gély du Fesc, France, will manufacture both the active and placebo Viaskin® in 
accordance with the requirements of Good Manufacturing Practices (GMP) and will perform the 
primary packaging activities (i.e. place one Viaskin® patch per pouch). 
 
8.5.3 Study Treatment Labelling and Packaging 
 
The secondary packaging and pharmaceutical release activities will be performed by 
CREAPHARM (Le Haillan, France). This manufacturer will label and package the investigational 
product: the containing boxes as well as each pouch will be labeled. The labeled pouches will be 
placed in labeled treatment boxes/kits to be delivered to subjects at each visit, with enough quantity 


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of Viaskin® to cover the period between two consecutive visits. The labeled and packaged 
investigational product will be stored according to the requirements of GMP under the storage 
conditions established by stability studies performed with Viaskin® Milk. 
 
Upon reception at the clinical site, the study drug will be stored in the Investigational Pharmacy.  
The pharmacist will receive and store the study drug until the time of dispensing to the Investigators. 
Patients will return unused patches and they will be destroyed by Investigational Pharmacy.  At the 
end of the study, the pharmacist will be responsible for destroying any unused investigational 
product and will provide a corresponding certificate of destruction. 
 
8.5.4 Blinding of Study Medication 
 
This is a randomized, double-blind, placebo-controlled study with limited access to the 
randomization code. Active and placebo Viaskin® will be similar in physical appearance. The 
treatment each subject will receive will not be disclosed to the Investigator, study center 
personnel, subject, Sponsor or their representatives. The treatment codes will be held according 
to the interactive Web response system (IWRS).   
 
The second phase of the study will be on open-label extension with all patients receiving 
unblinded Active Viaskin® milk patch. There will be no blinding of study medication during this 
part of the study.  
 
For details of the emergency procedure for unblinding of individual subjects, see Section 8.5.10, 
below. 
 
8.5.5 Study Treatment Storage and Accountability 
 
It is forbidden to use investigational drug material for purposes other than as defined in this protocol.  
 
8.5.5.1 Study Treatment Storage 
 
All investigational product will be stored between 2°C to 8°C ([35.6oF to 46.4oF]; see USP 
Controlled Room Temperature) until time of dispensing. However, storage at ambient temperature 
for short and/or intermittent periods of time, including transportation is accepted. 
 
8.5.5.2 Study Treatment Accountability 
 
All supplies of Viaskin® (active and placebo) will be accounted for in accordance with GCP. There 
will be an individual study drug accountability record for each subject and the Investigator will 
maintain accurate records of the disposition of all trial medication supplies received during the study. 
These records will include the amounts and dates that clinical drug supplies were received, 
dispensed to the subject, returned by the subject, and returned to the Investigator or destroyed on 
site.  The unused Viaskin patches will be returned on subsequent study visits.  The excessive and 
used study drug will be destroyed by The Children’s Hospital of Philadelphia Research Pharmacy 
using standard protocols.  The research pharmacist will provide a corresponding certificate of 
destruction. 
 


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8.5.6 Dose Adjustments and Dose Escalation 
 
No dose adjustments or dose escalation are planned apart from the adjustment in the duration of 
application during the first weeks of treatment. 
 
Even though the subjects should ideally reach the daily 24-hour application regimen from the 15th 
day of patch application onwards, for subjects who may experience some severe local reactions at 
the initiation of the treatment, the daily duration of patch application should be adapted/reduced if 
necessary, to limit the severe reactions. 
 
In case of local unbearable skin reactions or in case of systemic allergic reactions, the Viaskin® 
patch should be removed immediately in order to allow the reactions to subside rapidly. The next 
patch would be re-applied only the following day at the expected time and the reactions will be 
observed. If or when the local severe reactions recur, the patch can be removed at that time. This 
process can be repeated the following days until the time the subject can bear the patch for 24 hours 
a day.  
 
If a subject is having systemic symptoms including worsening of EoE symptoms, the subject will 
have return for study visit and possible decrease in daily exposure to the Viaskin patch with 
gradually increase in exposure as tolerated. 
 
Only one dose is being investigated in this pilot study, at the highest dose of Viaskin Milk currently 
under development (500 µg of cow’s milk proteins) due to the limited number of subjects to be 
recruited.  
 
8.5.7 Prior and Concomitant Therapy 
 
All medications used in the last 6 months or being administered at the time of screening and 
along the study will be recorded on the appropriate eCRF pages.  
 
Application of a topical corticosteroid to treat any local AE (eczematous lesions, pruritus, 
edema, etc.) is allowed. An ointment with 1% hydrocortisone will be distributed to each 
randomized subject at discharge on Day 1 (V4). In case the 1% hydrocortisone ointment is not 
sufficient to treat the local reaction, an ointment containing a more potent corticosteroid can be 
prescribed and locally applied.  Should skin reactions not be resolved by topical steroid, see 
Section 8.5.6 above. 
 
Oral antihistamine or oral corticosteroids are allowed to treat AE determined as being allergic 
reactions. These treatments should be limited in time and stopped as soon as the AE has 
resolved. The Investigator will determine the best choice of treatment(s), the dose and the 
regimen according to the subject’s age, and the type and the degree of severity of the reaction. 
Cetirizine is recommended as the oral antihistamine of choice.  Medications will be 
documented in the concomitant medication log (including dosage, duration, and indication.). It 
is expected the subjects will maintain constant medications for asthma and allergic rhinitis 
during the trial.  
 


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All other treatments prescribed by the Investigator or any other physician to treat an AE are 
also permitted. Administration of concomitant medications must be reported in the appropriate 
section of the eCRF along with dosage information, dates of administration, and reasons for 
use. Generic names for concomitant medication should be used. The total daily dose should be 
provided.  
 
Prohibited Treatments during participation in the study include: 
- 
Any investigational drug or device other than Viaskin Milk or placebo 
- 
Swallowed corticosteroids or anti-leukotrienes 
- 
Beta-blocking agents, angiotensin-converting enzyme inhibitors, angiotensin-receptor 
blockers, calcium channel blockers or tricyclic antidepressant therapy 
- 
Immunotherapy to any food or aeroallergens 
- 
Anti-TNF or anti-IgE drugs (such as omalizumab), or any other biologic immunomodulatory 
therapy 
 
8.5.8 Treatment Compliance 
 
It is the Investigators’ responsibility to ensure that subjects are correctly instructed on how to take 
their study medication. Records of study medication used and intervals between visits will be kept 
during the study.  Subjects will be asked to return their unused medication (box(es)) when they come 
back for their study visits. All unused medication (boxes) should be returned at the end of the study. 
The study drug will be dispensed by the Investigator, or by a qualified individual under the 
Investigator’s supervision. An up-to-date treatment inventory/dispensing record must be maintained 
(see Section 8.5.5.2). 
At each visit, prior to dispensing trial medication, previously dispensed trial medication will be 
retrieved by the Investigator and compliance assessed. A compliance of > 80% over the treatment 
period is sought. Subjects exhibiting poor compliance as assessed by counts and response to the 
question “Did you take your Viaskin® regularly?” will be counseled on the importance of good 
compliance to the study dosing regimen. 
 
Non-compliance is defined as taking less than 80% of trial medication during any evaluation period 
(visit to visit). Subjects who are persistently non-compliant may be withdrawn from the study. 
 
8.5.9 Assignment to Treatment 
 
Throughout the screening period until allocation of a treatment number or treatment kit, subjects 
will be assigned a screening number. The screening number will be a number combining the site 
number plus the number assigned to a subject according to her/his chronological order of 
screening at that site. The screening number will be used as the subject identifier throughout the 
study. An IWRS will randomize subjects and assign the appropriate treatment number or kit 
number.  
 
8.5.10 Unblinding Procedures 
 
In case of emergency, the Principal Investigator can ask for unblinding of a subject, i.e., informing 
the nature of the investigational product (active or placebo) to which the subject has been assigned. 
Such procedures should only be utilized in emergency situations when the identity of the treatment 


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group must be known by the Investigator in order to provide appropriate medical treatment. Before 
unblinding the subject, the unblinding request will be sent to the chair of the DSMB, Stacie Jones, 
MD.  She will notify the study investigator, Dr. Cianferoni, if the unblinding is necessary for 
treatment.  The unblinding will be done by our pharmacovigilance agent, Jennifer Heimall, MD.  
 
Reasons for unblinding must be clearly explained and justified in the eCRF, along with the date on 
which the subject was unblinded. 
 
Unblinding of the study can also be done at the request of the regulatory agency or DSMB at any 
point in the study for safety or other concerns.  In this case, unblinding will be done by our 
pharmacovigilance agent, Jennifer Heimall, MD.  
 
8.6 Efficacy and Safety Variables 
 
8.6.1. Efficacy Measurements 
 
8.6.1.1 Primary Efficacy Endpoint: 
The primary efficacy endpoint will be each patient’s maximum esophageal eosinophil count on 
all specimens obtained on the biopsy at the end of treatment (Visit 10), after milk reintroduction 
at Visit 9.  
 
8.6.1.2 Secondary Efficacy Endpoints: 
The following secondary efficacy endpoints will be assessed: 
• The symptom score at the end of each treatment period  at 11 and 22 months. 
• The change in symptom score at the end of each treatment period  at 11 and 
22 months compared to baseline. 
• Mean Esophageal Eosinophil Count which is the average of all of the samples 
taken at the end of each treatment period  at 11 and 22 months. 
• Percentage of subjects with ≤1 eosinophils/HPF (excellent response) at the 
end of each treatment period  at 11 and 22 months. 
• Percentage of subjects with 2-14 eosinophils/HPF (good response) at the end 
of each treatment period  at 11 and 22 months. 
• Percentage of subjects with ≥15 eosinophils/HPF (poor response) at the end 
of each treatment period  at 11 and 22 months. 
• Change in mean and maximum esophageal eosinophil count from baseline to 
the end of each treatment period at 11 and 22 months. 
• Esophageal Endoscopy Score at the end of each treatment period at 11 and 22 
months. 
• Change in Esophageal Endoscopy score from baseline to the end of each 
treatment period at 11 and 22 months. 
• Change in the Eosinophilic Esophagitis Quality of Life Score from baseline 
to the end of each treatment period  at 11 and 22 months. 
• Combination Score of four measures (Eosinophils/HPF, EREFS, investigator 
assessment and parental assessment of symptoms) 
• Time to development symptoms after milk reintroduction at month 9 and 20. 


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• Changes in exploratory biologic markers, including T-regulatory cells, TSLP, 
CBC with differential and milk-specific Immunoglobulin level, as well as 
epigenetics. 
 
8.6.2 Safety Measurements 
 
The following safety criteria will be determined: 
• Adverse events (AEs) and Serious Adverse Events (SAEs) by system organ 
class, preferred term, severity and relatedness to Viaskin® Milk. 
• Duration of local Viaskin® Milk-induced AEs, as assessed by the subjects. 
• Use of medications to control local AEs. 
• Systemic allergic symptoms and relatedness to Viaskin® Milk. 
• Laboratory data, physical examinations and vital signs. 
 
9. 
STUDY EVALUATIONS BY VISIT 
 
Subjects with known established Eosinophilic Esophagitis (EoE) based on 2011 consensus 
diagnosis criteria will be considered for participation in the study. All subjects for whom a written 
informed consent has been obtained will enter the screening period, and only subjects who fulfill 
all eligibility criteria will be eligible and randomized for the double-blind treatment period. The 
duration of the screening period may vary among subjects and will be dependent of the exact 
duration of the milk-introduction period (from 1 week to 2 months) and of the duration of the 
milk- diet period (minimum of 6 weeks). 
 
All screening records for potential eligibility by the gastroenterology collaborators will be 
reviewed and confirmed before entry into the double-blind treatment period; thereafter, dates of 
all study visits will be scheduled relative to the date of entry into the double-blind treatment 
period (Visit 4). 
 
9.1 Visit 1: Screening 
 
At the time of the screening Visit 1, the following assessments/procedures will be performed: 
• Signed written informed consent for screening questionnaires, CBC, CMP and chart 
review. Medical history (including milk allergy history, other allergies, diet history). 
• Demographics (including weight in kg and height in cm). 
• Physical examination (including a complete skin examination). 
• Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• Eosinophilic Esophagitis Symptom Score (see Section 11.12). 
• Blood collection for laboratory tests (hematology, biochemistry). 
• Urine pregnancy test for female of childbearing potential. 
• Milk introduction (30 ml/day for 1 week to 2 months) while the subject is on a proton pump 
inhibitor. 
• Dietary History. 
• Record all AEs (volunteered or in response to an open question) since the ICF was 
signed. 


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• Record prior (over last six months) and all concomitant medications. 
 
9.2 Visit 2: Screening; 1 week to 2 months after Milk Re-Introduction 
 
Subjects will have a minimum of two standard of care upper endoscopies and biopsy performed 
to confirm the diagnosis of Eosinophilic Esophagitis.  They will have an upper endoscopy from 
1 week to 2 months after introduction of a minimum of 30 ml of milk daily into their diet, and 
while on proton pump inhibitor.  When the subjects are symptomatic, they will have an 
endoscopy 1-2 weeks after symptoms occur.  We will review the medical records to review the 
number of eosinophils in the esophageal biopsy.  Research parts of the visit will include EoE 
Quality of life measures and research blood samples.  Subjects’ clinical care GI and Allergy 
physicians will determine the order of screening standard of care endoscopies.   
 
 
The following assessments/procedures will be performed: 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.12). 
• 
Milk-free Diet. 
• 
Diet History. 
• 
Eosinophilic Esophagitis (Age-specific) Quality of Life Measure (Appendix 2). 
• 
Upper endoscopy and biopsies of the esophagus, stomach and duodenum (see section 
11.8) with upper endoscopy score (Appendix 2). 
• 
Record all AEs (volunteered or in response to an open question). 
• 
Record of all concomitant medications. 
 
9.3 Visit 3: Screening; Minimum 6 weeks after Removing Milk  
 
Subjects will have a minimum of two standard of care upper endoscopies and biopsy to confirm 
milk induced EoE performed, after a minimum of 6 weeks under milk-free diet and while on 
proton pump inhibitor.  Results of the standard of care endoscopy and biopsy will be obtained by 
review of medical records.   Research procedures at this visit include EoE Quality of life measure, 
and collection of any AEs. Subjects’ clinical care GI and Allergy physicians will determine the 
order of screening standard of care endoscopies.   
 
The following assessments/procedures will be performed: 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.12) 
• 
Eosinophilic Esophagitis (Age-specific) Quality of Life Measure (Appendix 2). 
• 
Milk-free Diet 
• 
Diet History 
• 
Upper endoscopy and biopsies of the esophagus (see Section 11.8) with upper endoscopy 
score (Appendix 2) 
• 
Record all AEs (volunteered or in response to an open question). 
• 
Record of all concomitant medications. 
 


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9.4 Visit 4: Eligibility/Randomization Treatment Period; Day 1  
 
Visit 4 corresponds to the first day of treatment.  
The following assessments/procedures will be performed: 
• 
Review Pathology reports of the upper endoscopy and biopsy. Confirm eligibility by chart 
review of clinical records/randomize subject. 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.12). 
• 
Urine pregnancy test for female of childbearing potential. 
• 
Milk-free Diet 
• 
Dispense diary cards (instruct subject how to complete). 
• 
Dispense the first treatment box of investigational product to the subject. 
• 
The investigator will take one Viaskin® patch from the box, apply the first Viaskin® to 
the subject, and train the subject on the proper technique and timing for applying the other 
patches. 
• 
The subject will remain either in the CHOP clinic exam room or in the waiting room for 
at least 3 hours under observation.  Patients will regularly be assessed by study staff.  
Should a patient experience an adverse reaction, or emergency, the patch will 
immediately be removed and the site cleaned.  Patient will then be treated per CHOP 
allergy clinic emergency procedures. 
• 
Check the skin under the Viaskin® and grade any local skin reaction after 1 hour after the 
patch is applied (see Section11.13).  
• 
Take a photograph of the site of application of the Viaskin® and keep it in the subject’s 
medical records or source documents 
• 
Record all AEs (volunteered or in response to an open question). 
• 
Record all concomitant medication(s). 
 
The subject may be discharged after a minimum observation period of 3 hours. 
 
9.5 Visits 5, 6 and 7: Treatment Period; Day 8 (± 3 days), Month 1 (± 7 days), Month 3 
(±14 days) 
 
The following assessments/procedures will be performed: 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.12). 
• 
Milk-free Diet 
• 
Record all AEs (volunteered or in response to an open question). 
• 
Record all concomitant medication(s). 
• 
Dispense diary cards (re-instruct subject on use if necessary). 
• 
Review ‘diary’ and ensure that the diary has been completed accurately and that the 
subject is comfortable with using the diary. 
• 
Check unused medication and assess medication compliance. 
• 
Dispense the new treatment box to subject. Apply one Viaskin® patch to subject. 
• 
Check skin under the Viaskin® and grade any local skin reaction (see Section 11.13). 
• 
Take a photograph of site(s) of application of Viaskin® and keep in the subject’s medical 
records or source documents. 


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The subject may be discharged after a minimum observation period of 1 hour (for Visit 5 only). 
There is no specific observation period required for Visits 6 or 7. 
 
9.6 Visit 8: Treatment Period; Month 6 (± 14 days) 
 
The following assessments/procedures will be performed: 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.12) 
• 
Blood collection for laboratory tests (hematology, biochemistry) 
• 
Milk-free Diet 
• 
Record all AEs (volunteered or in response to an open question). 
• 
Record all concomitant medication(s). 
• 
Dispense diary cards (re-instruct subject on use if necessary). 
• 
Review ‘diary’ and ensure that the diary has been completed accurately and that the 
subject is comfortable with using the diary. 
• 
Check unused medication and assess medication compliance. 
• 
Dispense the new treatment box to subject. Apply one Viaskin® patch to subject. 
• 
Check skin under the Viaskin® and grade any local skin reaction (see Section 11.13). 
• 
Take a photograph of site(s) of application of Viaskin® and keep in the subject’s medical 
records or source documents. 
 
9.7 Visit 9: Treatment Period; Month 9 (±14 days) 
 
The following assessments/procedures will be performed: 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.12) 
• 
Milk reintroduction (similar amount and duration as done during the screening 
period) while the subject is on a proton pump inhibitor. 
• 
Dietary History. 
• 
Record all AEs (volunteered or in response to an open question). 
• 
Record all concomitant medication(s). 
• 
Dispense diary cards (re-instruct subject on use if necessary).  
• 
Review ‘diary’ and ensure that the diary has been completed accurately and that the 
subject is comfortable with using the diary. 
• 
Check unused medication and assess medication compliance. 
• 
Dispense the new treatment box to subject. Apply one Viaskin® patch to subject. 
• 
Check skin under the Viaskin® and grade any local skin reaction (see Section 11.13). 
• 
Take a photograph of site(s) of application of Viaskin® and keep in the subject’s medical 
records or source documents. 
 
9.8 Visit 10: Treatment period; (1 week to 2 months after Visit 9,  3rd endoscopy) 
 
Subjects will have an upper endoscopy and biopsy performed at this visit.  They will have an 
upper endoscopy from 1 week to 2 months after reintroduction of a minimum of 30 ml of milk 


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daily into their diet, and while on proton pump inhibitor, as done during the screening period.  
When the subjects are symptomatic, they will have an endoscopy 1-2 weeks after symptoms 
occur. 
 
The milk consumption should be equivalent to what the subjects were taking at the beginning 
of the study. 
 
Visit 10 corresponds to the last day of double-blind treatment and the start of open-label 
treatment period. Standard Operating Procedures will be followed for endoscopy procedure67.  
Patients will need to be healthy for this procedure.  Any subject who has had a viral upper 
respiratory infection or gastroenteritis within 7 days will need to be rescheduled.   
 
The following assessments/procedures will be performed: 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis (Age-specific) Quality of Life Measure (Appendix 2) 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.12) 
• 
Blood collection for laboratory tests (hematology, biochemistry) 
• 
Urine pregnancy test for female of childbearing potential. 
• 
Diet History 
• 
Upper endoscopy and biopsies of the esophagus (see Section 11.8) with upper endoscopy 
score (Appendix 1) 
• 
Record all AEs (volunteered or in response to an open question). 
• 
Record all concomitant medications. 
• 
Dispense diary cards (re-instruct subject on use if necessary). 
• 
Review ‘diary’ and ensure that the diary has been completed accurately and that the 
subject is comfortable with using the diary. 
• 
Check unused medication and assess medication compliance. 
• 
Check skin under the Viaskin® and grade any local skin reaction (see Section 11.13) 
• 
Take a photograph of site(s) of application of Viaskin® and keep in the subject’s medical 
records or source documents. 
• 
Dispense the new treatment box to subject. Apply one Viaskin® patch to subject. It is 
permitted at the discretion of the Investigator, to postpone the application of the first patch 
up to a maximum of 7 days after V10. 
 
9.9 Visit 11: Treatment period; 8 days (±3 days) after visit 10  
 
The following assessments/procedures will be performed: 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.12) 
• 
Milk diet options 
o If the 3rd upper endoscopy (Visit 10) has≥15 eosinophils/HPF isolated in 
the esophagus, the subject will stop milk consumption 
o If the 3rd upper endoscopy (visit 10) has < 15 eosinophils/HPF, the subject 
may continue milk consumption at the previous levels as per 
Investigator’s recommendations. 
• 
Dietary History. 


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• 
Record all AEs (volunteered or in response to an open question). 
• 
Record all concomitant medication(s). 
• 
Dispense diary cards (re-instruct subject on use if necessary).  
• 
Review ‘diary’ and ensure that the diary has been completed accurately and that the 
subject is comfortable with using the diary. 
• 
Check unused medication and assess medication compliance. 
• 
Dispense the new treatment box to subject. Apply one Viaskin® patch to subject. 
• 
Check skin under the Viaskin® and grade any local skin reaction (see Section 11.12). 
• 
Take a photograph of site(s) of application of Viaskin® and keep in the subject’s medical 
records or source documents. 
 
9.10 Visits 12, 13, and 14: Treatment Period; Month 1 (± 7 days), Month 3 (±14 days), 
Month 6 (±14 days),  
 
The following assessments/procedures will be performed: 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.11). 
• 
Milk-free Diet (if applicable) 
• 
Record all AEs (volunteered or in response to an open question). 
• 
Record all concomitant medication(s). 
• 
Dispense diary cards (re-instruct subject on use if necessary). 
• 
Review ‘diary’ and ensure that the diary has been completed accurately and that the 
subject is comfortable with using the diary. 
• 
Check unused medication and assess medication compliance. 
• 
Dispense the new treatment box to subject. Apply one Viaskin® patch to subject. 
• 
Check skin under the Viaskin® and grade any local skin reaction (see Section 11.13). 
• 
If the subjects develops symptoms of EoE, they may support milk during this period 
 
 
9.11 Visit 15: Treatment Period; Month 9 (±14 days) after visit 10 
 
The following assessments/procedures will be performed: 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.12) 
• 
Milk reintroduction (similar amount and duration as done during the screening 
period) if not already on milk 
o Otherwise, continue the current milk dose while the subject is on a proton 
pump inhibitor. 
• 
Dietary History. 
• 
Record all AEs (volunteered or in response to an open question). 
• 
Record all concomitant medication(s). 
• 
Dispense diary cards (re-instruct subject on use if necessary).  
• 
Review ‘diary’ and ensure that the diary has been completed accurately and that the 
subject is comfortable with using the diary. 
• 
Check unused medication and assess medication compliance. 


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• 
Dispense the new treatment box to subject. Apply one Viaskin® patch to subject. 
• 
Check skin under the Viaskin® and grade any local skin reaction (see Section 11.13). 
• 
Take a photograph of site(s) of application of Viaskin® and keep in the subject’s medical 
records or source documents. 
 
9.12 Visit 16: Treatment period; 1 week to 2 months after Visit 15 
 
Subjects will have an upper endoscopy and biopsy performed at this visit.  They will have an 
upper endoscopy from 1 week to 2 months after reintroduction of a minimum of 30 ml of milk 
daily into their diet, and while on proton pump inhibitor, as done during the screening period. If 
subjects develop symptoms between visits 11 and 14, they will also restart milk with the same 
milk consumption should be equivalent to what the subjects were taking at the beginning of the 
study. 
 
Visit 16 corresponds to the last day of treatment. Standard Operating Procedures will be 
followed for endoscopy procedure67.  Patients will need to be healthy for this procedure.  Any 
subject who has had a viral upper respiratory infection or gastroenteritis within 7 days will need 
to be rescheduled.   
 
The following assessments/procedures will be performed: 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis (Age-specific) Quality of Life Measure (Appendix 2) 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.12) 
• 
Blood collection for laboratory tests (hematology, biochemistry) 
• 
Urine pregnancy test for female of childbearing potential. 
• 
Diet History 
• 
Upper endoscopy and biopsies of the esophagus (see Section 11.8) with upper endoscopy 
score (Appendix 1) 
• 
Record all AEs (volunteered or in response to an open question). 
• 
Record all concomitant medications. 
• 
Dispense diary cards (re-instruct subject on use if necessary). 
• 
Review ‘diary’ and ensure that the diary has been completed accurately and that the 
subject is comfortable with using the diary. 
• 
Check unused medication and assess medication compliance. 
• 
Check skin under the Viaskin® and grade any local skin reaction (see Section 11.13) 
• 
Take a photograph of site(s) of application of Viaskin® and keep in the subject’s medical 
records or source documents. 
 
 
9.12.1 Telephone Calls: 
 
• Patients will be called monthly between visit 5 and visit 16  to monitor for reoccurrence of 
symptoms while wearing the Viaskin® milk patch.  
• When the subject has reoccurrence of symptoms after milk re-introduction (or maximum 
exposure of 2 months to milk), the research endoscopy will be scheduled. 
 


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9.13 Visit 17: End of Study; Visit 16 plus 2 weeks or Early Termination (± 3 days) 
 
Visit 17 will be performed 2 weeks after Visit 16 for completers. This visit and assessments 
procedures have also to be performed for subjects prematurely withdrawn. This will be the End of 
Study Visit. 
  
The following assessments/procedures will be performed: 
• 
Physical examination (including a complete skin examination). 
• 
Vital signs (including heart rate, blood pressure, respiratory rate, and temperature). 
• 
Eosinophilic Esophagitis Symptom Score (see Section 11.11). 
• 
Record all AEs (volunteered or in response to an open question). 
• 
Record all concomitant medication(s). 
• 
Collect and review ‘diary’ and ensure that the diary has been completed accurately. 
• 
Check skin where the Viaskin® patch was applied and grade any local skin reaction (see 
Section 11.13). 
• 
Take a photograph of site(s) of application of Viaskin® and keep in the subject’s medical 
records or source documents. 
 
Additional days up to 21 days may be added to visit period if due changes in patient’s school 
calendar, vacation, or illness.  
 
 
10. 
RISK AND RISK-BENEFIT RATIO 
 
10.1 Risks from epicutaneous immunotherapy (EPIT). 
 
In the previous pilot clinical study in cow’s milk-allergic children with a related drug product 
(patch test with the same technology as diallertest), there was no serious AEs reported during 
the trial and no child required interruption of treatment because of an AE. The expected 
Adverse reactions with Viaskin Milk during EPIT are described in the Viaskin Milk 
Investigator’s Brochure. 
 
The potential risks observed in other Viaskin studies have been primarily localized dermatitis 
not considered serious in any subjects.  There have been no reports of systemic reactions with 
Viaskin patch.  But, if systemic reactions occurred in this study, the symptoms would be 
worsening EoE with abdominal pain and possible vomiting.  
 
10.2 Risks from Upper Endoscopy and Biopsy. 
 
The safety of multiple biopsies is supported by studies on adult patients with Barrett’s esophagus 
that have shown that multiple esophageal biopsies (as many as 35 to 120 esophageal biopsies in 
an individual patient) do not produce esophageal perforation or bleeding when performed by an 
experienced team of physicians, nurses, and technicians68.  In addition, a recent NIH study 
demonstrated that obtaining multiple mucosal biopsies for research purposes during elective 
endoscopy is well-tolerated and appears to have no more than minimal risk without appreciably 
increasing the risk of otherwise routine endoscopy69. Importantly, there was no statistically 


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significant association between the number of biopsies, type of procedure, anatomic location of 
research biopsies, endoscopist, or the use of nonsteroidal anti-inflammatory drugs and the risk of 
complications. 
 
The incidence of perforation associated with upper endoscopy was recently reviewed in an 11 
year retrospective study at CHOP. A total of 21,345 esophagogastroduodenoscopy (EGD) were 
performed between February 1998 and November 2008 including patients with esophageal 
strictures or crepe-paper esophagus. Three perforations occurred with EGD (0.02%, 95% CI 0-
0.04%), and 2 with colonoscopy (0.04%, 95% CI 0-0.11%). Two of the three EGD-related 
perforations occurred after therapeutic EGD (foreign body removal, and dilatation of a proximal 
esophageal stricture and esophageal web removal), for an incidence of 0.18% (95% CI 0-0.47%). 
None of the EGD-related perforations was the result of esophageal mucosal biopsies.  The 
presence of crepe-paper esophagus or strictures does not increase the risk for EGD-related 
perforations based on this review, thus these patients were not excluded from our proposed 
cohort.  Identified risk factors for perforation on diagnostic (non-therapeutic) endoscopy were 
Crohn’s disease (2 colonoscopy perforations) and severe hemorrhagic gastritis (1 EGD 
perforation of the stomach). The incidence of perforation associated with pediatric 
gastrointestinal endoscopy performed by pediatric gastroenterologists in this case series from 
CHOP was low and less than that previously reported in adults. Based upon this retrospective 
study, the estimated incidence of perforation from EGD at CHOP is 1 in 7,115 EGD 
procedures.70,71  
 
There are standard risks from moderate intravenous sedation or general anesthesia for the one 
research biopsy.  To minimize the risks, all anesthesia will be done by pediatric anesthesiologist. 
For the intravenous sedation, the risk of assisted ventilation is 0.1-0.2% and no patients have 
required intubation and no history of permanent injury based on current literature. For general 
anesthesia, the overall risk for a serious adverse event is 1/250,000. Total adverse events with 
nausea and vomiting being the most common are seen in 1/29 cases72-74.  
 
Since the EGD procedure with biopsy is conducted under conscious sedation or anesthesia, this 
needs to be considered for the total risk assessment. The investigative team considers the overall 
risk of the single research EGD procedure with biopsy under conscious sedation or anesthesia to 
be at most a minor increase above minimal risk75.   
 
10.3 Risk-Benefit Ratio 
 
While subjects in the active arm are in a study group that is exposed to greater than minimal risk, 
there is the prospect of direct benefit, in that these subjects may potentially be cured of milk-
induced Eosinophilic Esophagitis or have reduced symptoms.  Currently, the only therapy for 
this life-long disease is milk avoidance or off-label use of topical steroids.  In addition, there will 
be additional knowledge gained about the disease and potential development of tolerance in 
Eosinophilic Esophagitis.   
 
Both patients on the placebo arm and non-responders to therapy, we may have exacerbations of 
EoE symptoms including abdominal pain, and vomiting.  To minimize this issue, we are using 
3:1 randomization of active to placebo therapy.  Also, we have incorporated a period of 1 week 
to 2 month to milk re-exposure to minimize symptoms of EoE. 
 


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The placebo arm will be at risk of the single research endoscopy with biopsy under sedation or 
anesthesia, which the investigative team believes is a minor increase above minimal risk. This 
arm will help inform the natural history of the disease and will serve as a meaningful control 
group. There is no treatment for the disease other than that outlined in section 6.2. Thus, 
avoidance of milk would be the continued recommendation for the placebo study arm.  If the 
therapy is effective, the placebo subjects may benefit of the active treatment during the open-
label treatment period. 
 
In summary, the risks include application of Viaskin® Milk EPIT patches and the two research 
upper endoscopies and biopsies under conscious sedation or anesthesia.  The main risk from the 
EPIT include rashes with local erythema or other local skin reactions, but serious adverse 
reactions cannot be excluded. Based on the experience at CHOP, the risk from upper endoscopy 
with biopsy under sedation or general anesthesia is a minor increase above minimal.  Therefore, 
there is a prospect of direct benefit for the treatment arm with greater than minimal risk to these 
subjects, while there is no prospect of direct benefit for the placebo arm during the double-blind 
period, with minor increase above minimal risk. 
 
11. 
METHODS OF ASSESSMENT 
 
11.1 Medical History 
 
Complete medical history will include history and duration of all allergies (including milk allergy) 
and current medical conditions, number of allergic reactions and treatments in the previous 
12 months, past or present cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, 
endocrine, lymphatic, hematologic, immunologic, dermatological, psychiatric, and genitourinary 
disorders, drug and surgical history and any other diseases or disorders. 
 
11.2 Pregnancy Test 
 
Pregnancy will be determined by evaluation of urine pregnancy tests. Subjects who are pregnant at 
screening are excluded from the study. Subjects who become pregnant during treatment must be 
discontinued from the study. 
 
The Principal Investigator will collect information on any female subject who becomes pregnant 
while participating in this study. The subject will also be followed to determine the outcome of the 
pregnancy.  
 
11.3 Physical Examination 
 
Physical examinations will be performed by a physician or nurse practitioner and will include 
examination of the following: general appearance, head, ears, eyes, nose and throat, neck, complete 
skin examination, cardiovascular system, respiratory system, abdominal system and nervous 
system. For each body system an assessment of normal or abnormal will be recorded in the eCRF 
at screening and the abnormality will be documented. During the study, any clinically relevant 
changes observed during physical examinations will be reported as AEs. 
 
Physical examinations must be performed before the upper endoscopy/biopsy.  


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11.4 Vital Signs and Weight 
 
Vital signs will include sitting systolic and diastolic blood pressure, heart rate, respiratory rate 
and temperature. Systolic blood pressure and diastolic blood pressure will be measured on the 
same arm after the subject has been in a sitting position for 5 minutes. Heart rate will be recorded 
simultaneously with blood pressure measurements, followed by respiratory rate and body 
temperature. 
 
Body weight (kg) will be measured without shoes or jacket. Height (cm) will be determined at 
screening. 
 
During the study, the measurement of vital signs may be repeated at the discretion of the Investigator 
for safety reasons. Clinically relevant abnormal findings will be reported as AEs. 
 
Vital signs must be performed before the upper endoscopy/biopsy.  
 
11.5 Eosinophilic Esophagitis Quality of Life 
 
Quality of life is a measurement of a subject’s overall well-being. QOL will be measured by the 
validated age specific Eosinophilic Esophagitis tool for 5-7 years of age, 8-12 years of age, and 13- 
18 years of age (Appendix 2) developed by Franciosi and colleagues, based on the age of the subject 
at Visit 2.   The subjects will complete the same questionnaire throughout the study. 
 
11.6 Clinical Laboratory Testing 
 
Venous blood samples will be taken for hematology and biochemistry testing. The following 
parameters will be determined: 
Hematology: hemoglobin, hematocrit, platelets, red blood cells, white blood cells.  
Biochemistry: aspartate aminotransferase, alanine aminotransferase, total bilirubin, total protein, 
blood urea nitrogen, creatinine. 
 
Analysis of blood samples will be conducted by CHOP laboratory.  Fresh blood will be collected 
from the above described patients per above protocol. Blood (max lesser of 50 ml or 3 ml/kg in a 6-
8 week period) will be obtained by venipuncture during outpatient visit or obtained by IV during 
endoscopy procedure. Blood will be collected only after informed consent/assent is given.  
Participants will be given an opportunity and the time of consent to opt in or opt out of future use in 
subsequent research.  The estimated volume of blood collected from each subject during the entire 
(22 month) study will be approximately 215mL.Additional and repeat laboratory safety testing may 
be performed at the discretion of the Investigator. 
 
11.7 Research Laboratory Testing 
 
Research labs include TSLP, Epigenetics, and T cell studies.  They will be processed and stored at 
the Cianferoni Research Laboratory at the Children’s Hospital of Philadelphia. 
 
11.8 Upper Endoscopy with Biopsy 


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All subjects will undergo a minimum of four upper endoscopies with biopsies during their 
participation in the study (two each of proximal and distal, plus any inflamed areas) as per 
standard clinical practice: at least two at Screening as Standard of Care (Visit 2 and Visit 3) and 
two at the end of each treatment period as Research (Visit 10 and Visit 16).  The results of 
additional SOC endoscopies will be allowed to assess eligibility, if the endoscopies are required 
for clinical care purposes   The samples will be processed by the Department of Pathology at The 
Children’s Hospital of Philadelphia and the number of eosinophils will be counted using 
hematoxylin and eosin stain.  The handling of samples will be done following ASGE Standard 
on Endoscopic Mucosal Tissue Sampling.67  
 
Upper endoscopy will be scored using a validated standardized measure. 57  The measure 
examines four major esophageal features (rings, furrows, exudates and edema) and the presence 
of minor features of narrow caliber esophagus, feline esophagus, stricture and crepe paper 
esophagus. The features are graded: 
• Rings (0-none, 1 mild, 2-moderate, 3-severe)  
• Exudates (0-none, 1-mild, 2-severe) 
• Furrows- (0-mild, 1-present) 
• Edema- (0-mild, 1-present) 
• Stricture (0-mild, 1-present) 
• 
Crepe paper esophagus (0-mild, 1-present) 
11.9 Histological Evaluation 
 
Prior to randomization, esophageal biopsy samples will be evaluated to confirm eligibility. 
Biopsy samples will be stained with hematoxylin and eosin stain. Intraepithelial eosinophils will 
be counted in all HPFs using 400X light microscopy. A HPF will be counted only if at least half 
of the field is occupied by tissue. The maximum eosinophil count per HPF will be reported for 
each esophageal biopsy site (at each of 2 levels). In addition to the evaluation for eosinophilia, 
all biopsy samples will be assessed for other histologic changes including epithelial hyperplasia, 
intercellular edema, and fibrosis.  Histologic evaluation to be completed by a blinded Pathologist 
at CHOP. 
 
At the end of each treatment period (Visit 10 and Visit 16), the esophageal biopsy specimens 
from all subjects will be evaluated in a blinded fashion by an independent pathologist. Specimens 
will be examined with respect to the maximum eosinophil counts and other histologic changes. 
Together with the EoE Clinical Symptom Score, the maximum eosinophil count per HPF for 
each specimen (from the total of all specimens) will be used to determine response to treatment.  
 
The maximum eosinophil count will be defined as the highest number of eosinophils observed 
in any single HPF from an esophageal specimen. All specimens from all esophageal sites will be 
considered in determining the resolution of eosinophilia. A maximum eosinophil count will be 
recorded for the esophagus. The highest peak counts at a given timepoint (screening or end of 
each treatment visit) will be referred to as the maximum eosinophil count for that timepoint.  The 


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mean Esophageal Eosinophil count will be the mean score of each of the high power fields from 
the all biopsy specimens. 
 
As a confirmatory marker of EoE disease activity, we will use paraffin-embedded esophageal 
biopsies already obtained for routine clinical care to identify innate immune cell populations as 
well as chemokine expression through immunohistochemistry staining. 
 
11.10 Diet Diary 
 
Subjects will indicate the duration and amount of milk and milk products taken on a daily basis 
during the screening period and once milk is re-introduced into the subject’s diet during the 
treatment period (Milk reintroduction at Visit 9 and Visit 15).  
 
The milk introduction period and amount of milk and milk products taken should be the same, 
as much as possible, at both timeframes. 
 
11.11 Subject Diary 
 
Diary cards will be provided to each subject. Subjects will be asked to record on a daily basis in 
their diary cards for the first 3 months the time of application and removal of each Viaskin®, along 
with reason(s) for early removal (should that occur) and any observed AE(s) to the Viaskin®  (local 
and/or systemic) or any other AEs. After 3 months, the subjects are instructed to report only the 
day/period when the patch was not applied as per protocol. Subjects will also be instructed to record 
any concomitant medication or treatment taken for any type of AEs. 
 
The diaries may also be used to record the dietary information during the milk reintroduction periods 
at screening and at the end of treatment. In addition, the diary cards will also be used for the subjects 
to report any accidental consumption of milk that could have occurred in the study, during the milk-
diet required period. 
 
Subjects must bring their diary back to the Investigator at each visit, and the Investigator must check 
the diary for completeness and accuracy. It is the Investigators’ responsibility to instruct the subject 
about the use of the diary, and to ensure that the subject completes the diary accurately. Any 
problems with completing the diary will be addressed with the subject. Completed pages of the diary 
cards will be collected and kept by the investigator at each visit. The remaining blank pages of the 
diary cards will be given back to the subject at each visit before discharge. All diary cards must be 
returned at completion of the study, or if the subject discontinues.  
 
11.12 Eosinophilic Esophagitis Symptom Score 
 
Symptoms of Eosinophilic Esophagitis range from abdominal pain, gastroesophageal reflux, 
vomiting, and difficult swallowing.  The symptoms will range from none to very severe as in 
Spergel54.  The symptoms will be in 3 categories and individual symptoms and total symptoms 
scores will be collected on a range of 0-4 (0-none, 1-mild, 2-moderate, 3-severe and 4-very 
severe). 
 
Table 4: Eosinophilic Esophagitis Score 


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Symptoms 
Score 
Abdominal/Chest Pain 
0-4 
Vomiting/Regurgitation 
0-4 
Dysphagia 
0-4 
Total Score 
0-12 
 
 
11.13 Skin Reaction and Photography 
 
Skin reactions under the Viaskin® will be graded (ideally by the same site person) at each visit 
according to the modified recommendations of the EAACI/GA2LEN position paper in 
Turjanmaa et al (23):  
 
Table 5:  Skin Reaction Grading System 
 
Grade 
Skin Reaction 
Grade 0 
Negative 
Grade 1  
Only erythema, or erythema + 
infiltration 
Grade 2  
Erythema, few papules 
Grade 3  
Erythema, many or spreading papules 
Grade 4  
Erythema, vesicles 
 
Viaskin® patches are transparent and the degree of local reactions under the Viaskin® can be 
easily seen. Grades of local skin reactions will be recorded after 3 hours of application for the 
first day of treatment (V4), after 1 hour of application at Day 8 of treatment (V5) and when 
subjects arrive for a visit for other protocol visits. 
 
Photographic records will be taken of site(s) of application of the Viaskin® and filed in the 
subject’s medical records or source document in case a further review of local reactions is 
required. 
 
12. 
SAFETY MEASUREMENTS AND VARIABLES 
 
12.1 Adverse Events Definition 
 
An AE is any untoward medical occurrence that does not necessarily have a causal relationship with 
the investigational medicinal product. An AE can therefore be any unfavorable or unintended sign, 
including an abnormal laboratory finding, symptom or disease temporally associated with the use 
of an investigational medicinal product whether or not considered related to the investigational 
medicinal product. 
 
AEs will be monitored throughout the entire study. Investigators will ask the subject at each visit if 
they have experienced any untoward effects since the last study visit. All AEs will be recorded on 
the eCRFs provided. A description of the event, severity, time of occurrence, duration, any action 


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(e.g. treatment and follow up tests) and the outcome should be provided along with the Investigator’s 
assessment of the relationship to the study treatment. 
 
AEs will be recorded from the time written screening informed consent is signed until the time of 
the End of Study visit. AEs still ongoing at the time of End of study visit will be followed for an 
additional period to encompass a total period of 14 days of AE follow-up after administration of the 
last dose of treatment. 
 
If known, the name or diagnosis of the illness should be recorded, rather than a listing of individual 
signs or symptoms. AEs must be graded as being mild, moderate or severe and their start and end 
dates given. Definitions of severity are as follows: 
 
Mild:  
an AE usually transient in nature and generally not interfering with normal 
activities 
Moderate:  
an AE that is sufficiently discomforting to interfere with normal activities; 
Severe:  
an AE that is incapacitating and prevents normal activities. 
 
Even if the Investigator feels there is no relationship to the study drug, all adverse experiences 
MUST be recorded in the eCRF. The Investigator is requested to assess the relationship of any 
clinical adverse experience to treatment using the following definitions: 
 
Unrelated: those AEs which are clearly and incontrovertibly due to extraneous causes 
(concurrent drugs, environment etc.) and do not meet the criteria for drug relationship listed under 
Unlikely, Possible, Probable or Related. 
 
Unlikely: an adverse experience may be considered unlikely if it includes at least the first two 
features: 
• 
It does not follow a reasonable temporal sequence from administration of the drug. 
• 
It could readily have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject. 
• 
It does not follow a known pattern to the suspected drug. 
• 
It does not reappear or worsen when the drug is re-administered. 
 
Possible: an adverse experience may be considered possible if it includes at least the first two 
features: 
• 
It follows a reasonable temporal sequence from administration of the drug. 
• 
It could readily have been produced by the subject’s clinical state, environment or toxic 
factors, or other modes of therapy administered to the subject. 
• 
It follows a known response pattern to the suspected drug. 
 
Probable: an adverse experience may be considered probable if it includes at least the first three 
features: 
• 
It follows a reasonable temporal sequence from administration of the drug. 
• 
It could not be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors or other modes of therapy administered to the 
subject. 


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• 
It disappears or decreased on cessation or reduction in dose. There are exceptions when 
an AE does not disappear upon discontinuation of the drug (e.g. bone marrow depression, 
fixed drug eruptions, tardive dyskinesia, etc). 
• 
It follows a known pattern of response to the suspected drug. 
 
Related: an adverse experience may be considered related if it includes all of the following 
features: 
• 
It follows a reasonable temporal sequence from administration of the drug. 
• 
It could not be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors or other modes of therapy administered to the 
subject. 
• 
It disappears or decreased on cessation or reduction in dose. There are exceptions when 
an AE does not disappear upon discontinuation of the drug. For example: bone marrow 
depression, fixed drug eruptions, tardive dyskinesia, etc. 
• 
It follows a known pattern of response to the suspected drug. 
• 
It reappears or worsens if the drug is re-administered. 
 
12.2 Serious Adverse Events  
 
A SAE is any untoward medical occurrence or effect that fulfills any of the following criteria: 
• 
results in death; 
• 
is life-threatening; 
• 
requires hospitalization or prolongation of existing in-subject hospitalization; 
• 
results in persistent or significant disability or incapacity; 
• 
is a congenital abnormality/birth defect; 
• 
important medical events not captured by the above but which may, for example, require 
medical intervention to prevent one of the outcomes above. 
 
Events associated with hospitalization for the following will not be considered as an SAE: 
a) 
Evaluation or treatment of a pre-existing condition and non-exacerbating condition as 
long as the condition(s) associated with the hospitalization: existed prior to the subject’s entry 
into the study and has been recorded in the subject’s medical history as documented in the eCRF 
(e.g. degenerative disease) has not worsened in severity or frequency during the subject’s 
exposure to study medication has not required a change in treatment management during the 
subject’s exposure to the study medication 
 
b) 
Treatment which is elective or pre-planned of a pre-existing condition and non-
exacerbating condition. 
 
Unanticipated Problems Involving Risk to Subjects or Others:  
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators brochure, 
etc) 
• Related to participation in the research (i.e. related means there is a reasonable possibility 
that the incident experience, or outcome may have been caused by the procedures involved 
in the research) 


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• Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
Unexpected, suspected adverse reaction: A suspected adverse reaction is considered 
“unexpected” if it is not listed in the general investigational plan, clinical protocol, or elsewhere 
in the current IND application; or is not listed at the specificity or severity that has been 
previously observed and/or specified. 
 
12.3 Reporting of Serious Adverse Events, Unanticipated Problems, and Serious 
Unexpected Suspected adverse reactions 
 
This trial will be conducted under an investigator initiated IND held by Dr. Jonathan Spergel. 
The Principal Investigator will be responsible for the conduct of the trial and adherence to CHOP 
IRB SOP 408 Unanticipated Problems Involving Risks to Subjects and FDA Regulations 21 CFR 
312.32 IND Safety Reporting.  This includes but is not limited to collecting, assessing, reporting 
all adverse experiences, and monitoring/assessing the safety implications of any new pre-clinical, 
clinical, or manufacturing updates that occur during the course of the study investigation.  If the 
Principal Investigator determines the new information significantly impacts safety they will 
promptly notify the IRB, FDA, and any other protocol specified safety committee or monitor.   
 
Reporting requirements for SAEs will be managed by the investigator.  Full details of the procedures 
to be adopted will be documented in a safety management plan will be prepared by Westat: 
 
Any AE which occurs in any subject after signing the screening informed consent through the last 
visit must be reported. All SAEs that occur before the end of study following cessation of the last 
dose of treatment with the study drug, whether or not considered related to the investigational 
product must also be reported. All subjects with SAEs must be followed up for outcome. 
 
All SAEs will be reported to the CHOP IRB and FDA per current regulations (CHOP IRB SOP 408 
Unanticipated Problems Involving Risks to Subjects and FDA Regulations 21 CFR 312.32 IND 
Safety Reporting).  
 
See Appendix 4 for monitoring plan. 
 
12.4 Monitoring of Subjects with Adverse Events 
 
Each subject must be carefully monitored for AEs. This includes clinical laboratory variables. 
Assessments must be made of the seriousness, intensity and relationship to the administration of the 
study treatment. After the initial AE/SAE report, the investigator is required to follow up each 
subject proactively and provide further information as needed to the CHOP IRB and FDA as 
required. 
 
12.5 Procedures to be Followed in the Event of Abnormal Laboratory Test Values 


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In the event of unexplained abnormal laboratory test values, the tests should be repeated 
immediately and followed up until they have returned to the normal range and/or an adequate 
explanation of the abnormality is found. 
 
12.6 Clinical Laboratory Parameters and Abnormal Laboratory Test Results 
 
Clinically significant changes in laboratory parameters (abnormalities), in the judgment of the 
Investigator, will be recorded as AEs and appropriate countermeasures taken. 
 
12.7 Abnormal Physical Examination Findings 
 
Clinically significant changes in physical examination findings (abnormalities), in the judgment of 
the Investigator, will be recorded as AEs and appropriate countermeasures taken. 
 
12.8 Additional Safety Assessments 
 
Safety will be assessed using AEs, observed local and systemic allergic symptoms, physical 
examinations, including skin reactions, hematology, biochemistry, and vital signs. 
 
Drug accountability will be noted by the field monitor during site visits and at the completion of the 
trial. 
 
12.9 Treatment of Overdose of Study Medication 
 
There is no experience of overdosing with Viaskin® patches. No specific treatment for overdosing 
is known. Treatment given to a subject in case of overdosing should be symptomatic and supportive. 
 
Any overdose, with or without associated AEs, in a clinical study must be reported to the local IRB 
and FDA as required. Overdose will be reported in the eCRF. All reports of overdoses must be filed 
in the Study Center File. Any AEs associated with the overdose should be reported on relevant 
AE/SAE sections in the eCRF. 
 
12.10 Procedures in Case of Pregnancy 
 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. All pregnancies and outcomes of pregnancy must be reported to IRB. 
 
12.11 Adverse Events of Special Interest 


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AEs of special interest in this study include Grade 4 local skin reactions upon application and 
removal of the Viaskin®. Skin reactions at the site of Viaskin® Patch application will be examined 
at the time points specified at each visit and graded according to Section 11.13 (Table 5). 
Specifically, the appearance of any vesicle(s) or ulcerative skin lesion(s) or any other significant 
skin lesion which could potentially lead to skin barrier disruption at sites of Viaskin® applications 
will be considered AEs of special interest. Any occurrence of systemic (or distant) allergic reaction 
related to Viaskin® Milk application will also be considered an AE of special interest.  
 
13. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
 
The data management and statistical analysis of this study will be performed by an external BDMC 
(Biostatistics and Data management Core) at CHOP managed by Westat. 
 
13.1 Data Management 
 
An eCRF will be used for the current study, and a data management plan will be prepared by the 
BDMC (Biostatistics and Data management Core) at CHOP managed by Westat. 
 
Previous and concomitant medications will be coded using the latest available World Health 
Organization (WHO) Drug Reference Dictionary. Coexistent diseases and AEs will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA). 
 
When the database has been declared to be complete and accurate, the database will be locked. Any 
changes to the database after that time can only be made by written agreement between the 
investigator and the Westat BioStat unit. 
 
13.2 Sample Size Estimation 
 
This is a pilot study in which we aim to identify efficacy of the Viaskin® Milk treatment.  Sample 
size is based on projected subject volume.  If efficacy is shown, our pilot data could be used to 
perform a power analysis for a larger study. 
 
We will recruit 38 subjects and plan to have approximately 22 evaluable subjects with milk-
induced EoE confirmed by endoscopy and biopsy.  
 
A total sample size of 22 evaluable subjects (16 subjects in the active Viaskin® Milk group and 
6 subjects in the placebo group) will achieve 90% power to detect a difference of 40 in mean 
maximum eosinophil counts between the two treatment groups (mean maximum eosinophil 
counts of 10 and 50 in Viaskin® Milk and in placebo, respectively) assuming that a common 
standard deviation is 20 using a two group t-test with a two-sided significance level of 0.05. 
 
Approximately 22 subjects will be randomized to obtain 18 completed subjects with 10% drop-
out. 
 
13.3 Statistical Analysis Plan 
 


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A Statistical Analysis Plan (SAP) will be written and finalized prior to database lock. The SAP will 
provide a detailed description of the statistical methods and expand on the details provided in the 
protocol. Additional analyses may be added. Tables, listing and figures shells will also be provided. 
 
13.4 Randomization 
 
This is a double-blind, placebo-controlled study. The actual treatment given to individual subjects 
is determined by a randomization schedule. The associated treatment assignments giving details of 
individual subject treatment are assigned from a randomization list. After entry criteria are 
confirmed at the end of Visit 3, subjects will be randomized at Visit 4 (Day 1) using a 3:1 ratio to 
receive either the Viaskin® Milk or placebo. 
 
13.5 Analysis Populations 
 
All the analysis populations will be identified and finalized in the SAP. 
 
13.5.1 Safety Population 
 
The safety population will be comprised of all subjects who are randomized and received at least 
one dose of study drug. This population will be used to assess comparative safety information. 
 
13.5.2 Intent-to-treat Population 
 
The intent-to-treat (ITT) population (full analysis set) will be comprised of all subjects who are 
randomized. This population will be used to assess comparative efficacy information. 
 
13.5.3 Per Protocol Population 
 
The per protocol (PP) population will include all subjects in the ITT population who do not have 
pre-defined major deviations from the protocol that may affect the primary (and secondary) 
endpoints (for instance, subjects who have not gone through the third upper endoscopy and biopsy 
at the end of treatment, subjects with a compliance below 80% etc.) The deviations to consider will 
be listed more exhaustively in the SAP. The PP population will be used to perform confirmatory 
analyses of the primary efficacy evaluation. 
 
 
13.6 Statistical Methods 
 
The statistical analyses for the entire study as further outlined in the SAP will be included in the 
Clinical Study Report for this protocol. The SAP will give a detailed description of the summaries 
and analyses (primary and secondary) that will be performed and clearly describe when these 
analyses will take place. The SAP will be finalized prior to database lock to preserve the integrity 
of the statistical analysis and study conclusions. 
 
All pre-defined statistical analyses will be performed after the database is released for unblinding. 
Statistical analyses will be performed using SAS® Version 9.1 or higher (SAS Institute, Cary, NC 


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27513) 
 
Descriptive statistical analysis of all data obtained will be conducted using inferential and graphical 
exploratory data analytic techniques. Descriptive statistics will be presented as means and standard 
deviations or median and interquartile ranges or minimum and maximum for continuous variables 
and frequency counts and percentages for categorical variables.  The denominator for percentages 
will be the number of subjects in the population with data available unless otherwise stated.  
 
13.6.1 Missing Data 
 
Every attempt must be made by the Investigator to provide complete data. The primary analysis can 
be performed on data without imputation. However, exploratory analyses using the multiple 
imputation method and last observation carried forward should be utilized to assess the robustness 
of the data. 
 
Analyses of primary and secondary efficacy measures will be based on the intent-to-treat (ITT) 
population, with missing values imputed using the last value carried forward analysis.   
 
13.6.2 Demographic and Baseline Data 
 
Descriptive statistics will be produced as means, standard deviations, medians, and ranges for 
continuous demographic and baseline characteristics (including age, height, weight and maximum 
Esophageal Eosinophil Count) and frequency counts and percentages for the categorical 
demographic and baseline characteristics (including race, ethnicity, medical history) will be 
produced by treatment group and overall. Distribution of the continuous outcomes will be evaluated 
using histograms. Transformation of some of these continuous variables will be performed wherever 
deemed more appropriate.  The balance of the demographic and baseline measures between the 
treatment groups will be compared using two-sample t-tests or the Mann-Whitney tests as 
appropriate for continuous variables and the chi-square tests for categorical variables. 
 
All individual subject demographic and baseline characteristic data will be listed. 
 
13.6.3 Subject Disposition 
 
Subject disposition will be summarized for the intention-to-treat population. The number and 
percentage of subjects randomized, subjects in each study population (Safety, ITT, PP), and subjects 
who received study medication, who completed the double-blind period, who discontinued the 
double-blind period, and the primary reason for discontinuation from the double-blind period will 
be tabulated by treatment group and overall.  
 
13.6.4 Efficacy 
 
13.6.4.1 Primary Efficacy Variable 
 
The primary efficacy endpoint is defined as the maximum esophageal eosinophil count on all 
specimens obtained on the biopsy at end of double-blind treatment (Visit 10), after milk 
reintroduction at Visit 9.  The null hypothesis is that the mean maximum esophageal eosinophil 


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count in active treatment group is the same as that in the placebo group. This hypothesis will be 
evaluated using an analysis of covariance (ANCOVA) model with treatment group, baseline 
patient’s maximum esophageal eosinophil count, and age group (4-11 years old versus 12-17 years 
old) as covariates. The null hypothesis will be tested against the alternative hypothesis that the results 
are different in each treatment group at the 0.05 significance level.  The least square means for the 
treatment groups, difference in least square means between the treatment groups, effect size 
calculated as the absolute difference in least square means between active group and placebo divided 
by the root mean square, and p-value for difference between treatment groups will be presented. 
 
13.6.4.2 Secondary Efficacy Variables 
 
The following secondary efficacy endpoints will be assessed: 
Esophageal Eosinophil Count 
 
The mean Esophageal Eosinophil Count of all specimens obtained at the end of treatment as well as 
the change from baseline will be summarized by treatment group.  
 
The null hypothesis that the mean Esophageal Eosinophil Count eliciting doses at the end of 
treatment are the same in each treatment group will be analyzed using ANCOVA model with 
treatment group, baseline patient’s mean esophageal eosinophil count, and age group (4-11 years 
old versus 12-17 years old) as covariates. This null hypothesis will be tested against the alternative 
hypothesis that the results are different in each treatment group at the 0.05 significance level. 
 
Esophageal Endoscopy Score  
The total score for each subject will be calculated (for endoscopy) and summary statistics will be 
presented for each treatment group at baseline and the end of study. This will be based on each 
symptom being graded for severity as 0, 1, 2 or 3 (respectively none, mild, moderate and severe). 
The total scores at the end of treatment between two treatment groups will be examined using 
ANCOVA model with treatment group, baseline patient’s total score, and age group (4-11 years old 
versus 12-17 years old) as covariates. The change from baseline to end of treatment will also be 
presented. The change in Esophageal endoscopy scores between two treatment groups will be 
examined using a two sample Student’s t-test or Mann-Whitney test. 
 
 
Eosinophilic Esophagitis Symptom Score 
Improvement in symptom scores will be defined as a decrease in total symptom scores of two or 
more from baseline to end of treatment. Subjects will be categorized based on whether they 
improved their symptoms. Subjects who improved their symptom scores were considered as 
responders and patients who did not improve their symptom scores were considered as non-
responders. The percentage of responders between the active treatment group and placebo group 
will be compared using Fisher’s exact test. In addition, all of the summaries of severity of symptoms 
above will be repeated, split by responder/non-responder groups. 
 
In addition, the change from baseline to end of treatment of the total symptom score and individual 
symptom scores (Abdominal/chest pain score, Vomiting score, and Dysphagia score) will be 
generated by treatment group and overall. The comparison of the change of individual symptom 
scores between the two treatment groups will be evaluated by using Fisher’s exact tests. 
 


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The responses will be divided into three categories as suggested:  Poor <30% improvement, good 
30-70% improvement and excellent >70% improvement from baseline. 
 
Percentage of subjects per response rate 
The percentage of subjects showing an excellent response (≤1 eos/HPF), good response (2-14 
eos/HPF), or poor response (≥15 eos/HPF) at the end of treatment will also be presented and 
analyzed between the two treatment groups using Fisher’s exact test. 
 
Eosinophilic Esophagitis Quality of Life Score 
The Quality of Life score will also be reported for each treatment group at baseline and the end of 
treatment. The change from baseline to end of treatment will also be presented. The change in QOL 
scores between two treatment groups will be compared with two-sample t-test or Mann-Whitney 
test depending on the distribution of the change of the QOL score. 
 
Combination Score: 
Combination Score of four measures (Eosinophils/HPF, EREFS, investigator assessment and 
parental assessment of symptoms) will be calculated at baseline, end of treatment and end of study. 
The combination score will be calculated as (maximum eosinophils per high power field) + 
[10*esophageal endoscopy score (EREFS)]  + [2* Parent assessment of esophageal symptoms 
(PEESS)] + [5*investigator assessment of EoE symptom activity]. The change from baseline to end 
of treatment will also be presented. The change in QOL scores between two treatment groups will 
be compared with two-sample t-test or Mann-Whitney test depending on the distribution of the 
change of the QOL score. 
 
13.6.5 Pharmacokinetics 
 
Not applicable, no pharmacokinetic assessments will be performed during this study. 
 
13.6.6 Safety 
 
No formal statistical analysis of safety endpoints will be carried out. 
 
13.6.6.1 Adverse Events 
 
All AEs will be coded by system organ class and preferred term using MedDRA. 
Treatment-emergent AEs (TEAEs) will be defined as any AEs, regardless of relationship to study 
drug, which occur during AE collection period of study drug or any event already present that 
worsens in either intensity or relationship to study drug following exposure to the Viaskin®. If 
relationship information is missing, the TEAE will be considered drug-related.  
 
An overall summary of TEAEs will be provided showing the number and percentage of subjects in 
each treatment group with any TEAE, any potentially drug-related TEAE, any severe TEAE, any 
serious TEAE, any TEAE leading to discontinuation, and any TEAE leading to death. The number 
of events will also be presented.  


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The number of AEs as well as the number and percentage of subjects who experienced at least one 
AE will be summarized by system organ class, preferred term and treatment group. The incidence 
of the following events will be summarized: 
• Local skin tolerance: incidence, severity and duration of local TEAE at site of Viaskin® 
application as reported by subjects in the diary card 
• TEAEs: incidence, severity and duration. 
• Potentially drug-related TEAEs 
• Discontinuations due to TEAEs 
• Laboratory data, physical examinations, and vital signs Systemic allergic symptoms in 
the active and placebo groups  
• Potentially drug-related systemic allergic symptoms 
• SAEs 
• Potentially drug-related SAEs 
 
In addition, TEAEs will be summarized by relationship to study drug and by severity. If a subject 
has more than one occurrence of the same TEAE with different severities or relationship to study 
drug, then the TEAE will be assigned to the highest severity category and/or most related 
relationship category. If the intensity or relationship is missing, then the ‘worst case’ will be assumed 
(i.e., severe for intensity and drug-related for relationship). 
 
The proportion of subjects that experience systemic allergic symptoms will be summarized by 
treatment. All TEAEs will be listed. 
 
13.6.6.2 Laboratory Assessments 
 
Descriptive statistics will be calculated for clinical laboratory tests (hematology and biochemistry) 
performed at baseline (Day 1),  Visit 10 (end of DBPC treatment) and visit 16 (end of open label 
extension). Categorical variables will be summarized by frequency and percentages of subjects in 
corresponding categories. Changes from baseline will also be presented. 
In addition, summaries of laboratory values categorized based on CTC (common toxicity criteria) 
grade will also be presented.  
 
All laboratory data will be listed. Listing of values that are out of normal range will be flagged in 
the data listings. 
 
13.6.6.3 Vital Signs 
 
Observed vital sign values and changes from baseline will be descriptively summarized by visit and 
treatment group. All vital signs data will be listed. 
 
The analysis of vital signs will focus on the incidence of clinically relevant abnormalities. The 
number of subjects evaluated and the number and percentage of subjects with clinically relevant 
post-baseline abnormalities at each visit will be presented.  


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Table 6 Criteria to Determine Clinically Relevant Abnormalities in Vital Signs - Children 
Vital Sign 
Criteria for Abnormalities 
Temperature 
<35°C and a decrease from pre-dosing of at least 1°C 
> 38.5°C and an increase from pre-dosing of at least 1°C 
Pulse 
> 120 beats per minute or an increase from pre-dosing of 
> 20 beats per minute, or 
< 50 beats per minute or a decrease from pre-dosing of 
> 20 beats per minute 
Systolic blood pressure 
> 140 mmHg or an increase from pre-dosing of > 40 
mmHg, or < 90 mmHg or a decrease from pre-dosing of > 
30 mmHg 
Diastolic blood pressure 
> 90 mmHg or an increase from pre-dosing of > 30 
mmHg, or < 50 mmHg or a decrease from pre-dosing of > 
20 mmHg 
 
13.6.6.4 Concomitant Medications 
 
Concomitant medications will be coded using the WHO Drug Dictionary. A summary of 
concomitant medications will be produced by preferred drug name and treatment group. All 
concomitant medications will be listed. 
 
13.6.7 Additional Data 
 
Diary card data, Viaskin® site examination and physical examination data will be summarized 
where appropriate and listed. Study drug compliance and accountability will be listed. 
 
13.6.8 Data and Safety Monitoring Board 
 
A DSMB will be composed to review the safety and/or efficacy data of the study at any time judged 
necessary during the course of the study and after the first 3 patients are enrolled and then annually. 
Members of the DSMB will be selected and confirmed as early as possible, in any case before the 
first data review is convened. Ideally, the DSMB should be composed of experts in food allergy and 
in the methodology of clinical trials. The DSMB will review either blinded or unblinded data during 
the course of the study (see below). Various recommendations will then be made by the DSMB.  
The three members of the DSMB are Stacie Jones, MD, Chief of Allergy and Immunology, 
Arkansas Children’s Hospital, Univ. of Arkansas School of Medicine; Seema Aceves, MD, PhD, 
Director of Eosinophilic Esophagitis Center, Rady’s Children’s Hospital, University of California 
at San Diego; and David Fleischer, MD, Univ. of Colorado School of Medicine.    Westat will supply 
blinded study results to the DSMB unless unblinded results are requested by the DSMB for safety 
reasons. For details of the emergency procedure for unblinding of individual subjects, see 
Section 8.5.10 
 


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14. 
MONITORING PROCEDURES (QUALITY ASSURANCE) 
 
The Principal Investigator has ethical, legal, and scientific obligations to conduct this study in 
accordance with established research principles and ICH GCP guidelines. As such, in order to 
fulfill these obligations and to maintain current of study progress, the Investigator’s monitors or 
representatives will visit the investigative site during study conduct, in addition to maintaining 
telephone and written communication. On-site visits, telephone calls, and regular inspection of 
the eCRFs will be conducted in order to assess subject enrollment, compliance with protocol 
procedures, completeness and accuracy of data entered on the eCRFs, verification of eCRF data 
against original source documents, and occurrence of AEs. The Investigator must provide the 
monitor with full access to all source and study documents. 
 
14.1 Routine Monitoring 
 
Investigator assigned monitors will conduct regular site visits at the one clinical site (CHOP) for 
the purpose of monitoring various aspects of the study. The monitor will access to the clinical 
(or associated) files and clinical study supplies (dispensing and storage areas) for all study 
subjects considered for study entry for the purpose of verifying entries made in the eCRF, and 
assist with their activities, if requested. Adequate time and space for monitoring visits should be 
made available by the Investigator. 
 
CHOP staff must complete the eCRFs in a timely manner and on an ongoing basis to allow 
regular review by the study monitor. 
 
See Appendix 3 for monitoring plan. 
 
14.2 Inspections and Auditing Procedures 
 
The Investigator monitor may conduct audits at the investigative sites including, but not limited to, 
drug supply, presence of required documents, the informed consent process, and comparison of 
eCRFs with source documents. All medical records (progress notes) must be available for audit. The 
Investigator agrees to participate with audits conducted at a convenient time in a reasonable manner. 
 
Government regulatory authorities may also inspect the Investigator during or after the study. The 
Investigator or designee should contact the Sponsor /CRO immediately if this occurs. He/she must 
cooperate fully with regulatory authorities or other audits conducted at a convenient time in a 
reasonable manner. 
 
The purpose of an audit is to assess whether ethics, regulatory and quality requirements are fulfilled. 
 
 
 
 
15. 
STUDY MANAGEMENT AND MATERIALS 
 
15.1 Electronic Case Report Forms 


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An eCRF will be used to store and transmit subject information. The eCRF must be reviewed and 
electronically signed and dated by the Investigator. 
 
Access to the eCRF will be strictly password protected and limited to personnel directly participating 
in the study. Data should be entered into the eCRF completely by examining personnel or the study 
coordinator. The eCRF must be completed as soon as possible after any subject evaluation or 
communication. If data is to be changed due to erroneous input or other reason, an electronic audit 
trail will track these changes. The eCRFs and computers that store them must be accessible to study 
monitors and other regulatory auditors. 
 
15.2 Data Collection 
 
During each study visit, a physician participating in the study will maintain progress notes, in ink, 
in the subject’s medical records to document all significant observations. At a minimum, these notes 
will contain: 
• 
The date of the visit and the corresponding day or visit in the study schedule (e.g., screening, 
Day 1, Day 8, etc.). 
• 
General condition and status remarks by the subject, including any significant medical 
findings. The severity, frequency, duration, and resolution of any reported AE, and the 
Investigator’s assessment as to whether or not the reported AE is study drug-related should 
be recorded. 
• 
Changes in concomitant medications or dosages. 
• 
A general reference to the procedures completed. 
• 
The signature or initials of all physicians making an entry in the medical record (progress 
notes). 
 
In addition, any contact with the subject via telephone or other means that provides significant 
clinical information will also be documented in the medical record (progress notes), as described 
above.  
Information from the medical records (progress notes) and other source documents will be promptly 
transcribed to the appropriate section of the eCRF. 
 
Changes to information in the medical record (progress notes), eCRF, and other source documents 
will be initialed and dated on the day the change are made by the Investigator or designee. If the 
reason for the change is not apparent, a brief explanation for the change will be written adjacent to 
the change. 
 
 
 
 
15.3 Source Documents Maintenance 
 


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Source documents contain the results of original observations and activities of a clinical 
investigation. Source documents include, but are not limited to, medical records (progress notes), 
computer printouts, screening logs and recorded data from automated instruments.  
 
All source documents from this study will be maintained by the Investigator and made available for 
inspection by authorized persons. The original signed informed consent for each subject shall be 
filed with records kept by the Investigator, and a copy shall be given to the subject. 
 
15.4 Record Maintenance 
 
Records must be retained in accordance with the current ICH Guidelines on GCP. All essential study 
documents including records of subjects, source documents, eCRFs and study drug inventory must 
be kept on file. 
 
US Food and Drug Administration (FDA) regulations (21 Code of Federal Regulations [CFR] 
312.62[c]) require that records and documents pertaining to the conduct of this study and the 
distribution of investigational drug, including eCRFs, consent forms, laboratory test results, and 
medical inventory records, must be retained by the Principal Investigator for two years after 
marketing application approval. If no application is filed, these records must be kept two years after 
the investigation is discontinued and the US FDA and the applicable national and local health 
authorities are notified and in accordance with CHOP Policy No. A-3-6: Retention and Destruction 
of Records. 
 
The Investigator will take responsibility for maintaining adequate and accurate hard copy source 
documents of all observations and data generated during this study. Such documentation is subject 
to inspection by the regulatory authorities. 
 
15.5 Confidentiality 
 
All information obtained during the conduct of the study with respect to the subject’s state of health 
will be regarded as confidential. For disclosure of any such information, an agreement will be 
obtained in writing.  
 
The Investigator must ensure that each subject’s anonymity is maintained. On eCRFs and other 
documents, subjects must not be identified by name. Instead, subjects will only be known by the 
unique subject number allocated to them and by coded initials in order to ensure confidentiality on 
all study documentation. Subjects will retain this unique number throughout the study. The 
Investigator will keep a separate log of these codes. 
 
In order to comply with government regulatory guidelines and to ensure subject safety, it may be 
necessary for the Sponsor and its representative, the CRO personnel, the local research review board, 
or the US FDA to review subjects’ medical records as they relate to this study. Only the subject’s 
unique number on the eCRFs will identify him/her, but their full names may be made known to a 
drug regulatory authority or other authorized government or health care officials, if necessary, and 
to personnel designated by the Principal Investigator. 
 
Documents that are not for submission to the eCRF (e.g., consent forms) will be maintained by the 
Principal Investigator in strict confidence, except to the extent necessary to allow monitoring by the 


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Sponsor and the CRO, and auditing by regulatory authorities. No documents identifying subjects by 
name will leave the investigative site and subject identity will remain confidential in all publications 
related to the study. 
 
16. 
ETHICS 
 
16.1 Ethics Committee 
 
This study will be conducted in compliance with IRB and ICH GCP Guidelines including Title 21 
Part 56 of the USA CFR relating to IRBs and GCP as described in the US FDA CFR (21 CFR § 50, 
56, 312) - in accordance with applicable regulations regarding clinical safety data management 
(E2A, E2B(R3)), European Community directives 2001/20, 2001/83, 2003/94 and 2005/28 as 
enacted into local law, and with ICH guidelines regarding scientific integrity (E4, E8, E9 and E10). 
In addition, this study will adhere to all local regulatory requirements, and requirements for data 
protection. 
 
Before initiating a trial/study, the Investigator/institution must have written and dated 
approval/favorable opinion from the The Children’s Hospital of Philadelphia IRB  for the study 
protocol/amendment(s), written informed consent form (ICF), any consent form updates, subject 
recruitment procedures (e.g. advertisements), and any written information to be provided to subjects 
and a statement from the IRB that they comply with GCP requirements. The IRB approval must 
identify the protocol version as well as the documents reviewed. 
 
16.2 Ethical Conduct of the Study 
 
This study will be conducted in accordance with the Note for Guidance on GCP (ICH Harmonized 
Tripartite Guideline E6 (R1); FDA CFR (21 CFR § 50, 56, 312)), Declaration of Helsinki (Seoul 
2008) and all applicable regulatory requirements. 
 
16.3 Subject Information and Consent 
The Investigator is responsible for and will obtain informed consent from each subject in the study, 
in accordance with the ICH-GCP Guidelines, the Declaration of Helsinki, and applicable regulatory 
requirements. 
 
Subjects will be informed of the nature of the study, its aim, its possible risks and restrictions, its 
duration, and the compensation that they might receive. The protocol will be explained during a 
meeting prior to study enrollment, and each subject must be informed that participation in the study 
is voluntary and that he/she may withdraw from the study at any time. The subject should read the 
ICF before signing and dating it and a copy of the signed document should be given to the subject. 
No subject can enter the study before his/her informed consent has been obtained. Children if able  
will sign assent. The parents or legal representative(s) of all children and adolescents regardless of 
age must also sign the ICF.  
 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject. In this instance approval should 
always be given by the CHOP IRB and existing subjects informed of the changes and re-consented. 
This is documented in the same way as previously described. 


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The Investigator should keep a copy of the consent of the subject, inform the subject’s primary 
physician about participation in the clinical study. 
 
17. 
ADMINISTRATION PROCEDURES 
 
17.1 Regulatory Approval 
 
Antonella Cianferoni, MD, PhD or her agents will be responsible for ensuring that appropriate 
regulatory authority approvals are obtained, according to FDA regulations 21 CFR 312.  The 
Principal Investigator is also responsible for ensuring all study team members, monitors, and 
safety review committee members are appropriately trained and that the protocol is conducted in 
accordance to the IRB approved protocol and IND investigational plan. 
 
No subject may enter the study until this approval has been obtained. A copy of the approval (where 
one is provided, according to local country requirements) will be provided to the Investigator and to 
the IRB(s)/IEC(s). 
 
17.2 Protocol Amendments 
 
In accordance with ICH Topic E6 (R1) Guideline for GCP the Principal Investigator should not 
implement any deviation from, or changes of the protocol without approval from the CHOP IRB of 
a protocol amendment, except where necessary to eliminate an immediate hazard(s) to study 
subjects, or when the change(s) involves only logistical or administrative aspects of the study (e.g., 
change in monitor(s), change of telephone number(s)).  
 
Any change to the protocol must be handled as a protocol amendment. A written amendment must 
be submitted to the FDA and to the CHOP IRB assuming this responsibility. The Principal 
Investigator must await CHOP-IRB approval of protocol amendments before implementing the 
changes, except where necessary to eliminate apparent immediate hazard to subjects. In these cases, 
the CHOP-IRB must be notified within 5 days of the change. 
 
All amendments to the protocol must be approved in writing by the CHOP-IRB. Once approved, 
the protocol amendment will be distributed to all recipients of the original protocol, with instructions 
to append the amendment to the protocol. 
 
If, in the judgment of the local CHOP-IRB, the Sponsor, the protocol amendment alters the study 
design, procedures and/or increases the potential risk to the subject, the currently approved written 
ICF will require modification. The modified ICF must also be reviewed and approved by the 
Sponsor, FDA, and the CHOP IRB. In such cases, repeat informed consent must be obtained from 
subjects enrolled in the study before participation continues. 
 
17.3 Protocol Adherence and Deviations 


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The protocol must be read thoroughly and the instructions must be followed. However, exceptions 
will be made in emergency situations when the protection, safety, and well-being of the subject 
requires immediate intervention based on the judgment of the Investigator or a responsible, 
appropriately trained, and credentialed professional(s) designated by the Investigator as a sub-
Investigator.  
 
In the event of a significant protocol deviation due to an emergency, accident, or error, the Principal 
Investigator or designee should determine whether or not the subject should continue in the study, 
and the decision must be documented. 
 
 
17.4 Clinical Study Report 
 
A final clinical study report will be prepared according to the ICH guideline on Structure and 
Contents of Clinical Study Reports. A final clinical study report will be prepared regardless of 
whether the study is completed or prematurely terminated.  
 
17.5 Discontinuation of the Study 
 
This study may be terminated prematurely by the Principal Investigator as being in the best interests 
of subjects, and justified on either medical or ethical grounds, or for any other reasons. In terminating 
the study, Principal Investigator will ensure that adequate consideration is given to the protection of 
the subjects’ interests and the CHOP IRB and FDA are promptly notified. 
 
17.6 Study Center File Management 
 
The Investigator is responsible for assuring that the Study Center File is maintained. The Study 
Center File will contain, but will not be limited to, the information listed below: 
(1) 
Investigator’s Brochure; 
(2) 
Current, signed version of the protocol and any previous versions of the protocol; 
(3) 
Protocol amendments (if applicable); 
(4) 
Operations Manual (if applicable); 
(5) 
Current ICF (blank) and any previous versions of the ICF; 
(6) 
Curricula Vitae of Investigator(s) and sub-investigator(s) and photocopy of their 
respective license(s) where required by law; Original US FDA Form 1572 (for all studies 
conducted under US Investigational New Drug [IND] regulations), signed by all Principal 
Investigators. The names of any sub-investigators must appear on this form. Investigators 
must also complete all regulatory documentation as required the ICH GCP and by local 
or national regulations; 
(7) 
Documentation of CHOP-IRB approval of the protocol, the ICF, any protocol 
amendments, and any ICF revisions; 
(8) 
All correspondence between the Investigator, and  CHOP-IRB, relating to study conduct; 
(9) 
Laboratory certification(s); 
(10) Monitoring log; 
(11) Study drug invoices; 
(12) Signature list of all staff completing eCRFs; and 


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(13) Signature list of all staff completing drug accountability summaries; 
(14) FDA Correspondence for the IND. 
 
 


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18. 
APPENDICE 
APPENDIX 1: ENDOSCOPY SCORING SYSTEM57  
 


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Appendix 2: Eosinophilic Esophagitis Quality of Life Score 
 
• PEESS Patient (8-18 year of age) 
• PEESS Patient Proxy  (patients less 8 years of age) 
• EoE QOL 
o PedsQL™ Eosinophilic Esophagitis Module Version 3 Teen Report (ages 13-18) 
o PedsQL™ Eosinophilic Esophagitis Module Version 3 Child Report (ages 8-12) 
o PedsQL™ Eosinophilic Esophagitis Module Version 3 Parent Report for Child 
(ages 8-12) 
o PedsQL™ Eosinophilic Esophagitis Module Version 3 Parent Report for Young 
Child (ages 5-7) 
o PedsQL™ Eosinophilic Esophagitis Module Version 3 Parent Report for Toddler 
(ages 2-4) 
 
 
 
 
 


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Appendix 3:  CHOP Monitoring Policy 
 
 
Introduction: 
 
Description of the study: 
This is a double-blind, placebo-controlled, randomized trial to study the efficacy and safety of 
Viaskin® Milk, an allergen extract of milk administered epicutaneously using the Viaskin® 
epicutaneous delivery system in subjects from 4 to 17 years old with a milk induced Eosinophilic 
Esophagitis. The trial will be conducted at The Children’s Hospital of Philadelphia (CHOP).  
 
Study objectives: 
The objectives of this study are: 
• 
To assess the efficacy of Viaskin® Milk epicutaneous immunotherapy (EPIT) in subjects 
with milk-induced eosinophilic esophagitis. 
• 
To evaluate the safety of Viaskin® Milk EPIT in subjects with milk-induced eosinophilic 
esophagitis. 
 
Critical data and study procedures, with particular attention to data and procedures that are 
unusual in relation to clinical routine and require training of study site staff 
 
Specific risks to be addressed by monitoring: 
 
Upper Endoscopy and biopsy-Pain or bleeding 
Viaskin Patch-local skin reactions, any systematic reaction to Viaskin patch including rash, 
vomiting, abdominal pain or other GI symptoms 
 
 Treatment-emergent AEs (TEAEs) will be defined as any AEs, regardless of relationship to 
study drug, which occur during or after the initial Viaskin®  application of study drug or any 
event already present that worsens in either intensity or relationship to study drug following 
exposure to the Viaskin®. If relationship information is missing, the TEAE will be considered 
drug-related.  
 
Description of Monitoring Approaches 
 
The Office of Research Compliance (ORC) will begin monitoring activities for this study within 
three months of the first subject’s enrollment into the study. Thereafter, ORC will monitor this 
study annually unless circumstances necessitate more frequent monitoring, e.g., an increase in 
risk to the subjects, less than ideal study conduct, higher than expected accrual rates. 
 
Monitoring activities will be guided by ICH E6 section 5.18. 
 
Monitoring of subject data will be initiated at 100% verification of the data recorded. This may 
be amended, and a tapered approach to monitoring may be employed, if conduct and 
documentation of the study reaches a level of reliability that would permit valid conclusions 
based upon a sampling of data. 
 
 Communication of Monitoring Results 


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Monitoring reports will be communicated to the sponsor, and the IND/IDE Support Program 
within 30 days after the monitoring visit has concluded. 
 
 Management of Noncompliance 
Any serious or persistent noncompliant activity or violation that is observed during the course 
of monitoring will be reported to the investigator, and to the ORC Director. The ORC Director 
will evaluate the report of noncompliant activities and discuss with the sponsor and/or principal 
investigator any necessary reporting requirements and corrective and preventative actions 
plans. 
 
 Ensuring Quality Monitoring 
Selected monitors must be qualified by education and training to perform monitoring activities. 
Monitors must have completed all CHOP-specific training, e.g., CITI. The principal 
investigator or designee will provide protocol-specific training to the monitor. 
 
As part of ORC’s continuous quality improvement plan, the study may be audited for quality 
assurance to evaluate the effectiveness of the monitoring to ensure human subject protection 
and data integrity. 
 
 Monitoring Plan Amendments 
The monitoring plan will amended as needed to address increase in risk to the subject, new 
information, etc. 
 
 


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Appendix 4:  Safety of 500 mcg of milk Viaskin Patch 
 
The dose will be 500 mcg or top dose tolerated as recommended by the MILES data safety 
monitoring board. 
 


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19. REFERENCE: 
 
 
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Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med 2004; 
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effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative 
factors. Gastroenterology 2012; 142(7): 1451-9 e1; quiz e14-5. 
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with IgG4 and not mediated by IgE. Gastroenterology 2014; 147(3): 602-9. 
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36. 
Stone KD, Prussin C. Immunomodulatory therapy of eosinophil-associated 
gastrointestinal diseases. Clin Exp Allergy 2008; 38(12): 1858-65. 


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37. 
Schaefer ET, Fitzgerald JF, Molleston JP, et al. Comparison of oral prednisone and 
topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children. 
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2006; 131(5): 1381-91. 
39. 
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swallowed fluticasone for eosinophilic esophagitis. Clin Gastroenterol Hepatol 2004; 2(7): 
568-75. 
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immunopathological analysis and response to fluticasone propionate. Gastroenterology 2002; 
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eosinophilic esophagitis: a role for FKBP51. J Allergy Clin Immunol 2010; 125(4): 879-88 e8. 
42. 
Aceves SS, Bastian JF, Newbury RO, Dohil R. Oral viscous budesonide: a potential 
new therapy for eosinophilic esophagitis in children. The American journal of gastroenterology 
2007; 102(10): 2271-9; quiz 80. 
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in children with eosinophilic esophagitis in a randomized, placebo-controlled trial. 
Gastroenterology 2010; 139(2): 418-29. 
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childhood on adult height. N Engl J Med 2012; 367(10): 904-12. 
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with daily or periodical inhaled budesonide: the Helsinki Early Intervention Childhood Asthma 
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Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA. The use of skin prick tests 
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47. 
Spergel JM, Brown-Whitehorn T. The use of patch testing in the diagnosis of food 
allergy. Curr Allergy Asthma Rep 2005; 5(1): 86-90. 
48. 
Liacouras CA, Spergel JM, Ruchelli E, et al. Eosinophilic esophagitis: a 10-year 
experience in 381 children. Clin Gastroenterol Hepatol 2005; 3(12): 1198-206. 
49. 
Kagalwalla AF, Amsden K, Shah A, et al. Cow's Milk Elimination: A Novel Dietary 
Approach to Treat Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr 2012. 
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Kagalwalla AF, Shah A, Li BU, et al. Identification of specific foods responsible for 
inflammation in children with eosinophilic esophagitis successfully treated with empiric 
elimination diet. Journal of pediatric gastroenterology and nutrition 2011; 53(2): 145-9. 
51. 
Spergel JM, Brown-Whitehorn TF, Cianferoni A, et al. Identification of causative foods 
in children with eosinophilic esophagitis treated with an elimination diet. J  Allergy Clin 
Immunol 2012; 130(2): 461-7 e5. 
52. 
Sanchez-Garcia S, Rodriguez Del Rio P, Escudero C, Martinez-Gomez MJ, Ibanez MD. 
Possible eosinophilic esophagitis induced by milk oral immunotherapy. J Allergy Clin Immunol 
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tolerance induction for egg protein. Ann Allergy Asthma Immunol 2011; 106(1): 73-4. 
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Spergel JM, Rothenberg ME, Collins MH, et al. Reslizumab in children and adolescents 
with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. 
The Journal of allergy and clinical immunology 2012; 129(2): 456-63, 63 e1-3. 


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Version 8.0 (Amendment 7), 21 August 2017  
 
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55. 
Assa'ad AH, Gupta SK, Collins MH, et al. An antibody against IL-5 reduces numbers of 
esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterol 
2011; 141(5): 1593-604. 
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Franciosi JP, Hommel KA, Greenberg AB, et al. Development of the Pediatric Quality 
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Hirano I, Moy N, Heckman MG, Thomas CS, Gonsalves N, Achem SR. Endoscopic 
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impact on allergic reactivity. J Allergy Clin Immunol 2010; 125(5): 1165-7. 
61. 
Mondoulet L, Dioszeghy V, Larcher T, et al. Epicutaneous immunotherapy (EPIT) 
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in sensitized mice. PloS one 2012; 7(2): e31967. 
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Mondoulet L, Dioszeghy V, Puteaux E, et al. Intact skin and not stripped skin is crucial 
for the safety and efficacy of peanut epicutaneous immunotherapy (EPIT). Clin Transl Allergy 
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Franciosi JP, Hommel KA, DeBrosse CW, et al. Development of a validated patient-
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Mondoulet L, Dioszeghy V, Puteaux E, et al. Specific epicutaneous immunotherapy 
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function during oral desensitization in cow's milk allergy enabled with omalizumab. Mucosal 
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Cravero JP, Blike GT, Beach M, et al. Incidence and nature of adverse events during 
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SAP_000.pdf: 
i | P a g e  
 
 
A Double-Blind, Placebo-Controlled, Randomized Trial to Study Efficacy and Safety 
of the Viaskin® Milk for Treating Milk Induced Eosinophilic Esophagitis in Children 
(SMILEE Study) 
 
Test Drug 
Viaskin® Milk: Allergen extract of Milk in Viaskin® epicutaneous delivery system 
 
 
 
Statistical Analysis Plan  
Final Version 2.0 
 
 
Sponsored by: 
 
Jonathan M. Spergel, MD, PhD 
Division of Allergy and Immunology 
The Children’s Hospital of Philadelphia 
 
Protocol Number: SMILEE 
IND Number: 16518 
 
 
 
 
January 05, 2018 
 
 
 
 
Prepared by: 
Okan U. Elci, PhD 
CHOP-Westat Biostatistics and Data Management Core 
Roberts Center for Pediatric Research 
2716 South Street, #9362 
Philadelphia, PA 19146 
 
 
 


ii | P a g e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


iii | P a g e  
 
 


iv | P a g e  
 
Table of Contents 
Table of Contents.................................................................................................................... iv 
List of Abbreviations  ............................................................................................................. vi 
1. Introduction ........................................................................................................................ 1 
2. Study Overview .................................................................................................................. 1 
2.1. Study Design ................................................................................................................ 1 
2.2. Study objectives and endpoints.................................................................................. 3 
2.2.1. Primary efficacy objective ................................................................................ 3 
2.2.2. Primary efficacy endpoint ................................................................................ 3 
2.2.3. Secondary efficacy objectives ........................................................................... 3 
2.2.4. Secondary efficacy endpoints........................................................................... 5 
2.2.5. Safety objectives ................................................................................................ 6 
2.2.6. Safety endpoints ................................................................................................ 6 
2.3. Treatments ................................................................................................................... 7 
2.4. Procedures .................................................................................................................... 7 
2.4.1. Study population............................................................................................... 7 
2.4.2. Randomization and replacement ..................................................................... 8 
2.4.3. Study duration................................................................................................... 8 
2.5. Study visits ................................................................................................................... 9 
3. Statistical Considerations ................................................................................................. 11 
3.1. Statistical design ........................................................................................................ 11 
3.2. Sample size determination and power calculation ................................................. 11 
3.3. Missing data ............................................................................................................... 12 
4. Statistical Analyses ........................................................................................................... 12 
4.1. Analysis populations ................................................................................................. 13 
4.2. Descriptive analyses .................................................................................................. 14 
4.3. Subject disposition ..................................................................................................... 14 


v | P a g e  
 
4.4. Efficacy analyses ........................................................................................................ 14 
4.4.1. Primary efficacy analyses ............................................................................... 15 
4.4.2. Secondary efficacy analyses ........................................................................... 15 
4.4.2.1. 
Total esophageal endoscopy score ..................................................... 15 
4.4.2.2. 
Eosinophilic esophagitis symptom score .......................................... 16 
4.4.2.3. 
Percentage of subjects per response rate ........................................... 17 
4.4.2.4. 
Eosinophilic esophagitis quality of life score .................................... 17 
4.4.2.5. 
Composite Score .................................................................................. 18 
4.4.2.6. 
Development of symptoms ................................................................. 18 
4.4.2.7. 
Exploratory biologic markers ............................................................. 18 
4.5. Safety analyses ........................................................................................................... 18 
4.5.1. Adverse events ................................................................................................ 19 
4.5.2. Laboratory assessments .................................................................................. 19 
4.5.3. Vital signs ........................................................................................................ 20 
5. Appendices ....................................................................................................................... 20 
5.1. Statistical Analysis Plan table shells ........................................................................ 20 
5.2. Consort diagram ........................................................................................................ 52 
 
 
 
 
 


vi | P a g e  
 
List of Abbreviations 
 
AE 
 
 
Adverse Event 
ANCOVA 
 
Analysis of Covariance 
CBC  
 
Complete Blood Count 
CHOP 
 
The Children’s Hospital of Philadelphia 
CI 
 
 
Confidence Interval 
DBP  
 
Diastolic Blood Pressure 
EoE 
 
 
Eosinophilic Esophagitis 
EREFS 
 
Endoscopic Reference Score 
EPIT  
 
Epicutaneous Immunotherapy 
HPF  
 
High Power Field 
ITT 
 
 
Intention to Treat 
LOCF  
 
Last observation carried forward 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
OR 
 
 
Odds Ratio 
PP 
 
 
Per Protocol 
PEESS  
 
Pediatric Eosinophilic Esophagitis Symptoms Score 
RR 
 
 
Relative Risk 
SD 
 
 
Standard Deviation 
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical Analysis Plan 
SBP 
 
 
Systolic Blood Pressure 
SOC  
 
Standard of Care 
SMILEE 
Study Efficacy and Safety of the Viaskin® Milk for Treating Milk 
Induced Eosinophilic Esophagitis in Children 
TEAE  
 
Treatment-Emergent Adverse Event 
TSLP  
 
Thymic Stromal Lymphopoietin 
 


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1. 
Introduction 
This statistical analysis plan (SAP) is based on the SMILEE study (IND Number: 
16518) protocol version 7.0, dated April 27, 2017. The SAP summarizes key aspects of 
the study to provide the context of statistical methods for analyzing the data and the 
descriptive measures to be reported. 
2. 
Study Overview 
The SMILEE study is a Phase IIA double-blind, placebo-controlled randomized trial. 
This section describes the design, objectives, endpoints, and treatments of this study 
as well as the study population and randomization. 
2.1 
Study Design 
This is a double-blind, placebo-controlled, randomized trial to study the efficacy and 
safety of Viaskin® Milk, an allergen extract of milk administered epicutaneously using 
the Viaskin® epicutaneous delivery system in subjects from 4 to 17 years old with a 
milk induced Eosinophilic Esophagitis (EoE). The trial will be conducted at The 
Children’s Hospital of Philadelphia (CHOP). The first four patients will be 8-17 years 
old and after these patients are randomized, the study will be open to all ages 4-17 
years old.  
Subjects with a documented medical history of EoE after ingestion of milk and 
currently following a strict milk-free diet will be considered for participation in the 
SMILEE study. A screening/standard of care (SOC) upper endoscopy and biopsy will 
be performed after introduction of milk (minimum of 30 ml/day for 1 week to 2 
months). If the endoscopy shows greater than or equal to 15 eosinophils per high 
power field (HPF), it will confirm the diagnosis of EoE. In addition, milk will be 
removed from the diet and a SOC upper endoscopy and biopsy will be performed 


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after a minimum of 6 weeks under a milk-free diet to confirm the diagnosis of milk-
induced EoE. If the biopsy after milk elimination shows 0 to 10 eosinophils per HPF, 
the subjects will be eligible for participation in the study, and will be randomized in 
a 3:1 ratio into two different treatment groups, to receive epicutaneous 
immunotherapy (EPIT) with Viaskin® Milk (500 µg of milk proteins) or placebo.  If a 
subject has a SOC endoscopy in 12 months prior to the study, they will not need to 
repeat endoscopies to be eligible for the study and will be randomized as above. A 
minimum of two SOC endoscopy procedures will be performed to obtain milk EoE 
diagnostic results needed for study qualification, and the results of additional SOC 
endoscopies will be allowed to assess eligibility, if the endoscopies are required for 
clinical purposes.  Milk will be reintroduced into the diet of the subject after 9 months 
of treatment at equivalent amounts and duration as performed during the screening 
period. A third research upper endoscopy and biopsy will be performed at the end of 
the milk-reintroduction period. After the 3rd upper endoscopy, all subjects will 
continue treatment with open-label Viaskin® Milk (500 µg of milk proteins).  Subjects 
with ≥15 eosinophils/hpf on the 3rd upper endoscopy will restart milk-free diet for 9 
additional months while on treatment with active therapy.  Then, they will 
reintroduce milk into their diet at equivalent amounts and duration as performed 
during the screening period, at which time a 4th upper endoscopy will be done. For 
subject with < 15 eosinophils/hpf on the 3rd upper endoscopy, they will continue on 
milk for up to 11 additional months (if symptoms re-appear, milk-free diet should 
restart) while on treatment with active therapy, at which time a 4th upper endoscopy 
will be done. A final follow-up visit will be done 2 weeks after completion of treatment 
and after the last endoscopy. 
In total, during this study, eligible subjects will be required to attend 17 study visits.  
In addition to the endoscopy and biopsy, subjects will undergo other efficacy 
parameter assessments at months 1, 3, 6, 9, 11, 14, 17, 20, and 22. Key assessments of 


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safety will be performed at each study visit, including vital signs, physical 
examinations and laboratory assessments. In between visits, subjects will report safety 
data on the diary cards.  
2.2 
Study objectives and endpoints 
The primary and secondary efficacy objectives and safety objectives as well as 
endpoints of this study are as follows: 
2.2.1 Primary efficacy objective 
The main efficacy objective is to assess the efficacy of Viaskin® Milk EPIT to 
desensitize milk-induced EoE in subjects at the end of the double-blind treatment 
period. The study will analyze the maximum esophageal eosinophil count on all 
specimens obtained at the end of the double-blind treatment period in esophageal 
biopsy after milk reintroduction in subjects with EoE. This is the gold-standard for the 
diagnosis of EoE. 
2.2.2 Primary efficacy endpoint 
The primary efficacy endpoint is each patient’s maximum esophageal eosinophil 
count on all specimens obtained from the biopsy at the end of double-blind treatment 
(visit 10), after milk reintroduction at visit 9. 
2.2.3 Secondary efficacy objectives    
The secondary efficacy objectives are: 
a. To describe the EoE symptoms score and global assessment score at end of each 
treatment period at 11 months (end of the double-blind treatment) and 22 months 
(end of the open-label treatment) in each treatment group and to determine if there 


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is a difference in improvement of the EoE symptom score between the active 
treatment group and the placebo group. 
b. To assess if there is a difference in the mean esophageal eosinophil count between 
the active treatment group and the placebo group at end of each treatment period 
at 11 and 22 months. 
c. To assess if the changes in mean and maximum esophageal eosinophil count from 
baseline to end of each treatment period at 11 and 22 months are different between 
the active treatment group and the placebo group.  
d. To assess if the percentages of subjects with ≤ 1 eosinophils/HPF (excellent 
response), subjects with 2-14 eosinophils/HPF (good response), and subjects with 
≥ 15 eosinophils/HPF (poor response) at the end of each treatment period at 11 and 
22 months are similar between the active treatment group and the placebo group. 
e. To assess if there is a difference in esophageal endoscopy score at the end of each 
treatment period at 11 and 22 months and to examine the changes in esophageal 
endoscopy score from baseline to the end of each treatment period at 11 and 22 
months between the active treatment group and the placebo group. 
f. To examine the changes in the eosinophilic esophagitis quality of life score from 
baseline to the end of each treatment period at 11 and 22 months between the 
active treatment group and the placebo group. 
g. To examine the changes in the composite score, which will be calculated using four 
measures (Eosinophils/HPF, Esophageal Endoscopic Reference Score (EREFS), 
Pediatric Eosinophilic Esophagitis Symptoms Score (PEESS), and investigator 
assessment of EoE symptom activity), from baseline to the end of treatment period 
at 11 and 22 months between the active treatment group and the placebo group 
[Composite score = Maximum Eosinophils per HPF + 10*EREFS + 2*PEESS +5* 
(Investigator assessment of EoE symptom activity)]. 


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h. To assess if there is difference in time to development symptoms after milk 
reintroduction at month 9 and 20 between the active treatment group and the 
placebo group. 
i. To assess the changes in exploratory biologic markers including T-regulatory cells, 
thymic stromal lymphopoietin (TSLP), and complete blood count (CBC) with 
differential and milk-specific Immunoglobulin level and epigenetic changes 
between the active treatment group and the placebo group. 
2.2.4 Secondary efficacy endpoints 
The secondary efficacy endpoint measures are:  
a. The EoE symptom score and global assessment score at the end of each treatment 
period at 11 and 22 months (improvement in EoE symptom score will be defined 
as a decrease in total symptom score of two or more from baseline to the end of 
each treatment period at 11 and 22 months) as well as the change in EoE symptom 
score from baseline to the end of each treatment period at 11 and 22 months (e.g., 
the change in EoE symptom score at 11 month = the EoE symptom score at 11 
month – (minus) the EoE symptom score at baseline, the change score is the 
difference) and the EoE frequency and severity symptom scores measured by 
Pediatric Eosinophilic Esophagitis Symptoms Score (PEESS) at the end of each 
treatment period at 11 and 22 months as well as the changes in these symptom 
scores from baseline to the end of each treatment period at 11 and 22 months. 
b. Mean esophageal eosinophil count which is the average of all of the samples 
obtained on biopsy at the end of each treatment period at 11 and 22 months.  
c. The changes in mean and maximum esophageal eosinophil count from baseline to 
the end of each treatment period at 11 and 22 months. 
d. The percentages of subjects with ≤ 1 eosinophil/HPF (excellent response), subjects 
with 2-14 eosinophils/HPF (good response), and subjects with ≥ 15 


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eosinophils/HPF (poor response) at the end of each treatment period at 11 and 22 
months. 
e. Esophageal endoscopy score at the end of each treatment period at 11 and 22 
months and the change in the esophageal endoscopy score from baseline to the 
end of each treatment period at 11 and 22 months. 
f. Changes in the eosinophilic esophagitis quality of life score from baseline to the 
end of each treatment period at 11 and 22 months. 
g. Changes in the composite score from baseline to the end of each treatment period 
at 11 and 22 months. 
h. Time to development symptoms after milk reintroduction at month 9 and 20. 
i. Changes in exploratory biologic markers, including T-regulatory cells, TSLP, 
and CBC with differential and milk-specific Immunoglobulin level and 
epigenetic changes. 
2.2.5 Safety objectives    
The safety objectives are to evaluate the safety of Viaskin® Milk EPIT treatment in 
children and adolescents with milk-induced EoE. Adverse events (AEs) and Serious 
Adverse Events (SAEs) by system organ class, severity, and relatedness to Viaskin® 
Milk, duration of local skin reactions induced by Viaskin® Milk, use of medications to 
treat AEs, systemic allergic symptoms and relatedness to Viaskin® Milk, changes in 
laboratory results, physical exams and vital signs will be assessed. 
2.2.6 Safety endpoints  
The safety endpoints are: 
a. Local skin tolerance: incidence, severity and duration of local Treatment-Emergent 
Adverse Event (TEAE) at site of Viaskin® application as reported by subjects in the 
diary card. 


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b. Potentially drug-related TEAEs. 
c. Discontinuation due to TEAEs. 
d. Laboratory data, physical examinations, and vital signs.  
e. Systemic allergic symptoms and relatedness to Viaskin®. 
f. Potentially drug-related systemic allergic symptoms. 
g. SAEs. 
2.3 
Treatments 
Subjects will be randomized to receive Viaskin® with milk protein (500 μg of milk 
proteins) or placebo during the first year in the study. Viaskin® milk contains a dry 
deposit of natural milk protein formulated without adjuvant. The placebo treatment 
will consist of a similar formulation, but will be devoid of milk proteins. During the 
second year in the study (after third upper endoscopy), all subjects will receive open-
label Viaskin® (500 µg of milk proteins). 
2.4 
Procedures 
Study subjects, randomization, replacements of the withdrawn subjects, and duration 
of the study are described. 
2.4.1 Study Population 
Pediatric subjects, aged 4 to 17 years, with milk induced Eosinophilic Esophagitis will 
be enrolled and randomized following confirmation of all eligibility criteria.  
Inclusion Criteria: 
1. Well documented symptoms suggestive of EoE after ingestion of milk and 
currently following a strict milk-free diet. 


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2. Upper endoscopy and biopsy at clinical evaluation during screening showing 
greater than or equal to 15 eosinophils per HPF isolated to the esophagus meeting 
the consensus diagnosis of EoE, after milk was re-introduced into the subject’s diet 
(30 ml/day for 1 week to 2 months), while the subject was on a proton pump 
inhibitor. 
3. Upper endoscopy and biopsy at clinical evaluation during screening showing 0 to 
10 eosinophils per HPF isolated to the esophagus after a minimum of 6 weeks 
under a milk-free diet, and while the subject is on a proton pump inhibitor. 
4. A negative pregnancy test for female subjects of childbearing potential. Females 
of childbearing potential must use effective methods of contraception to prevent 
pregnancy and agree to continue to practice an acceptable method of 
contraception for the duration of participation in the study.   
2.4.2 Randomization and replacement 
Approximately 22 eligible subjects to obtain 18 completed subjects will be randomized 
in a 3:1 ratio into two different treatment groups, (1) to receive EPIT with Viaskin® 
Milk (500 μg of milk proteins) or (2) placebo (16 subjects in the active Viaskin® Milk 
group and 6 subjects in the placebo group). Subjects who are withdrawn after 
beginning the treatment phase of the study will not be replaced. However, sufficient 
subjects will be included to ensure the minimum sample size. 
2.4.3 Study duration  
The planned duration of the clinical study is approximately 3 years (Start-up + Screening 
period + Treatment period + Closeout). Subject participation will be approximately 2 
years (including up to 3 months and 2 weeks for the screening period; 11 months for the 
treatment period; 11 months for open label extension; and a 2-week follow-up visit). 
Recruitment into the study will stop when approximately 22 subjects have been 


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randomized to treatment. The study will be stopped when the last subject receiving the 
double-blind treatment completes the study or when the last ongoing subject has 
discontinued treatment, whichever occurs first. 
2.5 
Study visits 
There are at least three visits during the screening period that will occur before 
enrollment and randomization to the active treatment phase of the SMILEE study. 
Fully eligible subjects will be required to attend 17 study visits as follows: 
Screening period: Potentially eligible subjects will be enrolled into the study (Visit 1) 
to confirm Treatment Period study eligibility and obtain a number of study endpoints.  
The GI group will follow SOC procedures, but the dates of the first (Visit 2) and 
second (Visit 3) endoscopies with biopsies will not be mandated by the investigative 
team, but by the GI group for clinical care. The second upper endoscopy/biopsy will 
be done at a minimum of 6 weeks after milk-removal, per clinical care. If a patient 
meets eligibility criteria for the Treatment Period of SMILEE, s/he will be referred to 
the Allergy/Immunology division for continuation in the study. If the results of the 
first or second endoscopy with biopsies confirm ineligibility, the subject may be 
considered as screen failed and may not continue in the study.   
Visit 1: Informed Consent obtained: milk introduction. 
Visit 2: One week to 2 months after milk-introduction. Subjects have a SOC upper 
endoscopy/biopsy performed to confirm the diagnosis of EoE. Milk is removed from 
the diet. 
Visit 3: Subjects have a second SOC upper endoscopy/biopsy to confirm milk induced 
EoE performed after a minimum of 6 weeks under milk-free diet.  
If a subject has an endoscopy that confirms milk responsive EoE in the preceding 12 
months, they will not need a repeat endoscopy to be eligible for the study. 


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Treatment period: There will be seven visits during the treatment period:  
Visit 4 (Day 1): This visit corresponds to the first day of treatment and can be 
performed as soon as the results of the upper endoscopy and biopsy at Visit 3 are 
available and there is confirmed eligibility into the study. 
Visit 5: This corresponds to day 8 of treatment. 
Visit 6: This corresponds to month 1 of treatment. 
Visit 7: This corresponds to month 3 of treatment. 
Visit 8: This corresponds to month 6 of treatment. 
Visit 9: This corresponds to month 9 of treatment (milk-reintroduction).  
Visit 10: One week to 2 months after milk reintroduction. During this time, subjects 
will have weekly calls to monitor symptoms. Subjects have a third SOC upper 
endoscopy/biopsy. This is the end of double-blind treatment. The open-label 
treatment period will start on that day. 
Open label extension: There will be six visits during the open-label treatment period: 
Visit 11: This corresponds to day 8 after the Visit 10 research biopsy. 
Visit 12: This corresponds to month 1 after the Visit 10 research biopsy. 
Visit 13: This corresponds to month 3 after the Visit 10 research biopsy. 
Visit 14: This corresponds to month 6 after the Visit 10 research biopsy. 
Visit 15: This corresponds to month 9 after the Visit 10 research biopsy. 
Visit 16: Subjects have a fourth upper endoscopy/biopsy. This is the end of open-label 
treatment period. 
Last assessment and end of study period: There will be only one visit during this 
period. 


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Visit 17: This visit will be performed 2 weeks after Visit 16 for completers. This visit 
and assessment procedures have also to be performed for subjects prematurely 
withdrawn. This will be the End of Study Visit. 
3. 
Statistical Considerations 
This section provides a detailed description of the statistical design, study objectives, 
and sample size determination and power calculation. 
3.1 
Statistical design  
This is a randomized, double-blind, placebo-controlled clinical trial with Viaskin® 
Milk as Treatment 1 and placebo as Treatment 2. Primary and secondary efficacy 
objectives as well as the safety objectives are presented in Section 2.2.  
3.2 
Sample size determination and power calculation 
The primary objective of this study is to determine whether mean maximum 
eosinophil counts is different in the subjects on the Viaskin Milk group compared to 
those on the placebo group. This is a pilot study in which we aim to identify efficacy 
of the Viaskin® Milk treatment. Sample size is based on projected subject volume. If 
efficacy is shown, our pilot data could be used to perform a power analysis for a larger 
study. We will recruit 38 subjects and plan to have 22 evaluable subjects with milk-
induced EoE confirmed by endoscopy and biopsy. Approximately 20 subjects (15 
subjects in the active Viaskin® Milk group and 5 subjects in the placebo group) will be 
randomized to two treatment groups to obtain 18 completed subjects assuming 10% 
dropout rate. This sample size will have 90% power to detect a difference of 40 in 
mean maximum eosinophil counts between the subjects receiving Viaskin® milk 
(mean maximum eosinophil count of 10) and the subjects on placebo (mean maximum 


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eosinophil count of 50) assuming a common standard deviation of 20 using a two 
group t-test with a two-sided significance level of 0.05. 
3.3 
Missing data 
Every attempt must be made by the Investigator to provide complete data. The primary 
analysis can be performed on data without imputation. However, exploratory analyses 
using various imputation techniques (i.e., last observation carried forward (LOCF)) will 
be utilized to assess the robustness of the data. Analyses of secondary efficacy measures 
will be based on the intent-to-treat (ITT) population with missing values imputed using 
the last value carried forward analysis. 
4. 
Statistical Analyses 
This section provides a detailed description of the statistical analyses and methods, 
tables, listings, and figures. SAP Table shells are presented in Section 5.1.  
The definitions of the analysis populations are listed. The general description of the 
planned analysis is provided. Descriptive and baseline characteristics will be 
generated for the purpose of describing the study population. Because the sample size 
is small, sometimes the most informative way of presenting the data will be through 
graphs or listing of the raw data.  
The primary and secondary efficacy endpoints will be analyzed using the intent-to-
treat (ITT) and per protocol populations. The least squares mean and two-sided 95% 
confidence interval (CI) for the between-treatment differences will be estimated from 
the models. The Hodges-Lehmann analysis of median differences will be produced 
for some of the secondary efficacy endpoints. Relative risk (RR) or odds ratio (OR) 
with 95% CI will be presented for some of the binary endpoints. Longitudinal models 
will be used to analyze some of the efficacy endpoints. These models will focus on the 
difference between baseline and end of the double-blind treatment as well as end of 


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the open-label treatment; measurements taken before the end of the double-blinded 
treatment will be used to increase the precision of the estimates of the changes from 
baseline to the both end of the double-blind treatment and the end of the open-label 
treatment. Sensitivity analyses will be performed to examine the potential outliers and 
influential points. These measurements will be assessed by visual examination of 
histograms and normal probability plots of residuals from the models. The methods 
or statistical tests that will be used in the primary and secondary efficacy analyses and 
safety analyses are described. Details are provided below. 
4.1 
Analysis populations 
The analysis populations are: 
 Safety population: The safety population is comprised of all subjects who are 
randomized and received at least one dose of study treatment and all subjects in 
the control group who did not withdraw or were not withdrawn. This population 
will be used to assess comparative safety information. 
 Intent-to-treat population: The intent-to-treat (ITT) population (full analysis set) 
is comprised of all subjects who are randomized. Subjects in the ITT population 
will be categorized by their randomized treatment assignment. This population 
will be used to assess comparative efficacy information. 
 Per protocol population: The per protocol (PP) population includes all subjects in 
the ITT population who do not have pre-defined major deviations from the 
protocol that may affect the primary (and secondary) endpoints (i.e., subjects who 
have not gone through the third upper endoscopy and biopsy at the end of the 
double-blind treatment, subjects with a compliance below 80%, etc.). The PP 
population will be used to perform confirmatory analyses of the primary efficacy 
evaluation. 


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4.2 
Descriptive analyses 
Standard descriptive statistics will be used to describe subjects’ baseline 
characteristics and study endpoint measures overall and within each treatment group. 
Summary statistics such as means, standard deviations, medians, interquartile range 
and ranges for continuous variables (e.g., age, height, weight, and maximum 
esophageal eosinophil count) and frequency counts and percentages for categorical 
variables (e.g., race and ethnicity) will be generated. Medical histories will be 
summarized by system organ class and preferred term.   
Demographic characteristics (Table 1), medical history (Table 2), vital signs at baseline 
(day 1), end of the double-blind treatment (visit 10), and end of the open-label 
treatment (visit 16) (Table 3), and both hematology and chemistry laboratory test 
results at baseline, end of the double-blind treatment, and end of the open-label 
treatment (Table 4A and Table 4B) will be summarized. Transformation (e.g., 
logarithmic transformation) of some of the continuous variables will be applied if 
needed.  
4.3 
Subject disposition 
Subject disposition will be summarized for the ITT population. Subjects in each study 
population (ITT, PP, and Safety), subjects who received study medication, and 
subjects who completed and discontinued the double-blind period as well as the 
open-label period will be summarized (e.g., frequency counts and percentages) by 
treatment groups and overall (Table 5). The primary reason for discontinuation from 
the double-blind period and the open-label period will be listed by treatment groups.  
4.4 
Efficacy analyses 
The methods for the primary and secondary efficacy analyses are described.  


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4.4.1 Primary efficacy analyses 
Descriptive statistics for the maximum esophageal eosinophil count (the primary 
efficacy endpoint) on all specimens obtained on the biopsy at baseline (Day 1) and 
end of treatment (Visit 10) as well as the change from baseline to end of treatment will 
be presented by treatment groups and age groups (4-11 years old and 12-17 years old) 
(Table 6). The primary efficacy endpoint of the maximum esophageal eosinophil count 
will be analyzed using an analysis of covariance (ANCOVA) models with the 
treatment group (active versus placebo) and baseline patient’s maximum esophageal 
eosinophil count. The least square means for the treatment groups, difference in least 
square means between the treatment groups, and a two-sided 95% CI for the 
difference between treatment groups will be presented (Table 7). Analysis of the 
primary endpoint in the logarithmic scale will be considered. Geometric mean and 
geometric mean ratio (anti-log of the parameter estimates) with 95% CIs will be 
reported when analyses are performed in the logarithmic scale of the primary 
endpoint. 
4.4.2 Secondary efficacy analyses 
Descriptive statistics for the secondary efficacy endpoints will be presented by 
treatment groups. The following secondary efficacy endpoints will be assessed: 
4.4.2.1 Total esophageal endoscopy score 
The total score for each subject will be calculated and summary statistics at baseline, 
end of the double-blind  treatment, and end of the open-label treatment as well as the 
changes from baseline to end of the double-blind treatment and to end of the open-
label treatment will be presented by treatment groups (Table 8). Hodges-Lehmann 
estimate with 95% CI for difference of median of the changes in esophageal endoscopy 


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scores between two treatment groups will be reported. The total score at the end of 
the double-blind treatment and at the end of the open-label treatment between two 
treatment groups will be analyzed separately using ANCOVA as described in Section 
4.4.1. The least square means for the treatment groups, difference in least square 
means between the treatment groups, and a two-sided 95% CI for the difference 
between the treatment groups will be presented (Table 9).  
4.4.2.2 Eosinophilic esophagitis symptom and global assessment scores 
Summary statistics for individual eosinophilic esophagitis symptom score 
(Abdominal/Chest pain, Vomiting/Regurgitation, and Dysphagia) as well as 
investigator’s eosinophilic esophagitis global assessment score at baseline, end of the 
double-blind treatment, and end of the open-label treatment as well as changes from 
baseline to end of the double-blind treatment and to end of the open-label treatment 
will be presented by treatment groups and overall (Table 10). The total EoE symptom 
score for each subject will be calculated and summary statistics at baseline, end of the 
double-blind treatment, and end of the open-label treatment, as well as the changes 
from baseline to end of the double-blind treatment and to end of the open-label 
treatment will be presented by treatment groups and overall. Improvement in 
symptom scores will be defined as a decrease in total eosinophilic esophagitis 
symptom score of two or more from baseline to end of the double-blind treatment and 
to end of the open-label treatment. Subjects will be categorized based on whether they 
improved their symptoms in two different ways. First, subjects who improved their 
symptom scores are considered as responders and subjects who did not improve their 
symptom scores are considered as non-responders. Second, subjects who improved 
their symptom scores will be categorized as poor improvement (<30%), good 
improvement (30-70%), and excellent improvement (>70%). RR or OR  along with 95% 


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CI for the percentage of responders between two treatment groups  will be presented. 
(Table 11). 
In addition, frequency and severity EoE symptom scores measured by Pediatric 
Eosinophilic Esophagitis Symptoms Score (PEESS) will be examined. Summary 
statistics for the frequency and severity EoE symptom scores at baseline, end of the 
double-blind treatment, and end of the open-label treatment will be reported for each 
treatment group and overall. The changes in frequency and severity EoE symptom 
scores from baseline to end of the double-blind treatment and to end of the open-label 
treatment will be reported and Hodges-Lehmann estimates with 95% CIs for 
differences of medians of these changes between two treatment groups will be 
reported (Table 12). 
4.4.2.3 Percentage of subjects per response rate 
The percentage of subjects showing an excellent response (≤ 1 eosinophils/HPF), good 
response (2-14 eosinophils/HPF), and poor response (≥ 15 eosinophils/HPF) at the end 
of the double-blind treatment and at the end of the open-label treatment as well as RR 
(i.e., the percentage of subjects showing excellent response in the treatment group 
divided by the percentage of subjects showing excellent response in the placebo 
group) along with 95% CIs between two treatment groups will be presented (Table 
13). 
4.4.2.4 Eosinophilic esophagitis quality of life score  
Summary statistics for the EoE quality of life score at baseline, end of the double-blind 
treatment, and end of the open-label treatment will be reported for each treatment 
group and overall. The changes in quality of life score from baseline to end of the 
double-blind treatment and to end of the open-label treatment as well as the Hodges-


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Lehmann estimates along with 95% CIs for difference of medians of these changes 
between the two treatment groups will be reported (Table 14). 
4.4.2.5 Composite score 
Summary statistics for the composite score at baseline, end of the double-blind 
treatment, and end of the open-label treatment will be reported for each treatment 
group and overall. The changes in composite score from baseline to end of the double-
blind treatment and to end of the open-label treatment as well as the Hodges-
Lehmann estimates along with 95% CIs for differences of medians of these changes 
between the two treatment groups will be reported (Table 15). 
4.4.2.6 Development of symptoms 
Time to development of symptoms after milk reintroduction at month 9 and 20 will 
be described across two treatment groups.  
4.4.2.7 Exploratory biologic markers 
The Hodges-Lehmann estimates for median differences for continuous variables and 
RRs for categorical variables along with 95% CIs of the changes in exploratory biologic 
markers, including T-regulatory cells, TSLP, CBC with differential, and milk-specific 
immunoglobulin level, as well as epigenetic changes between the active treatment 
group and the placebo group will be reported. 
4.5 
Safety analysis 
AEs, laboratory tests (hematology and chemistry), and vital signs will be listed. No 
formal statistical analysis of safety endpoints will be performed. The details of the 
safety analysis are provided below. 


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4.5.1 Adverse events 
All AEs will be listed/described and reported by treatment groups, subject, start date, 
severity, grade, causality, action taken, stop date, outcome, and absence of serious AE 
(Table 16A and Table 16B). All AEs will be coded by system organ class and preferred 
term using the Medical Dictionary for Regulatory Activities (MedDRA). The number 
of subjects who experienced at least one AE as well as the number of AEs will be 
summarized by system organ class and treatment group (Table 17A and Table 17B). The 
Summary of AEs (total number of subjects with AEs, total number of AEs, number of 
AEs per subject, severity of AEs, any serious AEs, AEs leading to discontinuation and 
death, ongoing AEs, and outcome) by treatment group will be presented (Table 18).   
TEAEs will be defined as any AEs, regardless of relationship to study drug, which 
occur during the AE collection period of study drug or any event already present that 
worsens in either intensity or relationship to study drug following exposure to the 
Viaskin® Milk. TEAE will be considered drug-related if relationship information is 
missing. An overall summary of TEAEs (the number and percentage of subjects with 
any TEAE, total number of subjects with potentially drug-related TEAE, total number 
of TEAEs, total number of local TEAE, number of TEAEs per subject, severity of 
TEAEs, any serious TEAE, any TEAE leading to discontinuation and death) by 
treatment groups will be provided (Table 19A and Table 19B).  
The number of subjects with adverse events on local skin reactions will be 
summarized (Table 20)  
4.5.2 Laboratory assessments 
Summary of both hematology and chemistry laboratory values categorized based on 
common toxicity criteria grade will be presented by treatment groups. All laboratory 
data will be listed and values that are out of normal range will be indicated (Table 21). 


20 | P a g e  
 
4.5.3 Vital signs 
Observed vital sign values and changes from baseline to visits will be summarized by 
treatment groups. All vital signs data will be listed. The analysis of vital signs will 
focus on the incidence of clinically relevant abnormalities. The number of subjects 
evaluated and the number and percentage of subjects with clinically relevant post-
baseline abnormalities at each visit will be presented (Table 22).  
5. Appendices 
5.1 
Statistical Analysis Plan Table shells 


21 | P a g e  
 
Table 1. Demographic Characteristics 
 
All 
Viaskin® milk 
Placebo 
 
Age, year  
 
 
 
 
n 
 
 
 
 
n missing 
 
 
 
 
Mean ± SD 
 
 
 
 
Median (IQR) 
 
 
 
 
Range 
 
 
 
 
4-11 years old, n (%) 
 
 
 
 
12-17 years old, n (%) 
 
 
 
 
Gender, n (%) 
 
 
 
 
Male  
 
 
 
 
Female 
 
 
 
 
Ethnicity, n (%)  
 
 
 
 
Hispanic or Latino  
 
 
 
 
Neither Hispanic nor Latino  
 
 
 
Race, n (%) 
 
 
 
 
American Indian or Alaska 
Native 
 
 
 
 
Asian 
 
 
 
 
Native Hawaiian or other 
Pacific Islander 
 
 
 
 
Black or African American 
 
 
 
 
White 
 
 
 
 
Does not know 
 
 
 
 
Refuse 
 
 
 
 
Values will be expressed as frequency counts (percentages) unless indicated. 
SD, Standard deviation; IQR, Interquartile range 
 
 
Table 1 specification Repeat with ITT population and per protocol (PP) population 
separately as Table 1A and Table 1B, respectively. 


22 | P a g e  
 
Table 2. Medical History by System Organ Class and Preferred Term 
 
All 
Viaskin® milk 
Placebo 
 
Constitutional 
 
 
 
 
Ears, Nose, Mouth, Throat 
 
 
 
 
Cardiovascular 
 
 
 
 
Respiratory 
 
 
 
 
Gastrointestinal 
 
 
 
 
Genitourinary 
 
 
 
 
Integumentary 
 
 
 
 
Musculoskeletal 
 
 
 
 
Neurological 
 
 
 
 
Hematologic 
 
 
 
 
Lymphatic 
 
 
 
 
Allergic 
 
 
 
 
Immunologic 
 
 
 
 
Endocrine 
 
 
 
 
Asthma 
 
 
 
 
Allergic Rhinitis 
 
 
 
 
Food Allergy 
 
 
 
 
Atopic Dermatitis 
 
 
 
 
Other 
 
 
 
 
Values will be expressed as frequency counts (percentages) [n (%)]. 
 
 
Table 2 specification  
Repeat with ITT population and PP population separately as Table 2A and Table 2B, 
respectively. 
 


23 | P a g e  
 
Table 3. Summary Statistics for Vital Signs 
 
All 
Viaskin® 
milk 
Placebo 
 
Height, cm 
 
 
 
 
Baseline # 
 
 
 
 
Visit 10 #  
 
 
 
 
Visit 16 # 
 
 
 
 
Weight, kg 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Blood pressure, mmHg 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Pulse rate, beats/min 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Respiratory rate, breaths/min 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Temperature, C 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
# Baseline, Visit 10, and Visit 16 correspond to day 1, end of the double-blind treatment and 
end of the open-label treatment, respectively.  
Values will be expressed as n, n missing, mean ± SD, median (IQR), and range. 
 
 
 
 


24 | P a g e  
 
Table 4A. Summary Statistics for Laboratory Results (Hematology) 
 
All 
Viaskin® 
milk 
Placebo 
 
RBC count, MIL/μL 
 
 
 
 
Baseline # 
 
 
 
 
Visit 10 # 
 
 
 
 
Visit 16 # 
 
 
 
 
WBC count, Thou/μL 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Hemoglobin, g/dL 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Hematocrit, % 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Platelet count, Thou/μL 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Segmented neutrophils, cells/μL  
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Lymphocytes, cells/μL 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Monocytes, cells/μL 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 


25 | P a g e  
 
Eosinophils, cells/ μL 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Basophils, cells/μL 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
# Baseline, Visit 10, and Visit 16 correspond to day 1, end of the double-blind treatment and 
end of the open-label treatment, respectively.  
Values will be expressed as n, n missing, mean ± SD, median (IQR), and range. 


26 | P a g e  
 
Table 4B. Summary Statistics for Laboratory Results (Chemistry) 
 
All 
Viaskin® 
milk 
Placebo 
 
Total protein, g/dL 
 
 
 
 
Baseline # 
 
 
 
 
Visit 10 # 
 
 
 
 
Visit 16 # 
 
 
 
 
Blood urea nitrogen, mg/dL 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Creatinine, mg/dL 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
ALP (Alkalin phosphatase), U/L 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
ALT (Alanine 
aminotransferase), U/L 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
AST (aspartate 
aminotransferase), U/L 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Total bilirubin, mg/dL 
 
 
 
 
Baseline 
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 


27 | P a g e  
 
# Baseline, Visit 10, and Visit 16 correspond to day 1, end of the double-blind treatment, and 
end of the open-label treatment, respectively. 
Values will be expressed as n, n missing, mean ± SD, median (IQR), and range. 
 
 
Table 4 (4A and 4B) Specification  
Laboratory results (Hematology and Chemistry) will also be summarized in the 
“Other” unit(s) if there is/are “Other” unit(s). 
 
 
 
 


28 | P a g e  
 
Table 5. Subject Disposition 
 
All 
Viaskin® 
milk 
Placebo 
Randomized, n (%)  
 
 
 
Yes 
 
 
 
No 
 
 
 
Study population, n (%) 
 
 
 
Safety  
 
 
 
Intent-to-treat 
 
 
 
Per protocol 
 
 
 
Received study medication, n (%) 
 
 
 
Yes 
 
 
 
No 
 
 
 
Completed double-blind period, n (%) 
 
 
 
Yes 
 
 
 
No 
 
 
 
Discontinued double-blind period, n (%) 
 
 
 
Yes 
 
 
 
No 
 
 
 
Completed open-label period, n (%) 
 
 
 
Yes 
 
 
 
No 
 
 
 
Discontinued open-label period, n (%) 
 
 
 
Yes 
 
 
 
No 
 
 
 
Values will be expressed as frequency counts (percentages). 
 
 
 
 
 
 
 
 
 
 


29 | P a g e  
 
Table 6. Descriptive Statistics for Maximum Esophageal Eosinophil Count (Primary 
Efficacy Endpoint) 
 
Viaskin® milk 
(n=xx) 
Placebo 
(n=xx) 
 
Baseline  Visit 10 
Change 
Baseline  Visit 10 
Change 
4-11 years old 
 
 
 
 
 
 
n  
 
 
 
 
 
 
n missing 
 
 
 
 
 
 
Mean ± SD 
 
 
 
 
 
 
Median (IQR) 
 
 
 
 
 
 
Range 
 
 
 
 
 
 
12-17 years old 
 
 
 
 
 
 
n  
 
 
 
 
 
 
n missing 
 
 
 
 
 
 
Mean ± SD 
 
 
 
 
 
 
Median (IQR) 
 
 
 
 
 
 
Range 
 
 
 
 
 
 
4-17 years old (All) 
 
 
 
 
 
 
n  
 
 
 
 
 
 
n missing 
 
 
 
 
 
 
Mean ± SD 
 
 
 
 
 
 
Median (IQR) 
 
 
 
 
 
 
Range 
 
 
 
 
 
 
SD, Standard deviation. 
Visit 10 is the end of treatment. Change = Visit 10 – Baseline. 
 
 
Table 6 specification  
Repeat with ITT population and PP population separately as Table 6A and Table 6B, 
respectively. 
 
 
 
 
 


30 | P a g e  
 
Table 7. Maximum Esophageal Eosinophil Count Analysis at the End of 
Double-blind Treatment (Primary Efficacy Analysis, ANCOVA models) 
 
Least square means 
95% CI 
Viaskin® milk 
xx.xx 
- 
Placebo 
xx.xx 
- 
Difference (Viaskin® milk – Placebo) 
xx.xx 
(xx.xx, xx.xx) 
Number of observations used: xxx 
Least square means from the analysis of covariance (ANCOVA) model including treatment 
group and baseline maximum esophageal eosinophil count as covariates will be reported. A 
two-sided 95% confidence interval (CI) for the difference in least square means between two 
treatment groups will be reported. 
 
 
Table 7 specification  
Repeat with ITT population and PP population with LOCF separately as Table 7A and 
7B, respectively. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


31 | P a g e  
 
Table 8. Summary Statistics for Total Esophageal Endoscopy Score (Secondary 
Efficacy Endpoint) 
 
All 
Viaskin® 
milk 
Placebo 
Median 
Difference 
(95% CI) # 
Total esophageal endoscopy score 
 
 
 
 
Baseline  
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Change from baseline to visit 10 
 
 
 
xx (xx, xx) 
Change from baseline to visit 16 
 
 
 
xx (xx, xx) 
Values will be expressed as n, n missing, mean ± SD, median (IQR) range.  
# Hodges-Lehmann estimate with 95% CI for median differences between two treatment groups 
will be reported.  
 
 
Table 8 specification  
Repeat with ITT population and PP population separately as Table 8A and Table 8B, 
respectively. 
 
 
 
 
 
 
 
 
 
 


32 | P a g e  
 
Table 9A. Total Esophageal Endoscopy Score Analysis at the End of the 
Double-blind Treatment (Secondary Efficacy Analysis, ANCOVA Models) 
 
Least square means 
95% CI 
Viaskin® milk 
xx.xx 
- 
Placebo 
xx.xx 
- 
Difference (Viaskin® milk – Placebo) 
xx.xx 
(xxxx,xx.xx) 
Number of observations used: xxx. 
Least square means from the analysis of covariance (ANCOVA) model including treatment 
group and total esophageal endoscopy score at baseline as covariates will be reported. A two-
sided 95% confidence interval (CI) for the difference in least square means between two 
treatment groups will be reported. 
 
 
 
Table 9B. Total Esophageal Endoscopy Score Analysis at the End of the Open-
label Treatment (Secondary Efficacy Analysis, ANCOVA Models) 
 
Least square means 
95% CI 
Viaskin® milk 
xx.xx 
- 
Placebo 
xx.xx 
- 
Difference (Viaskin® milk – Placebo) 
xx.xx 
(xx.xx, xx.xx) 
Number of observations used: xxx. 
Least square means from the analysis of covariance (ANCOVA) model including treatment 
group and total esophageal endoscopy score at baseline) as covariates will be reported. A two-
sided confidence interval (CI) for the difference in least square means between two treatment 
groups will be reported. 
 
 
Table 9 specification 
Repeat with ITT population and PP population separately as Table 9A-1 and Table 9A-2 
as well as Table 9B-1 and Table 9B-2, respectively. 


33 | P a g e  
 
Table 10. Summary Statistics for Eosinophilic Esophagitis Symptom and Global 
Assessment Scores (Secondary Efficacy Endpoints) 
 
All 
Viaskin® 
milk 
Placebo 
 
Eosinophilic esophagitis symptom 
score 
 
 
 
 
Baseline  
 
 
 
 
0 (None) 
 
 
 
 
1 (Mild) 
 
 
 
 
2 (Moderate) 
 
 
 
 
3 (Severe) 
 
 
 
 
4 (Very severe) 
 
 
 
 
Visit 10 
 
 
 
 
0 (None) 
 
 
 
 
1 (Mild) 
 
 
 
 
2 (Moderate) 
 
 
 
 
3 (Severe) 
 
 
 
 
4 (Very severe) 
 
 
 
 
Visit 16 
 
 
 
 
0 (None) 
 
 
 
 
1 (Mild) 
 
 
 
 
2 (Moderate) 
 
 
 
 
3 (Severe) 
 
 
 
 
4 (Very severe) 
 
 
 
 
Change from baseline to visit 10 
 
 
 
 
-4 (Very severe to None) 
 
 
 
 
-3  
 
 
 
 
-2 
 
 
 
 
-1 
 
 
 
 
 0 (No change) 
 
 
 
 
 1 
 
 
 
 
 2 
 
 
 
 
 3 
 
 
 
 
4 (None to Very severe) 
 
 
 
 
Change from baseline to visit 16 
 
 
 
 
-4 (Very severe to None) 
 
 
 
 
-3  
 
 
 
 
-2 
 
 
 
 
-1 
 
 
 
 


34 | P a g e  
 
Table 10. Summary Statistics for Eosinophilic Esophagitis Symptom and Global 
Assessment Scores (Secondary Efficacy Endpoints) 
 
All 
Viaskin® 
milk 
Placebo 
 
 0 (No change) 
 
 
 
 
 1 
 
 
 
 
 2 
 
 
 
 
 3 
 
 
 
 
 4 (None to Very severe) 
 
 
 
 
Values will be expressed as frequency counts (percentages).  
 
 
Table 10 specifications  
Repeat with each individual eosinophilic esophagitis symptom scores 
(Abdominal/Chest pain, Vomiting/Regurgitation, and Dysphagia) as well as the 
investigator’s global assessment scores on ITT population and PP population separately 
as Table 10-1A, Table 10-1B, Table 10-2A, Table 10-2B, Table 10-3A,  Table 10-3B, Table 
10-4A, and Table 10-4B, respectively. 


35 | P a g e  
 
Table 11. Summary Statistics for The Total Eosinophilic Esophagitis Symptom 
Score (Secondary Efficacy Endpoint) 
 
All 
Viaskin® 
milk 
Placebo 
 
Total eosinophilic esophagitis 
symptom score # 
 
 
 
 
Baseline  
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Change from baseline to visit 10 
 
 
 
 
Change from baseline to visit 16 
 
 
 
 
Improvement in eosinophilic 
esophagitis total symptom score at 
visit 10 *  
 
 
 
 
Yes (Responders), n (%) 
 
 
 
 
No (Non-responders), n (%) 
 
 
 
 
Improvement in eosinophilic 
esophagitis total symptom score at 
visit 10 ** 
 
 
 
 
Poor improvement (<30%), n (%) 
 
 
 
 
Good improvement (30-70%), n (%) 
 
 
 
 
Excellent improvement (>70%), n (%) 
 
 
 
 
Improvement in eosinophilic 
esophagitis total symptom score at 
visit 16 *  
 
 
 
 
Yes (Responders), n (%) 
 
 
 
 
No (Non-responders), n (%) 
 
 
 
 
Improvement in eosinophilic 
esophagitis total symptom score at 
visit 16 ** 
 
 
 
 
Poor improvement (<30%), n (%) 
 
 
 
 


36 | P a g e  
 
Table 11. Summary Statistics for The Total Eosinophilic Esophagitis Symptom 
Score (Secondary Efficacy Endpoint) 
 
All 
Viaskin® 
milk 
Placebo 
 
Good improvement (30-70%), n (%) 
 
 
 
 
Excellent improvement (>70%), n (%) 
 
 
 
 
# Values will be expressed as n, n missing, mean ± SD, median (IQR), and range. Hodges-
Lehmann median differences between two treatment groups will be reported. 
* Improvement in total eosinophilic esophagitis symptom scores is defined as a decrease in total 
symptom scores of two or more from baseline to end of the double-blind treatment (visit 10) 
and from baseline to end of the open-label treatment (visit 16). If change in total symptom score 
(Visit 10 – baseline or Visit 16 - baseline) is 2 or greater than 2, subject is responder; if not, 
subject is non-responder. Values will be expressed as frequency counts (percentages).  
** Improvement will be reported as Poor, Good, and Excellent as FDA requested.  
Relative risk with 95% CI of the improvement between two treatment groups will be presented.  
 
 
Table 11 specification  
Repeat with ITT population and PP population separately as Table 11A and Table 11B, 
respectively. 
 
 
 
 


37 | P a g e  
 
Table 12. Summary Statistics for Pediatric Eosinophilic Esophagitis Symptom 
Scores (PEESS) (Secondary Efficacy Endpoint) 
 
All 
Viaskin® 
milk 
Placebo 
Median 
Difference 
(95% CI) # 
Frequency Symptom Score 
 
 
 
 
Baseline  
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Change from baseline to visit 10 
 
 
 
 
Change from baseline to visit 16 
 
 
 
 
Severity Symptom Score 
 
 
 
 
Baseline  
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Change from baseline to visit 10 
 
 
 
 
Change from baseline to visit 16 
 
 
 
 
Frequency and Severity Symptom Score 
(Total score) 
 
 
 
 
Baseline  
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Change from baseline to visit 10 
 
 
 
 
Change from baseline to visit 16 
 
 
 
 
Values will be expressed as n, n missing, mean ± SD, median (IQR), and range.  
# Hodges-Lehmann estimate with 95% CI for median differences between two treatment groups 
will be reported. 
 
 
Table 12 specifications  
Repeat with ITT population and PP population separately as Table 12A and Table 12B, 
respectively. 
 
 
 
 


38 | P a g e  
 
Table 13A. Summary Statistics for Response rate at the End of the Double-blind 
Treatment (Secondary Efficacy Endpoint) 
 
All 
Viaskin® 
milk 
Placebo 
Relative Risk 
(95% CI) 
Response rate, n (%) 
 
 
 
 
Excellent (≤ 1 eosinophils/HPF)  
 
 
 
 
Good (2-14 eosinophils/HPF) 
 
 
 
 
Poor (≥ 15 eosinophils/HPF) 
 
 
 
 
Values will be expressed as frequency counts (percentages).  
 
 
 
Table 13B. Summary Statistics for Response rate at the End of the Open-label 
Treatment (Secondary Efficacy Endpoint) 
 
All 
Viaskin® 
milk 
Placebo 
Relative Risk 
(95% CI) 
Response rate, n (%) 
 
 
 
 
Excellent (≤ 1 eosinophils/HPF)  
 
 
 
 
Good (2-14 eosinophils/HPF) 
 
 
 
 
Poor (≥ 15 eosinophils/HPF) 
 
 
 
 
Values will be expressed as frequency counts (percentages).  
 
 
Table 13 specification  
Repeat on ITT population and PP population separately as Table 13A-1 and Table 13A-2 
as well as Table 13B-1 and Table 13B-2, respectively. 
 
 
 
 
 
 


39 | P a g e  
 
Table 14. Summary Statistics for Eosinophilic Esophagitis Quality of Life Score 
(Secondary Efficacy Endpoint) 
 
All 
Viaskin® 
milk 
Placebo 
Median 
Difference 
(95% CI) # 
Quality of life score 
 
 
 
 
Baseline  
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Change from baseline to visit 10 
 
 
 
xx (xx, xx) 
Change from baseline to visit 16 
 
 
 
xx (xx, xx) 
Values will be expressed as n, n missing, mean ± SD, median (IQR), and range.. 
# Hodges-Lehmann estimate with 95% CI for median differences between two treatment groups 
will be reported. 
 
 
Table 14 specifications  
Repeat with ITT population and PP population separately as Table 14A and Table 14B, 
respectively. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


40 | P a g e  
 
Table 15. Summary Statistics for Composite score (Secondary Efficacy 
Endpoint) 
 
All 
Viaskin® 
milk 
Placebo 
Median 
Difference 
(95% CI) # 
Quality of life score 
 
 
 
 
Baseline  
 
 
 
 
Visit 10 
 
 
 
 
Visit 16 
 
 
 
 
Change from baseline to visit 10 
 
 
 
xx (xx, xx)  
Change from baseline to visit 16 
 
 
 
xx (xx, xx) 
Values will be expressed as n, n missing, mean ± SD, median (IQR), and range.  
# Hodges-Lehmann estimate with 95% CI for median differences between two treatment groups 
will be reported. 
 
Composite score = Maximum Eosinophils per HPF + 10*EREFS + 2*PEESS +5* (Investigator assessment of 
EoE symptom activity) 
 
Table 15 specifications  
Repeat with ITT population and PP population separately as Table 15A and Table 15B, 
respectively. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


41 | P a g e  
 
Table 16A. Detailed Listing for All Adverse Events by MedDRA System Organ Class  
MedDRA 
System 
Organ 
Class 
Treatment 
Group 
Subject 
ID 
Adverse 
Event 
Descriptio
n 
Start 
Date 
Severity 
Grade Causality  Action 
Taken 
Stop 
Date 
Outcome Serious 
AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events were classified into SOC and PT using Version XX.0 of MedDRA. 
The following coding will be used: 
Severity: 1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening, and 5=Death. 
Grade: 1, 2, 3, and 4. 
Causality: 1=Unlikely related, 2=Possibly related, and 3=Probably related. 
Action taken: 0=None, 1=Prescribed medication, 2=Non-medication treatment, 3=Hospitalization or prolongation, 4=Discontinued treatment. 
Outcome: 1=Ongoing (no change), 2= Recovering/resolving (improving), 3=Worsened, 4=Recovered/resolved with no sequelae, 5= 
Recovered/resolved with sequelae (chronic stable) 6=Death. 
 


42 | P a g e  
 
Table 16B. Detailed Listing for All Adverse Events by MedDRA Preferred Term   
MedDRA 
Preferred 
Term 
Treatment 
Group 
Subject 
ID 
Adverse 
Event 
Description 
Start 
Date 
Severity 
Grade Causality  Action 
Taken 
Stop 
Date 
Outcome Serious 
AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events were classified into SOC and PT using Version XX.0 of MedDRA. 
The following coding will be used: 
Severity: 1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening, and 5=Death. 
Grade: 1, 2, 3, and 4. 
Causality: 1=Unlikely related, 2=Possibly related, and 3=Probably related. 
Action taken: 0=None, 1=Prescribed medication, 2=Non-medication treatment, 3=Hospitalization or prolongation, 4=Discontinued treatment. 
Outcome: 1=Ongoing (no change), 2= Recovering/resolving (improving), 3=Worsened, 4=Recovered/resolved with no sequelae, 5= 
Recovered/resolved with sequelae (chronic stable) 6=Death.


43 | P a g e  
 
Table 17A. Adverse Events by System Organ Class (Number of subjects) 
 
Viaskin® milk 
Placebo 
Number of subject with adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events were classified into SOC and PT using Version XX.0 of MedDRA. 
 
 
 
Table 17B. Adverse Events by System Organ Class (Number of adverse 
events) 
 
Viaskin® milk 
Placebo 
Total number of adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events were classified into SOC and PT using Version XX.0 of MedDRA. 
 
 
 
 
 
 


44 | P a g e  
 
Table 18. Summary of Adverse Events by Treatment Group  
 
All 
Viaskin® 
milk 
Placebo 
Number of subjects (%) with AEs 
 
 
 
Number of AEs 
 
 
 
Number of AEs per subject  
 
 
 
0 
 
 
 
1 
 
 
 
2 + 
 
 
 
Number of systemic allergic symptoms 
 
 
 
     Potentially drug-related  
 
 
 
          Yes 
 
 
 
          No 
 
 
 
Severity of AEs  
 
 
 
Mild 
 
 
 
Moderate 
 
 
 
Severe 
 
 
 
Life-threatening 
 
 
 
Death 
 
 
 
Serious AEs (SAEs) 
 
 
 
Yes 
 
 
 
No  
 
 
 
Number of potentially drug-related SAEs 
 
 
 
AE leading to discontinuation 
 
 
 
Yes 
 
 
 
 No 
 
 
 
AE leading to death 
 
 
 
Yes 
 
 
 
 No 
 
 
 
Ongoing 
 
 
 
Yes 
 
 
 
No 
 
 
 
Outcome 
 
 
 
Unchanged 
 
 
 
Worsened 
 
 
 
Recovered/resolved with no sequelae 
 
 
 
Recovered/resolved with sequelae 
 
 
 
Death 
 
 
 


45 | P a g e  
 
 
Table 19A. Treatment-Emergent AEs (TEAEs)* by Treatment Groups 
(Number of subjects (%)) 
 
All 
Viaskin® 
milk 
Placebo 
TEAEs 
 
 
 
Potentially drug-related TEAE 
 
 
 
Severity of TEAE 
 
 
 
Mild 
 
 
 
Moderate 
 
 
 
Severe 
 
 
 
Life-threatening 
 
 
 
Death 
 
 
 
Serious TEAE 
 
 
 
TEAE leading to discontinuation 
 
 
 
TEAE leading to death 
 
 
 
Number of TEAEs  
 
 
 
0 
 
 
 
1 
 
 
 
2 
 
 
 
3 + 
 
 
 
Ongoing 
 
 
 
Yes 
 
 
 
No 
 
 
 
Outcome 
 
 
 
Unchanged 
 
 
 
Worsened 
 
 
 
Recovered/resolved with no sequelae 
 
 
 
Recovered/resolved with sequelae 
 
 
 
Death 
 
 
 
* Treatment-emergent AE is defined as any AE, regardless of relationship to study drug, 
which occur during AE collection period of study drug or ant event already present that 
worsens in either intensity or relationship to study drug following exposure to Viaskin®.  
 
 


46 | P a g e  
 
Table 19B. Treatment-Emergent AEs (TEAEs)* by Treatment Groups 
(Number of TEAE) 
 
All 
Viaskin® 
milk 
Placebo 
Number of TEAEs 
 
 
 
Number of potentially drug-related TEAE 
 
 
 
Number of severity of TEAE 
 
 
 
Mild 
 
 
 
Moderate 
 
 
 
Severe 
 
 
 
Life-threatening 
 
 
 
Death 
 
 
 
Number of serious TEAE 
 
 
 
Number of TEAE leading to 
discontinuation 
 
 
 
Number of TEAE leading to death 
 
 
 
Number of TEAEs per subject  
 
 
 
0 
 
 
 
1 
 
 
 
2 
 
 
 
3 + 
 
 
 
Number of local TEAE 
 
 
 
Number of severity of local TEAE 
 
 
 
Mild 
 
 
 
Moderate 
 
 
 
Severe 
 
 
 
Life-threatening 
 
 
 
Death 
 
 
 
Outcome 
 
 
 
Unchanged 
 
 
 
Worsened 
 
 
 
Recovered/resolved with no sequelae 
 
 
 
Recovered/resolved with sequelae 
 
 
 
Death 
 
 
 
* Treatment-emergent AE is defined as any AE, regardless of relationship to study drug, 
which occur during AE collection period of study drug or ant event already present that 
worsens in either intensity or relationship to study drug following exposure to Viaskin®.  


47 | P a g e  
 
 
 
Table 20. Summary Statistics of Local Skin Reactions (Adverse Events) 
 
All 
Viaskin® milk 
Placebo 
 
Number of patients with reactions 
 
 
 
 
0 
 
 
 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
Values will be expressed as frequency counts (percentages) unless indicated. 
 
 
 


48 | P a g e  
 
Table 21. Summary of Laboratory Abnormalities based on CTC Grade by Visit and 
Treatment Groups  
 
Viaskin®Milk 
Placebo 
 
 
Visit 
1 
Visit 
8 
Visit 
10 
Visit 
16 
Visit 
1 
Visit 
8 
Visit 
10 
Visit 
16 
Hematology 
 
 
   RBC Count 
 
 
 
 
 
 
 
 
   WBC Count 
 
 
 
 
 
 
 
 
   Hemoglobin 
 
 
 
 
 
 
 
 
   Hematocrit 
 
 
 
 
 
 
 
 
   Platelet Count 
 
 
 
 
 
 
 
 
   Segmented Neutrophils 
 
 
 
 
 
 
 
 
   Lymphocytes 
 
 
 
 
 
 
 
 
   Monocytes 
 
 
 
 
 
 
 
 
   Eosinophils 
 
 
 
 
 
 
 
 
   Basophils 
 
 
 
 
 
 
 
 
Chemistry 
 
 
   Total Protein 
 
 
 
 
 
 
 
 
   Blood Urea Nitrogen 
 
 
 
 
 
 
 
 
   Creatinine 
 
 
 
 
 
 
 
 
   ALP 
 
 
 
 
 
 
 
 
   ALT 
 
 
 
 
 
 
 
 
   AST 
 
 
 
 
 
 
 
 
   Total Bilirubin 
 
 
 
 
 
 
 
 
Values (abnormalities) will be expressed as frequency counts (percentages). Number of subject 
evaluated at each visit will be reported. 
Treatment groups will be compared using Fisher’s exact test. 
ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase. 


49 | P a g e  
 
Table 22. Summary of Clinically Relevant Abnormalities in Vital Signs by Visit and Treatment Groups  
 
Viaskin® Milk 
Placebo 
 
Temperature Pulse 
SBP 
DBP 
Temperature Pulse 
SBP 
DBP 
Visit 1   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 2   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 3   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 4   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 5   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 6   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 7   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 


50 | P a g e  
 
Table 22. Summary of Clinically Relevant Abnormalities in Vital Signs by Visit and Treatment Groups  
 
Viaskin® Milk 
Placebo 
 
Temperature Pulse 
SBP 
DBP 
Temperature Pulse 
SBP 
DBP 
Visit 8   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 9   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 10   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 11   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 12   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 13   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 14   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 


51 | P a g e  
 
Table 22. Summary of Clinically Relevant Abnormalities in Vital Signs by Visit and Treatment Groups  
 
Viaskin® Milk 
Placebo 
 
Temperature Pulse 
SBP 
DBP 
Temperature Pulse 
SBP 
DBP 
Visit 15   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 16   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
Visit 17   
 
 
 
 
 
 
 
 
Abnormal, n (%) 
 
 
 
 
 
 
 
 
Number of subjects evaluated 
 
 
 
 
 
 
 
 
SBP, Systolic Blood Pressure; DBP, Diastolic Blood Pressure. 
Criteria for abnormalities: 
Temperature: < 35 C and a decrease from pre-dosing of at least 1 C or >38.5 C and an increase from pre-dosing of at least 1 C. 
Pulse: > 120 beats/minute or an increase from pre-dosing of > 20 beats/minute, or < 50 beats/minute or a decrease from pre-dosing of > 
20 beats/minute. 
SBP: > 140 mmHg or an increase from pre-dosing of > 40 mmHg, or < 90 mmHg or a decrease from pre-dosing of > 30 mmHg. 
DBP: > 90 mmHg or an increase from pre-dosing of > 30 mmHg, or < 50 mmHg or a decrease from pre-dosing of > 20 mmHg. 
 


52 | P a g e  
 
5.2 
Consort diagram
 
Figure 1: Consort Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of subjects screened 
N=xxx 
Number of subjects eligible and consented 
N=xxx 
Viaskin® Milk 
N=xxx 
Placebo 
N=xxx 
Completed  
 N=xxx 
Not completed  
N=xxx 
Not completed  
N=xxx 
Completed  
 N=xxx