Clinical trial NCT01846208
Conditions: Food Allergy
Keywords: Egg Allergy Egg Oral Immunotherapy Food Allergy
Sponsor: Hugh A Sampson, MD
Start date: 2013-07-01; Completion date: 2018-09-30
Enrollment: 92 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare Baked Egg vs. Egg Oral Immunotherapy for inducing sustained unresponsiveness to egg exposure in children.

Detailed description:
Food allergy affects 6-8 percent of children in the United States. In young children, reactions to egg can range from hives to severe life threatening allergic reactions called anaphylaxis. Current treatment for food allergy is complete avoidance of the food and to carry antihistamines and self-injectable epinephrine if an accidental reaction occurs. However, accidental exposure to allergens in processed foods may be difficult to avoid. Currently, several therapeutic strategies are being investigated to prevent and treat food allergies. Since immunotherapy injections for food allergy are associated with a high rate of allergic reactions, alternate approaches to treatment are needed. Oral (by mouth) immunotherapy (OIT) is one approach that has been tried in some studies in the treatment of food allergies. The purpose of this study is to compare baked foods with egg versus (vs.) egg OIT. The intent of the study is to investigate if participants will be able to consume egg after taking baked foods with egg or egg OIT for a period of time and then stopping for a certain period. This is referred to as tolerance or sustained unresponsiveness. This study will evaluate the effectiveness of the egg OIT vs. baked egg by having each participant ingest egg white solid or baked foods with egg. This will be done over 2 years.

This study will last 2 years. All eligible subjects will receive a baked egg oral food challenge (OFC). Those who pass the baked egg OFC will then have a 2 gm egg OFC. Those who react to the egg OFC will be randomized to Baked Egg or Egg OIT. Individuals who do not pass the initial baked egg OFC will be assigned to Egg OIT. Those who pass the egg OFC will not be eligible for the study and will be followed per site standard of care. All eligible and enrolled subjects will have a 1-year and a 2-year OFC.

At selected visits, blood and urine collection, physical examination, prick skin tests, and atopic dermatitis and asthma evaluations will occur.

Arms: arm 1: Subjects who passed a baked egg oral food challenge (OFC) at baseline were randomized to receive egg oral immunotherapy (OIT) in the form of egg white solid with up to four oral food challenges as directed by protocol. arm 2: Subjects who passed a baked egg oral food challenge (OFC) at baseline were randomized to receive baked egg in the form of home-baked goods and "safe" commercial products with up to four oral food challenges as directed by the protocol. arm 3: Subjects who failed a baked egg oral food challenge (OFC) at baseline were assigned to receive egg oral immunotherapy (OIT) in the form of egg white solid with up to four oral food challenges as directed by protocol.
Interventions: intervention 1: Egg Oral Immunotherapy intervention 2: Baked Egg
Intervention descriptions: intervention 1: Commercially available egg white solid dispensed by the central manufacturer. Study product will be dispensed in vials for low doses, capsules for mid-range doses, and bulk powder with dosing scoops for the higher doses. intervention 2: Predetermined food substances with known amounts of Baked Egg (egg protein) with standardized dosing/consumption instructions.

Protocol documents:
Prot_001.pdf: 
NCT#01846208 
Oral Desensitization to Egg With Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children Using Baked Egg or Egg Oral 
Immunotherapy (OIT) 
PI: Dr. Hugh A. Sampson 
Document Date: February 16, 2016
NCT#01846208 
Oral Desensitization to Egg With Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children Using Baked Egg or Egg Oral 
Immunotherapy (OIT) 
PI: Dr. Hugh A. Sampson 
Document Date: February 16, 2016
NCT#01846208 
Oral Desensitization to Egg With Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children Using Baked Egg or Egg Oral 
Immunotherapy (OIT) 
PI: Dr. Hugh A. Sampson 
Document Date: February 16, 2016
NCT#01846208 
Oral Desensitization to Egg With Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children Using Baked Egg or Egg Oral 
Immunotherapy (OIT) 
PI: Dr. Hugh A. Sampson 
Document Date: February 16, 2016
NCT#01846208 
Oral Desensitization to Egg With Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children Using Baked Egg or Egg Oral 
Immunotherapy (OIT) 
PI: Dr. Hugh A. Sampson 
Document Date: February 16, 2016
NCT#01846208 
Oral Desensitization to Egg With Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children Using Baked Egg or Egg Oral 
Immunotherapy (OIT) 
PI: Dr. Hugh A. Sampson 
Document Date: February 16, 2016
NCT#01846208 
Oral Desensitization to Egg With Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children Using Baked Egg or Egg Oral 
Immunotherapy (OIT) 
PI: Dr. Hugh A. Sampson 
Document Date: February 16, 2016


 
 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
PROTOCOL CoFAR7 
Oral Desensitization to Egg with Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children using Baked Egg or Egg Oral 
Immunotherapy (OIT) 
Baked Egg/ Egg OIT 
Version 6.0 (February 16, 2016)  
[IND 15276] 
This clinical study is supported and conducted by the Consortium of Food Allergy Research 
(CoFAR), is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). 
PRINCIPAL INVESTIGATOR 
[P
ROTOCOL CO-C
HAIR] 
Hugh A. Sampson, MD 
Professor of Pediatrics & Immunobiology 
Mount Sinai School of Medicine 
One Gustave L. Levy Place  
New York, NY  100029-6574 
 
CO-PRINCIPAL INVESTIGATOR 
[P
ROTOCOL CO-C
HAIR] 
Robert Wood, MD 
Johns Hopkins University 
CMSC 1102 
Johns Hopkins Hospital 
600 North Wolfe Street 
Baltimore, MD  21287 
 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff and applicable independent ethics 
committees or institutional review boards. The contents of this document shall not be 
disclosed to others without written authorization from CoFAR and NIAID, unless it is 
necessary to obtain informed consent from potential study subjects. 


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Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
 
NIH MEDICAL MONITOR: 
DAIT/NIAID /NIH 
5601 Fishers Lane 
Rockville, MD 20852  
NIH PROJECT MANAGER: 
DAIT/NIAID /NIH 
5601 Fishers Lane 
Rockville, MD 20852 
SACCC STATISTICIAN: 
The EMMES Corporation 
401 N. Washington Street 
Rockville, MD  20850 
 
SACCC MEDICAL OFFICER: 
 
The EMMES Corporation 
401 N. Washington Street 
Rockville, MD  20850 
 
SACCC PROJECT MANAGER: 
 
The EMMES Corporation 
401 N. Washington Street 
Rockville, MD  20850 
 
COFAR PRINCIPAL INVESTIGATOR 
Hugh A. Sampson, MD 
Professor of Pediatrics & Immunobiology 
Mount Sinai School of Medicine 
One Gustave L. Levy Place 
New York, NY  10029-6574 


Consortium of Food Allergy Research 
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Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
Protocol Approval 
Protocol CoFAR7 
Version/Date: 6.0, February 16, 2016 
 
IND: 15276 
Principal Investigator: Hugh A. Sampson, MD 
 
Short Title: Baked Egg/Egg OIT 
 
I have read protocol CoFAR7, and I approve it. As the principal investigator, I agree to 
conduct this protocol according to Good Clinical Practice (GCP), as delineated in the 
United States Code of Federal Regulations (CFR) – 21 CFR Parts 50, 54, 56 and 312 and 
in the International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) “Guidance for Industry: E6 Good 
Clinical Practice Consolidated Guidance” (April 1996), and according to the criteria 
specified in this protocol. Furthermore, I will conduct this protocol in keeping with local, 
state and federal requirements. 
 
 
_______________________________                                    
Principal Investigator (Print)                                                        
 
 
_______________________________                                    _______________ 
Principal Investigator (Signature)                                                Date 


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Protocol CoFAR7 
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Synopsis 
Title 
Oral Desensitization to Egg with Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children using Baked Egg or Egg Oral 
Immunotherapy 
Short Title 
Baked Egg/Egg OIT 
Clinical Phase 
2 
IND 
15276 
IND Sponsor 
Hugh A Sampson, MD  
Principal Investigator 
[or Protocol Chair] 
Chair: Hugh A. Sampson, MD 
Co-Chair: Robert Wood, MD 
Accrual Objective 
96 subjects tolerating Baked Egg will be randomized 1:1 to Baked Egg vs. Egg 
OIT. We plan to enroll approximately 40 subjects that fail the baked egg 
challenge into an Egg OIT assignment group. 
Accrual Period 
Targeted accrual will be 18 months. 
Study Design 
This is a multi-center, randomized, open label study to investigate sustained 
unresponsiveness induction and safety of Baked Egg vs. Egg OIT, for OFC 
documented egg allergy, in individuals who pass a 2 gm baked egg protein 
OFC. All eligible subjects will receive a double-blind placebo controlled baked 
egg OFC. Individuals who pass the baked egg OFC will then have a double-
blind placebo controlled egg OFC. Those who react at a cumulative dose of < 
1444 mg of egg white protein will be randomized 1:1 to Baked Egg or Egg OIT. 
Approximately 40 of the first individuals who do not pass the initial baked egg 
food challenge will be assigned to Egg OIT and are the Egg OIT assignment 
group. Those who tolerate more than 1444 mg of egg white protein on the egg 
OFC will not be eligible for the study and will be followed per site standard of 
care. All eligible and enrolled subjects will have a 1 year and a 2 year OFC. 
Study Duration 
Up to approximately 33 months per subject, with an additional phone follow-up 
annually through September 30, 2018. 
Primary Endpoint 
The primary end point is development of sustained unresponsiveness to egg 
consumption at 2 years. 
Secondary and Tertiary 
Endpoints 
-  The development of desensitization at 1 year and 2 years. 
-  Incidence of all serious adverse events during the study. 
-  Changes in egg-specific IgE and IgG4, changes in PST mean wheal 
diameters, basophil reactivity, and changes in egg-specific circulating T 
follicular (Tfh) helper cell and CD154+ CD4+ T cell profiles. 
Study Product 
We will provide commercially available egg white solid distributed by the 
central manufacturer. Study product will be dispensed in vials for low doses, 
capsules for mid-range doses and bulk powder with dosing scoops for the higher 
doses. 
 
Baked Egg subjects will use predetermined food substances with known 
amounts of Baked Egg (egg protein) with standardized dosing/consumption 
instructions. 
Inclusion Criteria 
-  Age 3 through 16 years with a serum IgE [UniCAPTM] to egg of > 5 kUA/L 
[determined by UniCAP
TM within the past 12 months]. 
-  Reacting to the initial baked egg OFC with dose limiting symptoms 
(approximately 40 subjects) OR 
-  Reacting on an initial egg OFC with dose limiting symptoms to a 


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cumulative dose of 1444 mg of egg white protein or less after passing the 
initial baked egg OFC. 
-  Written informed consent from subject and/or parent/guardian. 
-  Written assent from all subjects as appropriate. 
-  All females of child bearing age must be using appropriate birth control. 
Exclusion Criteria 
-  History of anaphylaxis to egg resulting in hypotension, neurological 
compromise or mechanical ventilation. 
-  Chronic disease (other than asthma, atopic dermatitis, rhinitis) requiring 
therapy (e.g., heart disease, diabetes). 
-  Active eosinophilic gastrointestinal disease in the past 2 years. 
-  Participation in any interventional study for the treatment of food allergy in 
the past 6 months. 
-  Subject is on “build-up phase” of immunotherapy (i.e., has not reached 
maintenance dosing). Subjects tolerating maintenance allergen 
immunotherapy can be enrolled. 
-  Severe asthma (2007 NHLBI Criteria Steps 5 or 6, see Appendix 2). 
-  Mild or moderate (2007 NHLBI Criteria Steps 1-4) asthma with any of the 
following criteria met: 
•  FEV1 < 80% of predicted, or FEV1/FVC < 75%, with or without 
controller medications (only for age 6 or greater and able to do 
spirometry) or 
•  ICS dosing of >500 mcg daily fluticasone (or equivalent inhaled 
corticosteroids based on NHLBI dosing chart) or 
•  1 hospitalization in the past year for asthma or 
•  1 ER visit in the past 6 months for asthma. 
-  Use of steroid medications (IV, IM, or oral) for asthma in the following 
manners: 
•  history of daily oral steroid dosing for >1 month during the past year 
or 
•  burst or steroid course in the past 3 months or 
•  >2 burst oral steroid course in the past year. 
-  A burst of IV, IM or oral steroids of more than 2 days for an indication other 
than asthma in the past 30 days. 
-  Inability to discontinue antihistamines for initial day escalation, skin testing 
or OFC. 
-  Use of omalizumab or other non-traditional forms of allergen 
immunotherapy (e.g., oral or sublingual) or immunomodulator therapy (not 
including corticosteroids) or biologic therapy (e.g., infliximab, rituximab, 
etc.) within the past year. 
-  Use of β-blockers (oral), angiotensin-converting enzyme (ACE) inhibitors, 
angiotensin-receptor blockers (ARB) or calcium channel blockers. 
-  Use of investigational drug within 90 days or plan to use investigational 
drug during the study period. 
-  Pregnancy or lactation. 


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Protocol CoFAR7 
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Treatment Description All eligible subjects will receive the baked egg OFC. Approximately 40 of the 
first subjects who react to baked egg will be treated with Egg OIT. Individuals 
who pass the baked egg OFC will then have an egg OFC. Those subjects who 
have dose limiting symptoms at 1444 mg of egg white protein or less will be 
randomized to Baked Egg or Egg OIT. 
Those randomized to the Baked Egg group will continue on the baked egg 
product through the remainder of the study. 
Subjects assigned to Egg OIT will receive daily oral dosing of egg white solid. 
Ideally, subjects who passed the baked egg OFC will on Day 1 escalate to 25 mg 
egg white solid followed by approximately 32 weeks of escalations on a 2 week 
basis. Those that fail the baked egg challenge and are assigned to Egg OIT will 
escalate to only 12 mg egg white solid on Day 1 as this may represent a more 
sensitive group. 
Therapy details are found in Sections 3 and 6 of the protocol. After 1 year of 
therapy, a 7444 mg egg white protein OFC is performed to test for 
desensitization. After 2 years of therapy, a 7444 mg egg white protein OFC is 
performed to again test for desensitization and in those who pass, an 8-10 week 
egg-free interval occurs followed by a repeat 7444 mg egg white protein OFC to 
test for sustained unresponsiveness. 
All escalation doses occur in a Clinical Research Center or monitored clinic 
setting. 
Study Procedures 
The following procedures will be performed according to the schedules in 
Appendix 1: 
Medical and allergy history (including dietary history) 
Physical examination 
Spirometry 
Peak flow rates 
Pregnancy tests 
Plasma analysis for IgE to egg (UniCAPTM) 
Whole blood for plasma studies and T cell studies 
Oral food challenge to egg 
Baked egg oral food challenge 
Prick skin test 
Study product administration 
Daily consumption of baked egg 
                       OR 
Initial day escalation Oral Immune Therapy (OIT) 
Build up and maintenance OIT 
Long Term Follow-Up Questionnaire 
Study Stopping Rules 
•  Any death related to Baked Egg or Egg OIT dosing. 
•  More than 1 severe anaphylactic reaction resulting in hypotension, 
neurological compromise or mechanical ventilation related to Baked Egg or 
Egg OIT dosing at any stage of the protocol. 
•  More than 3 severe suspected adverse reactions (including EoE). 
•  More than 1 serious suspected adverse reaction occurs (serious and related 
event). 
•  More than 3 subjects who require more than 1 injection of epinephrine for a 
single study product related allergic reaction during therapy. 


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TABLE OF CONTENTS 
1. 
BACKGROUND AND RATIONALE ............................................................................... 14
 
1.1   BACKGROUND 
.................................................................................................................. 14 
1.2   RATIONALE 
................................
................................
......................................................... 20 
1.3   RATIONALE FOR SELECTION OF STUDY POPULATION 
........................................... 22 
1.4   KNOWN AND POTENTIAL RISKS AND BENEFITS TO HUMAN SUBJECTS 
............ 22 
1.4.1  Risks 
................................
................................
................................
....................................... 22 
1.4.2  Benefits 
................................................................................................................................ 23 
2. 
OBJECTIVES 
............................................................................................................. 24 
2.1   PRIMARY AND SECONDARY OBJECTIVES 
................................
.................................. 24 
3. 
STUDY DESIGN 
......................................................................................................... 31 
3.1   PRIMARY EFFICACY OUTCOME MEASURE 
................................................................ 35 
3.2   SECONDARY ENDPOINTS ................................................................................................ 35 
3.3   CRITERIA FOR PREMATURE TERMINATION OF THE STUDY: STOPPING RULES35 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ......................................................... 37
 
4.1   INCLUSION CRITERIA 
................................
................................
....................................... 37 
4.2   EXCLUSION CRITERIA 
.................................................................................................... 37 
4.3   PREMATURE SUBJECT TERMINATION FROM THE STUDY 
...................................... 38 
4.3.1  Criteria 
................................................................................................................................. 38 
4.3.2  Follow-up of Subjects Who Discontinue Treatment Only 
..................................................... 39 
5. 
STUDY MEDICATION ................................................................................................. 40 
5.1   FORMULATION, PACKAGING AND LABELING 
........................................................... 40 
5.2   PREPARATION, ADMINISTRATION AND DOSAGE 
..................................................... 40 
5.3   DRUG ACCOUNTABILITY ................................................................................................ 40 
5.4   BAKED EGG THERAPY 
.................................................................................................... 41 


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5.5   ASSESSMENT OF COMPLIANCE WITH STUDY TREATMENT AND 
MONITORING 
................................
................................
...................................................... 41 
5.6   MODIFICATION OF STUDY TREATMENT 
................................
..................................... 41 
5.7   CONCOMITANT MEDICATIONS 
................................
...................................................... 41 
5.8   PROPHYLACTIC MEDICATIONS 
................................
..................................................... 41 
5.9   RESCUE MEDICATIONS 
................................
................................
.................................... 42 
5.10  PROHIBITED MEDICATIONS 
........................................................................................... 42 
6. 
STUDY PROCEDURES 
................................
................................
................................. 43 
6.1   ENROLLMENT AND RANDOMIZATION ........................................................................ 43 
6.2   SCREENING VISIT 
................................
................................
.............................................. 43 
6.3   BASELINE VISIT ................................................................................................................. 43 
6.4   STUDY TREATMENT VISITS 
................................
............................................................ 44 
6.4.1  Treatment for reactions to Baked Egg Dosing 
................................
....................................... 47 
6.4.2  Treatment for reactions during the Build-Up and Maintenance Phases 
................................. 53 
6.5   ORAL FOOD CHALLENGE DOUBLE-BLIND PLACEBO CONTROLLED 
................... 59 
6.6   EGG OFC 
.............................................................................................................................
 59 
6.7   BAKED EGG OFC 
................................
................................
................................................ 59 
6.8   PRICK SKIN TEST 
................................
................................
............................................... 60 
6.9   VISIT WINDOWS 
................................
................................
................................................. 60 
6.10  STUDY BLINDING PROCEDURES ................................................................................... 60 
7. 
SAFETY MONITORING 
................................
...............................................................
 61 
7.1   FOOD ALLERGY EPISODES 
............................................................................................. 61 
7.2   DEFINITIONS 
................................
................................
....................................................... 61 
7.2.1  Adverse Event (AE) or Medical Event 
.................................................................................. 61 
7.2.2  Serious Events (Serious Adverse Events, Serious Suspected Adverse Reactions or Serious 
Adverse Reactions) 
............................................................................................................... 62 


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7.2.3  Unexpected Adverse Event 
................................
................................
.................................... 62 
7.3   TOXICITY GRADING 
........................................................................................................ 62 
7.3.1  Guidelines for Determining Causality of an Adverse Event 
.................................................. 63 
7.4   ADVERSE EVENTS COLLECTION PROCEDURES 
........................................................ 64 
7.4.1  Recording and Reporting Procedures 
.................................................................................... 64 
7.4.2  SAE Recording and Reporting Procedures ............................................................................ 64 
7.4.2.1 Reporting Criteria 
................................
................................
.................................................. 65 
7.5   SERIOUS ADVERSE EVENT NOTIFICATION 
................................................................ 65 
7.5.1  Notifying the Sponsor ............................................................................................................ 65 
7.5.2  Notifying FDA and the Data and Safety Monitoring Board .................................................. 66 
7.5.3  Reporting SAEs to the DSMB 
.............................................................................................. 66  
7.5.4  Notifying the Institutional Review Board and Ethics Committee 
.......................................... 67 
8. 
MECHANISTIC ASSAYS 
................................
.............................................................. 68 
8.1   PBMC ASSAYS..................................................................................................................... 69 
8.2   BASOPHIL STUDIES 
................................
................................
........................................... 70 
8.3   EGG-SPECIFIC ANTIBODY................................................................................................ 71 
8.4   MICROARRAY 
................................................................................................................... 71 
8.5   TRANSCRIPTIONAL PROFILING OF WHOLE BLOOD 
................................................. 71 
8.6   TRANSCRIPTIONAL PROFILING OF ALLERGEN RE-STIMULATED PBMCS 
.......... 72 
9. 
STATISTICAL CONSIDERATIONS ................................................................... 73 
9.1   STUDY ENDPOINT ASSESSMENT 
................................
................................................... 73 
9.1.1  Primary Endpoint ................................................................................................................... 73 
9.1.2  Secondary Endpoints 
............................................................................................................ 73 
9.2   SUBJECT AND DEMOGRAPHIC DATA 
................................
........................................... 73 
9.2.1  Baseline Characteristics and Demographics .......................................................................... 73 


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9.2.2  Use of Medications 
............................................................................................................... 73 
9.2.3  Study Completion 
................................................................................................................. 73 
9.3   SAMPLE SIZE AND POWER CALCULATIONS 
...............................................................
 73 
9.4   THE EGG OIT ASSIGNMENT GROUP WHO FAILED THE INITIAL BAKED EGG 
CHALLENGE 
................................
................................
........................................................ 74 
9.5   MECHANISTIC STUDIES 
................................
................................
................................... 74 
9.6   INTERIM ANALYSES TO ENSURE SUBJECT SAFETY 
................................................. 74 
10. IDENTIFICATION AND ACCESS TO SOURCE DATA .................................................... 75
 
10.1  WEB-BASED DATA COLLECTION AND MANAGEMENT SYSTEM .......................... 75 
10.2  CERTIFICATION IN THE USE OF WEB-BASED DATA ENTRY SYSTEM 
.................. 75 
10.3  DATA MANAGEMENT 
................................
................................
....................................... 75 
10.4  ACCESS TO DATA .............................................................................................................. 75 
11. QUALITY CONTROL AND QUALITY ASSURANCE 
...................................................... 76
 
11.1  STATEMENT OF COMPLIANCE 
................................
....................................................... 76 
11.2  INFORMED CONSENT/ASSENT........................................................................................ 76 
11.3  PRIVACY AND CONFIDENTIALITY 
............................................................................... 76 
12. RESOURCE SHARING 
................................
................................
................................. 77 
13. PROTOCOL DEVIATIONS ........................................................................................... 78 
13.1  MAJOR PROTOCOL DEVIATION (PROTOCOL VIOLATION) 
...................................... 78 
13.2  NON-MAJOR PROTOCOL DEVIATION ........................................................................... 78 
13.3  REPORTING AND MANAGING PROTOCOL DEVIATIONS 
.......................................... 78 
Appendix 1.A.  Schedule of Events – Egg OIT Subjects 
...................................................................... 79 
Appendix 1.B.  Schedule of Events – Baked Egg Subjects 
................................................................... 81 
Appendix 1.C.  Subject Central Laboratory Assessments ................................................................... 83 
Appendix 1.D.  Egg Sustained Unresponsiveness Long Term Follow-up 
........................................... 83 
Appendix 2.  Evaluation of Asthma ..................................................................................................... 84 


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Appendix 3.  Anaphylaxis Staging System 
................................................................................. 85 
Appendix 4.  Allergic Reaction Toxicity Grading 
.................................................................... 86 
Appendix 5.  References ...................................................................................................................... 87 
 


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Glossary of Abbreviations 
 
ACE 
Angiotensin-converting enzyme inhibitors 
AE 
Adverse Event 
Ag 
Antigen 
ARB 
Angiotensin-receptor blockers 
CoFAR 
Consortium of Food Allergy Research 
CFR 
US Code of Federal Regulations 
CFSE 
Carboxyfluorescein Succinimidyl Ester 
CRC 
Clinical Research Center 
CRF 
Case Report Form 
CTC 
Common Toxicity Criteria 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DBPCFCs = OFC 
Double-Blind, Placebo-Controlled Food Challenges – Oral Food 
Challenge 
DCI, DC2 
Dendritic Cell subset 1 & 2 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EW 
Egg White 
FcεRI 
High affinity receptor of IgE 
FDA 
US Food and Drug Administration 
cGCP 
Current Good Clinical Practice 
HRQL 
Health Related Quality of Life 
ICH 
International Conference on Harmonisation 
IFNg 
Interferon Gamma 
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IL 
Interleukin 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
kUA/L 
Kilounits of Antibody per Liter 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIAID 
National Institute of Allergy and Infectious Diseases 
OFC = DBPCFC 
Oral Food Challenge – Double-Blind Placebo Controlled Food 
Challenge  
OIT 
Oral Immuno Therapy 
OVA 
Ovalbumin 
PBMC 
Peripheral Blood Mononuclear Cells 


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PI 
Principal Investigator 
PST 
Prick Skin Tests 
SACCC 
Statistical and Clinical Coordinating Center  
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SI 
Stimulation Index 
SUSAR 
Suspected Serious Adverse Reaction 
Th1 
T Helper 1 
Th2 
T Helper 2 
TLR 
Toll-like Receptor 
Tr1 
T Regulatory 1 
Tregs 
Regulatory T cells 
WHO 
World Health Organization 
 


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1.   Background and Rationale 
1.1  Background 
Food allergy affects up to 3.7% of the overall U.S. population and 6-8% of young children.1 
Based upon recent studies, an estimated 11 million Americans have food allergy with a 
significant impact on morbidity, mortality and quality of life.
2,3 Clinical reactions to egg, milk 
and peanuts account for 80% of the food allergic reactions in children in the United States.1 Egg 
allergy has an estimated cumulative prevalence of 2.6% by age 2.5 years.4 Young children can 
have allergic reactions to egg ranging from mild urticaria to systemic anaphylaxis. The current 
therapy for children with egg allergy is to place the child on an egg-free diet1 until the allergy is 
outgrown. Because egg white protein is included in a significant number of processed foods, it is 
difficult to avoid all egg proteins totally. While a whole egg contains 6000-7000 mg of protein, 
accidental ingestions leading to significant allergic reactions to egg can occur with a bite of a 
cookie (~70 mg of egg protein) or of a cake (~55 mg of egg protein). 
Food elimination diets often are complicated by the difficulty of interpreting labels correctly by 
subjects and their caregivers
5 and by the presence of undeclared or hidden allergens in 
commercially prepared foods.6,7 As such these avoidance diets are often problematic and affect 
the health-related quality of life (HRQL) of subjects and their families.
2,8,9 Previous studies have 
found significantly reduced HRQL in food allergic subjects and their families. 
2,8,9 Cohen et al., 
demonstrated a significant negative impact on several family and social activities that involve 
food, clearly indicating that the effects of food allergy extend beyond typical health-related 
outcomes such as episodes or severity of allergic reactions per year.8 A key reason for the 
impact of food allergy on HRQL is the potential for sudden and life-threatening reactions. 
It is to be expected that up to 50% of subjects with food allergies will have a reaction to 
accidental exposure over a 2 year time period.10 In a recent study from the Consortium of Food 
Allergy Research, children followed in a longitudinal study for a median of 35.5 months (range 
0-48.4) months showed an annualized reaction rate of 0.81/year.11 Further complicating matters 
is that there are no biomarkers to identify subjects at risk of a severe allergic reaction. In general, 
there is not a specific mechanism to predict the severity of a reaction as a child gets older.
12 At 
the present time, the standard of care for food allergy includes strict avoidance of food allergens 
and ready access to self-injectable epinephrine.13 
     Allergen immunotherapy 
Subjects who have allergic diseases such as asthma and allergic rhinitis can choose active forms 
of treatment for their disease either through medications or allergen immunotherapy. Allergen 
injection immunotherapy is highly effective in carefully selected subjects with IgE-mediated 
respiratory disease and insect sting allergy, and represents the only routinely administered 
antigen-specific immunomodulatory treatment given for immunologic disease of any kind. In 
children, immunotherapy has been shown to prevent onset of new sensitization14 and to reduce 
progression of rhinitis to physician-diagnosed asthma.15 Traditional allergen injection 
immunotherapy has not been shown to be effective for the treatment of food allergy because of 
the significant side effects due to systemic allergic effects.
16,17 
Novel immunotherapeutic strategies designed to alter the immune system’s response to food 
allergens are currently under examination as potential treatment modalities for food allergy. 
These include cytokine-modulated immunotherapy, immunostimulatory sequence-conjugated 


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protein-modulated immunotherapy, plasmid DNA immunotherapy, allergen-peptide 
immunotherapy and “engineered” (mutated) allergen protein immunotherapy.
18,19 All of these 
approaches strive to elicit a decreased Th
2-type response or tolerance by the immune system in 
response to a specific food allergen. Most of these studies are currently limited to animal 
models.20,21,22,23 While studies with the humanized, monoclonal anti-IgE antibody in peanut 
allergic subjects showed promise for partial protection from severe reactions, these studies have 
been discontinued.24,25 Each of these promising therapies is several years from use in clinical 
medicine. Ultimately, specific therapy that will result in long-lasting tolerance to the food is 
needed for egg allergy as well as for other food allergies. 
     Tolerance vs. desensitization 
Allergen immunotherapy involves administration of allergen extracts to achieve clinical 
tolerance to specific allergens causing symptoms.
26 
Tolerance to an allergen refers to the relatively long-lasting effects of immunotherapy, 
presumably due to effects on T cell responsiveness, that persist even after the treatment in this 
case allergen is discontinued (although tolerance may not always be permanent). With food OIT 
therapy, the goal is to develop the ability to consume the allergen after a period of time off 
therapy without allergic symptoms as tested with an OFC (sustained unresponsiveness). 
Whether this represents long lasting immune tolerance is unknown, but clinically this normalizes 
the subjects eating habits relative to the treated allergen. 
Desensitization refers to a state, typically induced by short-term exposure to allergen, in which 
subjects are transiently non-reactive to allergen. The desensitized state is presumably due to 
alteration in the releasibility of mast cells and basophils and is rapidly reversible upon 
discontinuation of allergen exposure. 
Allergen desensitization is clinically distinguishable from tolerance only by the rapid 
reversibility of the desensitized state when the allergen is discontinued, compared to the 
persistence of the tolerant state when the allergen is discontinued. It has been postulated that 
desensitization is mediated primarily by reduced reactivity or non-reactivity of effector cells 
secondary to down-regulation of activation pathways,
27 mainly mast cells and basophils (see 
“Allergen desensitization and basophils,” page 19); the role of T cells in this phenomenon is 
unknown. It is believed that desensitization may occur early in the course of allergen 
immunotherapy, and that prolonged administration of allergen may induce additional effects on 
immune and inflammatory cells, and may induce tolerance. The length of time to reach a 
tolerized state varies with the specific allergen used and the individual subject. 
Non-injection routes of immunotherapy have shown promise as viable alternatives to the 
injection route in the treatment of asthma and allergic rhinitis.
28,29,30,31 Some work recently has 
been conducted using oral and sublingual administration of allergens for allergic disease.31,32 
Immunotherapy and food allergy 
The use of immunotherapy in food allergy was initially suggested to be successful by case 
reports when immunotherapy was first used at the beginning of the last century.
33 However, 
subsequent studies have brought the utility and safety of immunotherapy in the treatment of food 
allergy into question. Nelson and colleagues evaluated injection immunotherapy in peanut-
allergic subjects. While the subjects could tolerate increased amounts of ingested peanut during 


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immunotherapy, the protocol could not be recommended for general use due to an unacceptably 
high rate of adverse reactions during the initial day escalation and maintenance protocols.17,34 
Since standard injection immunotherapy for food allergy is not a safe treatment, several groups 
have studied the effect of oral immunotherapy (OIT) in food allergy. Using a standardized oral 
immunotherapy protocol for treatment of various food allergies, Patriarca et al., reported that 
83% of food-allergic subjects completing the protocol could subsequently tolerate the food to 
which they were previously allergic.35 The most common food allergy in their cohort was milk, 
followed by egg and fish. In comparison to age-matched food allergic controls, subjects 
receiving OIT demonstrated a significant decrease in food specific IgE and an increase in 
specific IgG
4.
35 Meglio and colleagues employed an OIT protocol in children with proven IgE-
mediated sensitivity to milk in which they were able to fully desensitize 15 of 21 children in 6 
months with partial success in an additional 3 children. The authors stress the importance of the 
partial outcome in that it dramatically reduced the risk of severe reactions after accidental or 
unnoticed introduction of low quantities of cow’s milk.36 Both of these protocols began with a 
single daily dose of allergen ingested orally, which was then increased either daily or weekly 
until the desired final dose was reached. The failure of some subjects to tolerate the advancing 
schedule may have resulted from inadequate initial desensitization results. 
A proof of concept study, conducted in egg allergic subjects 1-16 years of age with egg specific 
IgE > 7 kU/L and 2 kU/L for children > 2 years of age, provided egg OIT in an open label 
fashion. The study product was provided with an initial modified rush day consisting of multiple 
doses followed by a build up period to establish a dose of egg protein of 300 mg per day. The 
300 mg dose was maintained for 24 months at which time an oral food challenge to egg was 
conducted. Seven subjects completed the protocol. All subjects tolerated more egg protein than 
at study onset and 2 subject’s demonstrated oral tolerance. Three subjects tolerated known or 
possible accidental exposures to egg. The OIT was well tolerated with mild allergic reactions in 
general and no subject required epinephrine for treatment. This pilot study supports the proof of 
concept that OIT can be used as therapy for food allergy.37 
In the most recent egg white solid study, CoFAR3, A Randomized, Double-Blind, Placebo-
Controlled, Multicenter Trial of Egg Oral Immunotherapy in Children, the primary objective was 
to determine whether daily oral administration of egg white solid escalated to a maximum of 
2000 mg/day in egg allergic children can induce sustained unresponsiveness as measured by the 
percentage of subjects who can tolerate 10,000 mg of egg white solid during OFC (at 
approximately 2 years of therapy and after stopping OIT for 4-6 weeks). The secondary 
endpoints included a planned data analysis to evaluate safety of OIT and clinical desensitization 
at both 10 and 22 months of therapy. 
Subjects were ages 5 to 18 years with a convincing clinical history of egg allergy and a serum 
IgE [ImmunoCAP
TM] to egg of >5 kU
A/L for those ≥ 6 years old, or ≥12 kU
A/L for those 5 years 
old. Inclusion criteria were selected to enroll subjects with persistent egg allergy on the basis of 
clinical history and egg IgE levels predictive of clinical allergy. A convincing clinical history 
was defined as developing allergic symptoms within minutes to 2 hours of ingesting egg. 
Individuals with a history of severe anaphylaxis (previous hypotensive episode) to egg were 
excluded. 


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Egg-allergic children (5-18 years) received daily OIT with egg white (n=40) or placebo (n=15). 
Initial escalation, build-up, and maintenance (2000 mg) phases were followed by an oral food 
challenge (OFC) to egg white at 10, 22, and 24 months. Immune mechanisms were evaluated. 
Results: 55 subjects enrolled; 6/40 (15%) egg OIT and 2/15 (13.3%) placebo subjects withdrew 
before 24 months. After 10 months of therapy, 0/15 (0%) placebo and 22/40 (55%) egg OIT 
subjects were desensitized; after 22 months, 30/40 (75%) were desensitized. Egg OIT was then 
stopped for 4-6 weeks and subjects underwent another OFC; 11/40 (27.5%) egg OIT subjects 
passed this OFC achieved sustained unresponsiveness. Symptoms during year 1 of dosing were 
mild-moderate; 75% of 11,860 egg doses and 96% of 4018 placebo doses were symptom-free. 
Egg OIT treatment led to the following mechanistic changes: basophil activation declined from 
baseline to 22 months (p<0.001); prick skin test size declined (p=0.02); egg-specific IgG4 
increased (p<0.001); egg-specific IgE declined (N.S.). Among egg OIT subjects, smaller PST 
size at 22 months was correlated with desensitization (p=0.009) and sustained unresponsiveness 
(p=0.005), as was change from baseline PST to the PST performed at 22 months (p=0.01). 
Conclusions: These results establish that egg OIT can induce desensitization in most patients and 
sustained unresponsiveness in some. Reductions in basophil and mast cell activation and 
increases in IgG4 antibody indicate effective immunomodulation and may predict desensitization 
and sustained unresponsiveness.38 
     Immunotherapy with heat-denatured (baked) egg protein 
Several studies have demonstrated that children with transient egg and milk allergy produce IgE 
antibodies directed primarily against conformational-IgE-binding epitopes that are destroyed 
during extensive heating or food processing.39,40 Based on these observations, it was 
hypothesized that children with transient milk and egg allergy, which comprises up to 80% of 
milk and egg allergic children, would tolerate baked products containing milk and egg. Two 
clinical trials investigated the tolerance of extensively heated (baked into other products) milk 
and egg in children with milk and egg allergy.41,42 In both studies, approximately 80% of 
children tolerated extensively heated (baked) milk and egg products during an initial physician-
supervised oral challenge. A recently published study suggested that the addition of baked-milk 
to the diet of milk-allergic children tolerating such foods appears to accelerate development of 
unheated-milk tolerance compared to strict avoidance.
43 Specifically, it was found that 60% of 
65 baked-milk tolerant children who incorporated baked-milk products into their diets became 
tolerant to regular unheated-milk over a median of 3 years. In addition, these children were 16 
times more likely than the comparison group to develop tolerance to unheated milk (P<0.001). 
Median casein-specific IgG4 levels increased significantly (P<0.001); median milk-specific IgE 
values did not change significantly, and milk-induced basophil activation decreased significantly 
in children ingesting baked-milk product and developing tolerance, similar to what has been 
reported in OIT. In egg-allergic children who tolerated baked-egg products, children 
incorporating baked-egg products into their diets were even more likely to develop tolerance to 
regular uncooked egg (Dietary Baked-egg Accelerates Resolution of Egg Allergy in Children, 
Leonard SA et al.; manuscript accepted for publication). The addition of dietary baked-milk or 
baked-egg was shown to be safe, convenient, and well-accepted by patients. These studies 
suggest that the addition of heat-denatured milk or egg into the diets of allergic children who 
tolerate these baked products may serve as a simple and safer form of immunotherapy. 
 


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     Allergen immunotherapy mechanisms 
Much of the initial research into allergen immunotherapy mechanisms examined the circulating 
antibody responses but more recently, the focus has shifted to allergen-specific T-cell responses. 
Factors that determine the evolution of Th1 responses, Th2 responses, or both include the route 
and dose of antigen and the nature of the antigen-presenting cell. For example, high doses of 
allergen might preferentially favor the induction of Th1-type responses.
44 Antigen-presenting 
cell subsets may direct the development of Th1 and Th2 responses. Additionally, DC1 and DC2 
dendritic cell subsets have been implicated in the development of Th1 and Th2 responses, 
respectively.
45 DC2-type dendritic cells have been identified in atopic subjects,
46 and their ability 
to drive Th2 responses appears to relate to low levels of IL-12 expression. In allergen 
immunotherapy it can be shown that there are increases in peripheral IL-10 production, serum 
allergen-specific IgG4 and IgG-dependent serum-inhibitory activity for allergen-IgE binding to 
B cells after treatment. 
     T regulatory cells 
The description of T regulatory cells (Tregs) as T cells that prevent development of autoimmune 
disease led to considerable interest in whether these Tregs also were normally involved in 
prevention of sensitization to allergens and whether it might be possible to manipulate Tregs for 
the therapy of allergic disease. Whether Tregs normally prevent atopic sensitization and how this 
regulatory process becomes defective or is bypassed in individuals developing allergic disease 
are areas of active research. The potential for manipulation of Tregs for therapeutic purposes is 
clearly attractive for many disease types. Traditional allergen-injection immunotherapy has been 
used for control of allergic disease for many years and appears to act through modulation of the 
Th2 response to the allergen, either by immune deviation of allergen-specific Th2 responses in 
favor of Th1 responses and/or through the induction of Tregs. 
There is a thymus-derived CD25+
 “natural” regulatory population and an inducible, antigen-
specific population that becomes CD25+ both of which express FoxP3, secrete IL-10 and have 
suppressive function in autoimmunity. Recent evidence of Tregs involvement in allergy was 
demonstrated by the induction of IL-10+ T cells during venom, dust mite, birch and grass 
immunotherapy
47,48,49,50 and the suppression of proliferation in milk-tolerant but not milk-
allergic subjects by a CD25+ population.51 Individuals who lack CD4+CD25+ T regulatory cells 
due to a mutation in their FoxP3 gene, which is needed for T regulatory cell development, 
develop severe atopic dermatitis, elevated serum IgE levels, eosinophilia and interestingly, food 
allergies.
49 Further understanding of the maturation of regulatory responses will be required if 
treatment and/or preventive vaccination strategies are to be developed for food-allergic disease. 


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     Humoral response to food allergens 
The determination of humoral immune responses, including the measurement of epitope-specific 
antibodies to allergens, and the immunoglobulin isotypes involved in the responses, appears to 
provide insight into mechanisms of immune regulation. It has recently been shown that increased 
IgE epitope-specific diversity may correlate with the severity of clinical reactions and the ability 
to induce allergen-specific degranulation in vitro. It has been demonstrated that qualitative 
differences in epitope recognition patterns correspond to differences in clinical phenotype for 
milk,39,51 egg, and peanut allergies.52,53 Individuals who develop tolerance early recognize fewer 
IgE epitopes than subjects with persistent clinical reactivity. This observation is consistent with 
the hypothesis that epitope or determinant spreading is a marker for the breakdown of tolerance 
as is seen in studies of autoimmunity.54,55 
Isotype class switching also reflects immune regulation. Increased levels of specific IgG
4 with or 
without decreased IgE has been associated with successful venom immunotherapy,56,57 lower 
levels of atopy in the presence of parasite infection,
58 transient rather than persistent milk 
allergy
54 and the apparent protective effect of high levels of cat allergen exposure.59,60 It has 
been demonstrated in vitro that IL-10 promotes IgG
4 class switching over IgE, although both are 
driven by IL-4.61 In the case of venom immunotherapy and natural high dose venom exposure 
(among beekeepers), IL-10-secreting regulatory T cells have been identified. We will monitor 
allergen-specific and epitope-specific IgG
4 to determine whether they provide a relatively non-
invasive biomarker to follow the natural course of sustained unresponsiveness development to 
eggs and the effects of OIT on the immune response. 
     Allergen desensitization and basophils 
In IgE-sensitized individuals, basophils represent the largest population of antigen-specific cells 
in the circulation. In addition, because they can be stimulated ex vivo, they provide the potential 
of measuring an IgE-dependent biological response from cells that were, until shortly before the 
assay, subject to the patient’s milieu. Basophils are also important effector cells in their own 
right and are known to migrate rapidly into sites of inflammation where they can release a wide 
variety of chemokines, cytokines and other inflammatory mediators.62 They are likely to be 
responsible for the majority of early local IL-4 and IL-13 production,
63 which may have 
important implications for the adaptive immune response.
63 
IgE-mediated hypersensitivity responses are known to be down-regulated during drug 
desensitization,64,65 and it has been shown in vitro that chronic FcεRI signalling induces a down 
regulation of Syk-dependent signal transduction.
27,66 It also has been reported that patients with 
chronic allergen exposure, for example food allergic children who are regularly consuming the 
offending antigen, may lack clinical signs and symptoms of an immediate hypersensitivity 
response yet at the same time have activated basophils undergoing piecemeal degranulation and 
cytokine production.67,68,69,70 Monitoring basophil activation status during therapy, both at 
baseline and after in vitro stimulation by IgE-dependent and independent pathways, will reveal 
whether these cells are chronically activated by OIT in some or all patients, whether acute 
desensitization is antigen or pathway specific and whether long-term tolerance is associated with 
a change in either baseline or antigen-induced basophil activation. 


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1.2  Rationale 
Food allergy is believed to result from a failure to develop or a breakdown of normal oral 
tolerance induction.
71 There is limited published information regarding active treatment for food 
allergy. While traditionally allergen injection immunotherapy has proven unsafe in food allergy, 
17,34 some investigators have reported apparent success in using the oral route for administration 
of immunotherapy in food allergy.35,36 Even if this therapy does not alter the natural history of 
food allergy, it may offer protection from potentially life-threatening reactions following 
accidental allergen exposure. Egg OIT and Baked Egg therapy are 2 distinct approaches to 
treating egg allergic individuals and a direct comparison of these 2 modalities will further 
advance the field both clinically and mechanistically. Clinically, the acceptability of the different 
treatment modalities within the same study and the ultimate differences in treatment successes 
will be assessed. Mechanistically, the study will compare the 2 active treatments and immune 
response parameters associated with each treatment arm and with those who become tolerant vs. 
those that do not. The primary objectives in this investigation are to study the clinical effects, as 
well as the safety and immunologic effects, of a Baked Egg vs. Egg OIT protocol. The long-term 
goal is to compare the use of Baked Egg vs. Egg OIT to induce sustained unresponsiveness to 
egg that will be sustained once the treatment protocol is completed. The short-term goal of the 
protocol is to induce a desensitized state to egg early in the course of Baked Egg/Egg OIT 
treatment that will protect subjects from allergic reactions following accidental egg ingestions. 
This study will seek to expand the knowledge already available regarding immunologic 
mechanisms about egg allergy and immunotherapy by addressing gaps in the current information 
where more exploration is warranted. Currently what is known regarding food allergy and other 
allergic diseases is that they are characterized by elevated allergen-specific IgE. IgE-mediated 
diseases are associated with a Th2-like T cell response characterized by secretion of high levels 
of IL-4, IL-5, IL-10, and IL-13 and low levels of IFN-γ. In particular, the induction and 
suppression of several Th2 and Th1 genes, respectively, is coordinated by the transcription factor 
GATA-3
72 while IFN-γ expression and Th1 differentiation is induced by the transcription factor, 
T-bet.73 The characterization of Th1 or Th2 dominance of immunologically mediated disease has 
taken advantage of the reciprocal and stable expression of these markers in mature, differentiated 
Th cells. 
There is evidence that egg allergy is characterized by an egg-specific Th2 T cell response, but 
the evolution of T cell immunity concerning food allergy or egg allergy specifically over the 
development of tolerance is not well understood. 
Another important immune mechanism potentially involved with the development of egg allergy 
includes modulation of regulatory T cells. Several regulatory T cell subsets have been identified 
including both thymus-derived ‘native’ as well as antigen-specific, adaptive Tregs, both of which 
have recently been associated with expression of the transcription factor, FoxP3.74 Evidence that 
this subset of cells may be important in food allergy comes from a study by Karlsson, which 
demonstrated the presence of a regulatory population among CD25+ T-cells in milk allergic 
subjects who had become tolerant to milk and was absent in those subjects with persistent milk 
allergy.
48 
 
 


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Food-specific IgE generally decreases in concentration over time in individuals who are in the 
process of “outgrowing” the specific food allergy.75 Aside from the degree of response (i.e., 
concentration of allergen-specific IgE antibodies), recent studies indicate that the specific profile 
of binding, with respect to the epitopes to which the IgE antibodies are directed, may also reflect 
clinical features of the allergy. For example, studies evaluating epitope binding patterns to 
sequential epitopes of major cow’s milk proteins, using synthesized overlapping decapeptides 
offset by 2 amino acids, revealed particular epitopes that are commonly targeted.76,77,78 
Moreover, IgE binding to particular epitopes of these milk proteins is associated with persistent 
milk allergy and can be determined before the child is at an age when resolution or persistence of 
the allergy would typically be known (e.g., at age 3 years rather than ages over 5 or 6 years). One 
hypothesis as to why certain epitopes are associated with persistence of allergy and others with 
transient allergy is that the ones associated with permanent allergy are comprised of sequential 
amino acids on the native protein, which remain stable despite denaturizing elements (such as 
cooking and digestion). Conversely, IgE antibodies directed to epitopes that represent portions of 
conformational structures that are more prone to denaturizing elements may be associated with 
transient allergy. 
Peanut OIT studies conducted at Duke University and Arkansas Children’s Hospital support the 
concept that sustained unresponsiveness can be achieved by a long period of OIT. In these 
studies, 9 of the original 29 subjects reached the 2.5 year point in the study. The study was 
designed where subjects who were on OIT longer than 2.5 years and who had a peanut IgE less 
than 2 kU
A/L, would have a food challenge while on therapy, then if they passed the challenge, 
they were taken off the OIT. One month later, they would have a food challenge off-therapy. If 
they passed this challenge, they would introduce peanuts into their diet. For the 9 subjects, 6 of 
them had a peanut IgE < 2 kU
A/L and followed the above protocol. All 6 have passed both 
challenges and have peanuts in their diet. Beyond the 2 year time frame, the peanut IgE 
continues to decline in all subjects (personal communication Drs. Burks and Jones).
37 Two-thirds 
of subjects developed sustained unresponsiveness after 2.5 years on therapy. Additional studies 
with larger cohorts and longer follow-up will be required to characterize the development of 
sustained unresponsiveness or tolerance with active OIT over time. 
The current protocol is based on the concept that Baked Egg and Egg OIT for children who have 
food allergy is a practical and safe method of active treatment. The study is designed to compare 
2 different treatment forms of immunotherapy that have already been shown to induce sustained 
unresponsiveness in egg allergic children. This is a comparative protocol to assess best practice, 
not determine whether one or the other is better than placebo, which has already been 
established. 
The overall goals of this study are to show that sustained unresponsiveness to specific food 
allergens can be induced by either OIT or baked egg administration with the Egg OIT group 
achieving a higher sustained unresponsiveness rate than the Baked Egg group at the 2 year time 
point. Also, children can be protected from adverse reactions due to accidental food ingestion 
(desensitized). In this prospective, multi-center interventional study, we will select subjects (3-16 
years of age) who have egg allergy for a randomized controlled trial of Baked Egg vs. Egg OIT. 
The optimal dose for Baked Egg is not known but a minimum daily dose of approximately 2 gm 
of baked egg protein is proposed in the study and will be similar to the 2500 mg egg OIT dose. 
Additionally, approximately the first 40 subjects who fail the initial baked egg challenge will be 
started on egg white solid OIT therapy and will become the Egg OIT assignment group. These 


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subjects would otherwise not be eligible to participate and would be followed on an egg 
restricted diet per standard of care. This protocol will allow a novel opportunity for active 
treatment of this subset of subjects to evaluate if they can be successfully dosed with OIT 
therapy. This subset may represent a different phenotype of egg allergic subjects who may or 
may not be more difficult to treat with OIT. This approach provides a unique opportunity to 
perform comparative investigations concerning biological and immunological outcomes. We will 
explore several primary hypotheses that should identify the major immune responses responsible 
for the evolution of egg allergy and thereby provide a rational basis for prediction of persons 
likely to experience resolution of egg allergy and provide a basis for risk-centered immune 
intervention. 
1.3  Rationale for Selection of Study Population 
We will enroll subjects between the ages of 3 through 16 years who have a serum IgE 
[UniCAP
TM] to egg of > 5 kU
A/L [determined by UniCAP
TM within the past 12 months]. 
Egg allergy will be confirmed with both a baked egg double-blind placebo controlled challenge 
(baked egg challenge) and an initial double-blind placebo controlled egg OFC. Those who react 
to a baked egg challenge (approximately the first 40 subjects) or to a cumulative dose ≤ 1444 mg 
of egg white protein on the initial egg OFC will be eligible for the study. 
Unlike younger children who may “outgrow” their egg allergy, and based on the investigators’ 
collective experience, no more than 10% of subjects fulfilling these criteria are likely to develop 
spontaneous tolerance to egg during the course of the study. 
1.4  Known and Potential Risks and Benefits to Human Subjects 
1.4.1 Risks 
• Precipitating an allergic reaction by administering an allergen to a subject with known 
allergy to that allergen. 
The initial day escalation immunotherapy followed by the build-up phase is developed based on 
the investigators previous experience with Egg OIT and the previous Egg OIT trial conducted at 
these sites. The initial escalation phase is included in an attempt to shorten the rather prolonged 
build-up phase. The likelihood of a subject experiencing allergic symptoms will be lessened by 
the OIT protocol, starting at extremely small amounts of the egg white solid for dosing. The 
CoFAR3 study did not report significant clinical reactions during the build-up phase of 
treatment. The daily OIT egg white solid dosing may cause allergic reactions. Oral food 
challenges are expected to induce an allergic response. The challenges are conducted in a CRC 
or a monitored clinic setting, are done with a gradual dose escalation and are aborted at the first 
sign of an allergic reaction to lessen the risk. To date the investigators have performed more than 
7500 oral food challenges [20% - 25% to egg] without a serious life-threatening anaphylactic 
reaction.
79 (Drs. Sampson, Wood, Burks, and Jones – personal communication). The expected 
rate of a serious life-threatening anaphylactic reaction is <0.1%. 
Other risks include those related to blood drawing and skin testing. Blood drawing may 
aggravate a pre-existing anemic condition, but this risk is negligible since the volume of blood to 
be drawn will be quite small (blood draws will not exceed 50 cc in a day). Additional risks are 
those attendant to any needle puncture, including slight bruising, local infection, or the 
possibility of the subject fainting. Prick skin tests (not intradermal) will be performed by 


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techniques reflecting general standard of care and cause minimal discomfort (the sensation of a 
scratch and a pruritic, transient hive may result). Such tests can induce a systemic allergic 
reaction, but this is exceedingly rare. Spirometry and peak flow may cause coughing and/or 
dizziness. 
1.4.2 Benefits 
The potential benefits for the subject include the possibility of a change in sensitivity to egg and 
diminished allergic reaction following an accidental ingestion of egg, and the possibility of 
favorably altering the natural course of the egg allergy. The subjects on baked egg may not react 
to an exposure of a baked egg product (i.e., cake or cookie) but may still react to a less baked 
product that contains egg. Based on preliminary studies, subjects receiving 2000 mg of egg white 
solid via OIT daily should not experience a reaction to an accidental ingestion of small amounts 
of egg in another food product (i.e., the amount of egg eaten accidentally contaminating another 
food is generally less than 500 mg of egg protein).
80 The potential benefit to the subject and 
family is that this active protocol may result in induction of sustained unresponsiveness to egg 
protein in a subject who may not otherwise “outgrow” his/her allergy by natural progression of 
disease. 


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2.   Objectives 
2.1  Primary and Secondary Objectives 
The primary objective of the protocol is to compare the clinical effects of a Baked Egg therapy 
program and an Egg OIT protocol. The study also will examine a set of immune-focused 
mechanistic studies and the safety of Baked Egg therapy vs. Egg OIT. The long-term goal is to 
use Baked Egg/Egg OIT to induce sustained unresponsiveness to egg once the treatment 
protocol is completed. The short-term goal of the protocol is to induce a desensitized state to egg 
early in the course of treatment that will protect subjects from allergic reactions following 
accidental egg ingestions. 
Our overall hypotheses are based on the probability that therapy will induce immunologic 
changes in the egg-allergic subject that will result in the initial desensitization of the subject and 
then in the longer term, the development of sustained unresponsiveness to egg. 
Primary Objective: 
Determine in baked-egg tolerant, but egg-allergic, children whether daily Baked Egg therapy vs. 
daily oral administration of egg white solid escalated to a maximum of 2500 mg/day, increases 
sustained unresponsiveness as measured by a 7444 mg egg white protein OFC performed 8-10 
weeks after therapy discontinuation by the 2 year time point. 
Rationale: Based on recent studies, an estimated 11 million Americans have food allergy with a 
significant impact on morbidity, mortality and quality of life.2,3 Clinical reactions to egg, milk 
and peanuts, account for about 80% of the food-allergic reactions in children in the United 
States.1 Egg allergy has an estimated cumulative prevalence of 2.6% by age 2.5 years.4 During 
the 8-10 week interval prior to the final 7444 mg egg white protein OFC, subjects will stop their 
maintenance dosing and will remain on an egg elimination diet. The 7444 mg egg white protein 
OFC in combination with immunologic profiling will provide new, important information on 
sustained unresponsiveness induction. The 8-10 week time frame for the sustained 
unresponsiveness OFC is chosen to allow adequate time off of therapy to test for sustained 
unresponsiveness. 
Overview of methods: Since standard injection immunotherapy for food allergy resulted in 
unacceptable adverse reactions, several groups have studied the effect of Baked Egg and OIT for 
the treatment of food allergy. Subjects will undergo Baked Egg therapy or an oral 
immunotherapy protocol with gradually increasing doses of egg white solid consisting of three 
phases – an initial escalation day, build up and maintenance. 
Endpoints and analysis: The primary endpoint of the study will be the development of sustained 
unresponsiveness to a 7444 mg egg white protein OFC followed by open consumption of a 
whole egg, 8-10 weeks after discontinuing 2 years of daily Baked Egg or Egg OIT. OFCs will be 
conducted in a supervised setting and safety parameters will be carefully monitored. 
Individuals off therapy for 8-10 weeks, successfully demonstrating consumption of 7444 mg egg 
white protein OFC without dose-limiting symptoms followed by consuming a whole egg will be 
considered “successes.” All others will be considered “failures” with respect to this endpoint. 
Among all subjects randomized, the number of subjects on each treatment successfully 
demonstrating sustained unresponsiveness will be compared to those failing to tolerate this 
quantity by Chi-square analysis. 


Consortium of Food Allergy Research 
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Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
Expected outcome/potential limitations: The expected outcome is that 40% of Baked Egg vs. 
70% of Egg OIT subjects will tolerate 7444 mg egg white protein OFC, 8-10 weeks after 
discontinuing Egg OIT or Baked Egg products. The primary limitation to the study is the 
possibility that we have over-estimated the number of subjects who will tolerate the therapies or 
subjects do not adhere to dietary restrictions. 
Secondary Objectives: 
1.  Determine the percentage of subjects who can successfully consume without dose limiting 
symptoms at least 4444 mg egg white protein of a 7444 mg egg white protein OFC after the 
initial desensitization phase of approximately 1 year of the study and at 2 years. 
Rationale: Subjects allergic to egg often have accidental allergic reactions to small amounts of 
egg in other foods. Generally, the amount of egg causing these accidental allergic reactions is 
less than 500 mg of egg protein. Previous studies suggest that the continuous administration of a 
food allergen leads to a “desensitized” state in which an allergic subject will be unresponsive to 
the ingestion of a food allergen as long as they continue to ingest a small amount of the food on a 
daily basis.80 Food challenges of egg white solid can be done to determine if accidental 
ingestions of typical amounts of egg could occur without adverse effects. 
Overview of methods: Subjects will undergo the defined therapy programs. At 1 year following 
8 weeks on a stable maintenance dose, the subjects will be challenged with a 7444 mg egg white 
protein OFC. Build up dosing will continue after the 7444 mg egg white protein OFC for 
subjects who did not reach the maximum daily dose. At 2 years an additional 7444 mg egg white 
protein OFC will be performed. To date, the investigators have performed more than 10,000 oral 
food challenges [20% - 25% to egg protein] without a serious life-threatening anaphylactic 
reaction (the anticipated rate of severe anaphylaxis would therefore be <0.1%).79 
Endpoints and analysis: Secondary endpoints of this study include the development of a 
desensitized state as determined from the food challenges while therapy is ongoing. The number 
of subjects on each treatment tolerating at least 4444 mg egg white protein of a 7444 mg egg 
white protein OFC will be compared to those who do not by Chi-square analysis. 
Expected outcome/potential limitations: It is expected that the majority of subjects will tolerate 
at least 4444 mg egg white protein of a 7444 mg egg white protein OFC following 40 to 48 
weeks of therapy. The primary limitations of the study will be ensuring the safe administration of 
the daily Baked Egg and Egg OIT dose to all subjects and the possibility that we have over-
estimated the number of subjects who will be maintained on maintenance treatment. If an 
insufficient number of subjects reach maintenance therapy, we may have insufficient power to 
attain a significant conclusion. 
2.  Determine the incidence of all serious adverse events. 
Rationale: Serious adverse events will serve as a marker of safety for this protocol. As all serious 
adverse events will be collected for all subjects enrolled in this study, comparison of event rates 
and types will be made between the treatment arms. 
Overview of methods: All serious adverse events will be collected through standard adverse 
event reporting. This information will be gathered on specific adverse event case report forms 
and submitted electronically to the Statistical and Clinical Coordinating Center (SACCC). The 
medical monitor will review each individual report. All serious adverse events will be MedDRA 


Consortium of Food Allergy Research 
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Page 26 of 91 
Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
coded for effective comparison of events. All expedited reports in addition to summary reports 
will be presented to the DSMB. 
Endpoints and analysis: Serious adverse event rates and types of events will be compared 
between those receiving Egg OIT and those receiving Baked Egg. 
Expected outcome/potential limitations: Comparing serious adverse event rates will serve as a 
measure of safety in implementing Egg OIT vs. Baked Egg as a therapy for food allergy. This 
comparison may be limited by the small sample size. It may also be limited if serious adverse 
events occur rarely. However, if serious adverse events occur rarely in both arms, it would 
support the safety of the therapy as administered in this protocol and not preclude further clinical 
investigation. 
3.  Characterize unrestricted egg consumption after conclusion of treatment via long term follow-
up 
Rationale: The durability of sustained unresponsiveness following Egg OIT is currently 
unknown. Previous studies in other foods have indicated a return to reactivity without continued 
consumption while results from the prior Egg OIT trial indicate that treatment effect may be 
durable. Following subjects longitudinally to assess diet and frequency of consumption will aid 
in understanding the long term impact of Egg OIT. 
Overview of methods: Subjects will be contacted annually through September 2018 to complete 
a phone questionnaire assessing diet and frequency of consumption. Questionnaires will be 
completed based on time from randomization. 
Endpoints and analysis: The endpoint of interest is unrestricted consumption of egg in the diet. 
Other endpoints including frequency of consumption and any reactions will also be solicited. The 
analysis will be primarily descriptive with rates of unrestricted consumption described by 
treatment group and final study status. Numbers permitting, formal comparisons between 
treatment groups may be performed similar to the primary analysis.  
Expected outcome/potential limitations: The number of subjects consenting to be followed 
longitudinally after two years of treatment may be lower than anticipated. Further, the 
questionnaire is self-report and likely will be subject to recall bias. As the purpose of this 
analysis is primarily descriptive these are considered acceptable limitations. 
Tertiary Objectives - Mechanistic: 
For each of the planned assay points, we will compare treatment differences in the Egg OIT vs. 
Baked Egg treated subjects, and in those who achieve sustained unresponsiveness vs. those who 
fail to develop sustained unresponsiveness. We will assess each with univariate nonparametric 
statistics and where applicable repeated measure methods will be applied with suitable 
transformations as necessary. 
Those assay endpoints with detected treatment differences will be considered Baked Egg or Egg-
OIT affected endpoints. Subsequently, we will evaluate whether immune states, as measured by 
the mechanistic assays, are predictive of the tolerized and/or desensitized states. 
Our hypotheses are based on the probability that Baked Egg therapy and Egg OIT will induce 
immunologic changes in egg-allergic subjects that will result initially in desensitization and 
eventually with prolonged administration, the development of sustained unresponsiveness to egg. 


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Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
Hypothesis 1: The development of clinical sustained unresponsiveness to egg is associated with a 
reduction in allergen-specific Th2 effector cells, an increase in allergen-specific T regulatory 
(Treg) cells, and an induction of allergen-specific T follicular helper (Tfh) cells. 
Antigen-specific CD4+ T cells can be identified by their upregulation of CD154 in response to 
short-term antigen re-stimulation in vitro. We expect that egg immunotherapy leading to 
sustained unresponsiveness will be associated with sustained changes in the adaptive immune 
response to egg. We anticipate that Th2 cells that provide T cell help to B cells in support of IgE 
class-switching will be lost, leading to the eventual decline in allergen-specific IgE. We 
anticipate that egg-specific Tregs will be induced, contributing to the suppression of the Th2 
response. This is based on literature showing that children who have outgrown their milk allergy 
have increased CD4+ CD25
+ cells after milk challenge, and that depletion of these cells enhances 
proliferation of milk-specific effector cells. In addition, we expect that boosting of IgG4 levels in 
response to immunotherapy will be associated with the expansion of egg-specific CD4
+ T cells 
bearing markers of T follicular helper cells. We anticipate that these 3 changes participate in 
development of sustained unresponsiveness and will therefore correlate with clinical outcome. 
PBMCs will be isolated at baseline and timepoints throughout immunotherapy. PBMCs will be 
stimulated for 6 or 18 h with egg antigen, followed by flow cytometric analysis of T cell 
phenotype. Allergen-specific T cells will be identified as CD3
+, CD4
+, CD154
+ cells. Function of 
these antigen-specific T cells will be inferred by their expression of cytokines, chemokine 
receptors, and regulatory markers. For example, Th2 effector cells at baseline would be IL-4 and 
IL-13-positive, and express variable levels of the chemokine receptors CCR4 and CCR6 that 
confer homing specificity to the skin and mucosal sites, respectively. After immunotherapy, we 
hypothesize that we will observe an expansion of antigen-specific CD4+ T cells with a 
phenotype of CD25-high and CD127-low, with potential co-expression of IL-10 and IFN-γ. 
Furthermore, antigen-specific Tfh cells will be identified by expression of the chemokine 
receptor CXCR5, and we hypothesize that we will observe an expansion of this population after 
immunotherapy, potentially co-expressing IL-10 but not Th2 cytokines. We hypothesize that this 
Tfh population would underlie the increase in IgG4 observed in response to immunotherapy. 
Hypothesis 2: The development of the desensitized state to egg is associated with the down-
regulation of basophils. 
We hypothesize that the development of a “desensitized state” in egg-allergic subjects on Baked 
Egg therapy or Egg OIT will be associated with allergen-specific basophil hyporesponsiveness. 
Two clinical observations, suggesting potentially different mechanisms, support this hypothesis. 
The first is that in conditions of ongoing ‘natural’ antigen exposure, such as individuals 
chronically infected with helminths or food-allergic children regularly consuming an offending 
antigen (e.g., milk-allergic infant on milk-based formula), patients do not experience intense 
immediate hypersensitivity symptoms, though there is evidence of chronic low grade basophil 
and/or mast cell activation and ‘spontaneous’ histamine release.
67,68,69 In vivo constitutive 
activation of basophils correlates with CD203c expression measured directly ex vivo.
70 The 
second observation is from drug sensitization studies, which similar to our protocol, achieved 
sustained unresponsiveness by administration of sub-threshold doses of antigen (hapten) 
followed by incremental increases. This has been shown to result in mast cell and basophil 
hyporesponsiveness.64,65 Mechanistically, IgE-dependent down regulation may occur by 
reduction in Syk-dependent signaling, as has been shown in vitro. 


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Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
Whole blood from baseline and each subsequent time point will be divided and stimulated in the 
presence of IL-3 with 3 dilutions of egg white antigen, peanut antigen, anti-IgE, fMLP, IL-3 
alone and media alone. After 30 minutes incubation, cells will be stained for flow cytometry, 
followed by RBCs lysis and fixation. Samples will be immediately shipped to the central 
laboratory for acquisition. Basophils will be identified as CD123
+ CD203c
+ lin
- (CD3, CD14, 
CD19, CD41) events and activation will be assessed by CD203c (ENPP3) and CD63 (LAMP-3), 
which are markers for piecemeal and classical degranulation, respectively. 
The primary analysis of these studies will be the percentage of CD63+ basophils. The percentage 
induced by egg antigen will be compared to IL-3 alone (control cells) at each time point and a 
longitudinal comparison to baseline pre-treatment levels will be made. Comparisons will be 
made using generalized linear models with repeated measures. 
Secondary endpoints will be the change in CD203c expression with comparison of unstimulated 
and IL-3-stimulated cells; IgE and fMLP-induced CD63; and CD203c will be examined as a 
determinant of antigen- and pathway-specific or non-specific basophil suppression. If possible, 
we will also compare the success of Baked Egg therapy and Egg OIT with the degree of 
suppression of egg antigen-induced CD63 up-regulation. 
We expect that there will be a significant decrease in egg antigen-induced CD63 expression on 
basophils. CD63 is a marker of degranulation by virtue of its localization to the basophil granule 
membrane that is fused with the plasma membrane during classical degranulation, resulting in 
the appearance of a population of CD63
+ basophils. The expression of CD63 is not restricted to 
basophils, and previous reports have observed that adherence of platelets (which have high 
expression of CD63) to basophils during activation can lead to disassociation of basophil 
degranulation as measured by histamine release and CD63 expression.81 We will address this as 
well as general concerns of specificity by identifying basophils using two markers (CD123 and 
CD203c) and by gating out cells expressing other markers including CD41, specific to platelets. 
Hypothesis 3: The persistence of egg allergy is associated with an epitope-specific IgE antibody 
profile that is distinct from persons who lose their clinical allergy to egg. 
We hypothesize that the balance of immunoglobulin isotype response and the epitope diversity 
within each isotype (IgE and IgG4 subtypes) is reflective of the antigen-specific immune 
response, and that this may give insight into mechanisms of immediate hypersensitivity reactions 
(e.g., “blocking” antibodies) and mediators of immune tolerance induction (e.g., IL-10 induced 
IgG4 as a marker of a modified Th2 response). 
Several authors have shown a relationship between epitope recognition patterns and/or diversity 
and clinical disease states including natural progression to tolerance and reaction severity.
52,53,82 
This relationship suggests that children with specific epitope recognition patterns, or more 
diverse IgE epitope recognition to egg, are less likely to benefit from Baked Egg therapy or Egg 
OIT. Similarly, baseline or treatment induced IgG4 and IgA responses, including the epitope 
diversity and pattern of that response, may reflect likelihood for sustained unresponsiveness 
induction and the degree of response to Baked Egg therapy or Egg OIT. 
If this is the case, epitope analysis of antibodies from young children may be a valuable 
biomarker to predict the clinical course and response to Baked Egg therapy or Egg OIT. 
Correlation with simultaneous T cell studies may provide more power to determine the most 
effective combination of biomarkers that indicate resolution or persistence of allergy. 


Consortium of Food Allergy Research 
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Page 29 of 91 
Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
Both short-term desensitization and longer-term immunotherapy protocols are known to induce 
both IgE and IgG antibody,83,84 and grass allergen immunotherapy has in fact been shown to 
induce new antibody epitope recognition.
85 
Using synthetic peptide microarray-based immunoassays, we propose to monitor the IgG and 
IgE epitope-binding specificities by using UniCAP to determine IgG4 and IgE. We will monitor 
humoral immune responses to the crude food proteins of the children at each time point in this 
prospective study. The unique opportunity to follow serial samples during the prospective study 
and to track clinical outcomes will allow investigation of several parameters: 
1. We will measure IgE- and IgG4-binding sequential epitopes at baseline and track 
progression over time (both changes in pattern and overall diversity as number of distinct 
epitopes recognized) for ovomucoid and ovalbumin among the treatment groups over the 
course of the study. 
2. We will determine food-specific IgE and IgG4 to egg as the allergy persists or resolves. 
Additionally, we will follow titrated prick skin testing to egg. 
The primary analysis of these studies will be the number of distinct IgG4- and IgE-binding 
epitopes to egg proteins defined by microarray immunoassay at each time point. These will be 
compared longitudinally to baseline in a repeated measures poisson regression model using a 
generalized linear model with poisson link function. 
 
Secondary analysis will evaluate: 
1. The change in egg-specific immunoglobulin isotypes. 
2. Correlation between successful induction of sustained unresponsiveness (primary clinical 
endpoint) and baseline and final IgE and IgG4 epitope diversity. 
3. Correlation between specific epitope recognition patterns (baseline and final as defined 
by hierarchical clustering of microarray data86) and induction of sustained 
unresponsiveness. 
4. Correlation between successful induction of sustained unresponsiveness vs. baseline and 
final specific immunoglobulin isotypes. 
We expect that subjects developing sustained unresponsiveness will develop an increase in the 
number of epitopes bound by IgG4 antibodies compared to epitopes bound by IgE antibodies, 
and that this will be accompanied by a rise in total egg-specific IgG4/IgE ratio. 
Hypothesis 4: Sustained unresponsiveness will be associated with a predictive transcriptional 
signature detectable in whole blood or allergen restimulated PBMCs. Transcriptional profiling 
approaches allow for an unbiased analysis of gene expression, and through pathway analysis 
provides an opportunity to uncover novel and unexpected mechanisms that may contribute to 
immune tolerance. It is a complementary approach to the hypothesis-based studies outlined 
previously, and one that we will pilot herein. We anticipate that whole blood transcriptional 
profiling will reflect antigen-induced reprogramming of the immune response driven by in vivo 
delivery of antigen during OIT. In order to test that hypothesis, we will isolate RNA from whole 
blood obtained at baseline and time-points throughout immunotherapy. Our first objective is to 
determine if we can obtain a transcriptional signature of egg allergy by microarray analysis. We 
will perform a pilot experiment running samples from 3 groups of subjects: Egg-tolerant subjects 
(obtained through CoFAR8), baked egg reactive, and baked egg tolerant. The latter two groups 


Consortium of Food Allergy Research 
CONFIDENTIAL 
Page 30 of 91 
Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
will be tested at baseline and after 1 year of OIT. The first 10 subjects per group will be analyzed 
to determine if a signature is detectable either between clinical groups or pre/post OIT. If piloting 
is successful (if we can detect a transcriptional signature), we will continue with the full study 
using samples obtained from all subjects and all time-points. 
Antigen-specific T and B cells constitute a small proportion of circulating cells and changes in 
these populations may be too subtle to be detected by this approach, although the use of this 
technique in vaccine trials suggests that it is feasible to track antigen-specific immune responses 
without ex vivo stimulation. Therefore we propose a second approach in which PBMCs are 
isolated and re-stimulated with egg allergen in vitro as will be done for the T cell profiling 
studies. After short-term stimulation, RNA will be isolated and transcriptional analysis will be 
done by microarray analysis. As for the whole blood analysis, this will first be piloted on the first 
10 subjects per group at baseline and after 1 year of immunotherapy. 
In addition to microarray analysis, we will pilot RNA sequencing for transcriptional analysis of 
PBMCs. We have chosen to begin with the microarray approach because of the wealth of data 
available from microarray analysis of whole blood or PBMCs from healthy subjects and other 
disease states. However, accurately quantifying the levels of all RNA transcripts and determining 
the structure of each transcript is critical for maximizing the power to elucidate the pathways and 
networks associated with changes in the immune response. RNA sequencing has quickly become 
the preferred technology for transcript profiling because of its high reproducibility, dynamic 
range and richness of data. Microarray expression profiling suffers from 3 limitations: 1) 
profiling is limited to only known genes/splice variants, 2) hybridization artifacts, and 3) 
difficulty in reproducibility. RNA sequencing on NGS/TGS technologies has several advantages: 
1) RNAseq has been estimated to span 5 orders of magnitude, significantly higher than 
microarray platform; 2) Excellent concordance between identical samples has been observed, 
which reduces the need for technical replicates; and 3) Characterization of relative abundance of 
splice variants is possible. 
This transcriptional analysis will be performed in collaboration with investigators at the Institute 
of Genomics and Multiscale Biology at the Icahn School of Medicine at Mount Sinai. 
The Egg OIT assignment group who failed the initial baked egg challenge: 
While the above objectives have been framed in terms of the randomized comparison that is 
central to this study, individuals who comprise the Egg OIT assignment group will have 
endpoints similar to the randomized cases. The assignment group will be compared to the 
randomized arms and evaluated for sustained unresponsiveness, desensitization, safety and 
immune system function. It is anticipated that this group will have less desensitization and 
sustained unresponsiveness success than the randomized Egg OIT subjects. If supported by the 
results, it will be an objective to determine if immune parameter studies can help explain the 
differences. 
In the Assigned OIT Group, the phenotype of antigen-specific T cells will be monitored at 
baseline and throughout immunotherapy using freshly isolated peripheral blood mononuclear 
cells re-stimulated with allergen in vitro, as done with the randomized group. Phenotyping will 
be performed by flow cytometry, and will assess cytokine profile and chemokine receptor 
expression in antigen-responsive CD4
+ T cells. Additional phenotyping will be performed by 
transcriptional analysis of RNA isolated from the allergen-restimulated peripheral blood 
mononuclear cells. 


Consortium of Food Allergy Research 
CONFIDENTIAL 
Page 31 of 91 
Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
3.   Study Design 
To effectively address the Primary and Secondary Objectives of this interventional study, we will 
enroll subjects, age 3 through 16 years, either sex, any race, any ethnicity with a serum IgE 
[UniCAP
TM] to egg of > 5 kU
A/L [determined by UniCAP
TM within the past 12 months]. All 
subjects will have documented consent and assent as is appropriate. Females of childbearing age 
will use appropriate birth control. These subjects will be recruited from 5 sites. All eligible 
subjects will receive the double-blind placebo controlled baked egg OFC. Approximately the 
first 40 individuals who do not pass this initial baked egg food challenge will be assigned to Egg 
OIT. Enrollment in this group will be capped at approximately 40 individuals though those 
consented but not yet challenged when this group reaches 40 will be allowed to proceed and if 
they fail the baked egg challenge will be assigned to the egg OIT assignment group. This may 
result in slightly over 40 cases in this group which is acceptable. Individuals who pass the baked 
egg OFC will then have an initial egg OFC. Those who have dose-limiting symptoms at a 
cumulative dose of < 1444 mg egg white protein will be randomized 1:1 to Baked Egg or Egg 
OIT. Those who successfully consume more than 1444 mg of egg white protein on the OFC will 
not be eligible for the study and will be followed per local standard of care. 
Those assigned or randomized to Egg OIT will escalate the dose of egg white solid to achieve 
the desired maintenance dose of 2500 mg. Those randomized to the Baked Egg group will 
continue on the baked egg product for the remainder of the study. 
Throughout this protocol, the doses of egg white solid for Egg OIT are given in milligrams of 
egg white solid, not egg white protein. It is estimated that 1 mg egg white solid is equivalent to 
approximately 0.70 mg of egg white protein. 
A schematic is presented below: 


Consortium of Food Allergy Research 
CONFIDENTIAL 
Page 32 of 91 
Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
CoFAR7 Schema 
Egg OFC
Fa
i
l Baked-
Egg OFC
Pass 
Baked-egg 
OFC
Pass Egg 
OFC
Fa
i
l Egg OFC
Random
ized
Pass 
OFC
Fa
i
l 
OFC
Stop 
Dos
ing
In
it
ia
l 
Esc
la
lat
ion
Bu
i
ldup
Ma
intenance
Da
i
ly 
Ingest
ion
1 Year Egg 
Desens
it
izat
ion 
OFC
2 year  
Egg 
Desens
it
izat
ion 
OFC
D
iscont
inue 
Dos
ing 
(8-10 weeks)
2 year
Egg OFC
Success
Fa
i
lure
Screen
ing 
Baked Egg 
OFC
Egg 
OIT
Egg 
OIT
In
it
ia
l  
Esc
la
lat
ion
Bu
i
ldup
Ma
intenance
Baked 
Egg
Fa
i
l 
OFC
Not Enro
l
led
Pass 
OFC
Annua
l 
Phone 
Fo
l
low-up 
through 
September 
30 2018
 


Consortium of Food Allergy Research 
CONFIDENTIAL 
Page 33 of 91 
Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
 
For the purposes of this study, clinical details and blood samples will be collected at specified 
intervals. If a subject is removed from therapy because of failing escalation or build-up, a blood 
sample for mechanistic studies will be obtained within approximately 1 week of removal from 
therapy. 
Subjects will have an annual phone follow-up at 1, 2 and 3 years after completing the active 
portion of the study through September 30, 2018. 
The Baked Egg Group 
The Baked Egg group will use approximately 2 gm of baked egg as a daily dose throughout the 
study as described below. 
Baked Egg therapy will consist of a muffin or equivalent (1/3 of egg in serving, approximately 
2 gm). 
Home baked products will have no more than 2 eggs per batch of recipe (yield 6 servings). 
Serving size is indicated by the yield of the recipe. Products will be baked for 25-50 minutes at 
325-425 degrees Fahrenheit. Recipes will be provided. The daily dose can be administered at a 
single sitting or divided throughout the dosing day. Adjustments in the daily dosing may be made 
at the investigators discretion based on symptoms experienced by the subjects in the baked egg 
group. 
Dietary information will be provided to the subject regarding allowed consumption of various 
commercial foods consistent with approximately 2 gm of baked egg per daily dose. Subjects in 
this arm will be encouraged to ingest “safe” commercial products in addition to their daily 2 gm 
intake of baked egg protein. These foods will be recorded on the daily logs. 
The Egg OIT Group 
The Egg OIT treatment consists of 2 groups that may experience different paths for OIT 
treatment. The group that fails the baked egg challenge may be more sensitive to egg dosing, and 
may experience more reactivity and adverse reactions. These subjects will stop at 12 mg egg 
white solid on the initial day escalation and thereby have a slightly slower escalation time course. 
The Egg OIT treatment is comprised of an initial escalation day, an initial build-up phase to last 
a maximum of 44 weeks, and followed by at least 8 weeks of daily therapy at the maximum 
achieved dose (350 mg - 2500 mg egg white solid). 


Consortium of Food Allergy Research 
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Protocol CoFAR7 
Baked Egg/Egg OIT 
Version 6.0 
February 16, 2016 
Dosing Schedule for Egg OIT 
 
Daily Dosing and Delivery Method 
Dose # 
Dose egg 
white 
solid  
Dose 
Method 
Interval 
(weeks)   % Increase 
8      12 mg    Vial      2      
 
9      25 mg    Vial      2      
108% 
10     50 mg    capsule*    2      
100% 
11     75 mg    capsule    2      
50% 
12     100 mg   capsule    2      
33% 
13     150 mg   capsule    2      
50% 
14     225 mg   capsule    2      
50% 
15     260 mg   scoop 0
†    2      
15% 
16     350 mg   scoop 1    2      
35% 
17     450 mg   scoop 2    2      
30% 
18     550 mg   scoop 3    2      
20% 
19     700 mg   scoop 4    2      
25% 
20     830 mg   scoop 5    2      
20% 
21     1100 mg   scoop 6    2      
30% 
22     1320 mg   scoop 7    2      
20% 
23     1720 mg   scoop 8    2      
30% 
24     2130 mg   scoop 9    2      
25% 
25     2500 mg   scoop 10   2      
15% 
* Capsules are opened and contents sprinkled over an age-appropriate 
food. 
†All scoops are approximate weights based on scoop size and leveling. 
                                 
 
 
 
 
 
 
Those subjects who achieved a dose of 2500 mg egg white solid during the initial build-up 
period will continue maintenance therapy for up to 12 months after the 1 year 7444 mg egg white 
protein OFC. Those subjects who achieved less than 2500 mg during the initial buildup phase 
will be escalated from their maintenance dose (pre-1-year 7444 mg egg white protein OFC) up to 
2500 mg, if tolerated, following the same escalation time table from the initial build-up phase. 
No dose escalation will be performed within 1 month of a subject’s planned 2 year 7444 mg egg 
white protein OFC. 
Follow-up OFCs 
At 1 year: 
A 7444 mg egg white protein OFC will be performed at 1 year to identify desensitized 
individuals. 
At 2 years: 
Those subjects still on active treatment (Baked Egg or Egg OIT) will have a 7444 mg egg white 
protein OFC on therapy at 2 years. Those subjects still on active therapy, but escalating doses, 
will discontinue escalation for 1 month prior to their 2 year 7444 mg egg white protein OFC and 
will be maintained on their highest tolerated dose. Those who pass the 2 year egg 7444 mg egg 
white protein OFC on therapy will have a repeat 7444 mg egg white protein OFC after 8-10 
Initial Day Escalation Schedule 
Dose no.       Egg white solid dose (mg)     Cumulative Egg dose (mg)* 
1         0.1 mg             0.1 mg 
2         0.2 mg             0.3 mg 
3         0.4 mg`             0.7 mg 
4         0.8 mg             1.5 mg 
5         1.5 mg             3.0 mg 
6         3.0 mg             6.0 mg 
7         6.0 mg             12  mg 
8         12 mg              24  mg 
9         25 mg              49  mg 
* If no de-escalation 
Frequency standard every 30 min 
 
Subjects at the end of the first day, tolerating less than 3 mg single dose, will be 
considered an initial day escalation desensitization failure. 
The Egg OIT assignment group (that failed the Baked Egg challenge) will only 
escalate to 12 mg maximum on Day 1. 
 
Subjects tolerating only 3, 6 or 12 mg single dose will go home on the greatest 
tolerated dose to be given daily (first dose given in Clinical Research Center under 
observation). All escalations will occur no sooner than 2 weeks and single dose 
increases in the Clinical Research Center from 3 to 6 to 12 to 25 mg will be 
attempted. These doses will be weighed doses in individual vials until the 
maximum 25 mg dose is reached. 
 
All subjects will return on Day 2 and receive their maximum tolerated dose under 
direct observation. 
 
Subjects with moderate symptoms observed on Day 2 will return on Day 3 for the 
next lower dose under observation in the Clinical Research Center or monitored 
clinic setting. 
Doses on Day 2, 3, and 4 must be at least 3 mg or the subject will be considered an 
escalation failure. 


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weeks off therapy to test for sustained unresponsiveness. If they pass this OFC off therapy 
(including open feeding), they will add egg to their diet and will be followed at 3 months by 
phone and at 6 months in clinic to assess their egg diet history and reactivity status to egg. They 
will be contacted annually for additional phone follow-up through September 30, 2018. 
If they fail the 2 year 7444 mg egg white protein OFC on or off therapy, they will stop therapy 
and the study physician will review treatment options. They will also be contacted annually for 
additional phone follow-up through September 30, 2018.   
Mechanistic Laboratory Assessments 
Mechanistic labs are obtained at screening (Visit 00), 3 month (Visit 02), 6 month (Visit 03), 
1 year (Visit 04), 16 months (Visit 05), 20 months (Visit 06), the 2 year visit (Visit 07), and at 
the 2 year sustained unresponsiveness visit (Visit 08), if applicable. 
Study Design Safety Considerations 
The design considers important safety issues: 
• All dose escalations will be supervised in the clinic. 
• The Egg OIT assignment group (that failed the baked egg challenge) will only escalate to 
12 mg egg white solid maximum during the initial escalation on Day 1. 
• OFC can delineate individuals who can ingest egg safely in a supervised setting.
79 
• The relationship of egg-specific IgE to OFC results is unknown in individuals consuming 
baked egg or 350 - 2500 mg of egg white solid daily for up to a year. Thus, after long-
term therapy, an egg OFC will be needed to determine sustained unresponsiveness 
irrespective of their egg-specific IgE level, and this will be performed safely in a 
supervised setting. 
3.1  Primary Efficacy Outcome Measure 
The primary clinical efficacy end-point is the development of sustained unresponsiveness to egg 
consumption at 2 years as assessed with a 7444 mg egg white protein OFC and open feeding, 
8-10 weeks after discontinuing therapy. 
3.2  Secondary Endpoints 
The secondary outcome measures are as follows: 
• The development of desensitization to >4444 mg egg white protein at 1 year and 2 years. 
• Incidence of all serious adverse events during the study. 
• Unrestricted consumption of unbaked egg as reported on the annual long term 
questionnaire 
• Changes in egg-specific IgE and IgG4, changes in PST mean wheal diameters, basophil 
reactivity, CD154+ CD4+ Th2 cells, Tregs, and Tfh cells as described in Section 2.1. 
3.3  Criteria for Premature Termination of the Study: Stopping Rules 
Study enrollment will be suspended pending expedited review of all pertinent data by the NIAID 
DSMB if the following occurs: 
• Any death related to Baked Egg or Egg OIT dosing. 


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• More than 1 severe anaphylactic reaction (see Appendix 3) related to Baked Egg or Egg 
OIT dosing at any stage of the protocol. 
•  More than 3 treatment-related non-anaphylaxis severe adverse events (including EoE). 
• More than 1 serious suspected adverse reaction occurs (serious and related). 
• More than 3 subjects who require more than 1 injection of epinephrine for a single study 
product related allergic reaction during the study therapy. 


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4.   Selection and Withdrawal of Subjects 
4.1  Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for enrollment as study subjects: 
• Age 3 through 16 years with a serum IgE [UniCAP
TM] to egg of > 5 kUA/L [determined 
by UniCAPTM within the past 12 months]. 
• Reacting to the baked egg challenge OFC with dose limiting symptoms (approximately 
40 subjects), OR 
• Reacting on an initial egg OFC with dose limiting symptoms to a cumulative dose of 
1444 mg egg white protein or less after passing the initial baked egg OFC. 
• Written informed consent from subject and/or parent/guardian. 
• Written assent from all subjects as is appropriate. 
• All females of child-bearing age must be using appropriate birth control. 
4.2  Exclusion Criteria 
Subjects who meet any of these criteria are not eligible for enrollment as study subjects: 
• History of anaphylaxis to egg resulting in hypotension, neurological compromise or 
mechanical ventilation. 
• Chronic disease (other than asthma, atopic dermatitis, rhinitis) requiring therapy (e.g., 
heart disease, diabetes). 
• Active eosinophilic gastrointestinal disease in the past 2 years. 
• Participation in any interventional study for the treatment of food allergy in the past 6 
months. 
• Subject is on “build-up phase” of immunotherapy (i.e., has not reached maintenance 
dosing). Subjects tolerating maintenance allergen immunotherapy can be enrolled. 
• Severe asthma (2007 NHLBI Criteria Steps 5 or 6, see Appendix 2). 
• Mild or moderate (2007 NHLBI Criteria Steps 1-4) asthma with any of the following 
criteria met: 
o FEV1 <80% of predicted, or FEV1/FVC <75%, with or without controller 
medications (only for age 6 or greater and able to do spirometry), or 
o ICS dosing of >500 mcg daily fluticasone (or equivalent inhaled corticosteroids 
based on NHLBI dosing chart), or 
o 1 hospitalization in the past year for asthma, or
 
o 1 ER visit in the past 6 months for asthma. 
• Use of steroid medications (IV, IM or oral) for asthma in the following manners: 
o history of daily oral steroid dosing for >1 month during the past year, or 
o burst or steroid course in the past 3 months, or 
o >2 burst oral steroid course in the past year.
 


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•  A burst of IV, IM or oral steroids of more than 2 days for an indication other than asthma 
in the past 30 days. 
•  Inability to discontinue antihistamines for the initial day of escalation, skin testing or 
OFC. 
•  Use of omalizumab or other non-traditional forms of allergen immunotherapy (e.g., oral 
or sublingual) or immunomodulator therapy (not including corticosteroids) or biologic 
therapy (e.g., infliximab, rituximab, etc.) within the past year. 
•  Use of β-blockers (oral), angiotensin-converting enzyme (ACE) inhibitors, angiotensin-
receptor blockers (ARB) or calcium channel blockers. 
• Use of investigational drug within 90 days or plan to use investigational drug during the 
study period. 
• Pregnancy or lactation. 
4.3  Premature Subject Termination from the Study 
4.3.1 Criteria 
No subject initiating therapy in this trial will be replaced. 
Any subject may be prematurely terminated from additional allergen exposures, but maintained 
on longitudinal follow-up for the following reasons: 
• Anaphylaxis resulting in hypotension, neurological compromise or mechanical 
ventilation secondary to Baked Egg or Egg OIT dosing or any egg food challenge. 
Any subject deemed to have severe symptoms and receives aggressive therapy at any time 
should be discontinued from further therapy, including the following: 
• Poor control or persistent activation of secondary atopic disease (e.g., AD, asthma). 
• Started on ARBs, ACE inhibitors, beta-blockers, or other prohibited meds and there are 
no alternative meds available per the prescribing doctor, they will be removed from 
further treatment. 
• Pregnancy. 
• Egg OIT Group subjects: 
o Circumstances (e.g., concurrent illness, such as gastroenteritis) requiring missed 
Egg OIT maintenance dosing of >7 consecutive days (this does not include 
subjects intentionally removed from therapy to administer an OFC off therapy). 
o Non-adherence with home Egg OIT dosing protocol (excessive missed days; i.e., 
>3 consecutive days missed on 3 occasions), would be a safety issue warranting 
discontinuation. 
Any subject may be prematurely terminated from the study if: 
• The subject elects to withdraw consent from all future study activities, including follow-
up. 
• The subject is “lost to follow-up” (i.e., no further follow-up is possible because attempts 
to reestablish contact with the subject have failed). 
• The subject has biopsy documented Eosinophilic Esophagitis (EoE). 


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• The subject dies. 
4.3.2 Follow-up of Subjects Who Discontinue Treatment Only 
Subjects who prematurely discontinue treatment with Baked Egg or Egg OIT will remain in the 
study until normal termination. All willing subjects will be followed for the duration of the study 
to monitor safety and efficacy parameters, and they will be contacted annually by telephone for 
long term follow-up through September 30, 2018. 


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5.   Study Medication 
5.1  Formulation, Packaging and Labeling 
Study drug (commercially available egg white solid) will be centrally packaged, stored and 
distributed by EMINENT Services Corporation. Central manufacturing will consist of weighing 
individual doses of the egg white solid into vials or capsules and providing bulk egg white solid 
for use with scoops. A 37% egg white solid blended product as described in the manufacturing 
section of the IND will be used to provide specified dose levels as outlined in the dosing table in 
Section 3.0. 
Initial day dose escalation will be packaged in individual vials with each dose weighed. Initial 
day escalation kits will have 2 doses of each vial up to 25 mg egg white solid. Individual dose 
level kits will have 21 vials per kit. Kits will be used until a dose of 50 mg egg white solid is 
achieved. Starting at doses of 50 mg, the egg white solid doses will be packaged in pull-apart 
capsules with the appropriate dose in each capsule. One capsule will be used for each day’s dose. 
Capsules will be packaged in bottles of 21. 
Starting at doses of 350 mg egg white solid, bulk powder will be dispensed with a dose-specific 
scoop. Subjects will be instructed to use 1 scoop per day that is leveled across the top of the 
scoop. The bulk product will be in a supply of 500 gm. 
All study product will be packaged at the central manufacturer. Study drug will be shipped by 
the central manufacturer to the site pharmacist for distribution to the site study personnel. The 
site pharmacist will dispense study drug in a manner consistent with the current dose level and 
treatment assignment. 
All study drug will be labeled at the central manufacturer and shipped to the local pharmacy for 
distribution to the study subjects. The product will be labeled with the numbered dose level and 
package number. 
Every attempt to use a single lot of commercially available egg white solid will be made. If a 
new lot is required, and any subject is in an escalation phase of the study, they will have a single 
observed in clinic dose reduction with the new lot. Escalation to their previous dose may occur in 
1 week if the subject has the same or fewer symptoms than those occurring with the previous lot. 
5.2  Preparation, Administration and Dosage 
The egg white solid will be provided pre-packaged from the site pharmacy in appropriate doses 
or in bulk with appropriate scoops to deliver the specified dose as outlined in Section 3. The egg 
white solid may be added to apple juice, applesauce, yogurt, pudding or other age-appropriate 
food. The product must be consumed promptly after mixing. If there is a delay in consumption, 
the product will be discarded and a new product dose mixed and consumed. Subjects will be 
given an adequate supply for the interval between scheduled visits with an additional 1 week 
supply to be used in the event of missed or cancelled study visits. Every attempt will be made to 
administer the dose of study drug at the same time of the day, each day. A target of at least 12 
hours will pass between doses. 
5.3  Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator is required 
to maintain adequate records of the disposition of the investigational agent, including the date 


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and quantity of the drug received, to whom the drug was dispensed (subject-by-subject 
accounting) and a detailed accounting of any drug accidentally or deliberately destroyed. 
Records for receipt, storage, use and disposition will be maintained by the study site. A drug-
dispensing log will be kept current for each subject. This log will contain the identification of 
each subject and the date and quantity of drug dispensed. 
All records regarding the disposition of the investigational product will be available for 
inspection by the clinical trial monitor. 
5.4  Baked Egg Therapy 
Baked Egg therapy will be prepared using commercially available food ingredients and prepared 
according to pre-specified recipes, cooking temperatures, and times to administer consistent 
doses of baked egg. 
Baked Egg therapy will consist of a muffin or equivalent (1/3 of egg in serving or approximately 
2 gm of protein). 
Home baked products will have no more than 2 eggs per batch of recipe (yield 6 servings). 
Serving size is indicated by the yield of the recipe. Products will be baked for 25-50 minutes at 
325-425 degrees Fahrenheit. Recipes will be provided. The daily dose can be administered at 1 
sitting or divided throughout the dosing day. 
These methods will be outlined in the manual of procedures and instructions for the subjects and 
their families. 
5.5  Assessment of Compliance with Study Treatment and Monitoring 
Families will document daily dosing and any reaction from at-home dosing by diary logs. 
Central monitoring of compliance will be performed. Families will be provided with 24 hour 
emergency contact information from each site. 
All study medication will be brought back to the clinic with each visit for reconciliation of 
remaining vials, capsules or bulk powder. The bulk powder will be weighed at each clinic visit to 
assess that study product is being used but cannot assess the actual dose delivered on a daily 
basis. 
5.6  Modification of Study Treatment 
As described in the protocol, Egg OIT doses may be adjusted by the study physician if the 
subject is unable to tolerate the scheduled dose increase. 
5.7  Concomitant Medications 
All subjects may continue their usual medications, including those taken for asthma, allergic 
rhinitis and atopic dermatitis, during the study. However, they must be able to discontinue 
antihistamines prior to the initial day of escalation, skin testing and oral food challenges. Regular 
topical steroids use is permitted at the time of skin testing. 
5.8  Prophylactic Medications 
None 


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5.9  Rescue Medications 
Treatment of individual allergic reactions during Baked Egg or Egg OIT therapy should be with 
either an antihistamine and/or epinephrine, along with IV fluids, albuterol and steroids as 
indicated. Subjects and parents are likely to have EpiPens®, but for those who do not, EpiPens® 
or an equivalent device will be provided. Subjects and parents will be trained in proper use and 
will be able to demonstrate proper technique with the EpiPen® or its equivalent. 
5.10 Prohibited Medications 
1. Omalizumab (Xolair) 
2. Systemic corticosteroids of longer than 3 weeks duration at any time throughout the study 
3. β-blockers (oral) 
4. Angiotensin-converting enzyme (ACE) inhibitors 
5. Angiotensin-receptor blockers (ARB) 
6. Calcium channel blockers 
7. Introduction of allergen immunotherapy 
 
 


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6.   Study Procedures 
6.1  Enrollment and Randomization 
Subjects will be recruited over an 18 month period. Subjects will have an initial baked egg 
challenge. Approximately the first 40 subjects reacting on the initial baked egg challenge will 
directly start on Egg OIT. Those who pass the baked egg challenge will be given an initial egg 
OFC. Those unable to successfully consume < 1444 mg of egg white protein will be randomized 
in a 1:1 Baked Egg to Egg OIT ratio. Those able to successfully consume more than 1444 mg of 
egg white protein will not be eligible for the study and will be treated according to local standard 
of care. Randomization will be done via the project data system; the data system will send an 
email notification to the site pharmacist and the clinical coordinating center. If accrual capacity 
is adequate, each of the 5 sites will enter 26 subjects. Entry slots will be reassigned if accrual 
completion would be delayed because of slow accrual at a given site. Because of the requirement 
for the baked egg OFC and egg OFC, the screening and baseline visits will be conducted in more 
than 1 day. 
6.2  Screening Visit 
The screening visits which may occur over several days (Visit 00) will include the following 
procedures: 
• Consent and assent as applicable 
• Diet and allergy questionnaire 
• Physical examination 
• Blood draw for egg-specific IgE measurement 
• Physical examination 
• Prick skin test to egg extract, food and environmental allergens 
• Blood draw for mechanistic studies not to exceed 50 cc in a day (but no more than 5 
cc/kg in 24hrs or 9.5 cc/kg in 8 weeks) 
• Pregnancy test, if applicable 
• Spirometry* 
• Baked egg challenge 
* Spirometry is attempted in all subjects greater than 6 years of age. For subjects age 6-11, if 
valid spirometry results are not successfully obtained, the attempt is documented and peak flow 
measures will be accepted for the entry criteria with results >80% of predicted. For subjects 3 
through 5 years, peak flow rate will be attempted but the results are not required to move forward 
if they are unable to perform reliably. The attempt must be documented. A clinical assessment is 
required. 
6.3  Baseline Visit 
Subjects who meet eligibility criteria will return for a baseline visit (Visit 00A). This visit will 
include the following procedures and will take place over several days: 
• Targeted history and physical examination 
• Pregnancy test, if applicable 


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• Peak Flow Rate (PFR) 
• Egg OFC 
6.4  Study Treatment Visits 
After completion of the baseline assessment, those who failed the baked egg OFC will start Egg 
OIT as described below. Those who pass the baked egg OFC and fail the egg OFC at ≤ 1444 mg 
of egg white protein will be randomized to receive either Baked Egg or Egg OIT. 
Baked Egg Treatment Overview: 
The Baked Egg group will use approximately 2 gm of baked egg protein as a daily dose 
throughout the study as described below. 
Baked Egg therapy will consist of a muffin or equivalent (1/3 of egg in serving, approximately 
2000 mg of protein). 
Home baked products will have no more than 2 eggs per batch of recipe (yield 6 servings). 
Serving size is indicated by the yield of the recipe. Products will be baked for 25-50 minutes at 
325-425 degrees Fahrenheit. Recipes will be provided. The daily dose can be administered at 1 
sitting or divided throughout the dosing day. 
Dietary information will be provided to the subject regarding allowed consumption of 
commercial foods consistent with approximately 2 gm of baked egg protein per daily dose. 
Subjects in this arm will be encouraged to ingest “safe” commercial products in addition to their 
daily 2 gm intake of baked egg protein. These foods will be recorded on the daily logs. 
These subjects will have clinic assessments after 1 month of dosing and at 9 months. They will 
also be assessed at scheduled visits at month 3 (Visit 02) and month 6 (Visit 03) where blood 
will also be drawn. During year 2 they will be seen in clinic at 4 month intervals (Visit 05 and 
06) coupled with the mechanistic blood draws. A history, diet history and physical exam will 
also be performed at these designated visits. These visits are supplemented with monthly calls in 
between the visits to assess dosing and dietary compliance and any dosing symptoms. Subjects 
will also maintain daily logs of doses administered and any reactions that occur. 
They will have the 1 year 7444 mg egg white protein OFC (Visit 04) and the 2 year 7444 mg egg 
white protein OFC (Visit 07) while maintaining their daily dose of Baked Egg. If they pass the 
2 year 7444 mg egg white protein OFC, they will stop their Baked Egg dosing and return in 
approximately 8-10 weeks for a 7444 mg egg white protein OFC off therapy (Visit 08) to test for 
sustained unresponsiveness. A blood draw for mechanistic studies* will be performed prior to 
the egg oral challenges. 
* Mechanistic blood draw may not to exceed 50 cc in a day (but no more than 5 cc/kg in 24 hrs 
or 9.5 cc/kg in 8 weeks). 


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Egg OIT Treatment Overview: 
Egg OIT administration will include an initial escalation day (Visit 01) with egg oral 
immunotherapy dosing beginning at 0.1 mg egg white solid with graduated doses up to 25 mg (if 
tolerated) occurring in the Clinical Research Center or appropriate monitored clinic setting. The 
Egg OIT assignment group (that failed the baked egg challenge) will only escalate to 12 mg egg 
white solid maximum on Day 1. This will be followed by Egg OIT escalation every 2 weeks in 
the Clinical Research Center or monitored clinic setting. Subjects at the end of Day 1 tolerating 
less than 3 mg single dose will be considered an initial day escalation desensitization failure and 
followed longitudinally. 
Following attainment of daily dosing of the maximum tolerated dose (range 350 mg egg white 
solid to a target of 2500 mg), a maintenance period for at least 8 weeks followed by a 7444 mg 
egg white protein OFC will occur at 1 year (Visit 04). 
All subjects who did not reach a 2500 mg egg white solid maintenance dose will resume build-up 
starting at their current maintenance dose and stopping at a maximum 2500 mg maintenance 
dose, or earlier if symptoms prevent further build-up. The doses administered and parameters for 
build-up in the post 7444 mg egg white protein OFC phase will be identical to those in build-up 
prior to the 7444 mg egg white protein OFC. 
With each escalation, phone contact will occur after the first week on home dosing to assess 
symptoms and compliance. A targeted history and physical exam will be performed at each visit. 
Subjects will be assessed for exacerbation of atopic dermatitis or asthma (as determined by 
active wheezing) prior to each in clinic dosing. 
In addition to dosing visits, subjects will return to the Clinical Research Center at 3 months 
(Visit 02), 6 months (Visit 03), 16 months (Visit 05) and 20 months (Visit 06) for mechanistic 
blood draws. A medical and diet history, and physical exam will also be performed at these 
visits. 
At 1 year and 2 years, (Visits 04 and 07), a 7444 mg egg white protein OFC while on therapy, a 
history, diet history and physical exam will be performed. In addition, a blood draw for 
mechanistic studies* will be performed prior to the egg oral challenges and prior to the days 
allergen administration. Tests done at these visits also include a prick skin test and egg-specific 
IgE and IgG4 acquisition. Subjects that pass the 2 year 7444 mg egg white protein OFC will stop 
their Egg OIT dosing and return in approximately 8-10 weeks for a 7444 mg egg white protein 
OFC off therapy (Visit 08) to test for sustained unresponsiveness and have a mechanistic blood 
test*. 
* Mechanistic blood draw may not to exceed 50 cc in a day (but no more than 5 cc/kg in 24 hrs 
or 9.5 cc/kg in 8 weeks). 
DESENSITIZATION PHASE 
The desensitization portion of the protocol will consist of the following phases: 
• Baked Egg – maintenance 
• Egg OIT – initial dose escalation, build up and maintenance 


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Baked Egg: 
After passing the initial baked egg OFC and failing the initial egg OFC at ≤ 1444 mg of egg 
white protein, those subjects randomized to continue Baked Egg therapy will continue with the 
successfully consumed Baked Egg product for the remainder of the study. The food items will be 
consumed on a daily basis and can be consumed in a single sitting or throughout the day. Dietary 
information will be provided to the subject regarding allowed consumption of commercial foods 
consistent with the dose of Baked Egg. A daily diary will be maintained to document the dosing 
of the Baked Egg product and any reactions that occur. 
Reactions to Baked Egg Dosing: 
Reactions to Baked Egg dosing are rare and often the result of improperly prepared food or 
obtaining a food outside of the established dosing instructions. The primary action is to observe a 
dose in the Clinical Research Center or equivalent location where the baked product is prepared 
appropriately in the clinic setting. 
For oral/pharyngeal pruritus – the action is to continue the normal dosing at home but to 
confirm the food item that resulted in the symptoms as being appropriate. 
For mild symptoms, defined as: 
Skin – limited or localized hives/swelling, skin flushing or pruritus 
Respiratory – rhinorrhea/ sneezing, nasal congestion, occasional cough, throat discomfort 
GI – mild abdominal discomfort/ minor episode of vomiting 
The action is to continue the normal dosing at home but to confirm the food item that resulted in 
the symptoms as being appropriate or to have the subject return to clinic for an observed dose. 
If moderate symptoms occur, defined as: 
Skin – systemic hives/swelling 
Respiratory – throat tightness without hoarseness, persistent cough, wheezing without 
dyspnea 
GI – persistent moderate abdominal pain/cramping/nausea, increased vomiting 
The action is to have the subject return to clinic for an observed dose with the appropriate baked 
food prepared in the clinic. 
If symptoms resolve a careful review of the appropriate food preparation will be performed and 
dosing can continue at home. 
If greater than mild symptoms occur with the in-clinic dose, then consultation with the Study 
Chair or Co-Chair as listed on the cover page of the protocol is warranted to determine the next 
course of action. The Study Chair or Co-Chair will be available for questions and decision 
making for any questions related to the study protocol from 10 AM ET to 5 PM ET during the 
working week. 
If more severe symptoms occur, defined as: 
Respiratory – laryngeal edema, throat tightness with hoarseness, wheezing with dyspnea 
GI – significant severe abdominal pain/cramping/repetitive vomiting 
 


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The action is to have the subject return to clinic for an observed dose with the appropriate baked 
food prepared in the clinic. 
If symptoms resolve, a careful review of the appropriate food preparation will be performed and 
the subject would return the next day for an observed dose prior to resuming dosing. 
If greater than mild symptoms occur with the in-clinic dose, dosing will be stopped and the 
subject will be removed from further Baked Egg dosing. If oral pharyngeal or mild symptoms 
occur with the clinic dose then consultation with the Study Chair or Co-Chair as listed on the 
cover page of the protocol is warranted to determine the next course of action. The Study Chair 
or Co-Chair will be available for questions and decision making for any questions related to the 
study protocol from 8 AM ET to 5 PM ET during the working week. 
6.4.1 Treatment for reactions to Baked Egg Dosing 
Treatment of individual reactions should be with either an antihistamine and/or epinephrine, 
along with IV fluids, albuterol, and steroids as indicated. Generally, for mild and moderate 
symptoms, the subject should receive antihistamines, and for more severe symptoms, the 
subjects should receive epinephrine, antihistamines, and then the other medications as indicated. 
If severe anaphylaxis to egg resulting in hypotension, neurological compromise or mechanical 
ventilation occurs at any time secondary to baked egg, the subject will be prematurely terminated 
from dosing. 
Antihistamines 
If a subject receives antihistamines only, the dosing can be continued. 
Epinephrine 
If epinephrine is used at home for a baked egg dose, the subject will be brought into clinic for an 
observed dose with the baked egg product prepared in-clinic. Any individual reaction that 
requires 2 or more doses of epinephrine (in clinic or at home) counts towards the stopping rules 
for the protocol. 
Egg OIT: 
Initial Dose Escalation – the initial day will be done at the Clinical Research Center (or 
equivalent monitored clinic setting) and consist of Egg OIT dosing, beginning at 0.1 mg egg 
white solid with graduated doses every 30 minutes up to 25 mg (if tolerated) on Day 1. The Egg 
OIT assignment group (that failed the baked egg challenge) will only escalate to 12 mg egg 
white solid maximum on Day 1. Subjects will not have active wheezing or a current flare of 
atopic dermatitis. If symptoms occur preventing escalation to 25 mg (12 mg in the Egg OIT 
assigned group), the highest tolerated dose (at least 3 mg) will be accepted as the 
“desensitization” dose for further escalation (See Exhibit 1, Section 6). The maximum tolerated 
dose on Day 1 (e.g., 3 mg, 6 mg, 12 mg, or 25 mg egg white solid) will be given on Day 2 as a 
single dose under observation at the Clinical Research Center. If moderate symptoms occur on 
Day 2, the subject will return to the Clinical Research Center on Day 3 for the next lower dose 
(must be at least 3 mg) under direct observation. If moderate symptoms re-occur, consultation 
with the Study Chair or Co-Chair is warranted to determine the next course of action. If 
symptoms prevent initial escalation desensitization dosing to 3 mg, the subject will be dropped 
from active treatment due to desensitization failure and followed longitudinally. Subjects 
tolerating 3 mg, 6 mg, or 12 mg egg white solid will go home to remain on that dose daily and 


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then will return every 2 weeks to the Clinical Research Center for single dose escalation until a 
dose of 25 mg is achieved using the following dose escalation scheme: 3 mg to 6 mg to 12 mg to 
25 mg. Subjects will be called 1 week after each dose escalation visit to assess for dosing 
compliance and dose reactions. Subjects should withhold their daily home dose on the escalation 
day but should take all other scheduled medications. Note that the daily home dose should be 
taken as part of a meal. It is recommended that the dose be taken at a consistent time (within a  
4 hour time period), and it is critical to take the dose every day. Doses should be separated by at 
least 12 hours. Subjects who require dosing reduction during the 2 week period will reset their  
2 week escalation schedule to maintain the new dose for a 2 week period prior to attempting to 
escalate again. After tolerating 25 mg egg white solid, the subject will continue dose escalations 
every 2 weeks. Any dose escalation attempts may be postponed for 1-2 extra weeks based on 
clinical judgment. An escalation attempt must be made by 4 weeks, unless escalation is delayed 
due to administration of epinephrine as defined in Section 6.4.1. Failure to successfully escalate 
for 3 consecutive attempts will result in the subject being withdrawn from further therapy. The 
subject will be followed for the remainder of the study for safety and immunologic monitoring. 
(See schedule for initial day dose escalation, Section 6, Exhibit 1)  A physician will be available 
at all times during any of the Clinical Research Center Egg OIT dosing visits. 
Any subject who discontinues escalation dosing due to repeated allergic reactions to the egg 
product will have his/her mechanistic blood drawn within approximately 1 week of 
discontinuation of therapy. 
Subjects may have clear liquids and JELL-O during the day of the initial day escalation protocol 
while they are being given the desensitization doses. 
Reactions to Egg OIT During Initial Escalation: 
Process algorithm for symptoms during the initial escalation protocol. (See Section 6, Exhibit 1) 
Subjects may develop symptoms during the initial escalation protocol, similar to those seen 
during other desensitization protocols (e.g., venom immunotherapy, drug desensitization). The 
investigator’s judgment will be required to determine the best course of action with possible 
actions being the following: Extension of time interval between dosing (additional 30 minutes). 
• Return to previously tolerated dose (i.e., repeat of last tolerated dose) then advance 
forward. 
• Discontinuation of desensitization protocol. 
For oral/pharyngeal pruritus – the action should be to continue the normal dosing in 30 minutes. 
For mild symptoms, defined as: 
Skin – limited or localized hives/swelling, skin flushing or pruritus 
Respiratory – rhinorrhea/ sneezing, nasal congestion, occasional cough, throat discomfort 
GI – mild abdominal discomfort/ minor episode of vomiting 
Depending on the physician’s discretion, the action should be either: 
• Repeat the last dose in 30-60 min, or 
• Advance in 30-60 minutes. 
 
 


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If moderate symptoms occur, defined as: 
Skin – systemic hives/swelling 
Respiratory – throat tightness without hoarseness, persistent cough, wheezing without 
dyspnea 
GI – persistent moderate abdominal pain/cramping/nausea, increased vomiting 
The action should be to implement a 30-60 minute observation period and then proceed with a 
reduced dose [decrease by 1-2 dosing steps] only if prior symptoms resolve. If symptoms 
continue or worsen, the subject can be treated with antihistamines (see below). If symptoms 
resolve, repeat the same or reduced dose, and then continue. If symptoms require additional 
treatment, then consultation with the Study Chair or Co-Chair as listed on the cover page of the 
protocol is warranted to determine the next course of action. The Study Chair or Co-Chair will 
be available for questions and decision making for any questions related to the study protocol 
from 8 AM ET to 5 PM ET during the working week. 
If more severe symptoms occur, defined as: 
Respiratory – laryngeal edema, throat tightness with hoarseness, wheezing with dyspnea 
GI – significant severe abdominal pain/cramping/repetitive vomiting 
Neurological – change in mental status 
Circulatory – hypotension 
The action should be: discontinue the initial day escalation and administer the appropriate rescue 
medications. 
If the subject requires treatment for symptoms during the initial escalation protocol with 
antihistamines on 1 occasion, then the rest of the initial escalation may be followed. If the subject 
requires more than 1 medication (e.g., albuterol, diphenhydramine, epinephrine, or others) or 
multiple doses of antihistamines, the initial escalation should be terminated. For a completed 
initial escalation with no symptoms or only mild symptoms, subjects should have a 2-hour post-
protocol observation period. For moderate to severe symptoms, the observation period should be 
at least 4 hours, and up to 24 hours, based on symptoms and treatment regimen needed to 
stabilize. 
Day 2 after Initial Dose Escalation 
All subjects will return for the next dose to the clinic after the initial day escalation. This dose 
will be the previous day’s dose or the last tolerated dose from the initial day escalation. The 
maximum dose is 25 mg egg white solid (12 mg in the Egg OIT assigned group). The minimum 
dose for the second day is 3 mg. 
Those subjects administered: 25 mg (12 mg in the Egg OIT assigned group). 
If tolerated, return home on that dose for 2 weeks until the next escalation. 
If not tolerated, return for Day 3 dosing with a 1 or 2 step reduction. 
3-12 mg egg white solid. 
If tolerated, return home on that dose for 2 weeks until next escalation. 


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If not tolerated, return the next day with a 1 or 2 step reduction (if at 3 mg and require a dose 
reduction, that subject will be considered an escalation failure and followed as a longitudinal 
control). 
Day 3 after Initial Dose Escalation 
Those subjects with moderate symptoms on Day 2 will return on Day 3 for an observed dose. 
The maximum dose would be 12 mg egg white solid, the minimum dose 3 mg. 
      Those subjects administered: 3-12 mg egg white solid. 
If tolerated, return home on that dose for 2 weeks until next escalation. 
If not tolerated, call the Study Chair for further management. 
BUILD-UP PHASE PRE 1 YEAR 7444 MG EGG WHITE PROTEIN OFC 
Once 25 mg egg white solid is tolerated (12 mg in the Egg OIT assigned group), subjects will 
begin the Clinical Research Center dosing scheme as outlined until 2500 mg of egg white solid is 
reached. Subjects will return for a supervised dose escalation in the clinic every 2 weeks. 
Subjects will be called 1 week after each dose escalation visit to assess for dosing compliance 
and dose reactions. Any dose escalation attempts may be postponed for 1-2 extra weeks based on 
clinical judgment. An escalation attempt must be made by 4 weeks. Subjects should withhold 
their daily home dose on the escalation day but should take all other prescribed medications. 
Note that the daily home dose should be taken as part of a meal. It is recommended that the dose 
be taken at a consistent time (within a 4 hour time period), and it is critical to take the dose every 
day. Doses should be separated by at least 12 hours. Subjects who require dosing reduction 
during the 2 week period will reset their 2 week escalation schedule to maintain the new dose for 
a 2 week period prior to attempting to escalate again. 
Should significant systemic symptoms, which may include mild symptoms based on physician 
discretion or moderate or greater symptoms, be reported during the daily home dosing, the 
symptom/dosing algorithm will be followed (See Section 6, Exhibit 2) to determine the best 
course of action. The appropriate treatment will depend on the type and number of symptoms. If 
significant symptoms occur consistently following three attempts to increase the daily oral dose 
in the Clinical Research Center or clinic with each attempt spaced 2-4 weeks apart, dosing 
escalation will be halted at the last tolerated dose, the subject continued on that dose as their 
maintenance dose and at the scheduled 7444 mg egg white protein OFC performed at week 52. 
The minimally accepted dose for maintenance daily Egg OIT dosing is 350 mg egg white solid. 
If subjects do not reach this level by 44 weeks, Egg OIT will be discontinued and he/she will be 
followed until the end of the study. The maximum time allowed for the build-up phase is 44 
weeks; the dose achieved at 44 weeks will be the maintenance dose used in the subsequent 8 
weeks. If the subject reaches the maximum dose of OIT on or before week 44, the subject will 
return to the clinic for monthly assessments of dosing compliance and dosing symptoms until the 
1 year OFC. The maximum length of this phase prior to the 1 year 7444 mg egg white protein 
OFC challenge phase is 52 weeks with the last 8 weeks prior to the year 1 desensitization OFC 
challenge at a constant dose. 
Subjects  will  be  allowed  to  take  their  other  daily  medications  during  the  build-up  and 
maintenance phases of the study (i.e., antihistamines, albuterol). 
 
 


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BUILD-UP PHASE POST 1 YEAR 7444 MG EGG WHITE PROTEIN OFC 
Starting at the maintenance dose achieved prior to the 1 year 7444 mg egg white protein OFC, 
subjects will begin the Clinical Research Center dosing scheme as outlined until 2500 mg of egg 
white solid is reached. Subjects will return for a supervised dose escalation in the clinic every 2 
weeks. Subjects will be called 1 week after each dose escalation visit to assess for dosing 
compliance and dose reactions. Any dose escalation attempts may be postponed for 1-2 extra 
weeks based on clinical judgment. An escalation attempt must be made by 4 weeks. Subjects 
should withhold their daily home dose on the escalation day but should take all other prescribed 
medications. Note that the daily home dose should be taken as part of a meal. It is recommended 
that the dose be taken at a consistent time (within a 4 hour time period), and it is critical to take 
the dose every day. Doses should be separated by at least 12 hours. Subjects who require dosing 
reduction during the 2 week period will reset their 2 week escalation schedule to maintain the 
new dose for a 2 week period prior to attempting to escalate again. In year 2, when on 
maintenance dosing, the subject will return to the clinic every 4 months per the visit schedule 
with telephone contacts monthly to assess dosing compliance and any dosing symptoms. 
Should significant systemic symptoms, which may include mild symptoms based on physician 
discretion or moderate or greater symptoms, are reported during the daily home dosing, the 
symptom/dosing algorithm will be followed to determine the best course of action. The 
appropriate treatment will depend on the type and number of symptoms. If significant symptoms 
occur consistently following 3 attempts to increase the daily oral dose in the Clinical Research 
Center or clinic with each attempt spaced 2-4 weeks apart, dosing escalation will be halted at the 
last tolerated dose, the subject continued on that dose as their maintenance dose. If subjects do 
not reach the 2500 mg maintenance dose 4 weeks prior to the end of study egg OFC, build-up 
will stop and the highest achieved dose will be maintained until the end of study egg OFC. 
Maintenance will be 4 weeks long prior to the end of study egg OFC. 
Subjects will be allowed to take their other daily medications during the build-up and 
maintenance phases of the study (i.e., antihistamines, albuterol). 
Process algorithm for symptoms during build-up phase for Egg OIT (pre or post 1 year 7444 mg 
egg white protein OFC).  (See Section 6, Exhibit 2) 
Subjects will be free from active wheezing or a flare of atopic dermatitis prior to any dose 
escalation. Subjects will be maintained on their current dose of study product until their flare of 
asthma or atopic dermatitis resolve. Subjects may develop symptoms during dosing for the build-
up phase. The investigator’s judgment will be required to determine the best course of action 
with possible actions being the following: 
1.  Continue with daily home dosing. 
2.  Continue the same daily dose for the rest of the 2 week interval. 
3. Return for repeat dosing in Clinical Research Center. 
4.  Return for dosing of previously tolerated dose (without escalation) in Clinical 
Research Center. 
5.  Discontinuation of dosing. 


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If a subject has a dose escalation in the Clinical Research Center without symptoms, the action 
should be to continue per protocol with daily home dosing of the tolerated dose with the next 
escalation visit to the Clinical Research Center 2 weeks later. 
If the subject only experiences oral/pharyngeal pruritus during the administration of the daily 
dose, then the same dose can be repeated the next day at home and continued throughout the 
interval unless other symptoms begin to develop (see below). 
For mild symptoms, defined as: 
Skin – limited or localized hives/swelling, skin flushing or pruritus 
Respiratory – rhinorrhea/ sneezing, nasal congestion, occasional cough, throat discomfort 
GI – mild abdominal discomfort/ minor episode of vomiting 
The action should be either to repeat the dose the next day (Day 2) at home or to have the subject 
return to the Clinical Research Center the next day (Day 2) for a repeat of the previous day’s 
dose or the last tolerated dose (at the physician’s discretion). If the dose is tolerated, then the 
subject will continue on that dose and return at the normal interval. If the dose causes mild 
symptoms again, then the subject may return to the Clinical Research Center (Day 3) and be 
given the last tolerated dose or a 1-2 step dose reduction. If tolerated, the subject will continue on 
this dose for the normal time interval. If mild symptoms recur, a 1-2 step reduction should be 
administered the next day (Day 4).  If tolerated then that dose should be continued for 2 weeks. If 
not tolerated, consultation with the study chair should be indicated. 
If moderate symptoms occur, defined as: 
Skin – systemic hives/swelling 
Respiratory – throat tightness without hoarseness, persistent cough, wheezing without 
dyspnea 
GI – persistent moderate abdominal pain/cramping/nausea, increased vomiting 
The action should be to have the subject return to the Clinical Research Center the next day (Day 
2) for dosing with the previous days dose or the last tolerated dose under observation. If the dose 
is tolerated, the subject will continue on that daily home dose for the normal time interval per 
protocol. If the subject does not tolerate this dose, the subject should receive the last tolerated 
dose or a 1-2 step dose reduction (Day 3) in the Clinical Research Center or at home if the 
planned dose was previously tolerated. If this dose is tolerated, it will be continued as the daily 
home dose for the normal time interval, then escalation attempted in the Clinical Research 
Center as noted below. If this dose is not tolerated, then the next dose will be a 1-2 step reduction 
in dosing, and the dose will be given on the Clinical Research Center (Day 4). If this next dose is 
not tolerated, then a discussion with the Study Chair or Co-Chair will ensue to make a decision 
about whether to continue the subject on active treatment in the study. 
If more severe symptoms occur, defined as: 
Respiratory – laryngeal edema, throat tightness with hoarseness, wheezing with dyspnea 
GI – significant severe abdominal pain/cramping/repetitive vomiting 
 
 


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The action should be to treat the subject, and at the physicians discretion either 1) have them 
return to the Clinical Research Center the next day (Day 2) for dosing with a 2 step reduction in 
dose under observation or 2) discontinue them from the active treatment. If the subject tolerates 
the dose reduction, then they will remain on that dose for 2 weeks and then return to the Clinical 
Research Center for the dose escalation. A discussion with the Study Chair or Co-Chair may 
ensue to make a decision about whether to continue the subject on active treatment in the study. 
If a subject fails dose escalation after three consecutive (with 2-4 weeks between) attempts, 
he/she will be considered a dose escalation failure and the last tolerated dose will be accepted as 
the maintenance dose. For a completed dose escalation with no symptoms, subjects should be 
observed for 30 minutes. For mild symptoms, subjects should have a 1-2 hours post-protocol 
observation period. For moderate to severe symptoms, the observation period should be at least 
4 hours and up to 24 hours based on symptoms and treatment regimen needed to stabilize the 
subject. 
Any subject deemed to have severe symptoms including hypoxia, hypotension or change in 
mental status (stage 3 defined in Appendix 3) and receives aggressive therapy at any time should 
be discussed with the Study Chair or Co-Chair and discontinued from active therapy. 
For specific questions related to dosing escalation or continuation of the same dose that are not 
answered in the above protocol, the Study Chair or Co-Chair will be available for questions and 
decision-making. 
Any subject who discontinues build-up dosing due to repeated allergic reactions to the egg 
product will have his/her mechanistic blood drawn within approximately 1 week of 
discontinuation of therapy. 
6.4.2 Treatment for reactions during the Build-Up and Maintenance Phases 
Treatment of individual reactions should be with either an antihistamine and/or epinephrine, 
along with IV fluids, albuterol, and steroids as indicated. Generally, for mild and moderate 
symptoms, the subject should receive antihistamines, and for more severe symptoms, the 
subjects should receive epinephrine, antihistamines, and then the other medications as indicated. 
If severe anaphylaxis (stage 3 defined in Appendix 3) occurs at any time, dose escalation will 
stop and the dose will be reduced to the last tolerated dose (must be at least 350 mg egg white 
solid) and the subject continued on that dose as long-term maintenance without further 
escalation. 
Antihistamines 
If a subject receives antihistamines only, the dose escalation can be continued. If symptoms 
during a build up day require antihistamines in multiple doses or in combination with other 
medications (except epinephrine), there should be a dose reduction by 1-2 doses with the next 
dose given in the CRC. If dose escalation fails or requires treatment after 2 more escalation 
attempts each spaced 2 to 4 weeks apart, the dose should be reduced to the last tolerated dose 
(must be at least 350 mg egg white solid to continue) and continued long term without further 
escalation. 


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Epinephrine 
Any reaction (in clinic or at home) that requires 2 or more doses of epinephrine counts towards 
the stopping rules for the protocol. Further dose escalation would not occur in this individual and 
maintenance on the last tolerated dose (must be greater than 350 mg) would be maintained. 
Clinic 
If a single administration of epinephrine is required during in clinic escalation, the dose should 
be reduced by 2 doses, and the subject continued on that dose for 4 weeks. After 4 weeks at the 
reduced dose, an escalation attempt may be tried in clinic. 
If a single administration of epinephrine is required a second consecutive time during this 
escalation attempt, the dose should be reduced by 2 doses, and the subject continues on that dose 
for 6-8 weeks. After 6-8 weeks at the reduced dose, an escalation attempt may be tried in clinic. 
If a single administration of epinephrine is required a third consecutive time during this 
escalation attempt, the dose should be reduced by 2 doses (if the reduced dose is at least 350 mg 
egg white solid) and the subject continued on that dose as long-term maintenance without further 
escalation. 
Home 
If a single administration of epinephrine use occurs during dosing at home, this epinephrine use 
is not counted as one of the uses described above, unless severe anaphylaxis occurs at home. The 
subject should return to clinic for an observed dose prior to resuming any dosing at home. The 
investigator may or may not decide to dose reduce depending on the specific circumstances 
surrounding the reaction. 
MAINTENANCE PHASE (PRE 1 YEAR 7444 MG EGG WHITE PROTEIN OFC PHASE) 
This phase consists of the subject receiving the maximum achieved daily dose of either baked 
egg or egg white solid OIT (as described above) for at least 8 weeks at home. The subject will 
continue to follow an egg-restricted diet for the duration of the study. 
For any noted symptoms during the maintenance phase, the same general study dosing rules for 
the build-up phase will be followed. Dosing reductions during the maintenance phase will be 
determined by the investigator based on the circumstances surrounding the reaction and 
subsequent dosing reactions. 
Both Treatment Groups: 
One year 7444 mg egg white protein OFC (at the conclusion of the initial build-up and initial 
maintenance phase) - All subjects will undergo a 7444 mg egg white protein OFC at 52 weeks 
after reaching the maximum achieved daily dose for 8 weeks as described above. Even though 
subjects initially may not tolerate more than approximately 2 gm of baked egg protein or 350 mg 
of egg white solid, long-term administration of egg may result in the capacity to tolerate much 
higher doses, and indeed 80% of individuals on 300 mg of egg white solid maintenance therapy 
for 24 months were “protected” and passed a 10 gm OFC.
37 
All subjects who did not reach the maximum maintenance dose of Egg OIT will resume build-up 
starting at their current maintenance dose and stopping at the maximum maintenance dose or 
earlier if symptoms prevent further build-up. The doses administered and parameters for build-up 


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in the post 1 year 7444 mg egg white protein OFC phase will be identical to those in build-up 
prior to the 1 year 7444 mg egg white protein OFC. 
Long Term Maintenance: 
The year 2 maintenance portion of the study is to determine if the Baked Egg and/or Egg OIT 
can induce the development of sustained unresponsiveness to egg. Subjects in the treatment arm 
will remain on a daily dose of Baked Egg or Egg OIT (or resume build-up to reach the maximum 
maintenance dose as described above at least 4 weeks prior to the 2 year 7444 mg egg white 
protein OFC). 
Subjects on each arm of the study will be followed with visits at 4 months (Visit 05) and 8 
months (Visit 06) after the 1 year 7444 mg egg white protein OFC. At these visits, serum for 
egg-specific IgE and IgG4 will be obtained (up to 10 mL). Subjects will be called monthly to 
assess for dosing compliance, symptoms and a targeted history. 
Missed Baked Egg Doses: 
Baked Egg subjects will be encouraged to take the daily baked egg dose. Missed doses will be 
monitored for compliance through daily dosing diaries. 
Missed Egg OIT Doses at any Phase of the Study: 
Missed Egg OIT doses at any phase of the study can pose a significant risk to the enrolled 
subjects. The algorithm for missed consecutive doses is as follows: 
• Miss 1 dose – The next dose would be the current dose and could be given at home. 
• Miss 2 doses in a row – The next dose would be the current dose and could be given at 
home. 
• Miss 3 doses in a row – The next dose would be the current dose and would be given 
under observation (Clinical Research Center). 
• Miss 4 doses in a row – The next dose would be the current dose and would be given 
under observation (Clinical Research Center). 
• Miss five to 7 doses in a row –For those subjects on Egg OIT, initiate the next dose as 
approximately 25% of the last tolerated dose. This would be done under observation 
(Clinical Research Center). Dose escalation would occur in the Clinical Research Center 
with an escalation no sooner than weekly and no longer than every 4 weeks with dose 
increases of 1 dose levels at each escalation. If symptoms occur, the dosing symptom 
rules in the build-up phase would apply. 
• Missing more than 7 consecutive days of therapy (this does not include subjects 
intentionally removed from therapy to administer a 7444 mg egg white protein OFC off 
therapy) constitutes an individual stopping rule and the subject would no longer take 
active therapy but would be followed longitudinally. 
• Additionally; excessive missed Egg OIT doses, i.e., >3 consecutive days missed on 3 
occasions, constitutes an individual stopping rule and the subject would no longer take 
active therapy but would be followed longitudinally. 
 
 


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SUSTAINED UNRESPONSIVENESS 
Two Year OFC 
At the 2 year time point all subjects will have a 7444 mg egg white protein desensitization OFC 
on therapy. If the subject fails the 7444 mg egg white protein OFC on therapy, the subject will 
stop therapy and treatment options will be discussed with the subject. If the 7444 mg egg white 
protein OFC on therapy is passed, then the subject will be removed from therapy for 8-10 weeks 
and tested for sustained unresponsiveness with a second 7444 mg egg white protein OFC. If this 
7444 mg egg white protein OFC off therapy is passed with successful consumption of an open 
feeding of egg, the subject will be considered to have achieved sustained unresponsiveness and 
advised to add egg to their diet on a regular basis and will be followed at 3 months by phone and 
6 months in clinic to assess their egg diet history and reactivity to egg. If the subject fails the 
7444 mg egg white protein OFC off therapy, further treatment options will be discussed with the 
subject. 
ANNUAL LONG TERM FOLLOW-UP 
All subjects will be contacted by telephone at years 3, 4, and 5 (through September 30, 2018) to 
assess consumption of egg in the diet.


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Exhibit 1.  Schematic for Initial (Visit 01) Day Escalation 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose - Escalation Dose 
Location – GCRC 
Oral/pharyngeal pruritus 
Time to next dose 30-60 min 
Next dose – repeat last dose 
or advance 
Treatment - antihistamines 
as needed 
Severe Symptoms 
Respiratory - laryngeal edema, throat 
tightness with hoarseness, wheezing 
with dyspnea 
GI - significant severe abdominal 
pain/cramping/repetitive 
vomiting 
Neurological - change in mental status 
Circulatory - hypotension 
Moderate Symptoms 
Skin – systemic hives/swelling 
Respiratory – throat discomfort without 
hoarseness, persistent cough, wheezing 
without dyspnea 
GI – persistent moderate abdominal 
pain/cramping/nausea increased 
vomiting 
Time to next dose 30 min  
Next dose - advance 
Treatment as indicated for 
severe reaction, stop 
escalation and further 
dosing 
Time to next dose 30-60 
min 
1-2 step dose reduction for 
next dose 
      OR 
Stop escalation 
Treatment - antihistamines 
as needed 
Initial First Day Escalation Schedule 
Dose no.       Egg white solid dose (mg)     Cumulative Egg dose (mg)* 
1                0.1 mg             0.1 mg 
2                0.2 mg             0.3 mg 
3                0.4 mg`  
           0.7 mg 
4                0.8 mg             1.5 mg 
5                1.5 mg             3.0 mg 
6                3.0 mg             6.0 mg 
7                6.0 mg             12  mg 
8                12 mg             24  mg 
9                25 mg             49  mg 
Frequency standard every 30 min 
 
* If no de-escalation 
 
Subjects at the end of the first day, tolerating less than 3 mg single dose, 
will be considered an initial day escalation desensitization failure. 
The Egg OIT assignment group (that failed the Baked Egg challenge) will 
only escalate to 12 mg maximum on Day 1. 
Subjects tolerating only 3, 6, or 12 mg single dose will go home on the 
greatest tolerated dose to be given daily (first dose given in Clinical 
Research Center under observation). All escalations will occur no sooner 
than 2 weeks and dose increases in the Clinical Research Center from 3 to 
6 to 12 to 25 mg will be attempted. These doses will be weighed doses in 
individual vials until the maximum 25 mg dose is reached. 
 
All subjects will return on Day 2 and receive their maximum tolerated 
dose under direct observation. 
 
Subjects with moderate symptoms observed on Day 2 will return on Day 
3 for the next lower dose under observation in the Clinical Research 
Center or monitored clinic setting. 
Doses on Day 2, 3, and 4 must be at least 3 mg or the subject will be 
considered an escalation failure. 
Persistent symptoms, 
consult with study chair as 
needed 
Mild Symptoms 
Skin – limited or localized 
hives/swelling, flushing or pruritus 
Respiratory - rhinorrhea/sneezing, nasal 
congestion, occasional cough, throat 
discomfort 
GI - Mild abdominal discomfort/minor 
episode of 
vomiting 


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Exhibit 2.  Schematic for Build Up Phase (Pre or Post 1 Year 7444 mg Egg White Protein OFC) Dose Escalation – Day of 
Symptom 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose - Challenge Escalation 
Dose  
       
Oral/pharyngeal Pruritus 
 
Mild Symptoms 
Skin – limited or localized 
hives/swelling, flushing or 
pruritus 
Respiratory - rhinorrhea/sneezing, 
nasal congestion, occasional 
cough, throat discomfort 
GI - Mild abdominal 
discomfort/minor episode of 
vomiting 
Dose – PDD or LTD 
Location - Clinical 
Research Center or home 
 
 
 
Severe Symptoms*** 
Respiratory - laryngeal edema, 
throat tightness with hoarseness, 
wheezing with dyspnea 
GI - significant severe abdominal 
pain/cramping/repetitive vomiting 
 
Moderate Symptoms 
Skin – systemic hives/swelling 
Respiratory – throat discomfort 
without hoarseness, persistent 
cough, wheezing without dyspnea 
GI – persistent moderate abdominal 
pain/cramping/ nausea increased 
vomiting  
Dose – PDD 
Location – Home with 
phone follow-up 
Dose – PDD or LTD 
Location – Clinical 
Research Center 
Tolerated 
Dose – Continue on 
dose Escalation at 
normal time interval 
Location - Home 
Not Tolerated 
Dose – LTD or 1-2 step 
reduction 
Location – Clinical 
Research Center or home 
if planned dose was 
previously tolerated 
Tolerated 
Dose – Continue the 
reduced dose 
Escalation at normal 
time interval 
Day 1* 
Day 2** 
Tolerated – Symptoms no greater than oral/pharyngeal pruritus 
LTD – Last Tolerated Dose 
PDD- Previous Days Dose 
Clinical Research Center or monitored clinic setting 
Failure of dose escalation in 3 consecutive attempts – maintain 
dose at LTD if > 350 mg otherwise discontinue OIT 
 
* Day 1- Refers to the escalation dose day only (initial or 
build-up, symptoms observed in the clinic) 
** Day 2- After symptoms in the Clinical Research Center or 
at home 
*** Subjects in the initial day escalation with severe symptoms 
are considered an escalation failure and will be followed as a 
longitudinal control 
Escalation at normal time 
interval 
Not Tolerated 
Dose – 1-2 step 
reduction 
Location – Clinical 
Research Center 
Day 4 
 
 
 
 
 
Not Tolerated 
Consult with study 
chair 
Tolerated 
Dose – Continue on 
dose 
Escalation at normal 
time interval 
Remove from study 
treatment, follow for 
safety 
Physician discretion, consult 
with Study Chair 
Dose –2-step reduction 
Location – Clinical 
Research Center 
Tolerated 
Dose – Continue on the 
reduced dose 
Escalation at normal time 
interval 
Day 3 
 
 
 
 
 


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6.5  Oral Food Challenge Double-Blind Placebo Controlled 
Investigators in the Consortium have utilized powdered egg white solid for oral food challenges 
at their respective institutions for more than 10 years. The egg white solid will be the bulk drug 
substance sent to each site by the central manufacturer. The subject will be off antihistamines for 
an appropriate length of time (5 half-lives of the antihistamine that is being used). Oral food 
challenges will be undertaken under direct medical supervision in a Clinical Research Center or 
food challenge area with emergency medications and staff immediately available and will follow 
established study procedures. Prior to the OFC, subjects will be assessed for an exacerbation of 
asthma as determined by active wheezing or a peak expiratory flow rate <80% of predicted. A 
uniform approach for food challenges will be used. Frequent assessments will be made for 
symptoms affecting the skin, gastrointestinal tract, and/or respiratory tract. Dose limiting 
symptoms, typically objective symptoms, indicate a positive reaction and termination of dosing. 
6.6  Egg OFC 
All egg OFCs conducted in the study are double-blind placebo controlled food challenges. All 
egg doses for OFCs are described in mg of protein. The OFC is performed by feeding gradually 
increasing amounts of the suspected food under physician observation.
87,88 OFC is conducted as 
2 challenges during a single day visit or over 2 days using placebo for 1 challenge and the study 
egg white protein for the other. If conducted in a single day, at least 2 hours must separate the 
first half of the challenge from the second half of the challenge. The challenge is performed so 
that neither the subject, nor the subject’s caregiver nor the physician knows which challenge 
contains the egg white protein or the placebo. The initial OFC for eligibility will consist of 
administering egg white protein or placebo in gradually increasing doses at 15-30 minute 
intervals. Extra doses may be added if 1444 mg of protein is successfully consumed on the 
baseline challenge per standard of care at the investigators discretion. If more than 1444 mg of 
egg white protein is successfully consumed without dose limiting symptoms, the subject would 
not be eligible for the study. The doses for the initial egg OFC are 1, 3, 10, 30, 100, 300, and 
1000 mg of egg white protein. The 1 year 7444 mg egg white protein OFC will be done while on 
therapy and is not followed by a repeat OFC or open feeding. The 2 year 7444 mg egg white 
protein OFC will be done on therapy to assess desensitization. In those who pass the 
desensitization challenge, a follow up 7444 mg egg white protein OFC off therapy will be done 
followed with an open feeding of a meal sized portion of egg 1 hour later, if this challenge is 
passed. Although these minimum standards have been used safely in the past, the investigator 
may use clinical judgment to increase the intervals between doses; or repeat lower doses, if there 
is a concern that a reaction may be developing. The doses for the 7444 mg egg white protein 
OFC are 1, 3, 10, 30, 100, 300, 1000, 3000, 3000 mg of egg white protein. Though many 
published challenges begin with 5 mg initial doses, the minimum dose for this study was chosen 
to be 1 mg according to additional recent recommendations and consensus. 
6.7  Baked Egg OFC 
The baked egg challenge conducted in this study will be a double-blind placebo controlled 
challenge. A uniform approach for baked egg challenges will be used. 
A single baked food group will be used though the initial challenge will be a muffin product 
using a uniform SOP across all five participating centers. Recipes are included in the CoFAR7 
MOP. 


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The doses will be distributed in 6 escalating doses of approximately 5%, 10%, 15%, 20%, 25% 
and 25% of the total 2 gm baked egg protein dose. A successful challenge is the consumption of 
a cumulative dose of 2 grams of the baked egg protein challenge without dose limiting 
symptoms. 
6.8  Prick Skin Test 
Subjects will have prick skin tests performed using study approved procedures for food and 
environmental allergens. While the subject is off antihistamines for an appropriate length of time 
(5 half-lives of the antihistamine that is being used), a skin test probe is pressed through a 
commercial extract of an allergen into the epidermis. Positive (histamine) and negative (saline-
glycerin) controls are placed to establish that the response is not blocked and to determine if 
there is dermatographism, respectively. 
6.9  Visit Windows 
Dosing schedule should be adhered to strictly. Two days before, or 5 days after, a planned dosing 
visit is an acceptable window with continued daily dosing of the current dose level. Study visits 
will be completed approximately 7 days before or 7 days after the planned visit. Study visits for 
OFC should take place within 2 weeks of the scheduled visit. Monthly telephone contacts that 
occur between clinic visits will occur approximately 7 days before or 7 days after the planned 
contact. 
6.10 Study Blinding Procedures 
This study is not blinded. 


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7.   Safety Monitoring 
This section defines the types of adverse events that should be reported and outlines the 
procedures for appropriately collecting, grading, recording and reporting them. The investigator 
is responsible for the detection and documentation of events meeting the criteria and definition of 
an AE (Adverse Event) or SAE (Serious Adverse Event) as described in sections 7.2.1 and 7.2.2. 
All AEs and SAEs will be recorded in the source documents and on the appropriate electronic 
CRF(s). All data will be reviewed periodically by the DSMB, which may provide 
recommendations to DAIT/NIAID/NIH about withdrawing any participant and/or terminating 
the study because of safety concerns. 
Information in this section complies with 21CFR 312; ICH Guideline E2A: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting; and ICH Guideline E-6: 
Guidelines for Good Clinical Practice; and applies the standards set forth in the National Cancer 
Institute (NCI), Common Terminology Criteria for Adverse Events, Version 4.0 (May 28, 2009). 
This document is referred to herein as the “NCI - CTCAE Manual.” 
7.1  Food Allergy Episodes 
In order to report the occurrence of a safety event associated with accidental food ingestion, 
subjects will be instructed to contact the site study coordinator or investigator for any adverse 
event. The subject may be asked to return to the site. A Food Allergy Episode form will be 
completed for each of these events in addition to events where consumption of egg without a 
reaction occurs. If the accidental food ingestion safety event meets the definition of a serious 
adverse event, as defined below, the AE/SAE form will be completed as well. 
7.2  Definitions 
All safety events observed under this protocol are reported through the data system from the time 
of the first study procedure until the 2 year sustained unresponsiveness OFC (Visit 08).  
Additionally, safety events will be collected until the 6 month in clinic follow-up visit for those 
subjects who pass the 2-year sustained unresponsiveness challenge.  Safety events outside of 
food allergy episodes will not be collected during the annual phone follow-up period.  Safety 
events related to accidental food exposure are recorded on a Food Allergy Episode form and are 
not reported on an adverse event form unless the event is considered a serious adverse event, as 
defined below. Any systemic allergic symptoms due to dosing will be recorded on a Study 
Product Administration form. If the event meets the definition of a serious adverse event, it will 
also be recorded on an adverse event (AE)/serious adverse event (SAE) form. Prick skin test and 
food challenge reactions that occur in the clinic are captured on study specific forms and are not 
reported on an adverse event form unless the event is considered a serious adverse event, as 
defined below.  All serious adverse events are reported on the AE/SAE form set in addition to 
the Prick Skin form or an Oral Food Challenge form if the event occurred during one of these 
procedures. All other safety events that occur throughout the study are reported on the AE/SAE 
form set. 
7.2.1 Adverse Event (AE) or Medical Event 
Any untoward or unfavorable medical occurrence associated with the subject’s participation in 
the research, whether or not considered related to the subject’s participation in the research 
(modified from the definition of adverse events in the 1996 International Conference on 
Harmonization E-6 Guidelines for Good Clinical Practice) (from OHRP "Guidance on 


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Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and 
Adverse Events (1/15/07)" http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2). 
An AE will be followed until it resolves or until 30 days after a participant terminates from the 
study, whichever comes first. Any change in clinical status, ECGs, routine labs, x-rays, physical 
examinations, etc., that is considered clinically significant by the study investigator is considered 
an AE. For the purposes of this protocol, consider a pregnancy an adverse event and follow the 
event until resolution of the pregnancy. 
Suspected adverse reaction (SAR) is any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug 
and the adverse reaction. A suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any adverse event caused by a drug (21 CFR 
312.32(a)). 
Adverse reaction is any adverse event caused by the drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
7.2.2 Serious Events (Serious Adverse Events, Serious Suspected Adverse 
Reactions or Serious Adverse Reactions) 
An AE or SAR is considered “serious” if, in the view of either the investigator or 
DAIT/NIAID/NIH it results in any of the following outcomes (21 CFR 312.32(a)): 
1. Death: A death that occurs during the study or that comes to the attention of the 
investigator during the protocol-defined follow-up period must be reported 
whether it is considered treatment related or not. 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the 
view of either the investigator or DAIT/NIAID/NIH, its occurrence places the 
subject at immediate risk of death. It does not include an AE or SAR that, had it 
occurred in a more severe form, might have caused death.  
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5. An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based on appropriate 
medical judgment, it may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
6. Congenital anomaly or birth defect. 
7.2.3 Unexpected Adverse Event 
A SAR is considered “unexpected” when it is not listed in the Investigator Brochure at the 
specificity or severity that has been observed (21 CRF 312.32(a)). 
7.3  Toxicity Grading 
The study site assigns toxicity grades to indicate the severity of adverse experiences and 
toxicities. The CoFAR adopted usage of NCI-CTCAE v4.0 for application in adverse event 
reporting. We define allergic reactions in this protocol beyond the NCI-CTCAE system, and 


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further characterize anaphylaxis. Anaphylaxis is characterized as mild, moderate, or severe in 
Appendix 3, independent of the toxicity grade associated with the event. Toxicity grading for 
allergic reactions including anaphylaxis is modified from the NCI-CTCAE system to be more 
appropriate for this study population, and is displayed in Appendix 4. We reviewed the NCI-
CTCAE v4.0 specifically for this protocol and it is otherwise appropriate for this study 
population. The purpose of using the NCI-CTCAE system is to provide standard language to 
describe toxicities and to facilitate tabulation and analysis of the data and assessment of the 
clinical significance of treatment-related toxicities. 
The NCI-CTCAE provides a term and a grade that closely describes the adverse event. Each 
participating site received copies of the grading scales and event descriptions. 
Record adverse events not included in the NCI-CTCAE listing and grade them 1 to 5 according 
to the General Grade Definition provided below: 
Grade 1  Mild 
Transient or mild discomforts (<48 hours), no or minimal 
medical intervention/therapy required, hospitalization not 
necessary (non-prescription or single-use prescription therapy 
may be employed to relieve symptoms, e.g., aspirin for 
simple headache, acetaminophen for post-surgical pain). 
Grade 2  Moderate      Mild to moderate limitation in activity, some assistance may 
be needed; no or minimal intervention/therapy required, 
hospitalization possible. 
Grade 3  Severe      
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalization possible. 
Grade 4  Life-threatening   Extreme limitation in activity, significant assistance required; 
significant medical/therapy intervention required, 
hospitalization, or hospice care probable. 
Grade 5  Death 
Death 
For additional information and a printable version of the NCI-CTCAE v. 4.03 manual, consult 
the NCI-CTCAE website, http://ctep.cancer.gov/reporting/ctc.html. 
7.3.1 Guidelines for Determining Causality of an Adverse Event 
The Investigator will use the following question when assessing causality of an adverse event to 
study drug: Is there a reasonable possibility that the drug caused the event? 
An affirmative answer designates the event as a suspected adverse reaction. 
The relationship, or attribution, of an adverse event to the study therapy regimen or study 
procedure(s) will initially be determined by the site investigator and recorded on the appropriate 
AE/SAE eCRF. Final determination of attribution for safety reporting will be determined by 
DAIT/NIAID/NIH. The relationship of an adverse event to study therapy regimen or procedures 
will be determined using the descriptors and definitions described previously. 
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-
CTCAE web site: http://ctep.cancer.gov/reporting/ctc.html. 


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7.4  Adverse Events Collection Procedures 
Adverse events will be evaluated from the onset of the event until the time the event is resolved 
or medically stable, or until 30 days after the subject completes study treatment, whichever 
comes first. 
AEs may be discovered through any of these methods: 
• Observing the subject 
• Questioning the subject, which should be done in an objective manner 
• Receiving an unsolicited complaint from the subject 
• Review of medical records/source documents 
• Review of home dosing symptom logs (provided to record symptoms between visits) 
7.4.1 Recording and Reporting Procedures 
Throughout the study, the investigator will record all AEs on the appropriate eCRF regardless of 
their severity or relation to study participation. A multi-page adverse event form will be used 
allowing all adverse events to be submitted through a single reporting mechanism. Serious 
adverse events will require additional information reported on additional pages within the 
EMMES AdvantageEDCSM system. Source documents can be scanned and attached to the 
adverse event form as well. The investigator will treat subjects experiencing adverse events 
appropriately and observe them at suitable intervals until their symptoms resolve or their status 
stabilizes. 
7.4.2 SAE Recording and Reporting Procedures 
Serious AEs will be recorded on the SAE CRF and health authorities will be notified as outlined 
in Section 7.5.2. All centers are obligated to report SAEs within 24 hours of their occurrence 
and/or the sites knowledge of the event to the SACCC. The following attributes will be assigned: 
• Description 
• Date of onset and resolution (if known when reported) 
• Severity 
• Assessment of relatedness to test article 
• Action taken 
 
The site investigator will apply his/her clinical judgment to determine whether an adverse event 
is of sufficient severity to require that the subject be removed from treatment. If necessary, an 
investigator will suspend any trial procedures and institute the necessary medical therapy to 
protect a subject from any immediate danger. 
Subsequent review by FDA, the DSMB, ethics review committee or IRB, or the sponsor(s) may 
suspend further trial treatment or procedures at a site. The study sponsor(s), FDA and DSMB 
retain the authority to suspend additional enrollment and treatments for the entire study as 
applicable. 
A subject may voluntarily withdraw from treatment due to what he/she perceives as an 
intolerable AE, or for any other reason. If voluntary withdrawal is requested, the subject should 


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No 
 
 
 
Yes 
 
 
 
be asked to continue (at least limited) scheduled evaluations, and the study staff will complete a 
dosing termination form, and the subject will be given appropriate care under medical 
supervision until the symptoms of any AE resolve or their condition becomes stable. 
7.4.2.1 REPORTING CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Reporting Decisions for Adverse Events 
 
1. Notify the site’s investigator. 
2. Complete and transmit an AE Form through the Internet data entry system. Information 
regarding a SAE report must be recorded in the subject’s medical chart. 
3. SAE follow-up reports should include hospital admittance notes, hospital discharge 
summary, clinical notes, resolution date, treatment and any other pertinent information 
regarding the event. Reporting should not be delayed in order to provide these 
documents. 
4. In the event of a death, the SAE Form must be completed and transmitted along with 
other supporting data (e.g., death certificate, medical notes, etc.) 
7.5  Serious Adverse Event Notification 
7.5.1 Notifying the Sponsor 
The Consortium of Food Allergy Research (CoFAR) investigators will provide the SACCC with 
data of all SAEs as defined per the protocol on an ongoing basis. 
The CRO Medical Officer is responsible for notifying the sponsor and will do so simultaneously 
with the reporting to the clinical database. As noted above, this should be within 24 hours of site 
awareness of the event. The DAIT/NIAID/NIH Medical Monitor will review each SAE report 
and will determine whether the SAE must be reported to FDA on an expedited basis. The final 
decision for disposition regarding reporting to the FDA rests with the DAIT/NIAID/NIH 
Medical Monitor. The IND Sponsor is responsible for submitting the SAE reports to FDA. 
DAIT/NIAID/NIH will provide the DSMB with any safety report submitted to FDA. The 
SACCC will maintain copies of any SAE reports submitted to FDA by the sponsor. 
The SACCC will provide these expedited reports to the individual site investigators. Events that 
are serious, related to therapy and unexpected will be reported to FDA in 15 days or for deaths 
and life threatening events in 7 days (per 21 CFR 312.32). 
Standard Reporting (within 5-7 days)  
Use Adverse Event Form, and other 
CRFs 
Submit to SACCC 
Expedited Reporting (within 24 hours) 
Use the Adverse Event Form 
Submit to SACCC 
(also notify ethics board/IRB) 
Death, Life Threatening, 
or SAE 
Adverse Event requiring AE Form Submission: 
All serious adverse events 
All adverse events except: 
Those due to an accidental food ingestion 
Those occurring in the clinic during study product administration, prick 
skin test or oral food challenge 


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7.5.2 Notifying FDA and the Data and Safety Monitoring Board 
After the SAE has been reported by the principal investigator and assessed by the IND sponsor, 
the IND sponsor must report the event to the appropriate health authorities using one of these 
two options: 
• Standard reporting (report in the IND annual report). This option applies if the 
AE is classified as one of the following: 
1. Serious, expected, suspected adverse reactions described in Sections 7.2.2 and 
7.2.3. 
2. Serious and not a suspected adverse reaction described in Section 7.2.2 and 7.2.3. 
• Expedited reporting is required. This option applies if the AE is classified as one of 
the following: 
o Serious and unexpected suspected adverse reactions described in Section 7.2.2, 
and Section 7.2.3. 
o The sponsor must report any suspected adverse reaction that is both serious and 
unexpected. The sponsor must report an adverse event as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the 
study drug and the adverse event, such as: 
 A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure. 
 One or more occurrences of an event that is not commonly associated with 
drug exposure, but is otherwise uncommon in the population exposed to the 
drug. 
o Aggregate analysis of specific serious adverse events observed in a clinical trial 
(such as known consequences of the underlying disease or condition under 
investigation or other events that commonly occur in the study population 
independent of drug therapy) that indicates those events occur more frequently in 
the drug treatment group than in a concurrent or historical control group. 
o Any findings from clinical or epidemiological studies, analysis of data pooled 
across multiple studies, published or unpublished scientific papers, or from animal 
or in vitro testing that would result in a safety-related change in the protocol, 
informed consent, General Investigational Plan section of the IND or other 
aspects of the overall conduct of the trial. 
Safety reports must be reported by the IND sponsor to the appropriate health authorities within 
15 calendar days; fatal or immediately life-threatening, serious, unexpected, suspected adverse 
reactions must be reported within 7 calendar days. 
All principal investigators must report SAEs to their respective IRBs as mandated by them. 
7.5.3 Reporting SAEs to the DSMB 
The DAIT/NIAID/NIH will provide the DSMB with data of all SAEs on an ongoing basis. 


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7.5.4 Notifying the Institutional Review Board and Ethics Committee 
The investigator will ensure the timely dissemination of all AE information, including expedited 
reports and DSMB safety reviews, to the IRB and EC in accordance with applicable local 
regulations and guidelines. 


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8.   Mechanistic Assays 
Complementary studies will be performed to measure cellular and humoral immune responses at 
baseline and longitudinally. These assays have been selected based on hypothesized mechanisms 
of sustained unresponsiveness induction. The assays to be performed include: 
• immune phenotyping of antigen-specific T cells, with a focus on cytokine production and 
homing molecule expression, in peripheral blood by FACS 
• systemic and antigen-induced basophil activation assays 
• measurement of whole antigen and epitope-specific IgE and IgG levels 
• transcriptional analysis of whole blood and allergen re-stimulated PBMCs 
The phenotype of antigen-specific T cells will be monitored at baseline and throughout 
immunotherapy using freshly isolated peripheral blood mononuclear cells re-stimulated with 
allergen in vitro. Phenotyping will be performed by flow cytometry, and will assess cytokine 
profile and chemokine receptor expression in antigen-responsive CD154+ CD4+ T cells. 
Additional phenotyping will be performed by transcriptional analysis of RNA isolated from the 
allergen-restimulated peripheral blood mononuclear cells. 
To perform these assays, blood specimens will be obtained at screening (Visit 00), at 3 months 
(Visit 02), 6 months (Visit 03), at the 1 year 7444 mg egg white protein OFC (Visit 04), at the 
2 year desensitization OFC (Visit 07), prior to the sustained unresponsiveness portion of the 
2 year challenge and approximately 6 months after the sustained unresponsiveness challenge. 
Subjects that pass the 2 year 7444 mg egg white protein OFC will stop their Egg OIT dosing and 
return in approximately 8-10 weeks for a 7444 mg egg white protein OFC off therapy (Visit 08) 
to test for sustained unresponsiveness and have a mechanistic blood test. Blood volumes must be 
no more than 50 cc in a day. 
In summary, all 130 subjects entering the study will have specimens drawn as specified in this 
section. 
At screening, 3 months, 6 months, and the 1 year OFC and 2 year OFC visits and at the 6 month 
follow up, up to 50 ml of venous blood (but no more than 5cc/kg in 24hrs or 9.5 cc/kg in 8 
weeks) will be obtained. For optimal results, this volume includes 3 ml collected in a TempusTM 
tube for the purpose of RNA isolation, 3.5 ml for basophil studies, and the remainder subjected 
to mononuclear cell isolation at Mount Sinai. This PBMC sample will be utilized for T cell 
phenotyping studies by flow cytometry and transcriptional analysis. At the other time points, 
blood is drawn for basophil, IgE and IgG4 assessments and requires less blood volume (up to 10 
ml). 
Approximately 33 ml of whole blood plus the Tempus tube will be shipped overnight in 
thermally protected shipping containers to Mount Sinai for PBMC isolation and T cell 
immunophenotyping and profiling studies. This includes 20 ml for T cell phenotyping by flow 
cytometry, and 13 ml of blood for transcriptional analysis. 3.5 milliliters of blood will be 
retained at the site laboratories for basophil activation studies, i.e., antigen activation, staining 
and fixing as outlined in the MOP, and then shipped to the Mount Sinai Lab for cytoflow 
acquisition.
 


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8.1  PBMC Assays 
Immune responses to egg antigen will be assessed by stimulating PBMC in vitro and analyzing 
the phenotype of antigen-specific (CD154+) CD4+ T cells by flow cytometry. For this study, 4 x 
106 PBMCs will be cultured in egg antigen (1 mg/ml), media alone as negative control, or 
CD3/CD28 stimulator beads as positive control. Media will be AimV containing 2.5% 
autologous plasma. Duplicate cultures will be performed for media and antigen-stimulated 
cultures. Short-term stimulation (6h) will be performed followed by staining of cells as described 
in the sections below. Twenty million PBMCs are needed for this analysis. 
The overall objective of ingestion of baked-egg products and egg OIT is to down-regulate 
allergen-specific Th2 responses in patients with egg allergy. Induction of sustained 
unresponsiveness suggests a shift in the type of CD4+ T cell responses specific for egg-
associated antigens. To investigate this, we will apply a novel assay, which also has been 
reported by others in the evaluation of allergen-specific Th cell activation.
 89 This assay is based 
on the fact that antigen-specific CD4+ T cells can be detected by CD154 expression after short-
term (6h) stimulation in vitro. 
1.  Analysis of circulating CD4+ T cells that help humoral responses: Studies have shown 
that T follicular helper (Tfh) cells are a Th subset specialized for provision of help to B cells. Tfh 
cells and their precursors play a critical role in the formation of germinal centers (GCs),
90,91,92 a 
structure where high-affinity B cells are selected through somatic hypermutation.
93 Tfh cells 
express the chemokine receptor CXCR5, which guides them to migrate into B cell follicles,
94 
and secrete IL-21, a γc family cytokine that potently induces B cells to undergo proliferation, 
differentiation, and class-switching. Accordingly, Tfh cells promote proliferation and survival of 
B cells in GCs, and eventually induce their differentiation into either long-lived plasma cells or 
memory B cells capable of producing high-affinity antibodies. In human blood, a fraction of 
memory CD4+ T cells express CXCR5. Th2- and Th17-type Tfh cells, but not Th1-type Tfh 
cells produce IL-21, which promotes the differentiation and class-switching of naïve B cells. 
Th2-type Tfh cells are the most potent at inducing naïve B cells to produce IgE, while Th17-type 
Tfh cells are the most potent at promoting IgA production. 95  The analysis of blood CD4+ Tfh 
subsets may provide a more accurate reflection of the effects of egg OIT on changes in the 
composition of CD4+ T cell responses during immunotherapy and may better correlate with 
desensitization and sustained unresponsiveness induction. We will use a panel of monoclonal 
antibodies to assess the antigen-specific cytokine expression profiles in the blood Tfh 
compartment. The panel contains CXCR5, as well as four (4) cytokines, IL-4, IL-10, IL-13, and 
IFN-γ. CD154 up-regulation on CD4+ T cells cultured with egg protein, but not antigen control, 
will delineate activated egg-specific CD4+ T cells. Dead cells will be excluded using fixable 
Live/Dead dye. In addition to focusing on the Tfh cells, we will also determine the impact of 
intervention on cytokine expression in the total antigen-responsive (CD154
pos) population. 
2.  Analysis of homing antigen-specific T cells: 
Our expectation is that oral immunotherapy or baked egg diet will reduce Th2 skewing of egg 
antigen-specific T cells, and that this will be associated with the development of sustained 
unresponsiveness to egg. 
 
 


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This analysis will be essential to understand the treatment-related changes in blood leukocytes. 
We anticipate that in subjects treated with either baked-egg or egg OIT, the induction of allergen 
sustained unresponsiveness will be accompanied by changes in the blood CD4+ T cell 
compartment including a decrease in egg-specific Th2-type Tfh and an expansion of Tregs with a 
gut-homing phenotype. The table below indicates the fluorescence-labeled monoclonal 
antibodies will be utilized for immunophenotyping the T cell population: 
 
Staining Panel for T cell Phenotyping 
 
Live/Dead  Live CD4+ Lymphocytes 
CD3 
CD4 
CD154      Antigen-specificity 
CD25 
Tregs 
CD127 
IL-10 
IL-4 
Th2 
IL-13 
IFN-γ 
Th1 
CXCR5 
Tfh 
CCR6      Mucosal homing 
CCR4      
Skin homing 
 
CD154+ cells will be quantified per million CD4+ T cells. The profile of these cells will be 
quantified in two ways: the number of CD154+ cells of each phenotype (for example IL-4+ or 
IL-13+, or CD25
High CD127
low) per million CD4+ T cells, and the proportion of CD154+ cells of 
each phenotype. CD154+ cells induced by egg will be compared to those induced by CD3/CD28 
stimulator beads. In addition, CD154+ cells induced by egg before and after immunotherapy will 
be compared. 
8.2  Basophil Studies 
Allergen desensitization has been shown to induce basophil hyporesponsiveness to allergen-
induced degranulation, however, chronic exposure to allergens is also associated with 
constitutively activated basophils. We will use flow cytometry-based assessment of basophil 
activation/ degranulation longitudinally with and without in vitro stimulation to track changes 
induced by OIT and their relationship to clinical desensitization and sustained unresponsiveness. 
At each time point, 0.5 ml of whole blood will be stimulated as follows: 
• Medium alone 
• Medium w/ 2 ng/ml human IL-3 (basophil medium) 
• Basophil medium w/ 1 µM fMLP 
• Basophil medium w/ 0.001 µg EW 
• Basophil medium w/ 0.01 µg EW 
• Basophil medium w/ 0.1 µg EW 
• Basophil medium w/ 1 µg EW 
• Basophil medium w/ 1 µg anti-IgE 


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After a 30 minute incubation, cells will be stained, fixed, and shipped on ice to the central lab. 
Samples will be analyzed by flow cytometry for surface expression of activation markers (CD63, 
CD203c, and CD69). Basophils will be identified as CD203+ CD123+ lineage marker (CD3, 
CD19, CD14, and CD41) negative. 
8.3  Egg-specific antibody 
Antigen immunotherapy has been shown to induce antigen-specific humoral responses. The 
balance of isotypic response may play a role in allergen sensitivity (e.g., an increase of IgG/ 
IgE). 
At each of the mechanistic time points, a sample of plasma will be stored for assessment of egg- 
specific antibody levels. 
We will measure total IgE and specific IgE and IgG4 by UniCAP from each time point. Egg 
specific IgE and IgG4 blood draws will be measured at the screening (Visit 00), 3 month (Visit 
02), 6 month (Visit 03), the 1 year visit (Visit 04) and 16 months (Visit 05), 20 months (Visit 
06), at the 2 year visit (Visit 07) and at the 2 year sustained unresponsiveness visit (Visit 08), if 
applicable. 
8.4  Microarray 
Changes in antibody repertoire within isotype subsets may also correlate with clinical outcome. 
Epitope repertoire can be partially characterized using peptide array-based immunoassay. For 
microarray analysis, overlapping peptides 20 amino acids in length with an offset of 2 residues 
and covering the full sequence of the major egg allergens (ovomucoid and ovalbumin; 
approximately 260 peptides in total) will be robotically arrayed in triplicate to reactive substrates 
(chemically modified glass slides). Purified whole allergen will be printed to serve as positive 
controls. These arrays will be used to probe for epitope-specific IgE and IgG from subject 
plasma (<20 µL) at each time point. Bound IgE and IgG antibodies will be detected using 
fluorochrome-tagged secondary monoclonal antibody. Fluorescence emission will be measured 
using a GMS 418 Array Scanner (Affymetrix) and analyzed using commercial and custom 
software. The average plus 2 SD log intensity of the negative control elements will be used as an 
intra-slide cutoff to establish background. Array elements with CV >30% will be excluded from 
analysis. An inter-slide cutoff will be calculated as the average plus 2 standard deviation 
intensity of the corresponding signal from non-atopic control sera. 
The primary endpoint will be the number of distinct IgG4- and IgE-binding epitopes to egg 
proteins at each time point. The number of epitopes will be compared longitudinally to baseline 
during immunotherapy between subjects receiving active treatment vs. placebo as well as 
between those who become tolerant vs. those who do not. 
8.5  Transcriptional Profiling of Whole Blood 
A blood sample for genomic analysis will be obtained at baseline and at the 3, 6, and 12 month 
timepoints. A total of 4 time-points per subject will be assessed. 3 ml of blood will be drawn in 
Tempus tubes for RNA isolation, and shipped at room temperature to the central lab at Mount 
Sinai. Transcriptional signatures will be assessed by the Mount Sinai Genomic Core (Director 
Eric Schadt, PhD). The samples will be processed in batches and analyzed using Illumina Hu6 
V3 Beadchip arrays along with a universal reference sample. This generates information on 
∼48000 gene transcripts. Raw gene expression values will be normalized per gene to the median 


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gene expression value across all samples and supervised non-parametric analysis will be carried 
out using GeneSpring software. Canonical pathway analysis will be performed using Ingenuity 
Systems Pathway Analysis software. 
An additional 3 ml of whole blood will be used for flow cytometric analysis of the T cell, B cell, 
myeloid, and granulocyte subsets at each timepoint in order to normalize for changes in cell 
populations. 
8.6  Transcriptional Profiling of Allergen Re-stimulated PBMCs 
PBMCs will be isolated from 10 ml of whole blood. Replicates of 4 x 10
6 cells will be cultured 
in 2.5% autologous plasma in AimV media. Cells will be left unstimulated, or stimulated with 
egg antigen for 6 or 18 h. RNA will be isolated and transcriptional analysis assessed as above. 
An aliquot of cells will be used for flow cytometric analysis of the composition of cell subsets. 
Blood Volumes Required for Mechanistic Studies: 
Green top tubes: 
30 ml (20 ml minimum) for T cell profiling (and for obtaining plasma) 
13 ml for transcriptional profiling 
3.5 ml for basophil analysis 
Tempus tube: 
3 ml for transcriptional profiling 


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9.   STATISTICAL CONSIDERATIONS 
This protocol includes a randomized evaluation of Egg OIT vs. Baked Egg therapy for 
individuals with egg allergy selected to tolerate Baked Egg therapy. A separate cohort treated 
with the identical Egg OIT regimen in individuals incapable of tolerating Baked Egg therapy is 
included. 
9.1  Study Endpoint Assessment 
9.1.1 Primary Endpoint 
The primary endpoint is defined in Section 3.1.1. For the randomized portion of the study an 
intent-to-treat analysis will be performed. Sustained unresponsiveness can only be demonstrated 
after discontinuation of active therapy for 8-10 weeks. Individuals successfully demonstrating 
dose limiting symptom-free consumption of 7444 mg egg white protein by OFC (i.e., dose-
limiting symptom-free dosing followed by meal size portion) will be considered successes. All 
others will be considered to be failures with respect to this endpoint. Analysis will be via the 
Chi-square test. 
9.1.2 Secondary Endpoints 
The secondary endpoints are defined in Section 3.1.2. 
9.2  Subject and Demographic Data 
9.2.1 Baseline Characteristics and Demographics 
Summary descriptive statistics for baseline and demographic characteristics will be provided for 
all enrolled subjects. Demographic data will include age, race, sex, body weight, and height; 
these data will be presented in the following manner: 
• Continuous data (i.e., age, body weight and height) will be summarized descriptively 
by mean, standard deviation, median and range. 
• Categorical data (i.e., sex and race) will be presented as enumerations and 
percentages. 
Statistical presentation for baseline and demographic characteristics may be further summarized 
by treatment group and baseline egg-specific serum IgE. 
9.2.2 Use of Medications 
All medications used will be coded using the World Health Organization (WHO) drug 
dictionary. The number and percentage of subjects receiving concomitant medications or 
therapies will be presented. Statistical presentation of concomitant medications or therapies may 
be further summarized by treatment group. 
9.2.3 Study Completion 
The percent of subjects who complete the study, losses to follow-up, times to lost to follow-up 
and reasons for discontinuation (e.g., adverse events) will be presented. Statistical presentation of 
study completion will be further presented via analysis of the secondary endpoints summarized. 
9.3  Sample Size and Power Calculations 
The sample size target for the randomized portion of the study is 96 individuals with 1:1 random 
assignment to Baked Egg and Egg OIT. The sample size was selected to determine whether a 


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difference exists between the treatment groups in the primary endpoint rate for the sustained 
unresponsiveness-focused portion of the study. Specifically, the sample was designed to have 
85% power to detect with a two-sided 5% level test, a difference between a 40% and 70% 
sustained unresponsiveness rate. While a small dropout rate may occur, we will use all 
randomized cases who initiate treatment in the intent-to-treat analysis of the primary endpoint; 
failures associated with noncompliance are include in the denominator for event rates above. 
This sample size is sufficient to address the secondary endpoint of the desensitization 
components of the study for event rate differences of comparable size. 
9.4  The Egg OIT assignment group who failed the initial baked egg challenge 
The subset of individuals who are not baked egg tolerant at baseline comprise a selected group of 
individuals where Egg OIT will be examined. The size of the group will be capped at 
approximately 40 subjects. The study cohort should be useful for both clinical and mechanistic 
study with approximately 40 such individuals enrolled. The 2 year sustained unresponsiveness 
rate will be compared to historical experience as well as the protocol’s randomized Egg OIT arm. 
Mechanistic studies will be examined to determine if baseline immune system responses are 
similar in both Egg OIT groups. Immune parameter changes will be examined to determine if 
tolerant and non-tolerant cases have response profiles that are parallel for the 2 strata.
 
9.5  Mechanistic Studies 
The mechanistic studies performed as part of the study explore: 
• Temporal changes in immune parameters and their association with Baked Egg or Egg 
OIT. 
• The relationship of various immune states to clinical outcomes, including development of 
sustained unresponsiveness and desensitization. 
• The feasibility of transcriptional analysis of whole blood and allergen re-stimulated 
PBMCs for detection of signatures predictive of clinical reactivity or tolerance to egg. 
The study sample size has been selected to examine the clinical endpoints of the primary and 
secondary objectives. The mechanistic assessments will be exploratory. Specific planned 
analysis strategies for the mechanistic objectives are discussed along with each objective in 
Section 2. Because of the large number of potential comparisons, clinical associations with 
mechanistic study outcomes will be regarded as significant only if they are more extreme than 
the 0.01 significance level. This will help limit the number of falsely identified positive results. 
9.6  Interim Analyses to Ensure Subject Safety 
The DSMB will be convened to review safety data periodically. Given the relatively small total 
sample size for the study and the interest in precise treatment-specific endpoint estimates (in 
addition to the treatment contrast results), no formal efficacy-focused early stopping guidelines 
or plans are proposed. The DSMB will receive regular reports on accrual, dose escalation 
success, dose-limiting adverse events, OFC-related adverse events and other adverse events. 
Additional analyses may be requested by the DSMB. 


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10.  Identification and Access to Source Data 
10.1 Web-Based Data Collection and Management System 
Data collection will occur via a web-based data entry system provided by the SACCC to allow 
easy access to enrollment 24 hours a day, 7 days a week. Upon enrollment, a form submission 
schedule is generated for each subject and displayed as a grid of forms by study visit that permits 
direct access to each electronic CRF for data entry. As data are entered, they are validated 
through range and within-form consistency checks. The investigator must ensure that all web-
based CRFs are completed in a timely fashion for each subject in the study. 
10.2 Certification in the Use of Web-Based Data Entry System 
The SACCC will provide training and certification of clinic and laboratory staff in the use of the 
data entry and specimen-tracking systems. Once certified, users are permitted to enter data into 
the production system. Access is password controlled. Certification for use of the web-based data 
entry system will be completed via telephone and/or web-cast training. 
10.3 Data Management 
Information regarding the subject’s history, laboratory tests, nutritional intake, evaluation of 
allergic response and follow-up status will be stored and processed by the SACCC. Quality 
control procedures and a feedback system between the SACCC and the Consortium will be 
instituted to ensure the accuracy and completeness of the data collected. 
10.4 Access to Data 
The investigational sites shall periodically permit authorized representatives of the IND sponsor, 
DAIT/NIAID/NIH and/or regulatory health authorities to examine clinical records and other 
source documents for the purpose of safety monitoring, quality assurance reviews, audits and 
evaluation of the study progress throughout the entire study period. The investigator is required 
by law (21CFR312.62) to keep accurate case records for at least 2 years after the investigation is 
discontinued and FDA is notified, and record observations to assure the safe conduct of the 
study. 


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11.  Quality Control and Quality Assurance 
11.1 Statement of Compliance 
This study will be conducted using good clinical practice (GCP), as delineated in the United 
States Code of Federal Regulations (CFR) – 21 CFR Parts 50, 54, 56, and 312 and in the 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) “Guidance for Industry: E6 Good Clinical Practice 
Consolidated Guidance”, and according to the criteria specified in this study protocol. Before 
study initiation, the protocol and the informed consent documents will be reviewed and approved 
by an appropriate EC or IRB as well as FDA. Any amendments to the protocol must also be 
approved by the DAIT/NIAID/NIH, DSMB, EC/IRB and submitted to the FDA before they are 
implemented. Any amendments to the consent materials must also be approved by the 
DAIT/NIAID/NIH, DSMB, EC/IRB before they are implemented. 
11.2 Informed Consent/Assent 
The informed consent form is a means of providing information about the study to a prospective 
subject’s parent/guardian and allows for adequate time for review in making an informed 
decision about participation in the study. Because the study population is comprised of children, 
parents or legal guardians will be asked to read, sign, and date a consent form before entering the 
study, taking study drug, or undergoing any study-specific procedures. Children will sign an 
assent as appropriate. Consent materials for parents/guardians who do not speak or read English 
will be translated into the appropriate language. The informed consent form will be revised 
whenever the protocol is amended. A copy of the informed consent will be given to a prospective 
parent/guardian for review. The principal investigator or designee listed on the FDA 1572, will 
review the consent and answer questions. The prospective parent/guardian will be told that being 
in the study is voluntary and that he or she may withdraw his/her child from the study at any 
time, for any reason. 
All subjects will be contacted by telephone at years 3, 4, and 5 (through a maximum time of 
September 30, 2018) to assess consumption of egg in their diet For subjects who completed the 
study prior to the release of protocol version 6.0, an oral consent will be obtained using an IRB 
approved oral consent script.  
11.3 Privacy and Confidentiality 
A subject’s privacy and confidentiality will be respected throughout the study. Each subject will 
be assigned a sequential identification number and these numbers rather than names will be used 
to collect, store and report subject information. 


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12.  Resource Sharing 
All data derived from this study will be sent to the SACCC for storage and analysis. Subject data 
will be anonymized to maintain subject confidentiality. All data derived from these studies will 
be published in peer-reviewed scientific journals in a timely manner. The Executive Steering 
Committee will review all manuscripts prior to submission to journals for publication and all 
abstracts prior to submission to national and international meetings. All data sets will be archived 
by the Statistical and Clinical Coordinating Center and can be made available to interested, 
outside investigators with the approval by the Executive Steering Committee and the 
DAIT/NIAID/NIH during the tenure of the Consortium and by the DAIT/NIAID/NIH after the 
termination of the Consortium. 


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13.  Protocol Deviations 
The investigators and site staff will conduct the study in accordance to the protocol. Any change, 
divergence, or departure from the study design or procedures constitutes a protocol deviation. 
Whenever applicable, corrective actions will be developed by the site and implemented promptly 
as a result of protocol deviations. 
13.1 Major Protocol Deviation (Protocol Violation) 
A Protocol Violation is a deviation from the IRB approved protocol that may affect the subject
's 
rights, safety, or well-being and/or the completeness, accuracy and reliability of the study data. 
In addition, protocol violations include willful or knowing breaches of human subject protection 
regulations, or policies, any action that is inconsistent with the NIH Human Research Protection 
Program’s research, medical, and ethical principles, and a serious or continuing noncompliance 
with federal, state, local or institutional human subject protection regulations, policies, or 
procedures. 
13.2 Non-Major Protocol Deviation 
A non-major protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that does not have a major impact on the subject
's rights, safety 
or well-being, or the completeness, accuracy and reliability of the study data. 
13.3 Reporting and Managing Protocol Deviations 
Non-Major protocol Deviations related to data entry or visit adherence are captured within the 
AdvantageEDC system and are not additionally reported on a separate CRF. 
The study site Principal Investigator has the responsibility to identify, document and report 
protocol violations/deviations and appropriate corrective action plans which are described above. 
However, protocol violations/deviations may also be identified during site monitoring visits or 
during other forms of study conduct review. All protocol violations will be reported in the 
AdvantageEDC on a specific CRF. 
 


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Appendix 1.A.  Schedule of Events – Egg OIT Subjects 
Procedure 
Visit 00 
Screening 
Visit 
00A 
Baseline1 
Visit 01 
Initial 
Escalation 
Days 1-3
2 
Study 
Product 
Build-
up3,5 
Visit 
02 
3 
month 
(12 
weeks) 
Visit 
03 
6 
month 
(24 
weeks) 
Visit 
04 
1 year 
(52 
weeks) 
Visit 
05 
16 
month 
(68 
weeks) 
Visit 
06 
20 
month 
(84 
weeks) 
Visit 07 
2 year 
Desensitization12 
(104 weeks)
 
Visit 08 
2 year sustained 
unresponsiveness13,14(112-
114 weeks) 
Visit F 
03 
3 year 
long 
term 
follow-
up15  
Visit F 
04 
4 year 
long 
term 
follow 
up15 
Visit F 
05 
5 year 
long 
term 
follow 
up15 
Medical/Allergy 
History  
X      
      
      
      X      X      X      X      X 
X 
X 
             
Spirometry4      
X      
      
      
                               
 
 
             
Physical Exam      X      
      
      
                  X                  
X 
X 
             
Peak Flow Rate      X      
X      
      
                  X                  
X 
X 
             
Pregnancy Test6      X      
X      
      
                  X                  
X 
X 
             
Diet History      
X      
      
X      
      X      X      X      X      X 
X 
X 
             
Targeted 
History/Physical 
Exam 
      
X      
X      
X      X      X            X      X 
 
 
             
Egg specific IgE, 
IgG4 
X      
      
      
      X      X      X      X      X 
X 
X 
             
PST-food  
X      
      
      
                  X                  
X 
 
             
PST-
environmental 
X      
      
      
                  X                  
X 
 
             
Clinical Research 
Center  Egg OIT 
administration7 
      
      
X      
X                               
 
 
             
Daily home 
administration
11 
      
      
X      
X      X      X      X      X      X 
 
 
             
Oral food 
challenge - Initial 
      
X      
      
                               
 
 
             
Oral food 
challenge -7444 
mg egg white 
protein 
      
      
      
                  X                  
X 
X 
             
Oral food 
challenge - Baked 
Egg10 
X      
      
      
                               
 
 
             
Blood draw with 
processing8,9 
X      
      
      
      X      X      X      X      X 
X 
X 
             
Long term follow-
up questionnaire 
      
      
      
                               
 
 
X      X      X 
1 Performed only for subjects who pass the screening baked egg OFC. 
2 Egg OIT subjects will have initial escalation to at least 3 mg egg white solid on Day 1, return Day 2, return Day 3 if symptoms, return for dose escalation every 2 weeks until dose of 25 mg egg white solid is 
reached (12 mg for Egg OIT Assignment group). 
3 Egg OIT subjects will have escalation visits every 2 weeks, unless epinephrine is administered as described in Section 6.4.1. Phone calls will occur 1 week after each escalation visit to assess dosing compliance 
and symptoms. 
4 Only prior to any OFC, at baseline, a peak flow rate may be performed if spirometry results cannot be obtained. 
5 Egg OIT subjects have 44 weeks maximum to reach highest tolerated dose >350 mg egg white solid. Subjects may escalate after 1 year OFC if they have not reached 2500 mg of egg white solid. 


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6 For females of childbearing age. 
7 In Clinical Research Center or monitored clinic setting. 
8 Blood draws will not exceed 50 cc in a day but no more than 5cc/kg in a day or 9.5cc/kg in an 8 week period. 
9 All mechanistic blood draws are performed prior to any oral food challenges. 
10 If baked egg challenge is failed, the first 40 subjects will go directly to Egg OIT treatment. 
11 Daily home dosing for Egg OIT. Phone calls will occur monthly in between visits once maintenance is reached. 
12 Discontinue Egg OIT. 
13 Only if desensitization challenge is passed, a repeat challenge off therapy in approximately 8-10 weeks will be performed. 
14 Subjects who pass the sustained unresponsiveness oral food challenge will return for follow-up outlined in appendix 1-D 
15 All subjects will be annually contacted by telephone starting 3 years after randomization, through a maximum of September 2018.   


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Appendix 1.B.  Schedule of Events – Baked Egg Subjects 
Procedure 
Visit 00 
Screening 
Visit 
00A 
Baseline1 
Visit 
012 
 
Visit 
02 
3 
month 
(12 
weeks) 
Visit 
03 
6 
month 
(24 
weeks) 
Month 9 
Study 
Assessment10 
Visit 
04 
1 year 
(52 
weeks) 
Visit 
05 
16 
month 
(68 
weeks) 
Visit 
06 
20 
month 
(84 
weeks) 
Visit 07 
2 year 
Desensitization8 
(104 weeks)
 
Visit 08 
2 year 
sustained 
unresponsiveness9,11 
(112-114 weeks) 
 
Visit F 03 
3 year long 
term follow-
up12  
 
Visit F 04 
4 year long 
term follow 
up12 
 
Visit F 05 
5 year long 
term follow 
up12 
Medical/Allergy 
History  
X      
            X      X      
      
X      X      X      
X 
X 
 
 
 
Spirometry3      
X      
                        
      
             
 
 
 
 
 
Physical Exam      
X      
                        
      
X                  
X 
X 
 
 
 
Peak Flow Rate      X      
X                        
      
X                  
X 
X 
 
 
 
Pregnancy Test4 
X      
X                        
      
X                  
X 
X 
 
 
 
Diet History      
X      
      X      X      X      
X      
X      X      X      
X 
X 
 
 
 
Targeted 
History/Physical 
Exam 
      
X      X      X      X      
X      
      X      X 
 
 
 
 
 
Egg specific IgE, 
IgG4 
X      
            X      X      
      
X      X      X      
X 
X 
 
 
 
PST-food  
X      
                        
      
X                  
X 
 
 
 
 
PST-
environmental 
X      
                        
      
X                  
X 
 
 
 
 
Daily home 
administration
7 
      
      X      X      X      
      
X      X      X 
 
 
 
 
 
Oral food 
challenge - Initial 
      
X                        
      
             
 
 
 
 
 
Oral food 
challenge - 7444 
mg egg white 
protein 
      
                        
      
X                  
X 
X 
 
 
 
Oral food 
challenge - Baked 
Egg 
X 
                        
      
             
 
 
 
 
 
Blood draw with 
processing5,6 
X      
            X      X      
      
X      X      X      
X 
X 
 
 
 
Long term follow-
up questionnaire 
      
                        
      
             
 
 
x 
x 
x 
1 Performed only for subjects who pass the screening baked egg OFC.
 
2 Baked Egg subjects will come into the clinic on Day 1 to show what baked products will be used. 
3 Only prior to any OFC, at baseline, a peak flow rate may be performed if spirometry results cannot be obtained. 
4 For females of childbearing age. 
5 Blood draws will not exceed 50 cc in a day but no more than 5cc/kg in a day or 9.5cc/kg in an 8 week period. 
6 All mechanistic blood draws are performed prior to any oral food challenges. 
7 Daily home dosing for Baked Egg. Telephone contacts will occur monthly in between clinic visits. 
8 Discontinue Baked Egg therapy. 
9 Only if desensitization challenge is passed, a repeat challenge off therapy in approximately 8-10 weeks will be performed 
10 Subjects will return at month 9 to assess dosing compliance and any adverse events. 
11 Subjects who pass the sustained unresponsiveness oral food challenge will complete the follow-up outlined in Appendix 1-D 


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12 All subjects will be annually contacted by telephone starting 3 years after randomization, through a maximum of September 2018.   


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Appendix 1.C.  Subject Central Laboratory Assessments 
Study Visit      Visit 00     Visit 02**     Visit 03**      Visit 04**     Visit 05**    Visit 06**     Visit 07**     Visit 08 
Assessment*      Screening     3 month      6 month      (1 year)      16 month     20 month      (2 year)     ~26 months 
UniCAP 
X 
X 
X 
X 
X 
X 
X 
X 
Serum/Plasma 
based assays 
X 
X 
X 
X 
 
 
X 
X 
T cells based 
assays 
X 
X 
X 
X 
 
 
X 
X 
Basophil assays      X 
X 
X 
X 
X 
X 
X 
X 
Epitope 
microarray 
X 
 
 
X 
 
 
X 
X 
Estimated Blood 
draw needed for 
Processing1 
50cc      
50cc      
50cc 
50cc      
10cc      
10cc      
50cc      
50cc 
* Labs will be drawn prior to that days’ allergen dose. 
** Labs may be drawn early if, due to symptoms, subject is removed from study therapy during escalation or build up. 
1Blood draws will not exceed 50 cc in a day but no more than 5cc/kg in 24hrs or 9.5 cc/kg in 8 weeks. 
Appendix 1.D.  Egg Sustained Unresponsiveness Long Term Follow-up 
Study Visit 
Visit F 012 
Visit F 022 
3 months post final OFC 
Phone Assessment 
6 months post final OFC 
In person 
Egg Related Diet History 
X 
X 
Egg reaction history 
X 
X 
Blood draw with Processing1 
 
50cc 
1 Blood draws will not exceed 50 cc in a day but no more than 5cc/kg in 24hrs or 9.5 cc/kg in 8 weeks. 
2Visit F 01 and F 02 are to be completed by subjects who pass the sustained unresponsiveness oral food challenge. 


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Appendix 2.  Evaluation of Asthma 
The evaluation of asthma severity will be assessed using the NHLBI classification published August 28, 2007 as described in the table 
below. 
Classification   Symptoms 
Nighttime 
awakenings 
Lung Function 
Interference with 
normal activity 
Short acting beta-agonist use 
Intermittent 
(Step 1) 
<2 days per week      <2x/month    Normal FEV1 between 
exacerbations 
FEV1>80% predicted 
FEV1/FVC normal* 
None 
<2 days/week 
Mild Persistent 
(Step 2) 
>2 days per week but not 
daily 
 
3-4x/month   FEV1 > 80% predicted 
FEV1/FVC normal* 
Minor limitation   >2 days/week but not 
>1x/day 
Moderate 
Persistent 
(Step 3 or 4) 
Daily  
> 1x/week but 
not nightly 
FEV1 >60% but <80% 
predicted 
FEV1/FVC reduced 5%* 
Some limitation   Daily 
Severe 
Persistent 
(Step 5 or 6) 
Throughout the day     Often 7x/week  FEV1<60% predicted 
FEV1/FVC reduced >5%* 
Extremely limited  Several times per day 
*Normal FEV1/FVC: 8-19 yr = 85%; 20-39 yrs = 80 
 


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Appendix 3.  Anaphylaxis Staging System 
Staging System of Severity of Anaphylaxis 
Stage 
Defined By 
1. Mild (skin & subcutaneous tissues, GI, 
&/or mild respiratory) 
Flushing, urticaria, periorbital or facial angioedema; 
mild dyspnea, wheeze or upper respiratory symptoms; 
mild abdominal pain and/or emesis 
2. Moderate (mild symptoms + features 
suggesting moderate respiratory, 
cardiovascular or GI symptoms) 
Marked dysphagia, hoarseness and/or stridor; shortness 
of breath , wheezing & retractions; crampy abdominal 
pain, recurrent vomiting and/or diarrhea; and/or mild 
dizziness 
3. Severe (hypoxia, hypotension, or 
neurological compromise) 
Cyanosis or SpO2 < 92% at any stage, hypotension, 
confusion, collapse, loss of consciousness; or 
incontinence 
 
Criteria for Diagnosis 
Anaphylaxis is likely when any 1 of the three following sets of criteria are fulfilled: 
       
1.  Acute onset of an illness (minutes to hours) with involvement of: 
•  Skin/mucosal tissue (e.g., generalized hives, itch or flush, swollen lips/tongue/uvula) 
AND 
•  Airway compromise (e.g., dyspnea, stridor, wheeze/ bronchospasm, hypoxia, reduced 
PEF) AND/OR 
•  Reduced BP or associated symptoms (e.g., hypotonia, syncope, incontinence) 
2.  Two or more of the following that occur rapidly after exposure to the allergen (minutes to 
hours): 
•  Skin/mucosal tissue (e.g., generalized hives, itch/flush, swollen lips/tongue/uvula) 
•  Airway compromise (e.g., dyspnea, stridor wheeze/bronchospasm, hypoxia, reduced 
PEF) 
•  Reduced BP or associated symptoms (e.g., hypotonia, syncope, incontinence) 
•  Persistent GI symptoms (e.g., nausea, vomiting, crampy abdominal pain) 
3. Reduced BP after exposure to the allergen (minutes to hours): 
•  Infants and Children: low systolic BP (age-specific) or > 30% drop in systolic BP* 
•  Adults: systolic BP < 90 mm Hg or > 30% drop from their baseline 
* Low systolic BP for children is defined as < 70 mmHg from 1 month to 1 year; less than (70 mmHg + [2 x age]) from 
1-10 years; and < 90 mmHg from age 11-17 years. 
** Isolated skin or mucosal lesions following the ingestion of a food constitute a “food-induced allergic reaction”. 


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Appendix 4.  Allergic Reaction Toxicity Grading 
Current NCI-CTCAE v. 4.03 grading system for allergic reactions defined as a disorder 
characterized by an adverse local or general response from exposure to an allergen. 
Grade 1 - Mild   Grade 2 - Moderate     Grade 3 – Severe 
Grade 4 – Life-
threatening 
Grade 5 - Death 
Transient 
flushing or rash, 
drug fever <38 
degrees C 
(<100.4 degrees 
F); intervention 
not indicated 
Intervention or infusion 
interruption indicated; 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics); 
prophylactic medications 
indicated for <=24 hrs 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
Current NCI-CTCAE v. 4.03 grading system for anaphylaxis reactions defined as a disorder 
characterized by an acute inflammatory reaction resulting from the release of histamine and 
histamine-like substances from mast cells, causing a hypersensitivity immune response. 
Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of 
consciousness and may lead to death. 
 
Grade 1 - Mild  Grade 2 - Moderate  Grade 3 - Severe      
Grade 4 – Life-threatening  Grade 5- Death 
- 
-      
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
 
These tables will be replaced with the CoFAR specific  grading system for allergic reactions as 
displayed below. 
 
Grade 1 - Mild    Grade 2 - Moderate     Grade 3 – Severe      Grade 4 - Life threatening  Grade 5 - Death 
Transient or mild 
discomforts (<48 
hours), no or 
minimal medical 
intervention/thera-
py required. These 
symptoms may 
include pruritus, 
swelling or rash, 
abdominal 
discomfort or 
other transient 
symptoms. 
Symptoms that produce 
mild to moderate 
limitation in activity 
some assistance may be 
needed; no or minimal 
intervention/therapy is 
required. 
Hospitalization is 
possible. These 
symptoms may include 
persistent hives, 
wheezing without 
dyspnea, abdominal 
discomfort/ increased 
vomiting or other 
symptoms 
Marked limitation in 
activity, some assistance 
usually required; medical 
intervention/therapy 
required, hospitalization 
is possible. Symptoms 
may include 
Bronchospasm with 
dyspnea, severe 
abdominal pain, throat 
tightness with 
hoarseness, transient 
hypotension among 
others. parenteral 
medication(s) are usually 
indicated. 
Extreme limitation in 
activity, significant 
assistance required; 
significant 
medical/therapy. 
Intervention is required; 
hospitalization is 
probable. Symptoms may 
include persistent 
hypotension and/or 
hypoxia with resultant 
decreased level of 
consciousness associated 
with collapse and/or 
incontinence or other life 
threatening symptoms. 
Death 


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Appendix 5.  References 
                                                 
 
 
 
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69 Sampson HA, Broadbent KR, Bernhisel-Broadbent J. Spontaneous release of histamine from basophils and 
histamine-releasing factor in patients with atopic dermatitis and food hypersensitivity. N Engl J Med 1989; 
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70 Shreffler WG.  Evaluation of basophil activation in food allergy: present and future applications. 
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77 Busse PJ, Jarvinen KM, Vila L, Beyer K, Sampson HA. Identification of sequential IgE-binding epitopes on 
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78 Jarvinen KM, Beyer K, Vila L, Chatchatee P, Busse PJ, Sampson HA. B-cell epitopes as a screening instrument 
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86 Shreffler WG, Lencer DA, Bardina L, Sampson HA. IgE and IgG4 epitope mapping by microarray immunoassay 
reveals the diversity of immune response to the peanut allergen, Ara h 2. J Allergy Clin Immunol 2005; 116(4):893-
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89 Campbell, J.D., et al., Allergen-specific T cell responses to immunotherapy monitored by CD154 and intracellular 
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94 Ansel, K.M., et al., In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their 
response to lymphoid chemokines. J Exp Med, 1999. 190(8): p. 1123-34. 
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CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially 
support antibody secretion. Immunity 2011; 34(1):108-21. 

SAP_000.pdf: 
NCT #01846208
Statistical Analysis Plan for Oral Desensitization to Egg with Subsequent Induction of 
Sustained Unresponsiveness for Egg-Allergic Children Using Baked Egg or Egg Oral 
Immunotherapy (OIT)
PI: Dr. Hugh A. Sampson
Document Date: April 16, 2018


STATISTICAL ANALYSIS PLAN 
for 
Consortium of Food Allergy Research 
(CoFAR) 
Study Title: Oral Desensitization to Egg with Subsequent 
Induction of Sustained Unresponsiveness for Egg-Allergic 
Children using Baked Egg or Egg Oral Immunotherapy 
(OIT) 
Version 1.0 
April 16, 2018 
Prepared and distributed by: 
The Emmes Corporation 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL 


Statistical Analysis Plan 
Version 1.0 
CoFAR7 Baked Egg/Egg OIT 
April 16, 2018 
- 2 - 
THIS IS A PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
Study Title: Oral Desensitization to Egg with Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children using Baked Egg or Egg Oral Immunotherapy 
(OIT) 
Development Phase: 
Phase II 
Products: 
Egg Oral Immunotherapy or Baked Egg 
Form/Route: 
Oral 
Indication Studied: 
Egg Allergy 
Sponsor: 
NIAID 
Protocol Chairs: 
Hugh Sampson, MD 
Robert Wood, MD 
NIH Medical Officer: 
Marshall Plaut, MD 
SACCC Medical Monitor: 
Robert Lindblad, MD 
SACCC Biostatistician: 
Peter Dawson, PhD 
Clinical Trial Initiation Date: 
June 2013 
Clinical Trial Completion Date: 
November 2018 (estimated) 
Date of the Analysis Plan: 
April 16, 2018 
SAP Version Number: 
1.0 
This study was performed in compliance with Good Clinical Practice. 
 
 


Statistical Analysis Plan 
Version 1.0 
CoFAR7 Baked Egg/Egg OIT 
April 16, 2018 
- 3 - 
THIS IS A PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
SIGNATURE PAGE 
SPONSOR: 
 
National Institute of Allergy and Infectious Disease (NIAID) 
STUDY TITLE: 
Oral Desensitization to Egg with Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children using Baked Egg or Egg 
Oral Immunotherapy (OIT) 
 
Principal Investigator: Hugh Sampson, MD 
Signed: 
 
Date: 
 
Co-Principal Investigator: Robert Wood, MD 
Signed: 
 
Date: 
 
NIAID Representative: Marshall Plaut, MD 
Signed: 
 
Date: 
 
Emmes: Peter Dawson, PhD 
Signed: 
 
Date: 
 
 


Statistical Analysis Plan 
Version 1.0 
CoFAR7 Baked Egg/Egg OIT 
April 16, 2018 
- 4 - 
THIS IS A PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
TABLE OF CONTENTS 
Terms and Abbreviations ....................................................................................................... 6 
1 
PREFACE ............................................................................................................................ 7 
2 
INTRODUCTION ................................................................................................................ 7 
2.1 
Purpose of the Analyses ......................................................................................................... 7 
3 
STUDY OBJECTIVES AND ENDPOINTS .............................................................................. 7 
3.1 
Study Objectives ................................................................................................................... 8 
3.2 
Endpoints .............................................................................................................................. 9 
3.3 
Study Definitions and Derived Variables .................................................................................. 9 
4 
INVESTIGATIONAL PLAN ................................................................................................11 
4.1 
Overall Study Design and Plan .............................................................................................. 11 
4.2 
Discussion of Study Design, Including the Choice of Control Groups ....................................... 15 
4.3 
Selection of Study Population ............................................................................................... 15 
4.3.1 
Inclusion Criteria .............................................................................................................. 16 
4.3.2 
Exclusion Criteria.............................................................................................................. 16 
4.4 
Treatments ......................................................................................................................... 16 
4.4.1 
Treatments Administered .................................................................................................. 17 
4.4.2 
Method of Assigning Participants to Treatment Groups (Randomization) .............................. 17 
4.4.3 
Blinding ........................................................................................................................... 18 
5 
SAMPLE SIZE CONSIDERATIONS ....................................................................................18 
6 
GENERAL STATISTICAL CONSIDERATIONS ....................................................................18 
6.1 
General Principles ................................................................................................................ 19 
6.2 
Timing of Analyses .............................................................................................................. 19 
6.3 
Analysis Populations ............................................................................................................ 19 
6.4 
Covariates and Subgroups .................................................................................................... 19 
6.5 
Missing Data ....................................................................................................................... 19 
6.6 
Interim Analyses and Data Monitoring .................................................................................. 20 
6.7 
Multicenter Studies .............................................................................................................. 20 
6.8 
Multiple Comparisons/Multiplicity .......................................................................................... 20 
7 
STUDY PARTICIPANTS ....................................................................................................20 
7.1 
Participant Disposition ......................................................................................................... 20 
7.2 
Protocol Deviations .............................................................................................................. 20 
8 
EFFICACY EVALUATION ..................................................................................................20 
8.1 
Demographic and Other Baseline Characteristics ................................................................... 20 
8.1.1 
Concurrent Illnesses and Medical Conditions ...................................................................... 21 
8.1.2 
Prior and Concurrent Medications ...................................................................................... 21 
8.2 
Measurements of Treatment Compliance .............................................................................. 21 


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8.3 
Efficacy Analyses ................................................................................................................. 21 
8.3.1 
Primary Efficacy Analysis .................................................................................................. 21 
8.3.2 
Secondary Efficacy Analyses ............................................................................................. 21 
8.3.3 
Exploratory Efficacy Analyses ............................................................................................ 22 
9 
SAFETY EVALUATION ......................................................................................................22 
9.1 
Adverse Events.................................................................................................................... 23 
9.1.1 
Solicited Adverse Events and Symptoms – Dosing Symptoms .............................................. 23 
9.1.2 
Other Adverse Events ....................................................................................................... 23 
9.1.2.1 OFC Symptoms ............................................................................................................. 23 
9.1.2.2 Food Allergy Episodes ................................................................................................... 23 
9.1.2.3 Other Treatment Emergent Adverse Events .................................................................... 24 
9.2 
Deaths, Serious Adverse Events and other Significant Adverse Events .................................... 24 
9.3 
Pregnancies ........................................................................................................................ 24 
9.4 
Clinical Laboratory Evaluations ............................................................................................. 24 
9.5 
Vital Signs and Physical Evaluations ...................................................................................... 24 
9.6 
Concomitant Medications ..................................................................................................... 24 
10 
PHARMACOKINETICS ......................................................................................................24 
11 
MECHANISTIC ANALYSES ...............................................................................................24 
12 
OTHER ANALYSES ...........................................................................................................26 
13 
TECHNICAL DETAILS .......................................................................................................27 
14 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ....27 
15 
REFERENCES ...................................................................................................................27 
16 
LISTING OF TABLES, FIGURES AND LISTINGS ...............................................................27 
  


Statistical Analysis Plan 
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Terms and Abbreviations 
AE 
Adverse Event 
ATS 
American Thoracic Society 
CFR 
Code of Federal Regulations 
COFAR 
Consortium of Food Allergy Research 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DAIT 
Division of Allergy, Immunology and Transplantation 
DSMB 
Data and Safety Monitoring Board 
EOIT 
Egg Oral Immunotherapy 
FAE 
Food Allergy Episode 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
ITT 
Intention to Treat 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OFC 
Oral Food Challenge 
PEF 
Peak Expiratory Flow 
PT 
Preferred Term 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCD 
Successfully Consumed Dose 
SIT 
Specific Allergen Immunotherapy  
SOC 
System Organ Class 
SPT 
Skin Prick Test 
TEAE 
Treatment Emergent Adverse Event 


Statistical Analysis Plan 
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1 
PREFACE 
The Statistical Analysis Plan (SAP) for Oral Desensitization to Egg with Subsequent Induction of Sustained 
Unresponsiveness for Egg-Allergic Children using Baked Egg or Egg Oral Immunotherapy (OIT) describes 
and expands upon the statistical information presented in the protocol. This trial is sponsored by the NIAID 
and was designed and implemented at NIAID funded CoFAR sites. The Emmes Corporation serves as the 
SACCC for CoFAR. 
This document describes all planned analyses and provides reasons and justifications for these analyses. A 
listing of tables, listings, and figures planned for the final analyses are provided in a separate document. 
Regarding the final analyses and Clinical Study Report (CSR), this SAP follows the International Conference 
on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 
Guidelines, as indicated in Topic E3 (Structure and Content of Clinical Study Reports), and more generally is 
consistent with Topic E8 (General Considerations for Clinical Trials) and Topic E9 (Statistical Principles for 
Clinical Trials). The structure and content of the SAP provides sufficient detail to meet the requirements 
identified by the FDA and ICH, while all work planned and reported for this SAP will follow internationally 
accepted guidelines published by the American Statistical Association and the Royal Statistical Society for 
statistical practice. 
This document contains three sections: (1) a review of the study design, (2) general statistical 
considerations, and (3) comprehensive statistical analysis methods for efficacy and safety outcomes. Any 
deviation from this SAP will be described and justified in protocol amendments and/or in the CSR, as 
appropriate. The reader of this SAP is encouraged to also review the study protocol for details on conduct of 
the study and the operational aspects of clinical assessments. 
2 
INTRODUCTION 
The overarching goal of this study is to advance the development of safe and effective treatments for egg 
allergic patients. Previous research has shown efficacy for administration of egg oral immunotherapy (eOIT) 
in this population. This study compares the efficacy and safety of eOIT vs administration of baked egg in 
baked egg tolerant participants. The section below provides more detail on the purpose of the analysis. 
2.1 
Purpose of the Analyses 
The purpose of this trial is to assess the efficacy and safety of eOIT compared to baked egg in egg allergic 
but baked egg tolerant participants. This is an unblinded multicenter randomized trial without a placebo 
control.  Baked egg tolerant participants were randomized to receive either eOIT or baked egg daily. An OFC 
will be performed at Year 2 to assess desensitization followed by an OFC off-therapy with an open feeding to 
assess sustained unresponsiveness (the primary efficacy endpoint). In addition, 40 baked egg intolerant 
participants were enrolled and assigned to eOIT to facilitate comparison of the efficacy and safety of eOIT in 
baked egg tolerant compared to baked egg intolerant participants. Secondary endpoints address safety and 
alternate measures of efficacy as well as immunologic comparisons. The timing of the analyses are defined 
in Section 6.2. 
3 
STUDY OBJECTIVES AND ENDPOINTS 
This section focuses on protocol-specified study objectives (Section 3.1), protocol-specified endpoints 
(Section 3.2) and operational definitions for those endpoints (Section 3.3). Throughout the SAP, successfully 
consumed dose (SCD) refers to the cumulative dose consumed without dose limiting symptoms. 


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Throughout this document, the doses of egg white solid for Egg OIT are given in milligrams of egg white 
solid, not egg white protein. It is estimated that 1 mg egg white solid is equivalent to approximately 0.70 mg 
of egg white protein. 
3.1 
Study Objectives 
The primary objective of the study is to determine in baked-egg tolerant, but egg-allergic, children whether 
daily baked egg therapy vs. daily oral administration of egg white solid escalated to a maximum of 2500 
mg/day, increases sustained unresponsiveness as measured by a 7444 mg egg white protein OFC performed 
8-10 weeks after therapy discontinuation by the 2 year time point. 
Secondary objectives are to: 
1. Determine the percentage of subjects who can successfully consume without dose limiting 
symptoms at least 4444 mg egg white protein of a 7444 mg egg white protein OFC after the initial 
desensitization phase of approximately 1 year of the study and at 2 years. 
2. Determine the incidence of all serious adverse events. 
3. Characterize unrestricted egg consumption after conclusion of treatment via long term follow-up. 
Tertiary (mechanistic) objectives include testing the following hypotheses: 
1. The development of clinical sustained unresponsiveness to egg is associated with a reduction in 
allergen-specific Th2 effector cells, an increase in allergen-specific T regulatory (Treg) cells, and an 
induction of allergen-specific T follicular helper (Tfh) cells. 
2. The development of the desensitized state to egg is associated with the down-regulation of 
basophils. 
3. The persistence of egg allergy is associated with an epitope-specific IgE antibody profile that is 
distinct from persons who lose their clinical allergy to egg. 
4. Sustained unresponsiveness will be associated with a predictive transcriptional signature detectable 
in whole blood or allergen restimulated PBMCs.  
While the above objectives have been framed in terms of the randomized comparison that is central to this 
study, individuals who comprise the Egg OIT assignment group will have endpoints similar to the randomized 
cases. The assignment group will be compared to the randomized arms and evaluated for sustained 
unresponsiveness, desensitization, safety and immune system function. It is anticipated that this group will 
have less desensitization and sustained unresponsiveness success than the randomized Egg OIT subjects. If 
supported by the results, it will be an objective to determine if immune parameter studies can help explain 
the differences. 


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3.2 
Endpoints 
The primary clinical efficacy endpoint is the development of sustained unresponsiveness to egg consumption 
at 
2 
years 
as 
assessed 
with 
a 
7444 
mg 
egg 
white 
protein 
OFC 
and 
open 
feeding, 
8-10 weeks after discontinuing therapy. 
The secondary endpoints are as follows: 
 
The development of desensitization to ≥4444 mg egg white protein at 1 year and 2 years. 
 
Incidence of all serious adverse events during the study. 
 
Changes in egg-specific IgE and IgG4, changes in PST mean wheal diameters, basophil reactivity, 
CD154+ CD4+ Th2 cells, Tregs, and Tfh cells as described further in Sections 3.3 and 11.  
 
Unrestricted consumption of unbaked egg as reported on the annual long term questionnaire. 
3.3 
Study Definitions and Derived Variables 
The primary endpoint of the study will be the development of sustained unresponsiveness to a 7444 mg egg 
white protein OFC followed by open consumption of a whole egg, 8-10 weeks after discontinuing 2 years of 
daily Baked Egg or Egg OIT. OFCs will be conducted in a supervised setting and safety parameters will be 
carefully monitored. Individuals off therapy for 8-10 weeks, successfully demonstrating consumption of 7444 
mg egg white protein during OFC without dose-limiting symptoms followed by an open feeding of a meal-
sized portion of egg are considered successes; those not receiving the open feeding of a meal-sized portion 
of egg due to site error are also considered successes. Individuals who do not attempt this off therapy OFC 
or do not successfully consume 7444 mg egg white protein for this off therapy OFC will be considered 
“failures” with respect to this endpoint.  
For the desensitization endpoint, all individuals with an SCD ≥ 4444 mg egg white protein will be considered 
successes All others will be considered “failures” with respect to this endpoint. 
For safety endpoints, the pre-defined secondary endpoint is the incidence of serious adverse events. 
Additional safety endpoints of interest include the incidence of adverse events related to dosing which will be 
estimated from the dosing symptom logs. For the first 12 months on therapy, or for the time until reaching 
the maximum maintenance dose if this occurs after 12 months, all dosing symptom logs are required to be 
submitted. Otherwise, only doses with reactions or missed doses have dosing symptom logs reported in the 
data system. All non-reported doses are assumed to have been successfully administered without reaction or 
treatment required. To estimate the number of doses administered, the following algorithm will be used: 
Through Week 52: Date of last dose is calculated as the minimum of the completion date of the Week 52 
OFC, the drug discontinuation date and the study withdrawal date minus one day. It is assumed that a dose 
would not occur on the day of Week 52 OFC.  


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The number of expected doses will be calculated as days from treatment initiation to date of last dose and 
the percent of doses administered will be calculated as administered doses/expected doses. 
After Week 52: For subjects who discontinued dosing or withdrew from the study, the date of last dose is 
calculated as the minimum of the drug discontinuation date and the study withdrawal date minus one day. 
For subjects who did not discontinue dosing or withdraw, the date of last dose is calculated as the maximum 
of the date of last study visit and the day before their Year 2 desensitization OFC. Doses without dosing 
symptom logs that are to have occurred after 12 months but before the date of last dose are counted as 
doses that were administered with no symptoms. It is assumed that a dose would not occur on the day of 
the Year 2 desensitization OFC.  
The number of expected doses will be calculated as days from the day after the Week 52 OFC through the 
discontinuation above. The percent of doses administered will be calculated as administered doses/expected 
doses. 
Derived variables for mechanistic data are as follows: 
1. % antigen-specific IgE = (antigen specific IgE / total IgE) X 100 
Egg-specific IgG4/IgE: The egg specific IgG4/IgE ratio was calculated by converting IgG4 level from mgA/L 
to ng/mL and converting IgE level from kUA/L to ng/mL with the formula (IgG4 × 1000) ÷ (IgE × 2.4).  
2. Activated Basophils = % CD63+ cells 
3. Frequency and phenotype of egg-responsive T cells: 
From 6 hour flow cytometry data: 
a. CD154+CD3+CD4+ cell count (per million CD3+/CD4+) 
b. CD154+CD3+CD4+(X)+, where X is IL-4, IL-13, IFN-g, IL-10, CCR4, CCR6, or CXCR5:  
1. Cell count (per million CD3+/CD4+) 
2. Frequency of CD154+CD3+CD4+, shown as a percentage 
3. Delta (Egg-Media, CD3/CD28-Media).  
c. CD154+CD25+CD127-CD3+CD4+ cell count (per million CD3+/CD4+) 
From 18 hour data: 
a. CD154+CD25+CD127-Foxp3+CD3+CD4+ cell count (per million CD3+/CD4+) 
b. CD154+CD25+CD127-Foxp3+CD3+CD4+(X)+, where X is IFN-g, IL-10, CCR4, CCR6, or CCR9: 
1. Cell count (per million CD3+/CD4+) 
2. Frequency of CD154+CD25+CD127-Foxp3+CD3+CD4+, shown as a percentage 
3. Delta (Egg-Media, CD3/CD28-media) 
Effector regulatory ratio (Th2:Treg ratio): 
This ratio is defined as CD154+CD3+CD4+IL4+ cell count (from 6h assay)/CD154+CD25+CD127-
Foxp3+CD3+CD4+ cell count (at 18h), each adjusted with the same denominator (i.e., per million 
CD3+CD4+ cells). 


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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
To effectively address the Primary and Secondary Objectives of this interventional study, we will enroll 
subjects, age 3 through 16 years, either sex, any race, any ethnicity with a serum IgE [UniCAPTM] to egg of 
> 5 kUA/L [determined by UniCAPTM within the past 12 months]. All subjects will have documented consent 
and assent as is appropriate. Females of childbearing age will use appropriate birth control. These subjects 
will be recruited from 5 sites. All eligible subjects will receive the double-blind placebo controlled baked egg 
OFC. Approximately the first 40 individuals who do not pass this initial baked egg food challenge will be 
assigned to Egg OIT. Enrollment in this group will be capped at approximately 40 individuals though those 
consented but not yet challenged when this group reaches 40 will be allowed to proceed and if they fail the 
baked egg challenge will be assigned to the egg OIT assignment group. This may result in slightly over 40 
cases in this group which is acceptable. Individuals who pass the baked egg OFC will then have an initial egg 
OFC. Those who have dose-limiting symptoms at a cumulative dose of < 1444 mg egg white protein will be 
randomized 1:1 to Baked Egg or Egg OIT. Those who successfully consume more than 1444 mg of egg 
white protein on the OFC will not be eligible for the study and will be followed per local standard of care. 
Those assigned or randomized to Egg OIT will escalate the dose of egg white solid to achieve the desired 
maintenance dose of 2500 mg. Those randomized to the Baked Egg group will continue on the baked egg 
product for the remainder of the study. 
A schematic is presented below: 


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CoFAR7 Schema 
 


Statistical Analysis Plan 
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For the purposes of this study, clinical details and blood samples will be collected at specified intervals. If a 
subject is removed from therapy because of failing escalation or build-up, a blood sample for mechanistic 
studies will be obtained within approximately 1 week of removal from therapy. 
The Baked Egg Group 
The Baked Egg group will use approximately 2 gm of baked egg as a daily dose throughout the study as 
described below. 
Baked egg therapy will consist of a muffin or equivalent (1/3 of egg in serving, approximately 
2 gm). 
Home baked products will have no more than 2 eggs per batch of recipe (yield 6 servings). Serving size is 
indicated by the yield of the recipe. Products will be baked for 25-50 minutes at 325-425 degrees Fahrenheit. 
Recipes will be provided. The daily dose can be administered at a single sitting or divided throughout the 
dosing day. Adjustments in the daily dosing may be made at the investigators discretion based on symptoms 
experienced by the subjects in the baked egg group. 
Dietary information will be provided to the subject regarding allowed consumption of various commercial 
foods consistent with approximately 2 gm of baked egg per daily dose. Subjects in this arm will be 
encouraged to ingest “safe” commercial products in addition to their daily 2 gm intake of baked egg protein. 
These foods will be recorded on the daily logs. 
The Egg OIT Groups 
The egg OIT (eOIT) treatment is administered in 2 treatment groups, eOIT-Randomized and eOIT-Assigned, 
that may experience different paths for OIT treatment. The group randomized to receive eOIT treatment 
that have passed the baseline baked egg OFC (eOIT-Randomized) and the group assigned to receive eOIT 
(eOIT-Assigned) that have failed the baseline baked egg OFC. The group that fails the baked egg challenge 
may be more sensitive to egg dosing, and may experience more reactivity and adverse reactions. These 
subjects will stop at 12 mg egg white solid on the initial day escalation and thereby have a slightly slower 
escalation time course. 
The egg OIT treatment is comprised of an initial escalation day, an initial build-up phase to last a maximum 
of 44 weeks, and followed by at least 8 weeks of daily therapy at the maximum achieved dose (350 mg - 
2500 mg egg white solid). 


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Dosing Schedule for Egg OIT 
 
Daily Dosing and Delivery Method 
Dose # 
Dose egg 
white 
solid  
Dose 
Method 
Interval 
(weeks) 
% Increase 
8 
12 mg 
Vial 
2 
 
9 
25 mg 
Vial 
2 
108% 
10 
50 mg 
capsule* 
2 
100% 
11 
75 mg 
capsule 
2 
50% 
12 
100 mg 
capsule 
2 
33% 
13 
150 mg 
capsule 
2 
50% 
14 
225 mg 
capsule 
2 
50% 
15 
260 mg 
scoop 0† 
2 
15% 
16 
350 mg 
scoop 1 
2 
35% 
17 
450 mg 
scoop 2 
2 
30% 
18 
550 mg 
scoop 3 
2 
20% 
19 
700 mg 
scoop 4 
2 
25% 
20 
830 mg 
scoop 5 
2 
20% 
21 
1100 mg 
scoop 6 
2 
30% 
22 
1320 mg 
scoop 7 
2 
20% 
23 
1720 mg 
scoop 8 
2 
30% 
24 
2130 mg 
scoop 9 
2 
25% 
25 
2500 mg 
scoop 10 
2 
15% 
* Capsules are opened and contents sprinkled over an age-
appropriate food. 
†All scoops are approximate weights based on scoop size and 
leveling. 
 
 
 
 
 
 
 
 
 
 
Those subjects who achieved a dose of 2500 mg egg white solid during the initial build-up period will 
continue maintenance therapy for up to 12 months after the 1 year 7444 mg egg white protein OFC. Those 
subjects who achieved less than 2500 mg during the initial buildup phase will be escalated from their 
maintenance dose (pre-1-year 7444 mg egg white protein OFC) up to 2500 mg, if tolerated, following the 
Initial Day Escalation Schedule 
Dose no.       Egg white solid dose (mg)     Cumulative Egg dose (mg)* 
1 
 
0.1 mg 
 
 
 
0.1 mg 
2 
 
0.2 mg 
 
 
 
0.3 mg 
3 
 
0.4 mg`  
 
 
0.7 mg 
4 
 
0.8 mg 
 
 
 
1.5 mg 
5 
 
1.5 mg 
 
 
 
3.0 mg 
6 
 
3.0 mg 
 
 
 
6.0 mg 
7 
 
6.0 mg 
 
 
 
12  mg 
8 
 
12 mg 
 
 
 
24  mg 
9 
 
25 mg 
 
 
 
49  mg 
* If no de-escalation 
Frequency standard every 30 min 
Subjects at the end of the first day, tolerating less than 3 mg single dose, 
will be considered an initial day escalation desensitization failure. 
The Egg OIT assignment group (that failed the Baked Egg challenge) 
will only escalate to 12 mg maximum on Day 1. 
Subjects tolerating only 3, 6 or 12 mg single dose will go home on the 
greatest tolerated dose to be given daily (first dose given in Clinical 
Research Center under observation). All escalations will occur no sooner 
than 2 weeks and single dose increases in the Clinical Research Center 
from 3 to 6 to 12 to 25 mg will be attempted. These doses will be weighed 
doses in individual vials until the maximum 25 mg dose is reached. 
All subjects will return on Day 2 and receive their maximum tolerated dose 
under direct observation. 
Subjects with moderate symptoms observed on Day 2 will return on Day 3 
for the next lower dose under observation in the Clinical Research Center or 
monitored clinic setting. 
Doses on Day 2, 3, and 4 must be at least 3 mg or the subject will be 
considered an escalation failure. 


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same escalation time table from the initial build-up phase. No dose escalation will be performed within 1 
month of a subject’s planned 2 year 7444 mg egg white protein OFC. 
Follow-up OFCs 
At 1 year: 
Those subjects still on active treatment (baked egg or egg OIT) will have a 7444 mg egg white protein OFC 
on therapy at 1 year to identify desensitized individuals. 
At 2 years: 
Those subjects still on active treatment (baked egg or egg OIT) will have a 7444 mg egg white protein OFC 
on therapy at 2 years. Those subjects still on active therapy, but escalating doses, will discontinue escalation 
for 1 month prior to their 2 year 7444 mg egg white protein OFC and will be maintained on their highest 
tolerated dose. Those who pass the 2 year egg 7444 mg egg white protein OFC on therapy will have a 
repeat 7444 mg egg white protein OFC after 8-10 weeks off therapy to test for sustained unresponsiveness. 
If they pass this OFC off therapy (including open feeding), they will add egg to their diet and will be followed 
at 3 months by phone and at 6 months in clinic to assess their egg diet history and reactivity status to egg. 
If they fail the 2 year 7444 mg egg white protein OFC on or off therapy, they will stop therapy and the study 
physician will review treatment options. 
4.2 
Discussion of Study Design, Including the Choice of Control Groups 
The design considers important safety issues: 
 
All dose escalations will be supervised in the clinic. 
 
The Egg OIT assignment group (that failed the baked egg challenge) will only escalate to 12 mg egg 
white solid maximum during the initial escalation on Day 1. 
 
OFC can delineate individuals who can ingest egg safely in a supervised setting.  
 
The relationship of egg-specific IgE to OFC results is unknown in individuals consuming baked egg or 
350 - 2500 mg of egg white solid daily for up to a year. Thus, after long-term therapy, an egg OFC 
will be needed to determine sustained unresponsiveness irrespective of their egg-specific IgE level, 
and this will be performed safely in a supervised setting. 
In addition, study enrollment will be suspended pending expedited review of all pertinent data by the NIAID 
DSMB if the following occurs: 
 
Any death related to Baked Egg or Egg OIT dosing. 
 
More than 1 severe anaphylactic reaction (see Appendix 3 of the protocol) related to Baked Egg or 
Egg OIT dosing at any stage of the protocol. 
 
More than 3 treatment-related non-anaphylaxis severe adverse events (including EoE). 
 
More than 1 serious suspected adverse reaction occurs (serious and related). 
 
More than 3 subjects who require more than 1 injection of epinephrine for a single study product 
related allergic reaction during the study therapy. 


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4.3 
Selection of Study Population 
The study population was selected based on prior studies of egg OIT.  A pre-enrollment study OFC was 
required to demonstrate evidence of egg allergy. 
Detailed study inclusion and exclusion criteria are listed below. 
4.3.1 Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for enrollment as study subjects: 
 
Age 3 through 16 years with a serum IgE [UniCAPTM] to egg of > 5 kUA/L [determined by UniCAPTM 
within the past 12 months]. 
 
Reacting to the baked egg challenge OFC with dose limiting symptoms (approximately 40 subjects), 
OR 
 
Reacting on an initial egg OFC with dose limiting symptoms to a cumulative dose of 1444 mg egg 
white protein or less after passing the initial baked egg OFC. 
 
Written informed consent from subject and/or parent/guardian. 
 
Written assent from all subjects as is appropriate. 
 
All females of child-bearing age must be using appropriate birth control. 
4.3.2 Exclusion Criteria 
Subjects who meet any of these criteria are not eligible for enrollment as study subjects: 
 
History of anaphylaxis to egg resulting in hypotension, neurological compromise or mechanical 
ventilation. 
 
Chronic disease (other than asthma, atopic dermatitis, rhinitis) requiring therapy (e.g., heart 
disease, diabetes). 
 
Active eosinophilic gastrointestinal disease in the past 2 years. 
 
Participation in any interventional study for the treatment of food allergy in the past 6 months. 
 
Subject is on “build-up phase” of immunotherapy (i.e., has not reached maintenance dosing). 
Subjects tolerating maintenance allergen immunotherapy can be enrolled. 
 
Severe asthma (2007 NHLBI Criteria Steps 5 or 6, see Appendix 2 of the protocol). 
 
Mild or moderate (2007 NHLBI Criteria Steps 1-4) asthma with any of the following criteria met: 
o 
FEV1 <80% of predicted, or FEV1/FVC <75%, with or without controller medications (only 
for age 6 or greater and able to do spirometry), or 
o 
ICS dosing of >500 mcg daily fluticasone (or equivalent inhaled corticosteroids based on 
NHLBI dosing chart), or 
o 
1 hospitalization in the past year for asthma, or 
o 
1 ER visit in the past 6 months for asthma. 
 
Use of steroid medications (IV, IM or oral) for asthma in the following manners: 
o 
history of daily oral steroid dosing for >1 month during the past year, or 
o 
burst or steroid course in the past 3 months, or 
o 
>2 burst oral steroid course in the past year. 
 
A burst of IV, IM or oral steroids of more than 2 days for an indication other than asthma in the 
past 30 days. 
 
Inability to discontinue antihistamines for the initial day of escalation, skin testing or OFC. 


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 
Use of omalizumab or other non-traditional forms of allergen immunotherapy (e.g., oral or 
sublingual) or immunomodulator therapy (not including corticosteroids) or biologic therapy (e.g., 
infliximab, rituximab, etc.) within the past year. 
 
Use of -blockers (oral), angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor 
blockers (ARB) or calcium channel blockers. 
 
Use of investigational drug within 90 days or plan to use investigational drug during the study 
period. 
 
Pregnancy or lactation. 
4.4 
Treatments 
4.4.1 Treatments Administered 
Two treatments will be administered daily for this study, egg oral immunotherapy (eOIT) for participants in 
the eOIT-Randomized and eOIT-Assigned groups, and baked egg for participants in the Baked Egg group. 
Baked egg therapy will be prepared using commercially available food ingredients and prepared according to 
pre-specified recipes, cooking temperatures, and times to administer consistent doses of baked egg. 
Baked egg therapy will consist of a muffin or equivalent (1/3 of egg in serving or approximately 2 gm of 
protein). Home baked products will have no more than 2 eggs per batch of recipe (yield 6 servings). Serving 
size is indicated by the yield of the recipe. Products will be baked for 25-50 minutes at 325-425 degrees 
Fahrenheit. Recipes will be provided. The daily dose can be administered at 1 sitting or divided throughout 
the dosing day. These methods are outlined in the manual of procedures and instructions for the subjects 
and their families. 
Study drug (commercially available egg white solid) will be centrally packaged, stored and distributed by 
EMINENT Services Corporation. Central manufacturing will consist of weighing individual doses of the egg 
white solid into vials or capsules and providing bulk egg white solid for use with scoops. A 37% egg white 
solid blended product as described in the manufacturing section of the IND will be used to provide specified 
dose levels in capsules whereas 100% egg white solid will be used to provide specified dose in vials or in 
bulk product. 
Initial day dose escalation will be packaged in individual vials with each dose weighed. Initial day escalation 
kits will have 2 doses of each vial up to 25 mg egg white solid. Individual dose level kits will have 21 vials 
per kit. Kits will be used until a dose of 50 mg egg white solid is achieved. Starting at doses of 50 mg, the 
egg white solid doses will be packaged in pull-apart capsules with the appropriate dose in each capsule. One 
capsule will be used for each day’s dose. Capsules will be packaged in bottles of 21. 
Starting at doses of 350 mg egg white solid, bulk powder will be dispensed with a dose-specific scoop. 
Subjects will be instructed to use 1 scoop per day that is leveled across the top of the scoop. The bulk 
product will be in a supply of 500 gm. 


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All study product will be packaged at the central manufacturer. Study drug will be shipped by the central 
manufacturer to the site pharmacist for distribution to the site study personnel. The site pharmacist will 
dispense study drug in a manner consistent with the current dose level and treatment assignment. 
All study drug will be labeled at the central manufacturer and shipped to the local pharmacy for distribution 
to the study subjects. The product will be labeled with the numbered dose level and package number. 
Every attempt to use a single lot of commercially available egg white solid will be made. If a new lot is 
required, and any subject is in an escalation phase of the study, they will have a single observed in clinic 
dose reduction with the new lot. Escalation to their previous dose may occur in 1 week if the subject has the 
same or fewer symptoms than those occurring with the previous lot. 
4.4.2 Method of Assigning Participants to Treatment Groups (Randomization) 
Randomization was performed using an online data system with participants allocated in a 1:1 fashion to 
eOIT or baked egg consumption stratified by site. The first 40 participants to fail the initial baked egg 
challenge were assigned to receive eOIT. Further baked egg OFC failures were considered screen failures 
and not enrolled. 
4.4.3 Blinding 
This study is unblinded. 
5 
SAMPLE SIZE CONSIDERATIONS 
The sample size target for the randomized portion of the study is 96 individuals with 1:1 random assignment 
to Baked Egg and Egg OIT. The sample size was selected to determine whether a difference exists between 
the treatment groups in the primary endpoint rate for the sustained unresponsiveness-focused portion of the 
study. Specifically, the sample was designed to have 85% power to detect with a two-sided 5% level test, a 
difference between a 40% and 70% sustained unresponsiveness rate. While a small dropout rate may occur, 
we will use all randomized cases who initiate treatment in the intent-to-treat analysis of the primary 
endpoint; failures associated with noncompliance are include in the denominator for event rates above. This 
sample size is sufficient to address the secondary endpoint of the desensitization components of the study 
for event rate differences of comparable size. 
The subset of individuals who are not baked egg tolerant at baseline comprise a selected group of 
individuals where Egg OIT will be examined. The size of the group will be capped at approximately 40 
subjects. The study cohort should be useful for both clinical and mechanistic study with approximately 40 
such individuals enrolled. The 2 year sustained unresponsiveness rate will be compared to historical 
experience as well as the protocol’s randomized Egg OIT arm. Mechanistic studies will be examined to 
determine if baseline immune system responses are similar in both Egg OIT groups. Immune parameter 


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changes will be examined to determine if tolerant and non-tolerant cases have response profiles that are 
parallel for the 2 strata. 
6 
GENERAL STATISTICAL CONSIDERATIONS 
6.1 
General Principles 
All continuous variables will be summarized using the following descriptive statistics: n (non-missing sample 
size), mean, standard deviation (or median and interquartile range (IQR) as appropriate), maximum and 
minimum. Transformations of immune results may be required and appropriate transformations will be 
applied (e.g., log 10 transform). The frequency and percentages (based on the non-missing sample size) of 
observed levels will be reported for all categorical measures. Where appropriate, summary tables will be 
structured with a column for each treatment and assignment group in order (Baked Egg, eOIT – Randomized 
and eOIT - Assigned) and will be annotated with the total population size relevant to that table/treatment, 
including any missing observations.  
6.2 
Timing of Analyses 
The primary analysis will take place when all participants have completed the appropriate Year 2 OFCs and 
the OFCs have been appropriately monitored. The final analysis will take place when the last long term 
follow-up questionnaire is completed (targeted September 2018). 
6.3 
Analysis Populations 
The efficacy analysis population will consist of randomized participants who initiate treatment as well as all 
participants enrolled in the eOIT – Assigned group who initiate treatment. The safety population may vary 
based on time period and will consist only of treated participants. Mechanistic analyses will consider those 
with available samples.  
6.4 
Covariates and Subgroups 
As this is a small Phase II trial, analysis of covariates may be limited in scope. Mechanistic analyses will focus 
on temporal changes as well as using mechanistic factors as predictors of clinical response. Age will be 
considered as a possible covariate as previous studies have shown differential results based on age. 
Key subgroup comparisons will include the comparison of the eOIT – Randomized to eOIT – Assigned to 
determine if the efficacy, safety, or immunogenicity of eOIT differs based on tolerance to baked egg. 
6.5 
Missing Data 
Missing data for primary and secondary endpoints has been described in Section 3.3. At the current time, no 
other adjustments for missing data are currently planned. If upon analysis, missing data issues are identified 


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then appropriate methods based on the pattern and frequency of missing data will be applied. All methods 
and results will be provided to allow for sufficient interpretation of the results. 
6.6 
Interim Analyses and Data Monitoring 
The DSMB will convene to review safety data periodically.  Given the relatively small total sample size for the 
study and the interest in precise treatment-specific endpoint estimates (in addition to the treatment contrast 
results), no formal efficacy-focused early stopping guidelines or plans are proposed.  The DSMB will receive 
regular reports on accrual, dose escalation success, dose-limiting adverse events, OFC-related adverse 
events, and other adverse events.  The DSMB may request additional analyses. 
6.7 
Multicenter Studies 
Five sites participate in this study and randomization occurs within site. Site effects are not anticipated but 
demographics and baseline characteristics will be reported by site to assess unanticipated site differences. 
6.8 
Multiple Comparisons/Multiplicity 
A two-sided significance level of 0.05 will be used for primary, secondary, and safety endpoints. For planned 
mechanistic analyses (e.g., temporal changes, differences between responders and non-responders) a p-
value of 0.01 will be used to control for the multiplicity of tests. 
7 
STUDY PARTICIPANTS 
7.1 
Participant Disposition 
Participant disposition will be described in tables by site and treatment group.  
A CONSORT diagram will describe the participant disposition and loss to follow-up through the course of the 
study. 
7.2 
Protocol Deviations 
Participant-specific protocol deviations will be described by individual, treatment group and site. Site specific 
deviations will be described by site. Listings will include a description of the deviation and any action taken 
as a result. 
8 
EFFICACY EVALUATION 
8.1 
Demographic and Other Baseline Characteristics 
Demographics and baseline characteristics will be described by site and treatment group. Demographics 
include gender, age, and ethnicity. Baseline characteristics include medical history (i.e., asthma, other food 
allergies, etc.), mechanistic characteristics (i.e., egg IgE, egg SPT, etc.), and baseline SCD for the baked egg 
and egg white challenges. Continuous variables will be summarized using appropriate measures (means and 


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standard deviations or medians and interquartile ranges). Categorical variables will be described by 
frequencies and percentages. If the frequency of an individual category is low, the categories may be 
collapsed for display or analysis purposes. 
8.1.1 Concurrent Illnesses and Medical Conditions 
History of allergies, asthma, and atopic dermatitis are collected at baseline and at protocol scheduled follow-
ups. These factors will be described at baseline and atopic dermatitis will be described at follow-up 
timepoints. 
8.1.2 Prior and Concurrent Medications 
Prior and concurrent medications will be collected by self-report. Medications will be WHO Drug Dictionary 
coded, and described appropriately. 
8.2 
Measurements of Treatment Compliance 
Missed doses are captured on the dosing symptom logs. Number of expected doses and percentage of doses 
not administered will be calculated as described in Section 3.3. Participants who withdraw early will also be 
reported and described. 
8.3 
Efficacy Analyses 
The clinical efficacy endpoints are based on oral food challenge results. Mechanistic efficacy analyses are 
described in Section 11 below. The primary efficacy endpoint is based on the Year 2 sustained 
unresponsiveness OFC. 
8.3.1 Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is binary. This endpoint is based on passing the Year 2 sustained 
unresponsiveness OFC followed by a successful open feeding. The proportion of participants passing the 
Year 2 SU OFC will be compared between the Baked Egg and eOIT – Randomized groups using a two-sided 
5% level chi-square test (or Barnard’s exact unconditional test as appropriate). 
A secondary analysis of the primary endpoint will compare the eOIT-Randomized group to the eOIT-
Assigned group using a two-sided 5% level chi-square test (or Barnard’s exact unconditional test as 
appropriate). 
8.3.2 Secondary Efficacy Endpoint Analyses 
Secondary efficacy endpoints include: 
1. Desensitization ≥4444 mg egg white protein at 1 year and 2 year OFC 


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This endpoint will be described by group via frequencies and proportions and compared between the 
Baked egg and eOIT – Randomized group using a two-sided 5% level chi-square test (or Barnard’s 
exact unconditional test as appropriate). A secondary comparison will compare the eOIT-
Randomized and eOIT-Assigned using a similar method. 
2. Unrestricted consumption of unbaked egg at long term follow-up 
This endpoint will be assessed on the long term follow-up questionnaire (LFQ). Frequencies and 
proportions will be described by group and compared between the Baked egg and eOIT – 
Randomized group using a two-sided 5% level chi-square test (or Barnard’s exact unconditional test 
as appropriate). A secondary comparison will compare the eOIT-Randomized and eOIT-Assigned 
using a similar method. 
8.3.3 Exploratory Efficacy Analyses 
Although not specified in the protocol, changes in SCD from baseline to each protocol OFC are of scientific 
interest. The change in SCD will be compared between treatment using the Wilcoxon Rank Sum test to do 
pairwise comparisons between treatment groups. Effects of age will also be explored.  
Analyses will also consider participants who successfully passed the desensitization OFCs to 7444 mg of egg 
white protein at the Week 52 and Year 2 OFCs. Comparisons between groups will be assessed in a similar 
fashion to the secondary endpoints above. 
Clinical and immunological predictors of sustained unresponsiveness are of great scientific and medical 
interest. Of particular interest is the effect of age on treated effect and clinical outcomes. Logistic regression 
may be used to identify predictors of clinical response (i.e., desensitization and/or sustained 
unresponsiveness). Predictors will be incorporated into models adjusting for treatment where possible. 
Transformations will be implemented as appropriate and model fit will be assessed using the Hosmer-
Lemeshow goodness of fit test. Area under the curve (AUC) may be used as an assessment of predictor 
strength. If the number of successes permits, multivariable models may be fit and stepwise regression 
techniques applied to identify important predictors or combinations of predictors. 
9 
SAFETY EVALUATION 
The primary safety endpoint is incidence of all serious adverse events. An exploratory comparison will assess 
dosing symptoms as reported on the specific dosing symptom CRF. Note that as described above no 
adjustment for multiple comparisons will occur here as these are safety outcomes and detection of any 
potential signal is of interest. 


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9.1 
Adverse Events 
Adverse events are collected on all participants throughout the course of the study. Participants are provided 
a daily diary card (called a dosing symptom log) to record treatment-related events which are captured on 
specific dosing symptom CRFs. Adverse events related to OFCs are captured on a specific CRF as are 
adverse events related to accidental (or purposeful) food ingestion (i.e., food allergy episodes or FAEs). 
9.1.1 Solicited Adverse Events and Symptoms – Dosing Symptoms 
Symptoms reported on the dosing symptom CRFs are considered treatment related for the purpose of 
analysis. Systemic symptoms are recorded as mild, moderate or severe. 
The key outcome of interest is symptom free doses (defined as no oral pharyngeal or systemic symptoms). 
Exclusion of oral pharyngeal symptoms will also be considered. Other safety outcomes of interest include 
doses with moderate and/or severe reactions. Finally, doses requiring treatment will also be described with a 
focus on doses requiring epinephrine. 
Symptoms will be reported per dose, per participant, and proportion of doses per participant. The latter will 
be calculated by dividing the number of doses with each symptom by the total number of doses the 
participant received. Formal comparisons of safety outcomes will occur on this measure although significance 
testing may be performed on other measures if warranted. Proportion of doses with symptoms per 
participant will be compared using the Wilcoxon Rank Sum test to do pairwise comparisons between 
treatment groups. 
Finally, tables will be broken down by treatment, location, and timing (pre-Week 52 vs. post-Week 52) to 
illustrate potential dose level and temporal treatment effects.  
9.1.2 Other Adverse Events 
As described above, non-treatment related adverse events are captured separately and described below. 
9.1.2.1 OFC Symptoms 
At each OFC the dose limiting symptoms and severity are captured on a specific CRF. Symptoms will be 
reported for each OFC by initial randomization group. Treatment administered during the OFC (especially 
any epinephrine use) will be described. 
9.1.2.2 Food Allergy Episodes 
Food exposure related reactions are captured on the food allergy episode (FAE) CRF. The frequency, 
severity, and epinephrine use during such reaction will be described, as well as eliciting allergen, and shown 
by treatment group. Further details on egg related exposures will be provided as necessary. 


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9.1.2.3 Other Treatment Emergent Adverse Events 
Frequency, severity and resolution of other treatment emergent adverse events will be described by 
treatment group, system organ class and preferred term. 
9.2 
Deaths, Serious Adverse Events and other Significant Adverse Events 
The proportion of participants experiencing a SAE will be estimated within each group. Pairwise comparisons 
between treatment groups will be performed using Barnard’s exact unconditional test at the two-sided 5% 
level. If multiple SAEs are observed within a participant, alternate methods to account for the multiple 
events will be considered. If SAEs are infrequent (e.g. 1 or 2 events throughout the study), then hypothesis 
testing may not be performed. SAEs will also be described by relatedness to study product or procedure. 
9.3 
Pregnancies 
Given the age of the study population, pregnancies are unlikely to be observed. Any participant becoming 
pregnant will immediately terminate study treatment. Descriptive information about any pregnancies that 
occur will be provided.  
9.4 
Clinical Laboratory Evaluations 
No safety laboratory results will be systematically collected as part of this trial. 
9.5 
Vital Signs and Physical Evaluations 
No data on vital signs will be systematically collected. Height and weight are collected as part of the study 
and may be considered as potential factors if of scientific interest.  
9.6 
Concomitant Medications 
Concomitant medications will be collected and described. 
10 PHARMACOKINETICS 
No pharmacokinetics will be analyzed in this study. 
11 MECHANISTIC ANALYSES 
11.1 Skin Prick Test 
SPTs are performed at baseline, Week 52 and Year 2. SPT results and changes from baseline will be 
reported at each of these timepoints by treatment group and by Year 2 sustained unresponsiveness status. 
Change from baseline at Week 52 and Year 2 will be compared between treatment groups and by Year 2 
sustained unresponsiveness status using the Wilcoxon Rank-Sum test to do pairwise group comparisons. 
Repeated measures model may be fit using the post-baseline timepoints and adjusted for baseline value, 
treatment and visit to assess any treatment effect or Year 2 sustained unresponsiveness status effect on SPT 


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measures. An appropriate covariance structure will be selected (with preference given to unstructured 
models). 
11.2 Immunoglobulin Results 
Egg specific IgE, IgG4, and total IgE are measured at baseline, Week 12, Week 24, Week 52, Month 16, 
Month 20, Year 2, Month 26 and Month 30. Percent egg-specific IgE and IgG4/IgE ratio will be calculated as 
described in Section 3.3 above. Immunoglobulin results and changes from baseline will be reported at each 
of these timepoints by treatment group and by Year 2 sustained unresponsiveness status.  
Change from baseline will be compared between treatment groups and by Year 2 sustained 
unresponsiveness status using the Wilcoxon Rank-Sum test to do pairwise group comparisons. A repeated 
measures model will be fit using the post-baseline timepoints except for the Month 30 visit (which is after 
the final OFC) and adjusted for baseline value, treatment or Year 2 sustained unresponsiveness status, and 
visit to assess any treatment effect or Year 2 sustained unresponsiveness effect on immunoglobulin 
measures. An appropriate covariance structure will be selected (with preference given to unstructured 
models). If there are too few subjects who have completed the Year 2 sustained unresponsiveness OFC to 
allow for a reasonable model fit, the model may be adjusted accordingly.  
11.3 Activated Basophil Analysis 
Activated basophil outcomes will be constructed as described in Section 3.3. Activated basophils will be 
measured at baseline, Week 12, Week 24, Week 52, Month 16, Month 20, Year 2, Month 26 and Month 30. 
Activated basophil results for each stimulation level and changes from baseline will be reported at each of 
these timepoints by treatment group and by Year 2 sustained unresponsiveness status.  
Change from baseline will be compared between treatment groups and by Year 2 sustained 
unresponsiveness status using the Wilcoxon Rank-Sum test to do pairwise group comparisons. A repeated 
measures model will be fit using post-baseline timepoints except for the Month 30 visit (which is after the 
final OFC) and adjusted for baseline value, treatment or Year 2 sustained unresponsiveness status and visit 
to assess any treatment effect or Year 2 sustained unresponsiveness status effect on basophil measures. An 
appropriate covariance structure will be selected (with preference given to unstructured models). If there are 
too few subjects who have completed the Year 2 sustained unresponsiveness OFC to allow for a reasonable 
model fit, the model may be adjusted accordingly.  
For each of the egg stimulant levels within each treatment group, a Signed Rank test will be done for the 
egg value minus IL-3 (negative control), the anti-IgE value (positive control) minus IL-3, and the anti-IgE 
value minus the egg value at each time point to see if these values are significantly different than zero. A 
significant difference for egg minus IL-3 or anti-IgE minus IL-3 would indicate a response to egg or to beads, 
respectively. A significant difference for anti-IgE minus egg would indicate that the response was 
significantly different for anti-IgE than for egg. 


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11.4 Flow Cytometry Analysis (CD154+ Cells) 
Flow cytometry outcomes will be constructed as described in Section 3.3. Results will be measured at 
baseline, Week 12, Week 24, Week 52, Year 2, Month 26 and Month 30 and changes from baseline will be 
reported at each of these timepoints by treatment group and by Year 2 sustained unresponsiveness status.  
Change from baseline will be compared between treatment groups and by Year 2 sustained 
unresponsiveness status using the Wilcoxon Rank-Sum test to do pairwise group comparisons. A repeated 
measures model of delta egg minus media (value for media stimulant subtracted from value for egg 
stimulant) will be fit using the post-baseline timepoints except for the Month 30 visit (which is after the final 
OFC) and adjusted for baseline value, treatment or Year 2 sustained unresponsiveness status, and visit to 
assess any treatment effect or Year 2 sustained unresponsiveness status effect on flow cytometry measures. 
An appropriate covariance structure will be selected (with preference given to unstructured models). If there 
are too few subjects who have completed the Year 2 sustained unresponsiveness OFC to allow for a 
reasonable model fit, the model may be adjusted accordingly. Within each treatment group, a Signed Rank 
test will be done for delta egg minus media, delta beads minus media (value for media stimulant subtracted 
from value for beads stimulant), and delta beads minus egg (value for egg stimulant subtracted from value 
for beads stimulant) at each time point to see if these delta values are significantly greater than zero. A 
significant difference for delta egg minus media or delta beads minus media would indicate a response to 
egg or to beads, respectively. A significant difference for beads minus egg would indicate that the response 
was significantly different for beads than for egg. (Note that media is the negative control and beads is the 
positive control for the assay.)  
Additionally, correlations with egg specific immunoglobulin results will be explored. Spearman rank 
correlations may be estimated. Immunoglobulin measures may also be considered as covariates in the 
repeated measures models to assess the contemporaneous associations. 
12 OTHER ANALYSES 
The planned analyses are described above. Some mechanistic objectives and endpoints may be described 
further as data become available. Other analyses may be requested by investigators or scientific reviewers. 
Such analyses will be considered exploratory and hypothesis generating and will be described in detail at the 
time of analysis. 
Transcriptional data results at baseline for a subset of participants are located in the following manuscript:  
Kosoy R, Agashe C, Grishin A, Leung DY, Wood RA, Sicherer SH, Jones SM, Burks AW, Davidson WF, 
Lindblad RW, Dawson P, Merad M, Kidd BA, Dudley JT, Sampson HA, Berin MC. Transcriptional Profiling of 
Egg Allergy and Relationship to Disease Phenotype. PLoS One. 2016 Oct 27;11(10):e0163831. doi: 
10.1371/journal.pone.0163831. eCollection 2016. PubMed PMID: 27788149; PubMed Central PMCID: 
PMC5082817. 


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13 TECHNICAL DETAILS 
Industry standard software (e.g., SAS v9.4 or R v3.2.0) will be used for the analysis. 
14 SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
This section will be updated as necessary at the time of analysis or amendment to the SAP. 
15 REFERENCES 
Lydersen S, Fagerland MW, Laake P. Recommended tests for association in 2 × 2 tables. Stat Med. 2009 Mar 
30;28(7):1159-1175. 
16 LISTING OF TABLES, FIGURES AND LISTINGS 
A listing of potential tables and figures is provided as a separate document. Another document showing 
potential listings is also provided. Table titles are intended to be descriptive only and not restrict designation 
of the publication table titles. Further alternate data presentations (e.g., mechanistic figures) may be 
considered as requested by investigators or for publication. Details on analyses methods are contained in 
Sections 8, 9, and 11.